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How to Feed the Fetus

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Ferdinand Haschke, Salzburg

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Jatinder Bhatia, Augusta, GAWeili Lin, Chapel Hill, NCCarlos Lifschitz, Buenos AiresAndrew Prentice, Banjul/LondonFrank M. Ruemmele, ParisHania Szajewska, Warsaw

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Vol. 78, Suppl. 1, 20–21

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Contents

11 Editorial Haschke, F. (Salzburg)


1 3 Focus on: Gestational Diabetes Mellitus and Developmental Programming

14 Gestational Diabetes Mellitus and Developmental Programming

Chu, A.H.Y. (Singapore); Godfrey, K.M. (Southampton)

15 Focus on: Nutrition Management of Gestational Diabetes Mellitus

16 Nutrition Management of Gestational Diabetes Mellitus

Kapur, K. (Bangalore); Kapur, A. (Bagsvaerd); Hod, M. (Tel Aviv)

28 Focus on: Prenatal Nutritional Strategies to Reduce the Risk of Preterm Birth

29 Prenatal Nutritional Strategies to Reduce the Risk of Preterm Birth

Best, K.P.; Gomersall, J.; Makrides, M. (Adelaide, SA)

37 Focus on: Maternal Undernutrition before and during Pregnancy and Offspring Health and Development

38 Maternal Undernutrition before and during Pregnancy and Offspring Health and Development Young, M.F.; Ramakrishnan, U. (Atlanta, GA)

[email protected] © 2021 Nestlé Nutrition Institute, Switzerland/S. Karger AG, Basell

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Editorial

Reprinted with permission from:Ann Nutr Metab 2020;76(suppl 3):1–2


Ferdinand Haschke

Department of Pediatrics, PMU Salzburg, Salzburg , Austria

Prof. Ferdinand Haschke, MD Department of Pediatrics, PMU Salzburg 48 Muellner Hauptstrasse AT–5020 Salzburg (Austria) fhaschk @ gmail.com

© 2021 Nestlé Nutrition Institute, Switzerland/S. Karger AG, Basel

[email protected]

DOI: 10.1159/000511240

Many nutritional risks for maternal and child health begin

during the adolescent and young adult years prior to first

pregnancy. Because they affect fetal development before the

initiation of antenatal care, the arguments for preventive ac-

tions in the field of nutrition during the adolescent and young

adult years are compelling. Accelerating rates of female obe-

sity have further complicated nutritional risks arising in fe-

males between 15 and 25 years so that in many emerging

societies, obesity coexists with food insecurity and undernu-

trition. In 2017, the Nestlé Nutrition Institute provided an un-

restricted educational grant to support a series of publications

which summarize recent interventions and recommenda-

tions in the field of nutrition of young females before and dur-

ing pregnancy [1, 2] . The supplement “How to Feed the Fetus”

addresses short- and long-term consequences of nutrition

and health issues before and during pregnancy.

One in 6 pregnancies worldwide is affected by the inabil-

ity of the mother’s metabolism to maintain normoglycemia.

Insulin resistance and insufficient insulin secretion result in

gestational diabetes mellitus (GDM). Because of the increas-

ing number of pregnant women with higher body mass index

(BMI), the prevalence is likely to increase. In addition to short-

term consequences of non- or poorly treated GDM, such as

fetal overgrowth, exposure of the fetus to hyperglycemia will

predispose the offspring to noncommunicable diseases later

in life [3] : the effect of GDM on offspring overweight, obesity,

impaired glucose tolerance, and resulting cardio-metabolic

disease may be in part triggered by maternal obesity. Maternal

GDM may also be associated with offspring negative health

outcomes, such as allergy, and neurocognitive conditions,

such as ADHD and autism. GDM as a maternal intrauterine

trigger could play a role in influencing offspring long-term

outcomes through epigenetic modification of gene function

[3] . Human studies indicate a causal relation between GDM

and the epigenetic regulation of the leptin gene, which could

explain offspring adiposity. Furthermore, GDM and altered

methylation status has been reported of a gene associated

with autism spectrum disorder (OR2L13 promoter) and of the

serotonin transporter gene (SLC6A4), which is involved in de-

pression, anxiety, and autism. A combined diet and exercise

program before and during pregnancy can be useful in pre-

venting GDM in high-risk women. In addition, there is some

evidence that probiotic and myo-inositol supplementation

can work [4] . Medical nutrition therapy provides the basis for

the management of GDM. The conventional approach of lim-

iting carbohydrates at the cost of increasing energy from fat

source may not be the most optimal. Instead, allowing higher

levels of complex, low to medium glycemic index carbohy-

drates and adequate fiber through higher consumption of

vegetables and fruits seems more beneficial. For medical nu-

trition therapy to work it is vital that dietary advice and nutri-

tion counseling is provided by a dietician, is easy to under-

stand and use, and includes healthy food options, cooking

methods, and practical guidance that empowers and moti-

vates to make changes towards a healthy eating pattern.

Haschke Reprint with permission from:Ann Nutr Metab 2020;76(suppl 3):1–2

2

DOI: 10.1159/000511240

The literature on omega-3 LCPUFA fats supplementation

before and during pregnancy in higher income countries is

also summarized in this issue [5] : the updated Cochrane re-

view of marine oil supplementation includes 7 RCTs (19,927

pregnant women) with LCPUFA fats in any form or dose dur-

ing the second half of pregnancy. Results show high-quality

evidence that supplementation with omega-3 LCPUFA during

pregnancy reduces the risk of having a premature baby < 37

weeks’ gestation by 11% and < 34 weeks’ gestation by 42%

compared with no omega-3 supplementation. Prenatal ome-

ga-3 LCPUFA supplementation is safe because of no effect on

bleeding or postpartum hemorrhage, and it significantly re-

duces the incidence of low birth weight but increases the in-

cidence of pregnancies continuing beyond 42 weeks. The

2-day shift in mean gestation in the DOMInO trial (2,499 preg-

nant women) increases the number of post-term pregnancies

and, thus, the need for more obstetric interventions to initiate

birth by approximately 4% [5] . Studies on omega-3 LCPUFA

supplementation during pregnancy and improved cognitive

outcome in the offspring are still controversial. This supports

the need for further research to investigate the effects of pre-

natal omega-3 supplementation before adopting a universal

supplementation approach into routine antenatal care.

The WHO estimates that over 2 billion people are at risk for

micronutrient deficiencies, mainly from developing countries

in Asia and Africa. Of public health concern are iron, vitamin

A, iodine, zinc, folate, and B vitamins deficiencies. Regional

estimates of anemia and micronutrient deficiencies indicate a

high prevalence among women of reproductive age [6] . Ap-

proximately 50% of anemia among non-pregnant and preg-

nant women is amenable to iron supplementation. However,

the regional role of iron deficiency in anemia has been shown

to be extremely variable from < 1 to 75% and may be influ-

enced by many conditions, including malaria, infection, he-

moglobinopathies, or other micronutrient deficiencies. Pre-

conception anemia and maternal undernutrition are associ-

ated with an increased risk of low-birth-weight and

small-for-gestational-age births, while anemia in the first tri-

mester of pregnancy is associated with low birth weight, pre-

term birth, and neonatal mortality. Only a few trials report the

outcomes of preconception nutritional interventions with

supplements containing multiple micronutrients with or with-

out energy from lipids [6] : birth weight and length are higher

and the risk of stunting in the offspring is 12–13% lower at 2

years. There is strong evidence that during pregnancy multi-

ple micronutrient supplements together with protein and en-

ergy reduce the risk of stillbirth by 40% and the risk of small-

for-gestational age by 21%, increase birth weight, and are

cost-effective. In addition, limited data from several develop-

ing countries indicate better cognitive outcome in children

> 6 years after multiple micronutrient supplementation before

and during pregnancy and during the first 1,000 days of life.

In conclusion, metabolic imbalances during pregnancy,

such as GDM, might result in epigenetic changes which affect

the offspring and might predispose to noncommunicable dis-

eases later in life. Preventive measures for GDM must be initi-

ated during pre-pregnancy and early pregnancy, in particular

in women with high BMI. In pregnant women who develop

GDM, medical nutrition therapy has to be provided by health-

care professionals. Omega-3 LCPUFA supplementation dur-

ing the second half of pregnancy is effective to prevent pre-

mature birth and low birth weight. In developing societies,

multiple micronutrient supplementation before and during

pregnancy can contribute to better growth and cognitive de-

velopment of the offspring.

References

1 Salam RA, Hooda M, Das JK, Arshad A, Lassi ZS, Middleton P, et al. Interventions to improve adolescent nutrition: a systematic review and meta-analysis. J Adolesc Health . 2016 Oct; 59(4 Suppl):S29–S39.

2 Das JK, Salam RA, Thornburg KL, Prentice AM, Campisi S, Lassi ZS, et al. Nutrition in adolescents: physiology, metabolism, and nutri-tional needs. Ann N Y Acad Sci . 2017 Apr; 1393(1): 21–33.

3 Chu AHY, Godfrey KM. Gestational diabetes mellitus and develop-mental programming. Ann Nutr Metab . doi: 10.1159/000509902.

4 Kapur K, Kapur A, Hod M. Nutrition management of gestational diabetes mellitus. Ann Nutr Metab . doi: 10.1159/000509900.

5 Best KP, Goersall J, Makrides M. Prenatal nutritional strategies to reduce the risk of preterm birth. Ann Nutr Metab . doi: 10.1159/000509901.

6 Young MF, Ramakrishnan U. Maternal undernutrition before and during pregnancy and offspring health and development. Ann Nutr Metab . doi: 10.1159/000510595.

Focus

Reprinted with permission from: Ann Nutr Metab 2020;76(suppl 3):4–14

Gestational Diabetes Mellitus and Developmental ProgrammingAnne H.Y. Chu and Keith M. Godfrey


[email protected]

Key insights

Gestational diabetes mellitus (GDM) affects an estimated 14% of pregnancies worldwide. It is now clear that children born to mothers with GDM have an increased lifetime risk of metabolic diseases compared to unexposed children. Other long-term adverse consequences in the offspring include cardiovascular abnormalities, dysregulation of glucose metabolism, increased risk of allergic/respiratory disease, and neurodevelopmental abnormalities. Together, these findings highlight the importance of the intra-uterine environment as a driver of epigenetic changes in the offspring.

Current knowledge

Several human studies have examined the association be-tween in utero GDM exposure and DNA methylation in pla-centas, and offspring cord or infant blood. The findings have revealed several differentially methylated genes in the fetal tissues of babies born to mothers with GDM: of interest are those related to metabolic regulation, such as leptin, adipo-nectin, and the SLC2A1/GLUT1 and SLC2A3/GLUT3 genes. The effects of GDM, however, are not limited to offspring me-tabolism. Current research indicates that the epigenetic ad-aptations triggered by maternal glycemia also affect other de-veloping organ systems in the infant, including neurodevel-opment.

Practical implications

Infants born to mothers who receive GDM treatment (such as dietary advice, blood glucose monitoring, and insulin therapy) have improved perinatal outcomes. However, long-term fol-

low-up studies suggest that this treatment may not be suffi-cient to reduce childhood obesity in the offspring. The current evidence indicates that interventions delivered during preg-nancy may only partly alter fetal growth and development, pointing towards the peri-conceptional period as an early modulator of health outcomes in the offspring. Further studies are needed to understand how we can leverage the peri-con-ceptional period as a window of opportunity for optimizing the health of future generations.

Recommended reading

Antoun E, Kitaba NT, Titcombe P, Dalrymple KV, Garratt ES, Barton SJ, et al. Maternal dysglycaemia, changes in the infant’s epigenome modified with a diet and physical activity interven-tion in pregnancy: Secondary analysis of a randomised con-trol trial. PLoS Med. 2020;17(11):e1003229.

There is increasing epidemiological evidence linking early-life environmental exposures (i.e., maternal malnutrition/overnutrition, environmental chemicals, stress) with later-life health outcomese

Intra-uterineenvironment(GDM)

Immunesystem

Gutmicrobiome

AdiposityMetabolism

Neurodevelopment

Cardiovascularsystem

Gestational diabetes mellitus (GDM) affects many organ systems in the offspring through the mechanism of epigenetics.


Reprint with permission from:Ann Nutr Metab 2020;76(suppl 3):4–15

Gestational Diabetes Mellitus and Developmental Programming

Anne H.Y. Chu a Keith M. Godfrey b

a Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A * STAR), Singapore , Singapore ; b MRC Lifecourse Epidemiology Unit and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton , UK

Keith M. Godfrey NIHR Southampton Biomedical Research CentreUniversity of Southampton and University Hospital Southampton NHS Foundation Trust Mailpoint 95 , Southampton SO16 6YD (UK) kmg @ mrc.soton.ac.uk


[email protected]

Key Messages

• A mother’s glycaemic status and weight during before concep-tion and pregnancy influence the long-term health of the off-spring.

• The offspring’s future health can be programmed through the role of epigenetic changes induced by a hyperglycaemic envi-ronment in utero.

• More longitudinal studies are warranted to investigate the cau-sality and underlying mechanisms of GDM on offspring’s long-term health to provide a basis for developing effective interven-tions during this critical period, with the aim of improving life-long health and wellbeing.

DOI: 10.1159/000509902

Keywords Developmental origins of health and disease · Epigenetics ·

Gestational diabetes · Life course epidemiology ·

Non-communicable disease

Abstract During normal pregnancy, increased insulin resistance acts as

an adaptation to enhance materno-foetal nutrient transfer

and meet the nutritional needs of the developing foetus, par-

ticularly in relation to glucose requirements. However, about

1 in 6 pregnancies worldwide is affected by the inability of the

mother’s metabolism to maintain normoglycaemia, with the

combination of insulin resistance and insufficient insulin se-

cretion resulting in gestational diabetes mellitus (GDM). A

growing body of epidemiologic work demonstrates long-

term implications for adverse offspring health resulting from

exposure to GDM in utero. The effect of GDM on offspring

obesity and cardiometabolic health may be partly influenced

by maternal obesity; this suggests that improving glucose and

weight control during early pregnancy, or better still before

conception, has the potential to lessen the risk to the off-

spring. The consequences of GDM for microbiome modifica-

tion in the offspring and the impact upon offspring immune

dysregulation are actively developing research areas. Some

studies have suggested that GDM impacts offspring neurode-

velopmental and cognitive outcomes; confirmatory studies

will need to separate the effect of GDM exposure from the

complex interplay of social and environmental factors. Ani-

mal and human studies have demonstrated the role of epi-

genetic modifications in underpinning the predisposition to

adverse health in offspring exposed to suboptimal hypergly-

caemic in utero environment. To date, several epigenome-

wide association studies in human have extended our knowl-

edge on linking maternal diabetes-related DNA methylation

marks with childhood adiposity-related outcomes. Identifi-

cation of such epigenetic marks can help guide future re-

search to develop candidate diagnostic biomarkers and pre-

GDM and Developmental Programming 5Reprint with permission from:Ann Nutr Metab 2020;76(suppl 3):4–15DOI: 10.1159/000509902

ventive or therapeutic strategies. Longer-term interventions

and longitudinal studies will be needed to better understand

the causality, underlying mechanisms, or impact of GDM

treatments to optimize the health of future generations.

© 2021 Nestlé Nutrition Institute, Switzerland/

S. Karger AG, Basel

Introduction

Gestational diabetes mellitus (GDM) is a glucose tolerance

disorder with onset during pregnancy [1] . GDM has been es-

timated to affect 14.4% of pregnancies globally, ranging from

7.5% in the Middle East and North Africa region to 27.0% in the

South-East Asia region [2] . Although dysglycaemia usually im-

proves after delivery, untreated GDM increases the risk of

short-term complications including foetal overgrowth, shoul-

der dystocia, caesarean delivery, and hypertensive disorders

[3] . In the long term, exposure to GDM will likely predispose

both the mother and her child to non-communicable dis-

eases (NCDs) later in life.

NCDs are often seen as diseases of adult lifestyle and are

an important public health issue. Their aetiology is likely mul-

tifactorial, involving interactions between environmental and

genetic factors and multiple risk pathways. Substantial evi-

dence now suggests that NCDs partly originate through en-

vironmental exposures before and during pregnancy [4] ,

which have lasting effects on the developing foetus and serve

as potential targets in reversing the epidemic of NCDs. It has

become apparent that children born to mothers with GDM

have an increased lifetime risk for metabolic diseases com-

pared with unexposed children [5] . This concept of lasting

consequences of early-life nutrition for later disease risk is

widely termed “developmental programming” ( Fig. 1 ).

There is increasing epidemiological evidence linking the

early-life environmental exposures (i.e., maternal malnutri-

tion/overnutrition, environmental chemicals, and stress) with

later-life health outcomes – conceptualized as the “develop-

mental origins of health and disease” (DOHaD). Compelling

studies from animal models have provided strong evidence in

support of the DOHaD concept. These have, for example,

shown that in utero exposure to maternal diabetes and/or

obesity disrupts the development and function of the hypo-

thalamus, predisposing offspring to obesity [6, 7] . Several de-

cades ago, Pedersen [8] proposed that foetal adipogenesis

can result from foetal hyperinsulinemia induced by maternal

hyperglycaemia, with more recent evidence suggesting that

the mechanisms involved in lasting effects on obesity risk in-

clude epigenetic changes [9] . In this review, we highlight

some of the latest findings on the long-term health conse-

quences in offspring born to mothers with GDM, specifically

relating to body composition and cardiometabolic health, al-

lergic diseases, immune dysregulation/infections, and neu-

robehavioral outcomes and elaborate the epigenetic changes

as one of the major mechanisms linking GDM with long-term

“programmed” adverse effects on the offspring.

Offspring Body Composition and Cardiometabolic Health

While GDM has been linked with a higher offspring body mass

index (BMI), several studies have suggested that this associa-

tion is confounded by higher BMI in the mother. Table 1 sum-

marizes selected studies that have examined the association

Genetic predisposition Maternal obesity

Gestational diabetes

Insulin resistance + impaired insulin secretion

DNA methylation,histone modifications +

non-coding RNAsIncreased risk of meta-bolic diseases, allergy +neurodevelopmental

deficits

Early-life epigeneticmechanisms

Periconceptionalinfluences

Altered gene expressions+ physiological functions

Fig. 1. Gestational diabetes mellitus and developmental programming.

Chu/GodfreyReprint with permission from:Ann Nutr Metab 2020;76(suppl 3):4–15

6

DOI: 10.1159/000509902

Table 1. Selected studies linking GDM with offspring body composition and cardiometabolic health

Study Design Cohort Sample size GDM criteria Offspring age, years

Major outcomes for GDM-exposed offspring

Body composition

Chen et al. [11],China

Cohort Medical Birth Registry of Xiamen, China; a population-based retrospective cohort

33,157 International Association of Diabetes and Pregnancy Study Groups (IADPSG)

Range: 1–6 GDM and large-for-gestational age not associated with overweight (OR: 1.27, 95% CI: 0.96–1.68), adjusted for maternal pre-pregnancy BMI

Kawasaki et al. [12],Japan

Meta-analysis

Included 2 cohort studies adjusting for maternal BMI; UK, USA

5,941 Carpenter-Coustan, questionnaire

Range: 3–15.5 Not associated with BMI z-scores (pooled MD: −0.11, 95% CI: −0.33 to 0.12), adjusted for covariates including maternal pre-pregnancy BMI

Lowe et al. [10],USA

Cohort Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) study


Mean (SD): 11.4 (1.2)

Not associated with overweight/obesity (OR: 1.21, 95% CI: 1.00–1.46), adjusted for maternal BMI at OGTT during pregnancy

Glucose metabolism

Blotsky et al. [20],Canada

Matched cohort

A combination of health administrative data with birth registry information from Quebec, Canada

36,590 mother-child pairs with GDM and matched 1:1 with controls

Two abnormal values on a 75-g OGTT or a 50-g glucose screen ≥10.3 mmol/L

From birth to 22

Associated with incident diabetes (HR: 1.77, 95% CI: 1.41–2.22), not adjusted for maternal BMI

Kawasaki et al. [12],Japan

Meta-analysis

Included 4 cohort studies adjusting for maternal BMI; Denmark, Hong Kong SAR, USA

890 Self-report, questionnaire, WHO criteria 1999, OGTT

Range: 7–20 Associated with 2-h plasma glucose (pooled MD: 0.43 mmol/L, 95% CI: 0.18–0.69), adjusted for maternal pre-pregnancy BMI

Lowe et al. [21],USA

Cohort HAPO Follow-up Study (FUS)


Mean (SD): 11.4 (1.2)Range: 10–14

Associated with IGT (OR: 1.96, 1.41–2.73), insulin sensitivity (adjusted MD: −76.3, −130.3 to −22.4) and oral disposition index (adjusted MD: −0.12, −0.17 to −0.064), adjusted for family history of diabetes, maternal BMI, and child BMI z-scoreNot associated with IFG (OR: 1.09, 95% CI: 0.78–1.52)

Pathirana et al. [19],Australia

Meta-analysis

Included 11 cohort studies; China, Denmark, Greece, USA

6,423 NDDG, self-reported/confirmed with hospital records, Carpenter-Coustan, WHO criteria 1999, IADPSG, based on GDM risk factors followed by OGTT

Range: 7–27 Associated with fasting glucose (standardized MD: 0.43, 95% CI: 0.08–0.77), not adjusted for maternal BMI

Cardiovascular outcomes

Øyen et al. [23],Denmark

Cohort Data linkage of Denmark’s nationwide registers

2,025,727 Medical record From birth to 34

GDM in third trimester associated with any type of congenital heart defects (adjusted relative risk: 1.36, 95% CI: 1.07–1.69)No association for GDM in second trimester

Yu et al. [22],Denmark

Cohort Danish national health registries

26,272 Medical record From birth to 40

Associated with overall CVD (HR: 1.19, 95% CI: 1.07–1.32), hypertensive disease (HR 1.77, 1.27–2.48), adjusted for sociodemographic status and maternal/paternal history of CVD

CI, confidence interval; CVD, cardiovascular disease; GDM, gestational diabetes mellitus; HR, hazard ratio; MD, mean difference; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; NDDG, National Diabetes Data Group; OGTT, oral glucose tolerance test; OR, odds ratio; SD, standard deviation; WHO, World Health Organization.


of GDM with offspring body composition and cardiometa-

bolic health. In the Hyperglycaemia and Adverse Pregnancy

Outcomes (HAPO) follow-up study of children aged 10–14

years, no association was found between GDM and over-

weight/obesity defined by BMI after adjusting for maternal

BMI during pregnancy [10] . Similarly, a recent population-

based retrospective study of 33,157 children aged 1–6 years

showed that the significant associations of GDM coupled with

large-for-gestational age on childhood overweight were no

longer apparent after adjusting for pre-pregnancy BMI [11] .

These findings are consistent with those of a meta-analysis

[12] , suggesting that GDM was not associated with BMI z -

scores when accounting for maternal pre-pregnancy BMI, but

few studies have accounted for maternal treatment for GDM

as a moderating influence [13] . Higher maternal BMI could be

associated with higher childhood adiposity through genetic

transmission, shared postnatal lifestyle/environment, and in-

trauterine environment [14] . Alternatively, since BMI does not

distinguish the contributions of fat and lean mass, using direct

measures of child adiposity (based on skinfold or simple im-

aging measurements) could be feasible options in epidemio-

logical studies [10, 15, 16] . Positive associations between GDM

and skinfold thickness have been observed in children at birth

and later childhood (aged 5–10 years), with limited evidence

in children aged 2–5 years [17] .

Evidence for an effect of GDM on offspring abnormal glu-

cose tolerance is mixed as data from several meta-analyses

have provided somewhat inconsistent findings. Positive as-

sociations between GDM and

postnatal abnormal glucose

metabolism (fasting plasma glu-

cose, post-prandial, and diabe-

tes mellitus) in the offspring

were reported in a systematic

review of prospective cohort

studies [18] . In a meta-analysis

including 11 studies, marginally

higher fasting plasma glucose

levels were found in offspring

exposed to GDM compared with those who were not (stan-

dard mean difference: 0.43, 95% confidence interval [CI]:

0.08–0.77, 6,423 children) [19] . Likewise, in a retrospective

matched cohort study of Canadian mother-offspring pairs,

incident diabetes in offspring from birth to 22 years was high-

er in those born to mothers with GDM (hazard ratio [HR]: 1.77,

95% CI: 1.41–2.22) [20] . However, the aforementioned stud-

ies did not account for a potential confounding effect of ma-

ternal BMI. In contrast, an earlier meta-analysis showed no

association of GDM with childhood diabetes or fasting plas-

ma glucose but a higher level of 2-h plasma glucose from

pre-pubertal to early adulthood (pooled mean difference:

0.43 mmol/L, 95% CI: 0.18–0.69, 890 children) [12] . This find-

ing was independent of maternal pre-pregnancy BMI. Simi-

larly, GDM was associated with higher risk of impaired glu-

cose tolerance (based on 30-min, 1-h, and 2-h plasma glu-

cose) but not impaired fasting glucose in 4,160 children from

the HAPO follow-up study [21] .

The observed discrepancies in the relation of GDM with

impaired glucose tolerance and impaired fasting glucose may

result from distinct pathophysiology induced by in utero ex-

posure to GDM, in which skeletal muscle function (implicated

in the insulin resistance of impaired glucose tolerance), not

the liver, may be more vulnerable to GDM. Also, the HAPO

follow-up study found that GDM was associated with lower

child insulin sensitivity (Matsuda index) and β-cell compensa-

tion for insulin resistance (disposition index) [10] . These asso-

ciations were independent of maternal BMI during pregnancy

and child’s BMI z -score, reinforcing the hypothesis that intra-

uterine exposure to hyperglycaemia plays a part in glucose

intolerance among offspring. Foetal β-cell insulin dysfunc-

tion, arising from intrauterine hyperglycaemia and manifest-

ing as a decline in β-cell compensation, is likely to contribute

to a progressively increasing metabolic load and an increased

risk of impaired glucose tolerance in children of mothers with

GDM. This does not preclude the possibility that the above

associations could be partly due to some overlap in genetic

susceptibility to GDM and type 2 diabetes, given that insulin

resistance and/or insulin secretory defects are key players in

the pathogenesis of these con-

ditions.

To date there are relatively

few studies on the association

between GDM and cardiovascu-

lar morbidity. Nonetheless, a re-

cent 40-year follow-up study of

the Danish population-based

cohort found an increased rate

of early-onset cardiovascular

disease (HR: 1.19, 95% CI: 1.07–

1.32) and hypertensive disease (HR 1.77, 95% CI: 1.27–2.48) in

offspring of mothers with GDM [22] . These associations were

independent of sociodemographic status and maternal/pa-

ternal history of cardiovascular disease. A 34-year follow-up

of the Danish cohort with over 2 million births reported a

modest increase in risk of specific congenital heart defects in

offspring born to mothers with GDM compared with mothers

with pre-gestational diabetes [23] . Interestingly, a systematic

review suggested that the association between GDM and

congenital heart defects was evident only in women who had

both GDM and pre-pregnancy obesity [24] . The effect of GDM

The effect of GDM on

offspring obesity and

cardiometabolic health may

be in part influenced by

maternal obesity


8

DOI: 10.1159/000509902

on offspring obesity and cardiometabolic health may be in

part influenced by maternal obesity; this has led to the notion

that improving glycaemia and weight control during early

gestation, or better still before conceiving, has the potential

to lessen the risk.

Offspring Allergic Diseases

Children born to mothers with GDM may be at risk of immune

dysregulation. Table 2 summarizes selected studies that have

examined the association of GDM and offspring allergy. A re-

cent US study of 97,554 children (median age: 7.6 years) re-

ported evidence that the rate of childhood asthma might be

influenced by more severe GDM requiring medication use

[25] . Compared with no diabetes during pregnancy, an in-

creased risk of childhood asthma was reported only in GDM

cases requiring antidiabetic medications (HR: 1.12, 95% CI:

1.01–1.25) but not in those without requiring medications.

These findings were independent of maternal asthma. The

Boston Birth cohort found that GDM, independently of ma-

ternal pregnancy BMI and foetal growth, was associated with

atopic dermatitis and allergen sensitization (driven primarily

by food sensitization) in term births but not preterm, with

speculation that term births had longer exposure to the hy-

perglycaemic insult at a specific point of immunological de-

velopment [26] . A meta-analysis did not find an association of

maternal diabetes (defined as either chronic diabetes before

pregnancy or overt diabetes or glucose intolerance in preg-

nancy) with ever and recurrent wheezing in early childhood

from birth up to 1–2 years of age [27] .

Although the immune system is a complex network af-

fected by various environmental and genetic factors, the po-

tential role of the human microbiota in influencing the host

immune system has drawn considerable attention. It has been

proposed that GDM triggers gut microbiota dysbiosis (i.e., al-

tered gut microbial ecosystem) in both the mother and neo-

nate [28] , which could lead to alteration of T-cell subpopula-

tions, in turn implicated in maintaining immune tolerance. In-

deed, mothers with GDM exhibited higher levels of

peripheral Th2, Th17, and regulatory T cells, with these re-

maining unchanged from the third trimester of pregnancy up

to 6 months post-partum [29] . Hence, it is plausible that al-

tered levels of T cells in the mother have an epigenetic impact

on the immunological function of the offspring.

Offspring Neurocognitive Development and Behavioural Outcomes

While more is known about the association between maternal

diabetes (regardless of the type) and offspring neurodevelop-

mental outcomes, evidence on the adverse effect of GDM is

currently inconclusive. A systematic review reported that

while overall intellectual function may be within the normal

range in children born to mothers with GDM, they may have

an increased risk for problems related to fine and gross motor

coordination, attention span, and activity level compared to

children born to mothers without GDM [30] . A number of im-

portant confounding factors, such as socioeconomic status,

parental educational level, and family upbringing, contribute

to children’s cognitive performance [31] . Table 3 summarizes

selected cohort studies and meta-analyses that have exam-

Table 2. Selected studies linking GDM with offspring allergy

Study Design Cohort Sample size

GDM criteria Offspring age, years

Major outcomes for GDM-exposed offspring

Kumar et al. [26],USA

Cohort Boston birth cohort 680 Medical record

Mean (SD): 3.2 (2.3)

In term births, GDM associated with atopic dermatitis (OR: 7.2, 95% CI: 1.5–34.5), allergen sensitization (5.7, 1.2–28.0), food sensitization (8.3, 1.6–43.3)

Martinez et al. [25],USA

Cohort Kaiser Permanente Southern California hospitals (retrospective birth cohort)

97,554 Carpenter-Coustan

Median age: 7.6

GDM requiring antidiabetic medications associated with childhood asthma (HR: 1.12, 95% CI: 1.01–1.25), adjusted for maternal asthma

Zugna et al. [27],Italy

Meta-analysis

Eleven European birth cohorts participating in the CHICOS (developing a child cohort research strategy for Europe) project

85,509 Exposure: maternal diabetes

From birth to 1–2

Maternal diabetes (regardless of type) associated with ever wheezing (pooled RR: 1.02, 95% CI: 0.98–1.06) and recurrent wheezing (1.24, 0.86–1.79)

CI, confidence interval; GDM, gestational diabetes mellitus; HR, hazard ratio; SMD, standardized mean difference; RR, risk ratio.


ined the association of GDM and offspring neurodevelop-

mental outcomes. In a meta-analysis adjusting for parental

educational attainment, a deleterious effect of maternal dia-

betes (encompassing GDM and type 1 and type 2 diabetes) on

lower IQ score was observed in children aged 3–12 years, but

the authors cautioned against drawing conclusions due to

significant heterogeneity in included studies [32] . It is plausible

that women with pre-existing diabetes may have received

monitoring and counselling prior to pregnancy and therefore

have better controlled glucose levels. Offspring born to moth-

ers with GDM may have a higher exposure to a greater level

of circulating glucose during the early stages of pregnancy

than those with pre-existing diagnosed diabetes.

An increased risk for attention deficit hyperactivity disorder

(ADHD) in children born to mothers with GDM (risk ratio: 2.00,

95% CI: 1.42–2.81, 985,984 children) has been shown in a

meta-analysis [33] . Notably, a large-sample US study suggests

that severe GDM requiring antidiabetic medications was as-

sociated with increased ADHD risk (HR: 1.26, 95% CI: 1.14–

1.41) in children (median age: 4.9 years) compared to the non-

exposed group [34] . Neither GDM requiring no medications

nor gestational age at GDM diagnosis was associated with

offspring ADHD risk. These associations were independent of

sociodemographic factors, smoking and alcohol use, mater-

nal history of ADHD, and maternal pre-pregnancy BMI.

There are a number of observational epidemiologic studies

published on offspring autism spectrum disorder outcome. A

meta-analysis detected a positive association between GDM

and child autism spectrum disorders even after adjustment for

important covariates such as obesity, maternal age, and ges-

tational age [35] . However, a Finnish cohort of 649,043 births

followed up to 11 years reported no increased risk of child’s

autism spectrum disorders in women with GDM and normal

weight, after adjusting for important covariates including ma-

Table 3. Selected studies linking GDM with neurodevelopmental outcomes

Study Design Cohort Sample size

GDM criteria Offspring age, years Major outcomes for GDM-exposed offspring

Kong et al. [36],Sweden

Cohort Data linkage of Finland’s nationwide registers

649,043 Medical record From birth to 11 GDM + maternal obesity associated with autism spectrum disorders (HR: 1.56, 95% CI: 1.26–1.93)Non-significant increase in GDM + normal weight for autism, adjusted for maternal psychiatric disorder, maternal age at delivery, maternal smoking, and maternal systemic inflammatory disease

Nahum Sacks et al. [38],Israel

Cohort A university medical centre which serves the entire population of the southern region of Israel

231,271 Medical record Not specified (study population included all patients who delivered between the years 1991 through 2014 and their offspring)

Associated with autistic spectrum disorder (OR: 4.44; 95% CI: 1.55–12.69), adjusted for maternal age, obesity, gestational week

Robles et al. [32],Spain

Meta-analysis

Included 7 cohort studies; USA, Israel

6,140 Exposure: maternal diabetes (regardless of type)

1–2 years for mental and psychomotor development; 3–12 years for IQ

Maternal diabetes associated with mental development (SMD: −0.41, 95% CI: −0.59 to −0.24), psychomotor development (−0.31, −0.55 to −0.07), and IQ (−0.78, −1.42 to −0.13)

Wan et al. [35],China

Meta-analysis

Included 16 case-control/cohort studies; USA, Canada, Sweden, Israel, Australia, Egypt

Not specified

Exposure: maternal diabetes

Not specified Associated with autism spectrum disorders (relative risk: 1.48; 95% CI: 1.26–1.75), adjusted for obesity, maternal age, gestational age

Xiang et al. [34],USA

Cohort Kaiser Permanente Southern California hospitals (retrospective birth cohort)

29,534 Carpenter-Coustan Median age: 4.9 GDM requiring antidiabetic medications associated with ADHD (HR: 1.26, 95% CI: 1.14–1.41)No association for GDM not requiring medications

Zhao et al. [33],China

Meta-analysis

Included 4 cohort studies; Denmark, Greece, USA, China

985,984 Medical record, self-report, ADA criteria

Range: 4–19 Associated with ADHD (RR: 2.00, 95% CI: 1.42–2.81)

ADHD, attention deficit hyperactivity disorder; CI, confidence interval; GDM, gestational diabetes mellitus; IQ, intelligence quotient; HR, hazard ratio; OR, odds ratio; RR, risk ratio; SMD, standardized mean difference.


10

DOI: 10.1159/000509902

ternal psychiatric disorder, maternal age at delivery, maternal

smoking, and maternal systemic inflammatory disease [36] . Of

note, more-pronounced risk effects for child autism spec-

trum disorders were reported in obese mothers with GDM

and/or maternal pre-gestational diabetes [36, 37] . Joint ef-

fects of maternal obesity and pre-gestational diabetes were

also observed on conduct disorders with onset in childhood

as well as mixed disorders of conduct and emotions, disorders

of social functioning, and tic disorders with onset in childhood

and adolescence [36] . Possible explanations for the joint ef-

fects between obesity and maternal pre-gestational diabetes

are the stronger neural impact of long-term exposure to con-

comitant contribution of lipotoxicity, inflammation, metabol-

ic stress, and hyperglycaemia. Limited data exist regarding

other offspring neuropsychiatric disorders, with some show-

ing either higher rates [38] or null associations [36] with eating

disorders and positive associations of sleep disorders [36, 38]

in children exposed to GDM.

Developmental Programming by Epigenetic Mechanisms

In the context of foetal programming, epigenetic processes

are thought to be an important mechanism underpinning

lasting effects on the offspring [9] . Epigenetic modifications

are cell type and tissue specific, which involve changes in

gene expression and genomic structure without altering the

DNA sequence. Epigenetic processes include DNA methyla-

tion, histone post-translational modifications, and expression

of non-coding RNAs. GDM, as an example of maternal envi-

ronmental trigger, can play a role in influencing offspring out-

comes through epigenetic regulation of genes. DNA meth-

ylation is the classic and most studied epigenetic measure,

primarily found in the CpG (cytosine followed by a guanine)

sequence contexts. The identification of DNA methylation

patterns related to adverse health-related outcomes in off-

spring is a potentially useful tool to assess individuals at risk

for health problems in early life exposed to GDM, representing

an important window of opportunity for early interventions

during childhood.

Animal Studies

Evidence from non-human animal models suggests that in

utero GDM exposure leads, for example, to developmental

and functional alterations of the hypothalamus [6, 39] , height-

ening the risk of developing overweight/obesity in the off-

spring. Animal models of developmental programming have

to date mainly involved nutritional, toxin exposure, selective

breeding, and direct genetic manipulations.

A study of streptozotocin-induced maternal diabetes in

mice showed an inhibitory effect of intrauterine hyperglycae-

mia exposure on the development of brown adipose tissue

(BAT) in offspring, thereby impairing the glucose uptake func-

tion of BAT in adulthood [40] . The authors found a downreg-

ulation of BAT-associated genes, Ucp1 , Cox5b , and Elovl3 ,

which is accompanied by disorganized ultra-structure of mi-

tochondria in BAT, probably contributing to intracellular lipid

accumulation and fat-induced insulin resistance [40] . Anoth-

er GDM mouse model showed altered DNA methylation pat-

terns in pancreatic tissues, manifested as dyslipidaemia, im-

paired glucose tolerance, and insulin resistance with advanc-

ing age [41] . The authors rationalized that the pancreas has a

direct role in regulating blood glucose levels and should

hence serve as an important target tissue to demonstrate the

role of DNA methylation as opposed to the more widely stud-

ied samples such as the placenta, umbilical cord blood, or

maternal peripheral blood.

However, animal models using chemical approaches such

as streptozotocin to induce permanent pancreatic damage

with impaired insulin secreting function and irreversible dia-

betes may be of limited relevance to GDM, which is transient

in nature and usually returns to euglycaemia after childbirth.

A recent mice experiment studied the induction of transient

glucose tolerance in pregnant mice with an insulin receptor

antagonist ( S961 ), reporting that mice born from S961 -treated

dams showed no susceptibility to physical or reflexes devel-

opment in the early neonatal period but had long-term met-

abolic (glucose intolerance) and cognitive impairment conse-

quences in adulthood when administered a high-fat diet [42] .

The administration of high-fat diets in mice mimics typical

energy-rich diets in both developing and industrialized coun-

tries, implicating epigenetic alterations as an important mech-

anism underpinning the induction of altered phenotypes in

response to environmental cues.

Human Studies

The mechanistic pathways underlying long-term morbidity in

offspring exposed to GDM are incompletely understood so

far, but a growing number of studies have supported involve-

ment of epigenetic mechanisms in the association of GDM

with offspring health. Most human studies on epigenetic me-

diation examined the associations of in utero GDM exposure

and DNA methylation in placentas, offspring cord, or infant

blood, as summarized in a recent review [43] . Several differ-

entially methylated genes in foetal tissues of babies born to


mothers with GDM have been identified using a candidate

gene approach; these include loci related to the leptin (LEP),

adiponectin (ADIPOQ) , mesoderm-specific transcript (Mest) ,

ATP-binding cassette transporter A1 ( ABCA1 ), SLC2A1/GLUT1 ,

and SLC2A3/GLUT3 genes. Epigenetic modifications at these

loci in response to impaired glucose homeostasis during

pregnancy might lead to lifelong susceptibility to adiposity

development in offspring.

Two epigenome-wide association studies (EWAS) using Il-

lumina 450k methylation arrays have reported associations of

maternal diabetes‐related DNA methylation marks with child-

hood adiposity-related outcomes [44, 45] . One of these stud-

ies included data from 2 prospective cohorts – the EPOCH

(Exploring Perinatal Outcomes in Children) and the Colorado

Healthy Start – which identified 6 GDM exposure‐associated

DNA methylation marks that were linked to measures of child-

hood adiposity and fat distribution [44] . Peripheral/cord blood

samples of GDM-exposed and non-GDM-exposed offspring

( n = 285, aged 10.5 years) were profiled, revealing that DNA

methylation of the SH3PXD2A gene was associated with BMI,

waist circumference, skinfold thicknesses, subcutaneous adi-

pose tissue, and leptin levels, after adjustment for cell propor-

tions [44] . In the second study of 388 Pima Indian children of

Arizona (aged 13.0 years) [45] , the observed DNA methylation

marks altered by intrauterine exposure to maternal diabetes

and linked to offspring BMI and insulin secretory were differ-

ent from those detected by the EPOCH study. The discrepan-

cies in DNA methylation hits could be due to the different

population studied, covariates adjusted for, and outcomes of

interest.

A causal relation between maternal hyperglycaemia and

epigenetic regulation of the leptin gene (with biological rel-

evance to long-term programming of offspring excessive ad-

iposity) in offspring cord blood has been reported based on a

2-step epigenetic Mendelian randomized approach [46] . The

epigenetic adaptations triggered by maternal glycaemia re-

sulted in an association between lower DNA methylation lev-

els at the CpG site cg12083122 (in the leptin gene of the off-

spring) and higher cord blood leptin levels [46] . Using media-

tion analysis, higher DNA methylation levels of the key genes

responsible for glycaemic/lipid metabolism ( PPARGC1α ) were

found to be correlated with higher cord blood leptin levels in

offspring exposed to maternal hyperglycaemia [47] . DNA

methylation (increased methylation of PYGO1 and CLN8 ) has

also been reported to mediate effects of in utero GDM expo-

sure on adverse offspring cardiometabolic traits (increased

VCAM-1 levels) [48] .

For neurodevelopmental outcome, a recent meta-analysis

of EWAS data published by the Pregnancy and Childhood Epi-

genetics Consortium (with 3,677 mother-neonate pairs from

7 pregnancy cohorts) showed that GDM was associated with

offspring cord blood hypomethylation of the OR2L13 pro-

moter, a gene associated with autism spectrum disorder [49] .

Notably, the study accounted for numerous potential con-

founding influences, including cord blood cell heterogeneity,

which is one of the potential sources of variability in DNA

methylation.

In a human placenta study [50] , maternal dysglycaemia in

pregnancy was associated with altered DNA methylation of

the serotonin transporter gene ( SLC6A4 ), a principal regulator

of serotonin homeostasis. Serotonin, a neurotransmitter, is

involved in neurodevelopmental disorders (e.g., depression,

anxiety, and autism). SLC6A4 methylation levels were nega-

tively associated with maternal glucose levels (both fasting

and 2-h plasma glucose) in the 24–28 weeks of gestation,

after adjustment for maternal pre-pregnancy BMI and gesta-

tional weight gain. Further, placental SLC6A4 methylation was

inversely associated with SLC6A4 mRNA levels, suggesting a

functional role of the CpG sites in regulating SLC6A4 gene

expression and that epigenetic changes predominate over

genetic mechanism in the human placenta. A separate study

has shown differential SLC6A4 methylation as a predictive

epigenetic marker of adiposity from birth to adulthood [51] .

Such studies provide valuable information on epigenetic

marks that can guide future research in developing potential

diagnostic biomarkers and predictive/treatment strategies for

adverse health events.

Transgenerational Epigenetic Inheritance

Increasing research on animal models, mainly in mice and

rats, suggests that developmental programming is a transgen-

erational phenomenon. The programmed phenotype is

passed on through several possible mechanisms including

persistence of the adverse environmental exposures in sub-

sequent generations, altered maternal phenotype, and inher-

itance of epigenetic modifications via alteration of the epi-

genome (germline and/or somatic line). Whilst most literature

on transgenerational transmission of traits have focused on

the maternal contributions to offspring, impacts of paternal

contributions have also been observed [4] .

A GDM mice model of intrauterine hyperglycaemia in-

duced by streptozotocin showed a pattern of dysregulation at

key methylation sites in the placenta (reflected by downregu-

lation and upregulation of Dlk1 and Gtl2 genes, respectively)

of the F1 and F2 generations [52] . A reduction in placental

weight was found to be transmitted paternally to the F2 off-

spring, but not maternally, which was believed to be linked to


12

DOI: 10.1159/000509902

the susceptibility of the sperm under a suboptimal intrauterine

environment.

While the transgenerational transmission of traits has been

reported through to the F2 offspring, evidence on the trans-

mission through to F3 and subsequent generations remains

unclear [53] . Studying F3 and succeeding generations is im-

portant to eliminate the possible confounding effects by the

initial adverse maternal insults on the embryo.

Although there is substantial evidence on the transgenera-

tional inheritance of epigenetic modifications in mice and

rats, the application of this concept in humans has been chal-

lenged by others [54] , mainly due to a complex sum of many

confounding factors including ecological and cultural inheri-

tance [55] . Well-controlled experiments in mammalian animal

models and large-scale cohorts/well-characterized epidemi-

ological studies are required in the future.

Do GDM Treatment Interventions Improve Long-Term Offspring Health?

Infants born to mothers receiving treatment of GDM in the

form of dietary advice, blood glucose monitoring, and insu-

lin therapy have improved perinatal outcomes compared

with those born to women receiving routine care [56] . How-

ever, evidence from a Cochrane review of long-term fol-

low-up studies of GDM treatment interventions suggests

that treatment may not reduce

childhood obesity [13] . In 2 fol-

low-up studies of children

whose mothers participated in

pregnancy trials for the treat-

ment of mild GDM, there was

no difference in child’s BMI

(aged 4–10 years) by treatment

and control groups [57, 58] . A

possible reason for the null

finding is that more-pro-

nounced GDM might be neces-

sary to program long-term

treatment effects on the devel-

opment of offspring obesity.

Nonetheless, female offspring

of mothers treated for mild GDM had lower fasting glucose

levels, suggesting a beneficial effect of treatment of mild

GDM in relation to reducing the risk of offspring insulin re-

sistance in females [57] .

Compared with insulin treatment, findings from the Met-

formin in Gestational diabetes: The Offspring Follow-Up (MiG

TOFU) cohort reported no differences in the body fat percent

and metabolic measures in children (aged 7–9 years) whose

mothers had been randomized to metformin and insulin GDM

treatment [59] . However, metformin-exposed children at 9

years of age were larger than the insulin-exposed group [59] .

In line with this, a meta-analysis including 3 follow-up studies

of RCTs reported that children prenatally exposed to metfor-

min treatment for GDM were heavier than those whose moth-

ers received insulin treatment [60] . Larger studies with longer

follow-up will be needed to better understand the health im-

pact of GDM treatments on offspring to optimize the health

of future generations.

There is also evidence for the periconceptional period as

an early window for which poor environmental exposures can

induce adverse health effects in offspring [4] . Interventions

delivered during pregnancy may only partly alter foetal growth

and development, and therefore studies examining interven-

tions that begin before conception are warranted. A large

multi-centre RCT is underway to investigate the effectiveness

of a nutritional (containing myoinositol, probiotics, and addi-

tional micronutrients) intervention commencing before con-

ception and continuing during pregnancy to maintain good

maternal glycaemic control, with the aim of improving off-

spring health outcomes [61] .

Conclusion

Overall, there is increasing evi-

dence for an impact of in utero

GDM exposure on lifetime

health in the offspring. However,

whether maternal GDM contrib-

utes directly to childhood adi-

posity remains to be elucidated,

given that maternal BMI and

gestational weight gain are also

linked with childhood adiposity.

Other observed long-term off-

spring adverse consequences

include cardiovascular abnor-

malities, glucose/insulin dys-

function, allergic/respiratory

health, and neurodevelopmen-

tal outcomes. Most evidence is based on observational pro-

spective cohorts, and further studies are required to advance

our knowledge of the effect of GDM and its treatment on de-

velopment, function, and health in the offspring. Taken to-

gether, the adverse health impacts of in utero GDM exposure

on offspring may rely upon epigenetic changes in selected

genes. Notably, many of these epigenetic modifications may

Female offspring of mothers

treated for mild GDM had

lower fasting glucose levels,

suggesting a beneficial effect

of treatment of mild GDM in

relation to reducing the risk of

offspring insulin resistance in

females


not be reversible and may persist throughout the offspring’s

life course. More studies in both animal and human models

are needed to replicate the epigenetic findings, with careful

consideration of the selection of cell or tissue types for epi-

genetic analysis because epigenetic mechanisms are gener-

ally tissue specific. There is also a need for larger studies with

long-term follow-up to understand the health impact of GDM

treatments in preventing adverse programming of health out-

comes in offspring.

Conflict of Interest Statement

K.M.G. has received reimbursement for speaking at conferences sponsored by companies selling nutritional products and is part of an academic consortium that has received research funding from Abbott Nutrition, Nestec, BenevolentAI Bio Ltd., and Danone. K.M.G. is sup-ported by the UK Medical Research Council (MC_UU_12011/4), the National Institute for Health Research (NIHR Senior Investigator [NF-SI-0515-10042] and NIHR Southampton Biomedical Research Centre [IS-BRC-1215-20004]), the European Union (Erasmus + Project Im-pENSA 598488-EPP-1-2018-1-DE-EPPKA2-CBHE-JP), the British Heart Foundation (RG/15/17/3174), and the US National Institute On Aging of the National Institutes of Health (Award No. U24AG047867). The writing of this article was supported by Nestlé Nutrition Institute and the authors declare no other conflicts of interest.

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Focus


Nutrition Management of Gestational Diabetes MellitusKavita Kapur et al.


[email protected]

Key Insight

Gestational diabetes mellitus (GDM) is one of the most common metabolic disturbances that occurs during pregnancy. A successful approach for addressing GDM is the use of medical nutrition therapy. The goal of medical nutrition therapy is to meet maternal and fetal nutritional needs while maintaining optimal glycemic control. This strategy is based on providing individualized advice alongside practical tools and training to optimize nutrition self-management and healthy eating. Rather than focusing on dietary restriction, it is important to shift the emphasis towards the consumption of quality foods, such as fruits, vegetables, and complex carbohydrates high in fiber.

Current knowledge

The combination of high pre-pregnancy body mass index (BMI) and excessive weight gain during pregnancy increases the risk of complications including GDM, pre-eclampsia, and babies born large for gestational age. In spite of the well-es-tablished risks for mothers and babies, there is a lack of clear guidance on the best way to address GDM. The most widely used guideline for gestational weight gain is from the Institute of Medicine (IOM); however, the IOM does not provide spe-cific recommendations for women with GDM. The conven-tional strategy for addressing GDM is based on a rigid limita-tion of all types of carbohydrates. Although this may help to control glucose levels, this approach fosters maternal anxiety and is an important barrier to adherence. Considering the im-pact of GDM on future health of the mother and the offspring, preventive strategies could have several benefits.Practical im-plications


Besides conventional carbohydrate restriction, studies dem-onstrate that the type and quality of carbohydrate is an impor-tant consideration. In general, diets with a low to moderate glycemic index have been shown to have a positive effect on maternal outcomes with no adverse effects on the newborn. Intake of fiber (particularly soluble fiber) is beneficial for lower-ing serum lipids and reducing glycemic fluctuations. In addi-tion, limiting total and saturated fats, while ensuring adequate levels of protein, are important for maintaining optimal fetal growth. There is evidence that regimens such as the Mediter-ranean and DASH diets may be beneficial within this context. For women at risk of developing GDM, nutritional strategies, such as probiotics and myo-inositol, might help reduce the risk of GDM when associated with a healthy lifestyle.

Recommended reading

Reader DM. Medical nutrition therapy and lifestyle interven-tions. Diabetes Care. 2007;30(Suppl 2):S188–93.

Pregnancy provides an eminent window of opportunity for changing behaviour towards healthy eating and lifestyle

Signal system

Color-coding to categorize different foods

Portion size

Use of shaped plates provide a visual cue of portion sizes

Food exchangetablesEnables the user to substitute foods, providing flexibility yet maintaining tractability

Food journal

Facilitates user compliance and helps monitor the dietary plan

Nutrition counseling may be used alongside some easily implemented tools to promote nutritional self-awareness and enhance compliance.



Nutrition Management of Gestational Diabetes Mellitus

Kavita Kapur a Anil Kapur b Moshe Hod c

a Consultant Dietician, Bangalore , India ; b World Diabetes Foundation, FIGO Pregnancy and NCD Committee, Bagsvaerd , Denmark ; c Clalit Health Services and Mor Women’s Health Center, FIGO Pregnancy and NCD Committee, Tel Aviv , Israel

Moshe Hod Mor Women’s Health Center 18 Aba Ahimeir St. Tel Aviv 6949204 (Israel) hodroyal @ inter.net.il


[email protected]

Key Messages

• Medical nutrition therapy is the bedrock for managing GDM. • Many different approaches to nutrition therapy work and are

equally effective. More than restriction, it is important to focus on quality of carbohydrates and encourage consumption of vegetables, fruits, complex carbohydrates, and high-fibre foods.

• Monitoring gestational weight gain, self-monitoring of blood glucose and foetal growth is important to modify nutrition advice to achieve optimal outcome for the mother and the newborn.

• Key to success is to provide individualized advice supported by practical tools and training for nutrition self-management and healthy eating and regular follow-up with a dietician or other health care professional trained to provide nutrition counselling.

DOI: 10.1159/000509900

Keywords Gestational diabetes · Management · Nutrition

Abstract Medical nutrition therapy (MNT) is the bedrock for the man-

agement of gestational diabetes mellitus (GDM). Several dif-

ferent types of dietary approaches are used globally, and

there is no consensus among the various professional groups

as to what constitutes an ideal approach. The conventional

approach of limiting carbohydrates at the cost of increasing

energy from the fat source may not be most optimal. Instead,

allowing higher levels of complex, low-to-medium glycae-

mic index carbohydrates and adequate fibre through higher

consumption of vegetables and fruits seems more beneficial.

No particular diet or dietary protocol is superior to another as

shown in several comparative studies. However, in each of

these studies, one thing was common – the intervention arm

included more intensive diet counselling and more frequent

visits to the dieticians. For MNT to work, it is imperative that

diet advice and nutrition counselling is provided by a dietician,

which is easy to understand and use and includes healthy

food options, cooking methods, and practical guidance that

empower and motivate to make changes towards a healthy

eating pattern. Various simple tools to achieve these objec-

tives are available, and in the absence of qualified dieticians,

they can be used to train other health care professionals to

provide nutrition counselling to women with GDM. Given the

impact of GDM on the future health of the mother and off-

spring, dietary and lifestyle behaviour changes during preg-

nancy in women with GDM are not only relevant for immedi-

ate pregnancy outcomes, but continued adherence is also

important for future health.


S. Karger AG, Basel

Kapur/Kapur/HodReprint with permission from:Ann Nutr Metab 2020;76(suppl 3):17–29

18

DOI: 10.1159/000509900

Introduction

The rising prevalence of gestational diabetes mellitus (GDM)

globally and the recognition that medical nutrition therapy

(MNT) is the bedrock for its management have led to the

search for a pragmatic, feasible, and widely adaptable ap-

proach to nutrition therapy to help control maternal glycae-

mia effectively while also promoting normal foetal growth.

The conventional focus so far has been to rigidly limit all types

of carbohydrates; though it may help control glucose, it also

fosters maternal anxiety and is an important barrier to adher-

ence [1] . Carbohydrates in the form of rice, wheat, pulses, po-

tato, sugar, etc., account for a substantial portion of tradi-

tional diets across the world, and limiting their consumption

is challenging.

In general, nutrition requirements of women with GDM are

similar to non-GDM pregnancies but require a special focus

on dietary modification to ensure healthy and mindful eating

to achieve and maintain maternal euglycaemia, prevent wide

glycaemic excursions, and ensure appropriate gestational

weight gain (GWG) and foetal growth. MNT and lifestyle

changes are the key elements in the management of GDM. To

ensure success of the MNT programme, besides making ap-

propriate adjustments in diet and lifestyle, women with GDM

also need to learn about self-monitoring of blood glucose

(SMBG) and require education, counselling, emotional sup-

port, and regular follow-up [2] .

Despite several recent studies, the ideal diet (energy con-

tent, carbohydrate restriction, and quality and quantity of

macronutrients) for women with GDM remains unclear [3, 4] .

While Evert et al. [5] suggest individualizing dietary advice as

per the American Diabetes Association guidelines applicable

to all persons with diabetes (not restricted to pregnancy)

would suffice, the Academy of Nutrition and Dietetics latest

clinical guideline states that one type of nutrition plan would

not be appropriate for all women with GDM [6] , and various

national and sub-national strategies based on local culture

and eating habits may be needed.

GWG and Energy Intake

The combination of high pre-pregnancy body mass index

(BMI) and excessive weight gain during pregnancy increases

the risk of GDM, pre-eclampsia, large for gestational age ba-

bies, and complications for both the mother and the newborn

at delivery. Overweight or obese pregnant women are also

more likely to exceed weight gain recommendations. Fur-

thermore, post-partum weight retention is influenced by the

amount of weight gained during pregnancy. Excessive GWG,

irrespective of pre-pregnancy BMI, is a significant risk factor

for higher fat mass deposit during pregnancy and higher post-

partum fat retention [7] which adds to the already high risk of

future type 2 diabetes and cardiovascular disease in these

women. Overweight and obesity among women with GDM

complicate dietary management.

Globally, the most widely used guideline for GWG is the

Institute of Medicine (IOM) guideline [8] which recommends

appropriate amount of weight gain per trimester depending

on the pre-pregnancy BMI. The IOM guideline does not pro-

vide any specific recommendation for women with GDM. The

FIGO guideline [9] states that for normal-weight and under-

weight women, the IOM guidelines apply. Also, usual amount

of weight gain and no restriction in calories are recommend-

ed to ensure normal infant birth weight. For overweight and

obese women, there is no consensus regarding calorie intake

and weight gain during GDM pregnancy [9] . There is some

evidence to support no weight gain or weight loss in obese

women with GDM [10] .

Surprisingly, there are very few country-specific guidelines

on GWG and most follow the IOM guidelines [11] . Health Can-

ada [12] in their pre-natal guidelines for health professionals

has developed a GWG graph using the IOM guidelines to

monitor and motivate women to stay within the optimal

weight gain range.

There is limited research on caloric requirements and op-

timum weight gain for women with GDM, and a systemic re-

view of the guidelines from various professional organizations

shows varied recommendations. Some recommend between

1,500 and 2,000 kcal/day and others a 30% calorie restriction

for overweight or obese GDM women, while yet another rec-

ommends reducing calorie intake by 300 kcal/day [11] . Even

though the recommendations of various organizations vary,

there is an emerging consensus supporting calorie restriction

for overweight and obese women with GDM to avoid exces-

sive GWG [13] . When possible, sequential foetal growth mea-

Excessive GWG, irrespective

of pre-pregnancy BMI, is a

significant risk factor for

higher fat mass deposit

during pregnancy and higher

post-partum fat retention

GDM and Nutrition Management 19Reprint with permission from:Ann Nutr Metab 2020;76(suppl 3):17–29DOI: 10.1159/000509900

surements can provide a more useful benchmark to deter-

mine permissible energy intake (EI) in overweight and obese

women with GDM than GWG.

According to a WHO report [14] , high-risk women who fol-

low lifestyle change interventions (both diet and exercise) re-

duce the risk of excessive GWG, thereby reducing risk of peri-

natal complications. In a study by Vestgaard et al. [15] , there

was relatively lower mean birth weight in newborns of GDM

mothers on extended-duration MNT as compared to non-

GDM women or GDM women who had no MNT. Birth weight

above 4 kg was seen in 18% of MNT-treated GDM women

versus 27 and 24% ( p = 0.012) in non-diabetic and no MNT

GDM women, respectively. Early diagnosis of GDM and ear-

lier MNT intervention seem beneficial. A Cochrane report

states that a combined diet and exercise programme can be

useful in preventing GDM in high-risk women [16] .

Carbohydrate Restriction

Carbohydrate restriction remains the most common ap-

proach for MNT in GDM. The focus on carbohydrate restric-

tion seems to vary in recommendations from different orga-

nizations. The American College of Obstetricians and Gynae-

cologists (ACOG) [17] and the Endocrine Society [18]

recommend restricting carbohydrates in all GDM women on

the MNT programme, while the FIGO advises monitoring the

carbohydrate intake and the quality of carbohydrates con-

sumed and distributing them throughout the day to attain and

maintain euglycaemia [9] . On the amount of permissible car-

bohydrates, the guidance varies from 35 to 40% of total calo-

ries in the lower carbohydrate range to 50–60% in the mod-

erate carbohydrate range. However, there seems consensus

on not limiting carbohydrate intake to <175 g/day ( Table 1 ).

According to Romon et al. [19] , carbohydrate restriction to

<39% may result in higher birth weight. A lower carbohydrate

and higher fat and protein intake may increase the risk of GDM

in at-risk women [20] . While restricting carbohydrates helps

control hyperglycaemia, substituting fat for carbohydrate, es-

pecially in obese women with pre-pregnancy insulin resis-

tance (IR), could increase lipolysis and circulating free fatty

acids (FFA) available for transplacental transfer leading to ex-

cess foetal fat accumulation, as well as worsening maternal IR

[1, 21] which in turn may worsen hyperglycaemia in the moth-

er [22] .

To understand the effect of low carbohydrate on maternal

IR, adipose tissue lipolysis, and infant adiposity, a randomized

pilot study was undertaken by Hernandez et al. [23] . At 31

weeks, 12 diet-controlled overweight/obese women with

GDM were randomized to an isocaloric low-carbohydrate

diet (40% carbohydrate/45% fat/15% protein; n = 6) or a high-

er complex carbohydrate/lower fat (CHOICE) (60% carbohy-

drate/25% fat/15% protein; n = 6) diet. After 7 weeks on the

diet, fasting glucose ( p = 0.03) and FFAs ( p = 0.06) decreased

in those on the CHOICE diet, whereas fasting glucose in-

creased in those on the low-carbohydrate diet ( p = 0.03). The

CHOICE diet with higher complex carbohydrates may im-

prove maternal IR and lower infant adiposity [23] . Higher in-

take of nutrient-dense complex carbohydrates may result in

improved metabolic outcomes and reduce excess infant adi-

posity [24] .

In low-carbohydrate diets, the source of fat and protein

makes a difference. A pre-pregnancy low-carbohydrate diet

with high protein and fat from animal food sources is posi-

tively associated with GDM risk, whereas a pre-pregnancy

low-carbohydrate dietary pattern with high protein and fat

from vegetable food sources is not associated with the risk.

Women of reproductive age who follow a low-carbohydrate

dietary pattern may consider consuming vegetables rather

than animal sources of protein and fat to minimize their risk

of GDM [25] .

Low-Glycaemic Index Diets

The type and quality of carbohydrate is an important consid-

eration in nutrition advice for people with diabetes, as not all

carbohydrates have the same glycaemic response [26] . The

glycaemic index (GI) of foods is an important factor, as foods

with a low GI reduce post-meal glycaemic excursions and

flatten the glucose curve. People with diabetes on high-GI

diets (>70) exhibit higher post-prandial values, and in non-

pregnant patients with diabetes, low-GI diets lead to an ad-

ditional 0.4% reduction in haemoglobin A1C [27] .

Besides the conventional advice of restricting carbohy-

drates, studies demonstrate an important role for low-GI diets

in GDM [13] . In fact, in GDM, diets higher in unrefined/com-

plex carbohydrates have been shown to effectively blunt

post-prandial glycaemia [28, 29] , reduce the need for insulin

A pre-pregnancy low-

carbohydrate diet with high

protein and fat from animal

food sources is positively

associated with GDM risk


20

DOI: 10.1159/000509900

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I d

istr

ibu

ted

in 3

me

als

and

≥

2 s

nac

ks (

1 at

be

dti

me

)

Dia

be

tes

Car

e

Pro

gra

mm

e o

f N

ova

Sc

oti

a, C

anad

a, 2

014

Pro

mo

te o

pti

mu

m

nu

trit

ion

fo

r m

ate

rnal

/fo

eta

l he

alth

, pro

vid

e

ade

qu

ate

GW

G, m

ain

tain

n

orm

al B

G a

nd

ke

ton

e

abse

nc

e

Ye

sY

es

Ye

sE

nsu

re m

acro

an

d

mic

ro n

utr

ien

t ad

eq

uac

y. B

ase

d o

n

die

t h

isto

ry, G

WG

, 2

4-h

re

cal

l, fo

od

re

co

rds,

pre

-nat

al

nu

trit

ion

ass

ess

me

nt,

SM

BG

an

d k

eto

ne

s,

sen

siti

ve t

o c

ult

ure

, lif

est

yle

, SE

S,

will

ing

ne

ss, a

nd

ab

ility

to

ch

ang

e

In O

W/O

B <

30

0

kcal

/dC

HO

: 4

5–

60

%

EI

PR

O:

15–

20

%

EI

Fat:

20

–3

5%

EI

SFA

: <

7% E

I3

me

als

and

2

–4

sn

acks

/d

CH

O >

175

g/d

, mo

de

rate

C

HO

re

stri

cti

on

, pro

visi

on

o

f c

on

sist

en

t C

HO

am

ou

nts

, LG

I, lo

w-

bre

akfa

st C

HO

(fi

bre

[<

50

g

/d])

(so

lub

le f

ibre

oat

s,

be

ans,

psy

lliu

m, b

arle

y,

etc

.)

Firs

t tr

ime

ste

r:

0.8

g/k

g/d

Sec

on

d, t

hir

d

trim

est

er:

1.1

g/k

g/d

or

þ2

5

g/d

Mu

ltif

oe

tal

ge

stat

ion

: þ

50

g/d

fr

om

20

wk

un

til

de

live

ry

De

uts

ch

e D

iab

ete

s G

ess

ells

ch

aft/

De

uts

ch

e

Ge

sells

ch

aft

für

Gyn

äko

log

ie u

nd

G

eb

urt

shilf

e,

Ge

rman

y, 2

014

Ac

hie

ve t

he

rap

y o

bje

cti

ves:

pre

gn

anc

y-sp

ec

ific

BG

tar

ge

t le

vels

w

ith

ou

t ke

tosi

s/h

ype

rgly

cae

mia

, GW

G,

and

fo

eta

l gro

wth

Ye

sC

ove

r e

atin

g h

abit

s,

bas

al m

eta

bo

lic r

ate

, b

od

y w

eig

ht,

SE

S, a

nd

re

ligio

us

stat

us

to

ach

ieve

go

al B

G, G

WG

, an

d f

oe

tal g

row

th

wit

ho

ut

keto

sis/

hyp

erg

lyc

aem

ia

OB

: 3

0–

33

% o

f E

ER

EI:

1,6

00

–1,

80

0

kcal

/d

CH

O:

40

–5

0%

E

IP

RO

: 2

0–

25

%

EI

Fat:

30

–3

5%

EI

CH

O:

>4

0%

EI

Re

frai

n f

rom

fas

t ab

sorb

C

HO

wit

h H

GI.

Fib

re:

30

g

/d (

e.g

., g

rain

s, f

ruit

, an

d

veg

eta

ble

s)C

HO

allo

cat

ion

:3

me

diu

m m

eal

s an

d 2

–3

sn

acks

. Bre

akfa

st C

HO

15

–3

0 g

OB

pat

ien

ts m

ust

p

refe

r lo

w-f

at

pro

tein

inta

ke:

60

–8

0 g

/d

En

do

cri

ne

So

cie

ty,

inte

rnat

ion

al, 2

013

CH

O-c

on

tro

lled

me

al p

lan

p

rom

oti

ng

ad

eq

uat

e

nu

trit

ion

, ap

pro

pri

ate

G

WG

, eu

gly

cae

mia

, an

d

no

ke

ton

es

Ye

sH

eal

thy

foo

d c

ho

ice

s,

po

rtio

n c

on

tro

l, an

d

go

od

co

oki

ng

p

rac

tic

es,

tak

ing

into

ac

co

un

t p

ers

on

al a

nd

c

ult

ura

l eat

ing

p

refe

ren

ce

s, p

re-

gra

vid

BM

I, d

esi

red

b

od

y w

eig

ht,

ph

ysic

al

acti

vity

, an

d B

G le

vels

OW

/OB

EI:

1,

60

0–

1,8

00

kc

al/d

u

nd

erw

eig

ht/

no

rmal

we

igh

t n

o r

est

ric

tio

n

CH

O:

35

–4

5%

E

ID

istr

ibu

ted

in 3

sm

all-

to-

me

diu

m-s

ize

d m

eal

s an

d

2–

4 s

nac

ks, w

ith

1

eve

nin

g s

nac

k


Org

aniz

atio

n a

nd

re

gio

n, y

ear

MN

T g

oal

s an

d

rec

om

me

nd

atio

ns

Die

tic

ian

in

volv

e-

me

nt

me

nti

on

ed

Nu

trit

ion

e

du

cat

ion

m

en

tio

ne

d

Nu

trit

ion

as

sess

-m

en

t m

en

tio

ne

d

MN

T in

terv

en

tio

nE

ne

rgy

rest

ric

tio

n

rec

om

me

nd

a-ti

on

Mac

ron

utr

ien

t d

istr

ibu

tio

nC

HO

co

nsi

de

rati

on

PR

O

Inte

rnat

ion

al

Fed

era

tio

n o

f G

ynae

co

log

y an

d

Ob

ste

tric

s,

inte

rnat

ion

al, 2

015

Ye

sY

es

Bas

ed

on

pe

rso

nal

an

d

cu

ltu

ral e

atin

g h

abit

s,

ph

ysic

al a

cti

vity

, BG

le

vels

, an

d g

est

atio

n’s

p

hys

iolo

gic

al e

ffe

cts

EI:

2,0

50

kc

al/d

ir

resp

ec

tive

of

bo

dy

we

igh

t

CH

O:

35

–4

5%

E

I>

175

g C

HO

/d, L

GI,

CH

O

dis

trib

ute

d in

3 s

mal

l-to

-m

ed

ium

-siz

ed

me

als

and

2

–4

sn

acks

. Eve

nin

g

snac

k n

ee

de

d t

o p

reve

nt

ove

rnig

ht

keto

sis.

Fib

re:

<2

8 g

/d

Dia

be

tic

n

ep

hro

pat

hy:

low

P

RO

to

0.6

–0

.8

g/k

g id

eal

bo

dy

we

igh

t

Ho

ng

Ko

ng

Co

lleg

e

of

Ob

ste

tric

s an

d

Gyn

aec

olo

gy

(HK

CO

G),

Ho

ng

K

on

g, 2

016

Ye

sH

eal

thy

die

tLo

w G

I

Ital

ian

Ass

oc

iati

on

of

Dia

be

tes/

Dia

be

tes

Ital

ia/I

talia

n S

oc

iety

fo

r D

iab

ete

s, It

aly,

2

00

7

Ap

pro

pri

ate

mat

ern

al a

nd

fo

eta

l nu

trit

ion

(c

alo

rie

, vi

tam

in, a

nd

min

era

l in

take

), e

ug

lyc

aem

ia, a

nd

la

ck

of

keto

nu

ria

Ye

sY

es

Pe

rso

nal

ize

d, b

ase

d o

n

die

t h

abit

s an

d p

re-

gra

vid

BM

I

EI:

>1,

50

0

kcal

/dU

nd

erw

eig

ht:

4

0 k

cal

/kg

/dN

orm

al w

eig

ht:

3

0 k

cal

/kg

/dO

W:

24

kc

al/

kg/d

CH

O:

50

% E

IP

RO

: 2

0%

EI

Fat:

30

% E

IFi

bre

: 2

8 g

/dN

igh

t sn

ack:

25

g

CH

O, 1

0 g

P

RO

CH

O >

40

% E

I

Inte

rnat

ion

al

Dia

be

tes

Fed

era

tio

n,

inte

rnat

ion

al, 2

00

9

Ye

sIn

div

idu

aliz

ed

an

d

cu

ltu

rally

se

nsi

tive

OW

: <

30

% E

ER

LGI

Iris

h H

eal

th S

erv

ice

E

xec

uti

ve, I

rela

nd

, 2

010

Foo

d c

ho

ice

s fo

r m

ate

rnal

/fo

eta

l he

alth

, ap

pro

pri

ate

GW

G,

no

rmo

gly

cae

mia

, an

d

abse

nc

e o

f ke

ton

es

Ye

sC

ult

ura

lly a

pp

rop

riat

e,

bas

ed

on

gly

cae

mic

c

on

tro

l an

d g

est

atio

nal

ag

e

OW

/OB

: m

igh

t b

e n

ee

de

dM

od

est

CH

O r

est

ric

tio

n in

O

W/O

B. M

on

ito

r C

HO

in

take

. Pre

fer

fru

it,

veg

eta

ble

s, w

ho

le g

rain

s,

leg

um

es

Re

du

ce

fat

milk

Ind

ian

Min

istr

y o

f H

eal

th a

nd

Fam

ily

We

lfar

e, I

nd

ia, 2

014

35

0 k

cal

/d a

bo

ve R

DA

d

uri

ng

se

co

nd

an

d

thir

d t

rim

est

ers

OB

: 3

0%

EE

RC

HO

: 5

0–

60

%P

RO

: 10

–2

0%

Fat:

20

–3

0%

EI

SFA

<10

% E

IIn

OB

: lo

w-f

at

die

t

Spre

ad C

HO

fo

od

s o

ver

3

smal

l me

als

and

2–

3

snac

ks/d

. Pre

fer

co

mp

lex

CH

O. A

im f

or

2–

3 C

HO

se

rvin

gs/

me

al a

nd

1–

2

CH

O s

erv

ing

s/sn

ack

Bre

akfa

st:

1–2

CH

O s

erv

ing

s

+2

3 g

/d a

bo

ve

no

n-p

reg

nan

t R

DA

in 3

se

rvin

gs/

dB

reak

fast

: 1

serv

ing

of

pro

tein

-ric

h f

oo

ds

Mal

aysi

an H

eal

th

Te

ch

no

log

y A

sse

ssm

en

t Se

cti

on

, M

alay

sia,

20

17

Nu

trit

ion

dia

gn

osi

s an

d

the

rap

y w

ith

die

tary

in

terv

en

tio

n a

nd

c

ou

nse

llin

g

Ye

sY

es

He

alth

y, b

alan

ce

d

CH

O-c

on

tro

lled

me

al

pla

n f

or

app

rop

riat

e

GW

G

OB

: 3

0–

33

%

EE

R (

25

kc

al/

kg/d

)N

orm

al w

eig

ht:

3

5 k

cal

/kg

/d

CH

O:

45

–6

0%

PR

O:

15–

20

%Fa

t: 2

5–

35

% E

I

CH

O >

175

g/d

, LG

I, C

HO

e

xch

ang

es

dis

trib

ute

d

acc

ord

ing

to

SM

BG

, lif

est

yle

, an

d m

ed

icat

ion

s.

Suc

rose

inta

ke c

ou

nte

d in

to

tal C

HO

. Hig

h f

ibre

Nat

ion

al In

stit

ute

fo

r C

linic

al E

xce

llen

ce

(N

ICE

), U

K, 2

015

CH

O-c

on

tro

lled

me

al p

lan

p

rom

oti

ng

ad

eq

uat

e

nu

trit

ion

an

d G

WG

n

orm

og

lyc

aem

ia, a

nd

ab

sen

ce

of

keto

sis

Ye

sY

es

He

alth

y d

iet

Ta

ble

1 (c

on

tin

ue

d)


22

DOI: 10.1159/000509900

Org

aniz

atio

n a

nd

re

gio

n, y

ear

MN

T g

oal

s an

d

rec

om

me

nd

atio

ns

Die

tic

ian

in

volv

e-

me

nt

me

nti

on

ed

Nu

trit

ion

e

du

cat

ion

m

en

tio

ne

d

Nu

trit

ion

as

sess

-m

en

t m

en

tio

ne

d

MN

T in

terv

en

tio

nE

ne

rgy

rest

ric

tio

n

rec

om

me

nd

a-ti

on

Mac

ron

utr

ien

t d

istr

ibu

tio

nC

HO

co

nsi

de

rati

on

PR

O

Ne

w Z

eal

and

Min

istr

y o

f H

eal

th, N

ew

Z

eal

and

, 20

14

CH

O-c

on

tro

lled

me

al p

lan

w

ith

sp

ec

ific

die

tary

re

co

mm

en

dat

ion

s d

ete

rmin

ed

an

d r

eg

ula

rly

mo

dif

ied

by

ind

ivid

ual

as

sess

me

nt

Ye

sY

es

Ye

s>

1,8

00

kc

al/d

Low

SFA

175

g/d

, CH

O d

istr

ibu

ted

e

ven

ly t

hro

ug

ho

ut

the

d

ay, b

etw

ee

n m

eal

s/sn

acks

Lean

pro

tein

Po

lish

Dia

be

tes

and

P

reg

nan

cy

Stu

dy

Gro

up

, Po

lan

d, 2

017

Ye

s

Ro

yal A

ust

ralia

n

Co

lleg

e o

f G

en

era

l P

rac

titi

on

ers

(R

AC

GP

), A

ust

ralia

, 2

016

Ye

sY

es

Ro

yal C

olle

ge

of

Ob

ste

tric

s an

d

Gyn

aec

olo

gy

(RC

OG

), U

K, 2

011

Sco

ttis

h

Inte

rco

lleg

iate

G

uid

elin

e N

etw

ork

(S

IGN

), Sc

otl

and

, 2

017

Ye

sLo

w G

I

MN

T, m

ed

ical

nu

trit

ion

th

era

py;

GW

G, g

est

atio

nal

we

igh

t g

ain

; SM

BG

, se

lf-m

on

ito

rin

g o

f b

loo

d g

luc

ose

; EI,

en

erg

y in

take

; EE

R, e

stim

ate

d e

ne

rgy

req

uir

em

en

t; R

DA

, re

co

mm

en

de

d d

aily

allo

wan

ce

; C

HO

, car

bo

hyd

rate

; P

RO

, pro

tein

; LG

I, lo

w g

lyc

aem

ic in

de

x; M

GI,

me

diu

m g

lyc

aem

ic in

de

x; O

B, o

be

se;

BM

I, b

od

y m

ass

ind

ex;

OW

, ove

rwe

igh

t; S

FA, s

atu

rate

d f

atty

ac

ids.

Ta

ble

1 (c

on

tin

ue

d)


therapy [30] , lower fasting LDL cholesterol levels [28, 31] and

FFAs [28] , and improve insulin sensitivity [32] , HbA 1 C [31] , and

systolic blood pressure [31] .

The role of low-GI diets in GDM has been extensively stud-

ied. A meta-analysis of 5 randomized clinical trials with 302

participants studied the effect of low GI versus control diets

and found that low-GI diets reduced the risk of macrosomia

in women with GDM and low-GI diets with added dietary fibre

reduced usage of insulin [33] . The key effect of low-GI diet

was reduction in 2-h post-prandial glucose, fasting plasma

glucose, and lipid profile in women with GDM and a substan-

tial decrease in insulin requirement [34] .

Another meta-analysis of 11 trials involving 1,985 women

evaluated both maternal and newborn outcomes. Low-GI

diet was shown to have a positive effect on maternal out-

comes even for those at risk of hyperglycaemia without ad-

verse outcomes on newborns [35] .

Three recent meta-analysis and systematic reviews stud-

ied various diets and pregnancy outcomes. Viana et al. [36]

and Wei et al. [33] concluded that low-GI diets were associ-

ated with a decreased risk of infant macrosomia, whereas a

Cochrane review, including 19 trials randomizing 1,398 wom-

en, found no clear difference in large for gestational age or

other primary neonatal outcomes with the low-GI diet [37] . It

is nonetheless important to note that more than 9 guidelines

on nutrition recommendation for GDM from professional or-

ganizations recommend a low-to-moderate GI diet [11] .

Dietary Fibre

Fibre intake, particularly soluble fibre, is beneficial in lowering

serum lipid levels and reducing glycaemic excursions. Low-GI

foods often have higher fibre content, but that is not always

the case. High-fibre foods in a mixed meal can serve the same

purpose as low-GI diets.

To understand the difference between low-GI diets and

high-fibre diets, 139 women at high risk of GDM (mean [SD]

age: 34.7 [0.4] years and pre-pregnancy BMI: 25.2 [0.5] kg/m 2 )

were randomly assigned to either a low-GI diet (GI target ∼ 50)

or a high-fibre, moderate-GI diet (target GI ∼ 60) during 14–

20 weeks of gestation. The average daily amount of fibre in-

take in each diet group was not stated. Similar pregnancy out-

comes (glycosylated haemoglobin, fructosamine or lipids at

36 weeks, or differences in birth weight, Ponderal index birth

weight centile, % fat mass, or incidence of GDM) were seen in

both groups [38] .

No good quality studies on the benefits of fibre-rich diets

in women with GDM are available; it is however recommend-

ed that foods rich in fibre should be preferred. Up to 28-g fibre

intake per day is recommended for women. Fibre also helps

reduce constipation, a common problem in pregnancy. Apart

from the use of low-GI and high-fibre diets, another com-

monly used method to reduce high post-prandial levels and

wide post-meal glucose excursions and high fasting glucose,

recommended by most guidelines, is distributing the total dai-

ly allocated carbohydrate portions into 3 small meals and 2–3

snacks per day [11] .

Fat

MNT in GDM has primarily focussed on control of maternal

glycaemia; however, data suggest that maternal lipids, espe-

cially triglycerides, may be stronger drivers of foetal growth

than glucose [39, 40] .

Increased consumption of total and saturated fat could

worsen IR (Barbour LA, 2007) and increase foetal nutrient ex-

posure, promoting overgrowth patterns. In a randomized

study of women with GDM, CHO restriction (40% of total cal-

ories, compared to 60% complex CHO) was accompanied by

20% higher post-prandial FFAs [41] .

It is therefore important that the fat content total and sat-

urated fat of diets of women with GDM need to be moder-

ated. Most GDM guidelines of various professional organiza-

tions ( Table 1 ) do not specify the amount of recommended

fat intake; amongst those who do, there is a wide variation in

recommendations. Most fall in the range of 20–35% of daily

EI with the ACOG guideline being the outlier recommending

up to 40% of daily EI.

Protein

Adequate protein intake during pregnancy is essential to

prevent depletion of maternal stores and prevent muscle

breakdown to supply for the foetal needs. Most nutrition

guidelines recommend a protein intake between 10 and

20% of daily EI and between 60 and 80 g of protein intake

Maternal lipids, especially

triglycerides, may be

stronger drivers of foetal

growth than glucose


24

DOI: 10.1159/000509900

daily. The Indian guidelines recommend a minimum addi-

tional 23 g of protein intake daily during pregnancy over and

above the normal recommended daily allowance for adult

women. Protein intake restrictions may be required in pres-

ence of renal failure.

Several specialized dietary protocols have also been tested

in women with GDM. Some of these studies are briefly de-

scribed below.

DASH Diet

A randomized controlled trial was conducted to study the ef-

fects of the DASH (Dietary Approaches to Stop Hypertension)

diet on pregnancy outcomes in women with GDM. Fifty-two

participants were randomly assigned to either the control diet

or DASH diet for 4 weeks. The control diet contained 45–55%

carbohydrates, 15–20% protein, and 25–30% total fat while

the DASH diet was rich in fruits, vegetables, whole grains, and

low-fat dairy products and contained lower amounts of satu-

rated fats, cholesterol, and refined grains with a total of 2,400

mg/day sodium. Participants on the DASH diet had better

metabolic outcomes than those in the control group. Also,

infants born to mothers on the DASH diet had significantly

lower weight, head circumference, and Ponderal index com-

pared with those born to mothers on the control diet. Only

46.2% of women in the DASH diet group needed caesarean

section as compared to 80.8% ( p < 0.01) in the control group.

Similarly, only 23% participants on the DASH diet needed in-

sulin therapy as compared to 73% for the control group ( p <

0.0001) [42] .

Mediterranean Diet

The Mediterranean diet was studied as part of the St Carlos

GDM Prevention Study – a prospective randomized study

wherein both the intervention group and control group were

given the same basic Mediterranean diet (MedDiet) recom-

mendations of 2 servings/day of vegetables, 3 servings/day of

fruit (avoiding juices), 3 servings/day of skimmed dairy prod-

ucts and wholegrain cereals, 2–3 servings of legumes/week,

moderate to high consumption of fish, and a low consump-

tion of red and processed meat and avoidance of refined

grains, processed baked goods, pre-sliced bread, soft drinks

and fresh juices, fast foods, and precooked meals. All GDM

participants were advised Mediterranean diets plus a recom-

mended daily extra virgin olive oil intake ≥40 mL and a daily

handful of nuts. Results showed that the intervention group

had reduced incidence of GDM and improved several mater-

nal and neonatal outcomes [43] . Mediterranean diet interven-

tion advised early in the pregnancy or to pre-pregnant wom-

en has been shown to reduce GDM incidence and maternal-

foetal adverse outcomes [44, 45] .

Non-Nutritive Sweeteners

Several non-nutritive sweeteners have become available and

are widely used by women, but their use during pregnancy has

not been well studied, and there is still no clear understanding

on their use in pregnancy, with only a couple of international

guidelines approving the use of some of them during preg-

nancy. Aspartame, saccharin, acesulfame, and sucralose are

recommended by a few guidelines in moderate amounts. Be-

sides the above, the Academy of Nutrition and Dietetics also

accepts usage of advantame, neotame, luo han guo extracts,

and steviol glycosides as per the FDA ADI limits. Cyclamates

are not approved [11] .

Interventions to Prevent GDM – Probiotics and Myoinositol

Preventing GDM could have several benefits such as reduc-

tion in the immediate adverse outcomes during pregnancy, a

reduced risk of long-term sequelae, and a decrease in the

economic burden to health care systems. Current available

evidence about the prevention of GDM showed that the ma-

jority of the interventions done during pregnancy have non-

significant effect in preventing GDM [46, 47] . Dietary interven-

tion can reduce the risk of developing GDM and the propor-

tion of infants born with macrosomia among pregnant

women with obesity; physical activity interventions have not

had the same effect. However, conclusive evidence is not yet

available to guide practice [48, 49] . Supplement interventions

with probiotics and myoinositol during pregnancy showed a

decrease in the rates of GDM compared with a placebo [47,

50] . Intervention showed that probiotics ( Lactobacillus rham-

nosus and Bifidobacterium lactis Bb12) reduced the incidence

of GDM, from 36 to 13%; probiotic consumption may protect

against GDM because these microorganisms can modify in-

testinal microbiota, altering the fermentation of dietary poly-

saccharides and improving intestinal barrier function [50] .

Moreover, myoinositol supplements (4 g) were found to re-

duce 50–60% of the incidence of GDM in high-risk pregnant

women (overweight, obese, or first-degree relative of type 2

diabetes mellitus) [47, 51] . Myoinositol, an isomer of inositol,

is one of the intracellular mediators of the insulin signal and

correlated with insulin sensitivity in type 2 diabetes. The po-


tential beneficial effect on improving insulin sensitivity sug-

gests that myoinositol may be useful for women in preventing

GDM. In conclusion, in women at high risk of developing

GDM, the current evidence has showed that dietary advice,

probiotics, and myoinositol supplementation might reduce

the incidence of GDM.

Interventions to Enhance Healthy Eating and Meal Planning

Systematic reviews studying 19 trials and comparing the ef-

fects of 10 different types of dietary advice for women with

GDM found no conclusive evidence to show superiority of

one approach or diet programme over others [37] . These in-

cluded studies comparing a low-to-moderate GI diet versus

a moderate high-GI diet; an energy-restricted diet versus no

energy restriction; a DASH diet versus a control diet; a low-

carbohydrate diet versus a high-carbohydrate diet; a high-

unsaturated fat diet versus a low-unsaturated fat diet; a low-

GI diet versus a high-fibre moderate-GI diet; diet recommen-

dations and diet-related behavioural advice versus diet

recommendations only; a soy protein-enriched diet versus no

soy protein; a high-fibre diet versus a standard-fibre diet; and

an ethnic-specific diet versus a standard healthy diet.

However, other meta-analyses show that the low-GI diet,

characterized by intake of high-quality, complex carbohy-

drates, demonstrated lower insulin use and reduced risk of

macrosomia. Recent evidence suggests the Mediterranean

diet is safe in pregnancy [52] . In developing countries, a one-

on-one simple dietary advice for higher consumption of

whole grain, dairy products, and dietary fibre was inversely

associated with adverse neonatal outcomes in women with

GDM [53] .

Hrolfsdottir et al. [54] recommend a simple dietary screen-

ing questionnaire given early in the first trimester to help iden-

tify women with high-risk eating habits associated with GDM

and providing individualized dietary feedback and advice. This

could help improve eating habits and better manage the preg-

nancy.

Pregnancy provides an eminent window of opportunity for

changing behaviour towards healthy eating and lifestyle and

is considered a wonderful teachable moment for women and

their families. Change preparedness is high, as emotion is in-

creased because of perceived risk but with the possibility of

improved outcome with change. There is also greater motiva-

tion, sense of self-efficacy, and willingness to acquire new

skills. This is particularly relevant for GDM pregnancy where

nutrition and lifestyle change provides the bedrock for man-

aging the condition. Given the impact of GDM on the future

health of the mother and offspring, these changes are not

only relevant for the immediate pregnancy outcomes, but

continued adherence is also important for future health. De-

spite this, adherence to nutrition advice is often less than sat-

isfactory. An important barrier for non-adherence is the dif-

ficult to understand, impractical, and prescriptive advice that

is often given, rather than advice that is practical, contextual,

and empowers women to make healthy choices. Most of the

modifiable barriers to improving adherence to diet are related

to nutrition self-management training and counselling skills

of care providers [55] .

No particular diet or dietary protocol is superior to anoth-

er as mentioned earlier. However, in each of the studies eval-

uating different dietary protocols, one thing was common –

Table 2. Signal system [56]

Principles Green Yellow Red

Refined cereals and sugars Low Moderate to high High

Saturated fat Low Low High

Total fat Low Moderate High

Glycaemic index Low Moderate to high High

Fibre High Low Negligible

Cooking method Steaming, boiling, roasting, grilling, less fat in cooking

Pan fried, sautéed, moderate amount of fat in cooking

Deep fried, rich in fat and sugar, rich sauce/cream dressing

Processing Rich in fibre, parboiled Low fibre, refined, milled Low fibre, ready to eat, highly processed

How much to eat Eat as permitted Moderate Restrict


26

DOI: 10.1159/000509900

the intervention arm included more intensive diet counselling

and more frequent visits to the dieticians. Advice given by a

qualified dietician, more frequent visits to a dietician, advice

that includes elements to promote overall health not merely

control of blood sugar, nutrition counselling that is easy to

understand and use and includes healthy food options, cook-

ing methods, and practical guidance to deal with lifestyle is-

sues are the most important facilitators to improve nutrition

advice adherence [55] .

Several easy-to-implement tools are available to make nu-

trition counselling more effective. Some of these are dis-

cussed below.

Signal System

The signal system is an easy-to-use educational tool which

highlights the basic principle of healthy food and healthy

cooking methods to help patients make informed choices. It

follows a simple traffic light concept of red for “stop,” yellow

for “go slow,” and green for “go” and helps people make in-

formed choices on which foods are healthy and which are

not. The signal system focuses not only on the number of

calories and fat in the food, glycaemic load, and fibre content

of food but also on the cooking and processing method [56] .

It is similar to the traffic light diet promoted in Australia [57]

for healthy eating.

Mapping foods according to red, yellow, and green colour

codes helps in educating people on healthy and not so healthy

foods and how processing and different cooking methods

impact foods making healthy foods unhealthy. It has been

used as an educational tool which can be easily adapted to

different regional and local foods across the world [56] . The

basic principle of the signal system is shown in Table 2 .

Portion Size

The T-shaped plate model especially for the main meals is ef-

fective as a basic teaching tool to control portion size and plan

meals more effectively ( Fig. 1 ). The healthy plate models are

simple and accessible and help enhance the consumption of

fruits and vegetables [58] . Visuals of portion sizes and use of

household containers (cups and glass) as measures of food

quantity are practical and easy teaching tools to help improve

adherence to quantity of food consumed.

Food Exchange Tables

Food exchange tables is a great tool to enhance individualiza-

tion of dietary advice as it empowers patients to add variety to

the prescribed meal plan while at the same time ensuring a

balanced intake of all necessary nutrients. A retrospective co-

hort study showed reduced adverse events in the group re-

ceiving MNT using the food exchange tables as compared to

the group not receiving MNT [59] .

Food Journal

Maintaining a food journal and SMBG records and analyzing

them together help to understand the effect of different foods

on glucose levels, to adjust the diet to change portion size of

carbohydrates in different meals, and to improve glycaemic

control.

EnablingImpart skills on how to choosehealthy portion size

FeedbackUsing feedback to train andimpart knowledge

Meal and time8.00 a.m.Breakfast

10.00 a.m. Midmorning snack12.00 Lunch

16.00 Tea

20.00 Dinner

22.00 Post meal Empanada de pinoFrench friesBeef steak

White pastaCookies

Coffee with low fat milk

Coffee with low fat milkJam

Boiled eggLow fat cheeseWhite bread 2 nos.

1 slice1 nos.

1 cup1 medium1 serving

1 serving1 serving1 serving

1

1 serving1 glass1 cup2 nos.

2 servings

2 tsp

Food Color coding Portion

Soft drinkSalad (lettuce, tomato, onion)

White riceFish stew

Apple

25 g carb 13 g carb

Rice boiled – 80 gCarbohydrates – 20 g

Rice boiled – 160 gCarbohydrates – 40 g

Understanding portion sizes

Vegetables

Carbohydrate/starch

Protein

T-shaped plate model

Fig. 1. Tools to support sustained behaviour change.


Individualizing Diet Advice

A simple two-step process to individualize dietary advice is as

follows:

• Step 1: Identifying both the good eating habits and not so

good eating habits in the current eating pattern of the pa-

tient by colour coding the diet history using the signal sys-

tem/traffic light concept (see Fig. 1 ). Understanding the

portion sizes for each food consumed. Using the colour-

coded diet history to discuss and emphasize the good eat-

ing habits as well as identify unhealthy patterns. Are the

portion sizes appropriate? What are the sources for starch

and their quantity (bread, rice, pulses, potato, sweetened

beverages, juice, and sugar)? Are source and amount of fat

and salt intake in the diet at large? Are there sufficient veg-

etables and fruit in the diet? The information gathered is

used to first praise and motivate the patient on positive

aspects while highlighting the need to change unhealthy

eating habits.

• Step 2: Using shared decision-making skills, negotiating

goals, and keeping the patient’s target in mind to encour-

age appropriate intake of vegetables and fruits, whole grain

cereal, and starch, while discouraging excess intake of fat

and Na + -rich foods.

This combined with the signal system, plate model, food

journal, and food exchange tables helps empower patients to

understand and adapt healthy eating behaviour. Almost all

guidelines recommend health education sessions and using

the services of a dietician to give MNT [11] . Availability of

trained dieticians maybe a concern in many developing and

low-resource countries, but this shortfall can be overcome by

training other health care workers to give focussed guidance

on healthy eating using some of the principles and tools de-

scribed above.


The writing of this article was supported by Nestlé Nutrition Institute, and the authors declare no other conflicts of interest.

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Focus


Prenatal Nutritional Strategies to Reduce the Risk of Preterm BirthKaren Patricia Best et al.


[email protected]

Key insights

Preterm birth (PTB) is one of the most challenging problems in obstetric and neonatal care. Because of its complex etiology, the causes of PTB are unclear and there are currently no reliable strategies for prevention or treatment. Maternal nutrition before and during pregnancy plays a critical role in providing the necessary nutrients for fetal growth and may be an important modifiable risk factor for the prevention of PTB. Current evidence indicates that the use of omega-3 polyunsaturated fatty acids (PUFA) may be a promising approach for PTB prevention.

Current knowledge

A normal human pregnancy lasts around 40 weeks, with most babies delivered at 37–42 weeks’ gestation. The World Health Organization (WHO) defines PTB as all births occurring before 37 weeks’ gestation. Worldwide, PTB is the second leading cause of death in children under 5 years of age. An estimated 15 million babies are born preterm each year; among these, 20% are born before 34 weeks (referred to as early preterm birth [EPTB]). Infants born early preterm may require extended periods in hospital in-tensive care and some exhibit developmental problems that can last a lifetime, including problems with their lungs, gut, immune system, vision, and hearing. Furthermore, developmental difficul-ties may emerge in early childhood, with later societal and eco-nomic impacts caused by low educational achievement, high un-employment, and deficits in social and emotional well-being.


The homeostatic balance between the metabolites of ome-ga-3 and omega-6 fatty acids play a vital role in the mainte-

nance of normal gestational length, cervical ripening, and the initiation of labor. The standard Western diet is generally low in omega-3 but high in omega-6 fatty acids. Based on the available evidence, omega-3 supplementation during preg-nancy to prevent EPTB should be targeted towards women with low omega-3 status in early pregnancy. Women with re-plete omega-3 levels in early pregnancy should continue their current dietary practices to maintain their status. Correcting low maternal omega-3 levels through supplementation (such as the use of low-dose fish oil supplements) may reduce the risk of EPTB.

Recommended reading

Samuel TM, Sakwinska O, Makinen K, Burdge GC, Godfrey KM, Silva-Zolezzi I. Preterm birth: a narrative review of the current evidence on nutritional and bioactive solutions for risk reduc-tion. Nutrients. 2019;11(8):1811.

Nutrients contribute to a variety of mechanisms that are potentially important to preterm delivery, such as infection, inflammation, oxidative stress, and muscle contractility

LOW-

-

HIGH- -

Different nutritional solutions have the potential for preventing pre-term birth, but the strongest evidence supports the use of omega-3 polyunsaturated fatty acids (PUFA).



Prenatal Nutritional Strategies to Reduce the Risk of Preterm Birth

Karen Patricia Best a, b Judith Gomersall a, c Maria Makrides a, b

a Women and Kids Theme, South Australian Health and Medical Research Institute, Adelaide , SA , Australia ; b School of Medicine, University of Adelaide, Adelaide , SA , Australia ; c School of Public Health, University of Adelaide, Adelaide , SA , Australia

Karen Patricia Best Women and Kids, South Australian Health and Medical Research Institute 72 King William Road North Adelaide, ADL 5006 (Australia) karen.best @ sahmri.com


[email protected]

Key Messages

• Cost-effective primary prevention strategies to reduce preterm birth (PTB) are required to reduce the ∼ 15 million preterm ba-bies born every year worldwide. Nutritional interventions may offer a promising solution.

• The strongest evidence to date for a nutritional solution to re-duce PTB exists for omega-3 long-chain polyunsaturated fatty acids and suggests that women with low levels of omega-3 in early pregnancy may benefit from supplementation.

• Recent findings suggest that determining an individual wom-an’s polyunsaturated fatty acid status in early pregnancy may be a precise way to inform recommendations to reduce her risk of PTB.

DOI: 10.1159/000509901

Keywords Preterm birth · Nutrition · Pregnancy · Omega-3 ·

Prevention · Supplementation · Prematurity

Abstract Worldwide, around 15 million preterm babies are born annu-

ally, and despite intensive research, the specific mechanisms

triggering preterm birth (PTB) remain unclear. Cost-effective

primary prevention strategies to reduce PTB are required, and

nutritional interventions offer a promising alternative. Nutri-

ents contribute to a variety of mechanisms that are poten-

tially important to preterm delivery, such as infection, inflam-

mation, oxidative stress, and muscle contractility. Several ob-

servational studies have explored the association between

dietary nutrients and/or dietary patterns and PTB, often with

contrasting results. Randomized trial evidence on the effects

of supplementation with zinc, multiple micronutrients (iron

and folic acid), and vitamin D is promising; however, results

are inconsistent, and many studies are not adequately pow-

ered for outcomes of PTB. Large-scale clinical trials with PTB

as the primary outcome are needed before any firm conclu-

sions can be drawn for these nutrients. The strongest evi-

dence to date for a nutritional solution exists for omega-3

long-chain polyunsaturated fatty acids (LCPUFAs), key nutri-

ents in fish. In 2018, a Cochrane Review (including 70 studies)

showed that prenatal supplementation with omega-3 LCPU-

FAs reduced the risk of PTB and early PTB (EPTB) compared

with no omega-3 supplementation. However, the largest tri-

al of omega-3 supplementation in pregnancy, the Omega-3

to Reduce the Incidence of Prematurity (ORIP) trial ( n =

5,544), showed no reduction in EPTB and a reduction in PTB

only in a prespecified analysis of singleton pregnancies. Ex-

ploratory analyses from the ORIP trial found that women with

low baseline total omega-3 status were at higher risk of EPTB,

and that this risk was substantially reduced with omega-3

supplementation. In contrast, women with replete or high

baseline total omega-3 status were already at low risk of EPTB

Best/Gomersall/MakridesReprint with permission from:Ann Nutr Metab 2020;76(suppl 3):31–39

32

DOI: 10.1159/000509901

and additional omega-3 supplementation increased the risk

of EPTB compared to control. These findings suggest that

determining an individual woman’s PUFA status may be the

most precise way to inform recommendations to reduce her

risk of PTB. © 2021 Nestlé Nutrition Institute, Switzerland/

S. Karger AG, Basel

Preterm Birth

A human pregnancy usually lasts around 40 weeks, with most

babies delivered at term (between 37 and 42 weeks of gesta-

tion; Fig. 1 ). Preterm birth (PTB) is defined by the World Health

Organization (WHO) as all births before 37 completed weeks

of gestation or fewer than 259 days since the first day of a

woman’s last menstrual period [1] . PTB is the second leading

cause of death globally for children under 5 years of age [1] . It

is estimated that ∼ 15 million babies each year worldwide are

born preterm with 20% occurring before 34 weeks gestation,

referred to as early PTB (EPTB). EPTB is the major cause of

perinatal mortality, serious neonatal morbidity, and moder-

ate-to-severe childhood disability in developed countries [2–

4] . These infants often require extended periods in hospital

intensive care and may have developmental problems that

can last a lifetime, including problems with their lungs, gut,

and immune system function, in addition to problems with

their vision and hearing. In early childhood, developmental

difficulties may emerge, with later societal and economic im-

pacts due to low educational achievement, high unemploy-

ment, and deficits in social and emotional well-being [5] .

These outcomes have enormous economic and public health

impact [6] , and addressing PTB is an urgent priority.

Preventing PTB, a Challenging Issue

PTB is one of the most challenging issues in obstetric and

neonatal care and is caused by multiple etiologies [7] . About

half of the time, the causes of PTB are unclear, and there are

no current satisfactory prevention strategies or treatments.

Several Cochrane systematic reviews have been conducted

on the effects of interventions designed to prevent PTB with

treatments ranging from bed rest and smoking cessation to

therapeutic drugs such as betamimetics, magnesium sulfate,

and calcium channel blockers. While there has been some

success in reducing the risk of PTB in high-risk women with

tocolytic agents [8, 9] , these are not suitable as prophylactic

strategies because the risks associated with these interven-

tions are not acceptable to the general population. One phar-

macological intervention, which has been shown to be some-

what effective is progesterone, however, only in singleton

pregnancies with a history of PTB [10] . In the absence of pre-

dictive tests that are sensitive, specific, and feasible to imple-

ment, more general cost-effective primary prevention strate-

gies for PTB are required [7] . Nutritional interventions are

promising alternatives.

Maternal Nutrition

Maternal nutrition before and during pregnancy plays an im-

portant role in providing the necessary nutrients for fetal

growth [11] and may be a key factor in the risk of PTB [12] .

Several observational studies have explored the association

between dietary nutrients and PTB and present contrasting

results. A cohort study in 60,000 women with singleton preg-

Pregnancy

Early preterm birth(<34 weeks)

Completedweeks ofgestation

16 20 24

Second trimester Third trimester Postterm

Postterm

42weeks

Term(37–42weeks)

Preterm birth(<37 weeks)

28 32 36 40

Fig. 1. Gestation at birth definitions.

Nutritional Strategies to Reduce Risk of Prematurity

33Reprint with permission from:Ann Nutr Metab 2020;76(suppl 3):31–39DOI: 10.1159/000509901

nancies in Norway observed an association between higher

intake of artificially sweetened and sugar-sweetened bever-

ages and increased risk of PTB [13] . Another study based on

the same pregnancy cohort assessed the risk of PTB for 3 di-

etary patterns: “prudent” (vegetables, fruits, oils, water as bev-

erage, whole grain cereals, and fiber-rich bread), “Western”

(salty and sweet snacks, white bread, desserts, and processed

meat products), and “traditional” (potatoes and fish), reporting

that high scores on the “prudent” dietary pattern were associ-

ated with significantly reduced risk of PTB (hazard ratio for the

highest vs. the lowest third: 0.88, 95% CI 0.80–0.97). The “tra-

ditional” diet was associated with reduced risk of PTB for the

highest versus the lowest third (hazard ratio 0.91, 0.83–0.99),

and no independent association with PTB was found for the

“Western” diet [14] . Another cohort study, in Denmark (Danish

National Birth Cohort), showed consumption of a Mediterra-

nean diet in mid-pregnancy (including fish at least bi-weekly,

using olive or grape seed oil, >5 portions of fruit and vegeta-

bles/day, meat no more than twice a week, and at most 2 cups

of coffee/day) was associated with a 72% lower risk of EPTB

[15] .

The epidemiological evidence on dietary patterns and PTB

has been summarized in 3 recent systematic reviews [16–18] .

The review by Chia and colleagues [16] , a meta-analysis in-

cluding 6 studies, showed adherence to a “healthy” diet com-

prising high intakes of vegetables, fruits, whole grains, low-fat

dairy, and lean protein foods lowered the risk of PTB (odds

ratio [OR] for the top compared to bottom tertile [0.79, 95%

CI 0.68–0.91]). Kibret et al. [17] pooled data from 9 studies to

assess the association between adherence to a “healthy di-

etary pattern” defined as high intake of vegetables, fruits,

whole grain foods, poultry and fish, and PTB. Reduced odds

of PTB were observed (OR 0.75, 95% CI 0.57–0.93), although

there was significant heterogeneity between studies ( I 2 =

89.6%). Analysis based on 4 of the studies presented in this

review showed a “Western” diet, comprising mostly refined

grains, processed meats or snacks, high-sugar and high-fat

dairy products, eggs, and white potatoes had no effect on the

odds of PTB (OR 1.11, 95% CI 0.87–1.34), though again sub-

stantial heterogeneity was seen ( I 2 = 77.8%) [17] . Raghavan and

colleagues [18] performed a narrative review of the evidence

for associations between dietary patterns during pregnancy

and PTB. They concluded that although the evidence is lim-

ited, there is some evidence (mostly studies involving Cauca-

sian women) to support protective associations with PTB.

These protective dietary patterns are higher in vegetables;

fruits; whole grains; nuts; legumes and seeds; and seafood,

and lower in red and processed meats and fried foods [18] .

Fish is a rich source of essential nutrients for fetal develop-

ment which has been linked to a reduction in PTB since the

1980s when it was noticed that women who ate a lot of fish

in the Faroe Islands (in Scandinavia) had longer pregnancies

than their Danish neighbors [19] . A systematic review by Lev-

entakou et al. [20] assessed the evidence for associations be-

tween fish intake and PTB, adjusting for a wide range of po-

tentially important confounding variables in all meta-analy-

ses. A total of 19 population-based European birth cohort

studies and 151,880 mother-child pairs were included in this

Table 1. Summary of Cochrane reviews assessing RCT evidence on effects of nutrients during pregnancy on PTB and EPTB

Nutrients and outcome assessed Effects Quality of the evidence (grade)

Magnesium versus no magnesium and PTB [22] 7 trials, 5,981 women RR 0.89 (95% CI 0.69–1.14) Not applicablea

Calcium versus placebo/no treatment and EPTB [23] 4 trials, 5,669 women RR 1.04 (95% CI 0.8–1.36) Moderate

Calcium versus placebo/no treatment and PTB [23] 13 trials; 16,139 women RR 0.86 (95% CI 0.7–1.05) Moderate

Iron alone versus placebo/no treatment and PTB [24] 6 trials, 1,713 women RR 0.82 (95% CI 0.58–1.14) Not applicablea

Folic acid alone versus placebo/no treatment and PTB [25] 3 trials, 2,959 women RR 1.01 (95% CI 0.73–1.38) Not applicablea

Iron and folic acid versus placebo/no treatment and PTB [24] 3 trials, 1,479 women RR 1.55 (95% CI 0–4.6) Not applicablea

Supplements containing iron and folic acid versus same supplements without iron nor folic acid or placebo and PTB [24]

3 trials, 1,497 women RR 1.55 (95% CI 0.40–6.00) Low

MMN (with iron and folic acid) versus iron with or without folic acid and PTB [26] 8 trials, 91,425 women RR 0.95 (95% CI 0.90–1.01) Moderate

Zinc alone or in combination with other micronutrients versus placebo and PTB [29] 16 trials, 7,637 women RR 0. 86 (95% CI 0.76–0.97) Moderate

Vitamin D alone versus placebo/no treatment and PTB [27] 7 trials, 1,640 women RR 0.66 (95% CI 0.34–1.30) Low certainty

Vitamin D and calcium versus placebo/no treatment and PTB [27] 5 trials, 942 women RR 1.52 (95% CI 1.01–2.28) Low certainty

Omega-3 LCPUFA compared with no omega-3 and PTB [28] 26 trials, 10,304 women RR 0.89 (95% CI 0.81–0.97) High

Omega-3 LCPUFA compared with no omega-3 and EPTB [28] 9 trials, 5,204 women RR 0.58 (95% CI 0.44–0.77) High

EPTB, early preterm birth (<34 weeks); LCPUFA, long-chain polyunsaturated fatty acid; PTB, preterm birth (<37 weeks); RCT, randomized controlled trial; MD, mean difference; MMN, multiple micronutrients; RR, relative risk. a Quality of evidence not assessed in the review.


34

DOI: 10.1159/000509901

review. Findings were consistent across cohorts; the adjusted

RR of fish intake >1 but <3 times/week compared to ≤1 time/

week was 0.87 (95% CI 0.82–0.92) and of fish intake ≥3 times/

week compared to ≤1 time/week was 0.89 (95% CI 0.84–

0.96). This large international study indicates that moderate

fish intake during pregnancy is associated with lower risk of

PTB [20] . Although some conclusions regarding dietary pat-

terns and fish intake can be drawn from these reviews, inter-

pretation is difficult due to the methodological limitations of

epidemiological studies and the risk of bias from residual con-

founding [21] .

Randomized controlled trials (RCTs) are the most reliable

type of research to inform questions about cause and effect.

A substantial body of RCT evidence on the effects of supple-

mentation with individual nutrients, including magnesium,

calcium, iron, folic acid, zinc, vitamin D, omega-3, or multiple

micronutrients (MMNs), on PTB has accumulated. Samuel et

al. [7] have provided a systematic overview of the evidence on

nutritional solutions for PTB risk reduction, and various Co-

chrane reviews [22–28] assess the RCT evidence on the ef-

fects of these nutrients on PTB ( Table 1 ). A review of magne-

sium supplementation during pregnancy showed no differ-

ence in risk of PTB between women who received magnesium

versus no magnesium [22] . Another review found moderate

quality evidence indicating no reduction in PTB or EPTB risk

between women who received calcium during pregnancy

compared to placebo or no treatment [23] . Two early Co-

chrane reviews found no differences in PTB between women

who received iron alone compared with no treatment/pla-

cebo [24] ; folic acid alone compared with no treatment or

placebo [25] ; daily iron and folic acid supplements versus no

treatment/placebo [24] ; or any supplements containing iron

and folic acid compared with the same supplements without

iron nor folic acid or placebo [24] . More recently, a Cochrane

review evaluating benefits of MMNs supplementation with

iron and folic acid during pregnancy found moderate quality

evidence for a small effect of MMNs (with iron and folic acid)

compared to iron with or without folic acid on the risk of PTB

[26] .

There is some limited evidence for administration of zinc

supplements (5–44 mg/day) as well as vitamin D supplemen-

tation as potentially effective interventions to prevent PTB [7] .

A Cochrane review demonstrated moderate quality evidence

of a small but significant 14% reduction in PTB with antenatal

supplementation of zinc alone or in combination with other

micronutrients compared to placebo [29] . However, most of

the RCTs assessing zinc have been conducted in low-income

countries among women with poor nutritional status, likely to

have had low zinc concentrations. The reduction in PTB ob-

served in these studies has not been accompanied by a reduc-

tion in LBW or a difference in gestational age at birth, suggest-

ing that it is too early to be certain about the beneficial effects

of zinc [7] . Vitamin D deficiency in women of reproductive age

is widespread, and low maternal vitamin D status during preg-

nancy is a risk factor for several adverse birth outcomes in-

cluding PTB [30] . A recent review by De-Regil et al. [27] found

low-quality evidence showing no difference in PTB between

women who received vitamin D alone compared to placebo

or no treatment, or between women who received vitamin D

and calcium versus placebo or no treatment during pregnan-

cy. The only high-quality evidence to date for a nutritional

solution to prevent PTB (in singleton pregnancies) exists for

omega-3 long-chain polyunsaturated fatty acids (LCPUFAs).

Omega-3polyunsaturated fatty acids

Alpha-linolenic acid (ALA)18:3n-3

Eicosapentaenoic acid (EPA)20:5n-3

Omega-6polyunsaturated fatty acids

Linoleic acid (LA)18:2n-6

Arachidonic acid (AA)20:4n-6

Decosahexaenoic acid (DHA)22:6n-3

Omega-3 and omega-6compete for the same desaturation

and elongation enzymes

Fig. 2. Synthesis of polyunsaturated fatty acids.



Omega-3 and PTB

Omega-3 is an essential fatty acid which must be obtained

from the diet and is a key nutrient in fish. First observed in the

1980s and recently supported in the large Leventakou review,

long-chain omega-3 fatty acids from marine sources such as

fish and algae are thought to be responsible for longer preg-

nancies (and fewer preterm babies) [19, 20] . There are plau-

sible biological mechanisms to indicate that dietary insuffi-

ciency of omega-3 LCPUFA may play a role in the pathophys-

iology of preterm delivery, and this presents a potential target

for intervention. Prostaglandins and other oxylipins derived

from omega-6 and omega-3 fatty acids play essential roles in

normal and pathologic initiation of labor [31, 32] . The feto-

placental unit is supplied with LCPUFAs from the maternal

circulation, which is influenced by maternal LCPUFA intake

and endogenous synthesis ( Fig. 2 ). The prostaglandins and

oxylipins derived from omega-6 arachidonic acid within the

utero-placental unit in normal pregnancy are countered by

local production of prostaglandins and oxylipins derived from

omega-3 LCPUFA within the same tissues. The balance be-

tween the metabolites of omega-3 and omega-6 fatty acids

plays a vital role in the maintenance of normal gestational

length and is a critical element in cervical ripening and the

initiation of labor [33, 34] . If local production of omega-6-de-

rived prostaglandins within the feto-placental unit is too high,

or local accumulation of omega-3 LCPUFA is too low, the

cervix may prematurely ripen and uterine contractions in-

crease, which may in turn lead to PTB.

Current Western diets are low in omega-3 LCPUFAs and

high in omega-6 fatty acids. The WHO recommends an in-

take of 300 mg of omega-3 LCPUFAs per day in pregnant

women; however, the median intake among Australian and

American women of childbearing age is less than one-third

of this, compared with 1,000 mg/day in many women from

nations with high fish consumption, such as Japan, Korea,

and Norway [35] . Several epidemiological studies and RCTs

have investigated the effect of increased maternal omega-3

intake and PTB. Middleton et al. [28] recently updated the

Cochrane Review of Marine Oil Supplementation in Pregnan-

cy, which was first published in 2006 [36] . This updated re-

view includes all trials of LCPUFAs in any form or dose during

pregnancy (including as supplements, food, or dietary ad-

vice). The latest search of the literature was conducted in

August 2018. The review included 70 RCTs, involving 19,927

women. Most of the trials were conducted in high-income

countries (e.g., USA, England, The Netherlands, Australia, and

Denmark), and most included women were carrying single-

ton pregnancies. The intervention dose ranged between 200

and 2,700 mg omega-3 LCPUFA as docosahexaenoic acid

(DHA) or eicosapentaenoic acid (EPA) and was administered

mainly throughout the second half of pregnancy. Results

show high-quality evidence that supplementation with ome-

ga-3 LCPUFA during pregnancy reduced the risk of having a

premature baby <37 weeks’ gestation by 11% and <34 weeks’

gestation by 42% compared with no omega-3 supplementa-

tion. Additional outcomes for the systematic reviewed

showed that prenatal omega-3 LCPUFA supplementation

was safe (in terms of no effect on bleeding or postpartum

hemorrhage) and significantly reduced the incidence of low

birth weight and increased the incidence of pregnancies

continuing beyond 42 weeks, although there was no differ-

ence identified in induction of labor for post-term pregnan-

cies ( Table 2 ).

Table 2. Summary of 2018 Cochrane review of marine oil supplementation in pregnancy outcomes [35]

Variable Effect of omega-3 LCPUFA treatment relative to control Quality of the evidence (grade)

Birth <34 weeks 11 trials, 5,409 women RR 0.58 (95% CI 0.44–0.77) HighBirth <37 weeks 25 trials, 10,256 women RR 0.89 (95% CI 0.81–0.97) HighBirth >42 weeks 6 trials with 5,141 women RR 1.61 (95% CI 1.11–2.33) ModerateGestational length 41 trials with 12,517 women MD 1.67 days (0.95–2.39) ModeratePreeclampsiaa 20 trials with 8,306 women RR 0.84 (0.69–1.01) LowPerinatal death 10 trials with 7,416 women RR 0.75 (0.54–1.03) ModerateBirth weight, g 42 trials with 11,584 women MD 76 g higher (38 to 113 higher) Not applicableb

Low birth weight <2,500 g 15 trials with 8,449 women RR 0.90 (0.82–0.99) HighSGA 8 trials with 6,907 women RR 1.01 (0.90–1.13) ModerateLGA RR 1.15 (0.97–1.36) Moderate

LGA, large for gestational age; LCPUFA, long-chain polyunsaturated fatty acid; MD, mean difference; RR, relative risk; SGA, small for gestational age. a Defined as hypertension with proteinuria. b Quality of evidence for this outcome not assessed in the review.


36

DOI: 10.1159/000509901

It is important to note that this latest Cochrane review in-

cludes studies mainly from high-income countries with low-

risk, normal-risk, and high-risk women, and almost all women

had singleton pregnancies. Reporting biases may underesti-

mate or overestimate omega-3 effects on prematurity and

other adverse birth outcomes and further work is needed to

address concerns that supplementation in late pregnancy

may prolong gestation beyond term. For example, the 2-day

shift in mean gestation in our DOMInO trial (the largest trial

included in the systematic review with 2,499 women) in-

creased the number of post-term pregnancies and thus the

need for more obstetric interventions to initiate birth (17.6 vs.

13.7%; RR 1.28, 95% CI 1.06–1.54) [37] . This highlighted the

need for further research to investigate the effects of prenatal

omega-3 supplementation in a broad representation of wom-

en before adopting a universal supplementation approach

into routine antenatal care.

The Omega-3 to Reduce the Incidence of Prematurity

(ORIP) RCT of 5,544 pregnancies was published in 2019 [38] .

It is the largest trial to assess whether omega-3 LCPUFA

supplementation, mainly as DHA, reduced the risk of EPTB

(<34 weeks’ gestation) [39] . This trial was designed with the

unique feature of ceasing the intervention at 34 weeks’ ges-

tation (when the risk of EPTB has passed) to avoid prolonga-

tion of pregnancy requiring post-term obstetric interven-

tion. The ORIP trial was specifically designed to assess a

broad-based supplementation strategy inclusive of single-

ton and multiple pregnancies, inclusive of women regard-

less of prematurity risk, and inclusive of many women al-

ready taking low-dose omega-3 supplements. This con-

trasts with most other studies that included only singleton

pregnancies and/or focused on women with low intakes.

This heterogeneity may, in part, explain why the results of

the ORIP trial are discordant with those of the systematic

review. The ORIP trial found that supplementation of preg-

nant women with 900 mg per day of omega-3 LCPUFA (800

mg DHA/100 mg EPA) did not reduce the overall risk of EPTB

or PTB, even though omega-3 PUFA concentrations in the

intervention group at 34 weeks’ gestation were elevated rel-

ative to the control group ( Table 3 ).

Prespecified secondary analyses of only singleton preg-

nancies in the ORIP trial suggested a reduction in the risk of

PTB with omega-3 supplementation in singleton but not mul-

tiple pregnancies (RR 0.81, 95% CI 0.67, 0.99) [39] . The ORIP

trial also comprised the valuable inclusion of blood samples

to determine maternal baseline omega-3 status prior to com-

mencing supplementation (trial entry <20 weeks’ gestation), a

design feature most of the prior trials lack. Exploratory analy-

ses in women with a singleton pregnancy ( n = 5,070) found

that women with low baseline total omega-3 blood PUFA sta-

tus (<4.1%, n = 885) were at higher risk of EPTB and that this

risk was substantially reduced by 77% with omega-3 supple-

mentation (relative risk = 0.23, 95% CI 0.07–0.79) [40] . In con-

trast, women with higher or replete total omega-3 status at

Table 3. Summary of the ORIP trial outcomes [39]

Variable Omega-3 group (n = 2,734), n (%)

Control group (n = 2,752), n (%)

Adjusted RR (95% CI)a

Birth <34 weeks 61 (2.2) 55 (2.0) 1.13 (0.79–1.63)Birth <37 weeks 211 (7.7) 246 (8.9) 0.86 (0.72–1.03)Prolonged gestation 12 (0.4) 12 (0.4) N/AGestational length, daysb 273.2±15.2 273.2±14.9 0.02 (−0.78 to 0.82)Preeclampsia 96 (3.5) 91 (3.3) 1.07 (0.80–1.43)Perinatal death 32 (1.1) 25 (0.9) 1.28 (0.76–2.17)Birth weight, gb 3,351±628 3,340±591 10.56 (−23.87 to 44.99)Low birth weight <2,500 g 204/2,787 (7.3) 173/2,800 (6.2) 1.18 (0.95–1.47)SGA 206/2,787 (7.4) 196/2,800 (7.0) 1.06 (0.87–1.28)LGA 392/2,787 (14.1) 355/2,800 (12.7) 1.11 (0.97–1.27)

g, grams; LGA, large for gestational age; LCPUFA, long-chain polyunsaturated fatty acid; MD, mean difference; RR, relative risk; SGA, small for gestational age; ORIP, Omega-3 to Reduce the Incidence of Prematurity. a The effect sizes are relative risks (omega-3 group vs. control group) unless otherwise indicated. The adjusted values were adjusted for randomization strata: recruitment hospital and consumption of dietary supplements containing n-3 LCPUFA in the previous 3 months (yes or no). Except in the case of the primary outcome, the 95% CI were not adjusted for multiplicity and therefore should not be used to infer treatment effects. b The effect size is the difference in means (omega-3 group minus control group).



baseline (>4.9%, n = 2,277) were at lower risk of EPTB, and

supplementing these women with omega-3 increased the risk

of EPTB compared to control (relative risk = 2.27, 95% CI 1.13–

4.58) [40] .

This observation that EPTB is altered by baseline omega-3

status is consistent with epidemiological data showing that

low fish intake [20] or low omega-3 status [41] is associated

with an increased risk of EPTB in singleton pregnancies. In a

case-control study nested within the Danish National Birth

Cohort, 376 EPTB cases were identified. When comparing

concentrations of EPA plus DHA, women in the lowest quintile

of the distribution had a 10 times (95% CI 6.8–16, p < 0.0001)

increased risk of EPTB, and women in the second lowest quin-

tile had a 2.9 times (95% CI 1.8–4.6, p < 0.0001) increased risk

of EPTB, when compared to women in the 3 aggregated high-

est quintiles [41] . A moderate fish intake during pregnancy

(1–2 fish meals per week) would generally be associated with

a total omega-3 status of >4.1% of total omega-3 fatty acids

in whole blood, the conservative cutoff reported in the ORIP

exploratory analysis showing a protective association with

EPTB [40] .

The unexpected findings from the ORIP exploratory analy-

sis suggesting an increased risk of EPTB in women with re-

plete omega-3 status have been proposed previously. Kle-

banoff et al. [42] conducted a secondary analysis of a prenatal

omega-3 supplementation RCT and report that for women at

risk of recurrent PTB, the probability of PTB was highest at low

and high intakes, and lowest with moderate fish consumption.

Similar patterns have been seen for several micronutrients and

higher risks of adverse health outcomes for both low and high

nutrient intakes – a U-shaped relationship [43] . Determining

a woman’s omega-3 status in early pregnancy and likelihood

of benefiting from omega-3 supplementation to reduce her

risk of EPTB would be the most precise way to inform supple-

mentation practices. We would recommend that women with

replete omega-3 status in early pregnancy should continue

their current dietary practices to maintain their status. How-

ever, correcting low maternal omega-3 status through sup-

plementation may reduce her risk of EPTB.

Summary

Despite intensive research, the mechanisms triggering the

∼ 15 million PTBs occurring worldwide every year remain un-

clear. Nutritional interventions are promising primary preven-

tion strategies, yet to date, many broad-based interventions

with the potential to reduce the risk of PTB are effective only

in specific groups of women, most likely due to the hetero-

geneity of the population and the etiopathogenesis of PTB. At

present, omega-3 PUFA seems to be the nutrient holding the

most promise for the prevention of EPTB. Based on the avail-

able evidence, omega-3 supplementation during pregnancy

to prevent EPTB should be targeted to women with low ome-

ga-3 status in early pregnancy. Clinicians should discuss the

importance of a good diet with pregnant women and in the

absence of measured maternal omega-3 PUFA levels, advise

dietary source essential fatty acids be regularly consumed

during pregnancy, and low-dose fish oil supplements may be

explored to provide the necessary omega-3 required for op-

timal maternal and fetal outcomes. Advancement of this field

requires the development and implementation of a targeted

approach and evidence-based precision nutrition in antenatal

care [7] .

Statement of Ethics

No approval was required for this review.


The writing of this article was supported by Nestlé Nutrition Institute. Professor Makrides serves at the Board of Directors for Trajan Nutri-tion. Dr. Best and Dr. Gomersall have nothing to disclose.

Funding Sources

Dr. Best is supported by a MS McLeod Post-Doctoral Fellowship. Pro-fessor Makrides is supported by a National Health and Medical Re-search Fellowship.

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Focus


Maternal Undernutrition before and during Pregnancy and Offspring Health and DevelopmentMelissa F. Young and Usha Ramakrishnan


[email protected]

Key Insights

Maternal undernutrition remains a critical public health problem with large regional and intra-country disparities in the prevalence of underweight, anemia, and micronutrient deficiencies. The greatest burden is seen among the poorest women in poor countries. While the obesity epidemic is growing, the persistence of underweight in some countries in South Asia and Africa remains unacceptably high. Another major problem that disproportionately affects women of reproductive age is anemia, which is also associated with an increased risk of poor maternal and infant outcomes. A key driver of poor nutrition is food insecurity. Despite the existence of evidence-based strategies for improving maternal nutrition during pregnancy, there are still large gaps in program implementation and outreach.

Current knowledge

Globally, 9.7% of women are underweight and 14.9% are obese. The nutritional and health status of women as they enter pregnancy is known to play a key role in placental func-tion and the subsequent growth and development of the fe-tus. The placenta regulates nutrient availability for fetal growth and ultimately influences the long-term health of the new-born. Micronutrients, including iron, zinc, folic acid, and oth-er vitamins, contribute to genome-wide alterations and/or epigenetic modifications during the critical period of organo-genesis. These changes influence subsequent outcomes, such as body composition, metabolism, immunity, and cogni-tive function, in the offspring.


At the political level, women’s nutrition has not received suf-ficient prioritization. Furthermore, restricting the focus of women’s nutrition to pregnancy places a significant limit on the effectiveness of interventions. For women who live in con-ditions of extreme food insecurity (with anemia, micronutrient deficiencies, and undernutrition), maternal nutrition interven-tions during pregnancy may arrive too late. We urgently need to reach women earlier, in order to provide preconception care and family planning services. Programs focused on school-aged or adolescent girls have been identified as prom-ising strategies in this context. Future efforts need to ensure that programs reach vulnerable and marginalized communi-ties in order to address regional disparities in maternal under-nutrition.

Recommended reading

Black RE, Victora CG, Walker SP, Bhutta ZA, Christian P, de Onis M, et al.; Maternal and Child Nutrition Study Group. Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet. 2013;382(9890):427–51.

Care for women includes women having adequate access to food and health care to prevent illness, availability of fertility regulation and birth spacing options, sufficient time for rest, and protection from abuse

Diet quality,nutritionstatus

Adverse maternal and child outcomes

Food insecurity Poverty Lack of access

to services (health, water, sanitation)

Lack of education Social and political

environment Maternal undernutrition

Maternal undernutrition is highly prevalent among the poorest women and is driven by a complex series of factors.



Maternal Undernutrition before and during Pregnancy and Offspring Health and Development

Melissa F. Young Usha Ramakrishnan

Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta , GA , USA

Usha Ramakrishnan Hubert Department of Global Health, Rollins School of Public Health Emory University, 1518 Clifton Road, NE Atlanta, GA 30322 (USA) uramakr @ emory.edu


[email protected]

Key Messages

• Maternal undernutrition remains a critical public health problem with large regional and within-country disparities in the burden of underweight, anemia, and micronutrient deficiencies across the globe.

• Maternal preconception nutrition may influence birth outcomes and merits further research and program focus.

• Several evidence-based strategies exist to improve maternal nutrition during pregnancy; however, there remain key gaps in program implementation and equity.

DOI: 10.1159/000510595

Keywords Maternal undernutrition · Micronutrients · Child growth and

development

Abstract Maternal undernutrition remains a critical public health prob-

lem. There are large regional and within-country disparities

in the burden of underweight, anemia, and micronutrient de-

ficiencies across the globe. Driving these disparities are com-

plex and multifactorial causes, including access to health ser-

vices, water and sanitation, women’s status, and food insecu-

rity as well as the underlying social, economic, and political

context. Women’s health, nutrition, and wellbeing across the

continuum of preconception to pregnancy are critical for en-

suring positive pregnancy and long-term outcomes for both

the mother and child. In this review, we summarize the evi-

dence base for nutrition interventions before and during

pregnancy that will help guide programs targeted towards

women’s nutrition. Growing evidence from preconception

nutrition trials demonstrates an impact on offspring size at

birth. Preconception anemia and low preconception weight

are associated with an increased risk of low birth weight and

small for gestational age births. During pregnancy, several ev-

idence-based strategies exist, including balanced-energy

protein supplements, multiple micronutrient supplements,

and small-quantity lipid nutrient supplements for improving

birth outcomes. There, however, remain several important

priority areas and research gaps for improving women’s nutri-

tion before and during pregnancy. Further progress is needed

to prioritize preconception nutrition and access to health and

family planning resources. Additional research is required to

understand the long-term effects of preconception and

pregnancy interventions particularly on offspring develop-

ment. Furthermore, while there is a strong evidence base for

maternal nutrition interventions, the next frontier requires a

greater focus on implementation science and equity to de-

crease global maternal undernutrition disparities.


S. Karger AG, Basel

Young/Ramakrishnan Reprint with permission from:Ann Nutr Metab 2020;76(suppl 3):41–53

42

DOI: 10.1159/000510595

Introduction

Maternal undernutrition remains a critical public health prob-

lem across the globe. While there is growing recognition of

the importance of maternal nutrition for child health and de-

velopment, women’s nutrition has historically not received

the political or program prioritization required to make mean-

ingful progress. In this review, we summarize the current

global status of women’s nutrition, provide an overview of the

driving causes and consequences of maternal undernutrition,

and summarize the evidence base for nutrition interventions

before and during pregnancy that will help guide programs

targeted towards women’s nutrition.

Global Status of Maternal Undernutrition

Globally, 9.7% of women are underweight and 14.9% are

obese [1] . While the obesity epidemic is growing, the persis-

tence of underweight in some countries in South Asia and

central and east Africa remains unacceptably high. There are

large regional and within-country disparities in the burden of

underweight, with the highest burden among the poorest

women in the poor countries [2] . This is concerning given that

both over- and undernutrition are associated with poor birth

outcomes [3] . Maternal overweight and obesity are associated

with increased maternal morbidity, preterm birth (PTB), and

infant mortality [3] . Maternal underweight is likewise associ-

ated with offspring growth and development, including in-

creased risk for PTB, low birth weight (LBW), under-five mor-

tality, and poor mental and physical development [3] . Anoth-

er major public health problem that affects women of

reproductive age disproportionately is anemia, which has

been associated with an increased risk of poor birth outcomes

(LBW, PTB, small for gestational age, stillbirth, and perinatal

and neonatal mortality) and adverse maternal outcomes (ma-

ternal mortality, postpartum hemorrhage, preeclampsia, and

blood transfusion) [4] . Globally, 29% of nonpregnant women

and 38% of pregnant women are anemic [5] . Similar to under-

weight, there are large disparities in the global burden of ane-

mia, particularly across South Asia and Central and West Af-

rica ( Fig. 1 ). The etiology of anemia is diverse and context spe-

cific, but a high burden of anemia may be an indicator of an

even greater burden of micronutrient deficiencies among

women. It is estimated that approximately 50% of anemia

among nonpregnant and pregnant women is amenable to

Prevalence of anemia in pregnant women, 2016Prevalence of anemia in pregnant women, measured as the percentage of pregnantwomen with a hemoglobin level less than 110 g per liter at sea level

No data 0% 10% 20% 30% 40% 50% 60% 70%

Source: World Bank OurWorldInData.org/micronutrient-deficiency/ •CC BY

Fig. 1. Global prevalence of anemia in pregnant women. Reproduced from World Bank [92] .

Undernutrition before and during Pregnancy and Child Outcomes


iron supplementation; however, at the national and sub-na-

tional level, the role of iron deficiency in anemia has been

shown to be extremely variable from < 1 to 75% [6] and may

be influenced by many conditions, including malaria, infec-

tion, hemoglobinopathies, or other micronutrient deficien-

cies (folate, vitamins B 12 and B 6 , riboflavin, vitamins A and C).

The World Health Organization (WHO) estimates that over

two billion people are at risk for micronutrient deficiencies [7] .

Micronutrients deficiencies of public health concern include

iron, vitamin A, iodine, zinc, folate, and B vitamins. Figure 2 il-

lustrates the current regional estimates of micronutrient de-

ficiencies and anemia among women of reproductive age

across the globe [8] .

Conceptual Framework

The conceptual framework shown in Figure 3 provides an

overview of the underlying complex and multifactorial causes

and consequences of maternal undernutrition. This concep-

tual framework has been adapted based on the current un-

derstanding of the causes of child malnutrition [9–14] . Distal

causes of malnutrition include social, economic, and political

context and lack of capital (financial, human, physical, social,

and natural). These factors may affect maternal and child

health either directly or indirectly, through more proximal fac-

tors, including access to health services, water and sanitation,

women’s status, and food insecurity. Poor water and sanita-

tion increase the risk for infectious diseases, malnutrition, and

mortality and may disproportionately affect women [15–18] .

Women’s status, including reduced access to education, ear-

ly age at marriage, limited maternal empowerment, and gen-

der inequality, remain critical barriers across the globe. In ad-

dition, 9.3% of the population are affected by severe food in-

security, with a slightly higher prevalence among women.

Food insecurity is a key driver of poor nutrition across the

globe and can be influenced by food affordability, availability,

and distribution of food among household members [19] .

Collectively, these factors influence the conditions (inade-

quate dietary intake, care for women, and disease) before

pregnancy and during pregnancy. Diet quality remains a ma-

jor concern globally [20] , and women are particularly vulner-

able. The vicious cycle of inadequate dietary intake and dis-

ease is well known. Poor nutrition lowers immunity and in-

creases susceptibility to disease; disease in turn perpetuates

poor nutrition by decreasing appetite, inhibiting nutrient ab-

sorption and increasing risk for micronutrient deficiencies and

undernutrition.

Care for women includes women having adequate access

to food and health care to prevent illness, availability of fertil-

ity regulation and birth spacing options, sufficient time for

rest, and protection from abuse [11, 21] . Women who marry

early are more likely to have children at a young age, when

they are still growing and developing themselves. Adolescent

pregnancy can adversely affect both maternal health and nu-

trition and increase the risk for poor birth outcomes [22] . In

some contexts, women may have limited decision-making

authority on the number of children or when they have them

[23] . Early age at pregnancy and short interpregnancy intervals

(< 6 months) have been associated with increased risks for ad-

verse pregnancy outcomes (PTB, LBW, stillbirth, and early

neonatal death), highlighting the importance of women’s

100

80

% De

ficien

cy 60

40

20

0Africa Americas Eastern-

MediterraneanEuropean South-East

AsianWesternPacific

LMIC

Vitamin AFolateVitamin B12Vitamin DIodineZincAnemiaIDA Fig. 2. Regional estimates of micronutri-

ent deficiencies and anemia among women of reproductive age. Reproduced from Bourassa et al. [8] , 2019. Data calcu-lated from 52 national and regional sur-veys, published between 2013 and July 2017 using the World Health Organization VMNIS database. Missing bars means no data were found for that micronutrient in the specific region. LMIC, low- and mid-dle-income countries; IDA, iron deficien-cy anemia. Black circles are not represen-tative (<3 countries).


44

DOI: 10.1159/000510595

health and nutritional status prior to conception [24–26] .

Women who experience interpersonal violence may also be

at increased risk of poor pregnancy outcomes [27] . The im-

portance of a woman’s nutrition before pregnancy, especial-

ly during adolescence and preconception, on infant and ma-

ternal outcomes is gaining recognition [28–31] ; and this con-

nection is both through the direct effect on outcomes as well

as indirectly though influencing a women’s nutritional status

during pregnancy.

Maternal short stature is a risk factor for caesarean delivery

and complications at childbirth [32] . A woman’s height is a

product of her poor nutritional status as a child and is an im-

portant predictor of her own child’s health as well. For ex-

ample, in India, maternal height has been associated with

child mortality, growth failure, and anemia [33] . Likewise, oth-

er measures of maternal nutritional status, such as her body

mass index (BMI) or weight gain during pregnancy, are associ-

ated with adverse birth outcomes, such as LBW, PTB, and in-

trauterine growth restriction [30, 34–36] . As described in fur-

ther depth below, maternal anemia and micronutrient status

are likewise powerful determinants of pregnancy outcomes

and child health and nutrition [37] . Collectively, women’s

health, nutrition, and wellbeing across the continuum of pre-

conception through pregnancy are critical for ensuring posi-

tive pregnancy and long-term outcomes for both the mother

and child.

Importance of Maternal Nutritional Status before and during Pregnancy

The nutritional and health status of women as they enter

pregnancy may play a key role in placental function and sub-

sequent growth and development of the fetus [38, 39] . The

placenta regulates nutrient availability for fetal growth and ul-

timately influences the long-term health of the newborn.

Periconceptional nutrition may also influence offspring health

and cognitive outcomes by affecting the growth and develop-

ment of the brain, liver, and pancreas during the first few

weeks of pregnancy [29] . Animal studies have shown that fe-

tal growth and development are sensitive to maternal nutri-

tion during implantation [38, 40] . Dietary restriction studies in

Childconsequences

Maternalconsequences

Proximalcauses

Distalcauses

Birthoutcomes

Morbidity/mortality

Child health and nutrition

Before pregnancy

Inadequatedietary intake

Access to health services &water/sanitation

Women’s status(education/age at marriage, gender

equality)Foody insecurity

Social, economic & political context Lack of capital:financial, human, physical, social and natural

Inadequatedietary intakeCare for women Care for womenDisease Disease

During pregnancy

Morbidity/mortality

Growth &body composition

Brain & cognitivedevelopment

Short stature Micronutrientdeficiencies

Micronutrientdeficiencies

Pre-pregnantBMI

Gestationalweight gain

Fig. 3. Conceptual framework of the causes and consequences of maternal undernutrition. The conceptual frame-work provides an overview of the underlying complex and multifactorial causes and consequences of maternal un-dernutrition. This conceptual framework has been adapted based on the current understanding of the causes of child malnutrition [9–14] .



normal and overweight sheep have demonstrated the pro-

gramming effects of periconceptional nutrition on fetal adi-

pose tissue development and regulation of IGF1R signaling

pathway postnatally [41, 42] . Findings from the Dutch Famine

Study have also documented alterations in epigenetic signa-

tures among offspring born to women exposed to acute mal-

nutrition during the periconceptional period [43] . Micronutri-

ents, including iron, zinc, folic acid (FA), and other vitamins,

contribute to genome-wide alterations and/or epigenetic

modifications during the crucial period of organogenesis [29] .

These changes influence subsequent outcomes, such as body

composition and cognitive function [44, 45] .

Evidence, primarily from observational studies, shows that

fetal growth during the first trimester is especially sensitive to

preconceptional nutrition [38] . A systematic review by Young

et al. [4] has shown that preconception anemia was associ-

ated with an increased risk of LBW and small for gestational

age (SGA) births, while anemia in the first trimester of preg-

nancy was associated with LBW, PTB, and neonatal mortality.

Studies have also demonstrated the role of maternal precon-

ception nutrition on child linear growth from conception

through the child’s second birthday (the “first 1,000 days”)

[46, 47] . Women with a preconception weight less than 43 kg

or a gestational weight gain less than 8 kg were around 3

times more likely to give birth to a SGA or LBW infant. Fur-

thermore, women with preconception height less than 150

cm or a weight less than 43 kg were at nearly twice the in-

creased risk of having a stunted child at age 2 years. The ev-

idence based on intervention studies that have been con-

ducted before and during pregnancy is summarized in the

following sections.

Maternal Nutrition Interventions and Birth Outcomes

In a systematic review that evaluated the role of nutrition in-

terventions or exposures that were measured before 12 weeks’

gestation but did not continue through pregnancy, Ramak-

rishnan et al. [30] found that most studies were observational

and focused primarily on perinatal outcomes, including birth

defects, pregnancy loss, or stillbirths. The quality of the evi-

dence was also low to very low, with the exception of inter-

vention trials that demonstrated the benefits of providing

periconceptional FA to reduce the risk of birth defects, espe-

cially neural tube defects [48] . More recently, a few random-

ized controlled trials (RCTs) have evaluated the benefits of

preconception nutrition interventions on maternal and child

health outcomes as summarized in Table 1 [49–51] . In a trial

conducted in Mumbai, India, low-income urban women were

recruited prior to conception and randomized to receive a

micronutrient and energy-dense snack before and/or during

pregnancy [49] . This study found that among women with a

BMI > 21.5 kg/m 2 , those who took the snack for at least 90 days

prior to conception gave birth to heavier babies ( ∼ 113 g) when

compared to those who received the intervention only during

Table 1. Preconception nutrition interventions and impact on maternal and child health outcomes

Setting Design Impact First author [ref.], year

Mumbai, India RCT of micronutrient- and energy-dense snack before and/or during pregnancy

Women with a BMI >21.5 kg/m2, who took the snack for at least 90 days prior to conception, gave birth to heavier babies (~113 g) when compared to those who received the intervention only during pregnancy

Potdar [49], 2014

Vietnam RCT of preconception weekly supplements containing multiple micronutrients, iron-folate, or folic acid (PRECONCEPT; NCT 1665378)

No differences in birth outcomes in the intent-to-treat analysis; however, birthweight was ~60 g higher for offspring born to women who received the weekly MM supplement for at least 6 months compared to the other 2 groups

Ramakrishnan [50], 2016

India, Pakistan, Guatemala, and the Democratic Republic of Congo

Multisite RCT of lipid-based micronutrient supplement (WOMENS First trial)

Significant increases in mean birth length of offspring born to women who received lipid-based micronutrient supplements daily for at least 3 months before conception through pregnancy when compared to those born to women who received only routine prenatal care

Hambidge [51, 52], 2014, 2019


46

DOI: 10.1159/000510595

pregnancy; effects on offspring growth and development

have not been reported. Ramakrishnan et al. [50] evaluated

the benefits of providing preconceptional weekly supple-

ments containing multiple micronutrients (MMs), iron-folate

(IFA), or FA in a large RCT (PRECONCEPT) that was conducted

in rural Vietnam. All women who conceived received daily

prenatal IFA supplements. Although there were no differenc-

es in birth outcomes in the intent-to-treat analysis, birth-

weight was ∼ 60 g higher for offspring born to women who

received the weekly MM supplement for at least 6 months

compared to the other 2 groups [50] . Finally, findings from the

WOMENS First trial, a large multisite RCT conducted in India,

Pakistan, Guatemala, and the Democratic Republic of Congo,

showed significant increases in mean birth length of offspring

born to women who received lipid-based micronutrient sup-

plements daily for at least 3 months preconception through

pregnancy when compared to those born to women who re-

ceived only routine prenatal care [52] .

In contrast to the dearth of evidence for preconception

interventions, considerable evidence has accumulated over

the past few decades on the benefits of improving maternal

nutrition during pregnancy. Several evidence-based interven-

tions for improving maternal and child nutrition across the

lifecycle have been reviewed, including a range of approach-

es from population-level fortification, nutrition education,

and targeted supplementation for vulnerable populations [53] .

Although prenatal IFA supplementation has been standard of

care for over 50 years, recent evidence has demonstrated a

promising impact of prenatal balanced energy protein sup-

plements, MM supplements, and small-quantity lipid nutrient

supplements for improving birth outcomes. Balanced protein

and energy supplements reduced the risk of stillbirth by 40%

and of SGA by 21%, and mean birth weight was increased by

41 g [54] . Several recent reviews of prenatal MM supplements

have demonstrated clear benefits for cost-effectively improv-

ing birth outcomes; thus, leading to calls for revised WHO

guidelines to support widescale adoption and replacement

over traditional IFA supplementation programs [8, 55–60] .

MM supplementation in pregnancy reduced the risk of LBW

by 12–14%, PTB by 8–4%, and being born SGA by 8–3%, de-

pending on the analytic approach used in a Cochrane Review

meta-analysis versus an individual participant data meta-

analysis [8, 55, 56] . Although some concerns about a potential

increase in the risk of neonatal mortality associated with MM

supplementation have been raised in the past, updated analy-

ses indicate no adverse risk. Results from the Smith et al. [56]

seminal paper on modifiers of the effect of prenatal MMs

( Fig. 4 ) demonstrated improved survival of female offspring

and increased benefits of micronutrient supplementation

among infants born to undernourished or anemic mothers.

Another promising intervention are small-quantity lipid-based

nutrient supplements that have shown improved birth weight

(53.3 g) and birth length (0.24 cm) compared to IFA supple-

ments [61] .

Maternal Nutrition and Offspring Growth and Body

Composition

To our knowledge, very few studies have examined the role

of preconception micronutrient status on later offspring

growth and body composition, including fat mass (FM), lean

body mass, bone mineral content (BMC), and bone mineral

density. The PRECONCEPT trial showed differences in off-

spring linear growth during the first 2 years of life. At age 2

years, children in the IFA group had significantly higher length-

for-age z scores (LAZ; 0.14; 95% CI: 0.03, 0.26), reduced risk

of being stunted (0.87; 95% CI: 0.76, 0.99), and smaller decline

in LAZ from birth (0.10; 95% CI: 0.04, 0.15) than the children

in the FA group. Similar trends were found for the children in

the MM group compared with the FA group for LAZ (0.10; 95%

CI: 20.02, 0.22) and the risk of being stunted (0.88; 95% CI:

0.77, 1.01) [62] . Although data on the effect of preconception

nutrition on body composition are lacking, there is some evi-

dence suggesting that micronutrient intakes during pregnan-

cy may affect later offspring body size and composition as

described below.

Several studies have evaluated the effects of prenatal nutri-

tion on offspring growth during early childhood and beyond.

Most notably, follow-up studies of the food-based supplemen-

tation trials that were conducted in the 1970s to 1980s have

shown improved child growth and attained adult height among

the offspring, but many of these interventions were not restrict-

ed to the prenatal period [63] . Devakumar et al. [64] (2016) con-

ducted a systematic review of studies that included follow-up

data from 6 RCTs and found no differences in weight-for-age

z score (0.02; 95% CI: –0.03 to 0.07), height-for-age z score

(0.01; 95% CI: –0.04 to 0.06), or head circumference (0.11 cm;

95% CI: –0.03 to 0.26) among offspring born to women who

received antenatal MM supplements compared to routine IFA.

Some of the limitations of these studies, however, are the varia-

tion in the age at follow-up and loss to follow-up.

Micronutrient intakes during

pregnancy may affect later

offspring body size and

composition



Infant sexMaleFemale

Gestational age at enrolment<20 weeks

20 weeksMaternal adherence to regimen

<95% adherence

Maternal age<20 years

ParityFirst birthSecond+ birth

Maternal underweight at enrolmentBMI <18.5 kg/m2

2Maternal stature

Height <150 cm

Maternal haemoglobin at enrolmentAnaemic (haemoglobin >110 g/L)

Maternal educationNone

Skilled birth attendantYesNo

Overall

0.5 0.75d Low birthweight e Preterm birth f Small-for-gestational age

1 1.25 1.5 0.5 0.75 1 1.25 1.5 0.5 0.75 1 1.25 1.5

a Stillbirth b Neonatal mortality c Infant mortality

Infant sexMaleFemale

Gestational age at enrolment<20 weeks

20 weeksMaternal adherence to regimen

<95% adherence

Maternal age<20 years

ParityFirst birthSecond+ birth

Maternal underweight at enrolmentBMI <18.5 kg/m2

2Maternal stature

Height <150 cm

Maternal haemoglobin at enrolmentAnaemic (haemoglobin >110 g/L)

Maternal educationNone

Overall

0.6 0.7 0.8 0.9 1 1.1 1.2 0.6 0.7 0.8 0.9 1 1.1 1.2 0.6 0.7 0.8 0.9 1 1.1 1.2Pooled relative risk with 95% CI

Fig. 4. Modifiers of the effects of prenatal MM supplementation on birth outcomes. Reproduced from Smith et al. [56] , 2017.


48

DOI: 10.1159/000510595

In Nepal, antenatal supplementation with FA, iron, and zinc

resulted in lower offspring adiposity as assessed by skinfold

thicknesses at age 6–8 years [65] . Maternal multivitamin use

was also associated with a slower rate of FM accretion during

infancy compared to offspring of control women (non-users)

in the United States [66] . Regarding bone density, increased

maternal intake of calcium-rich foods and higher folate status

during mid-pregnancy were associated with greater offspring

BMC and bone mineral density at age 6 years in India [67] .

Findings from a Dutch cohort study (median age, 6 years)

showed that vitamin B 12 status

during the first trimester was as-

sociated with greater offspring

BMC, adjusted for total bone

area [68] . Overall, there is a lack

of consistent and robust data on

the influence of maternal mi-

cronutrient intake, either before

or during pregnancy, on off-

spring body composition. Addi-

tionally, the effects of precon-

ceptional micronutrient intakes may only emerge during the

pre-pubertal years of 9–14 years when rapid adipose tissue

deposition occurs [69] . Potential mechanisms include epi-

genetic modifications that may occur early in pregnancy and

influence offspring body composition in late childhood. For

example, hypermethylation of the umbilical retinoic acid X-

receptor, a key regulator of adipocyte proliferation, has been

associated with increased offspring FM at 9 years of age [70] .

Maternal Nutrition before and during Pregnancy Is Important

for Brain Development and Cognitive Functioning

Brain development begins shortly after conception [71, 72] .

Most of the structural features of the brain appear during the

embryonic period (about the first 8 weeks after fertilization);

these structures then continue to grow and develop through-

out pregnancy [71, 72] . Iron, in particular, plays an important

role in early fetal brain development [73] , and other micronu-

trients, such as vitamin B 6 , B 12 , FA, and zinc, are influential [74] .

FA, vitamin B 12 , and zinc participate in brain DNA and RNA

synthesis, which begins early in gestation [75] . Vitamin B 12 has

also been shown to affect myelination, which begins during

gestation and may affect cognitive functioning [76, 77] . As

women may not realize they are pregnant during the first 1–2

months, optimal nutrition prior to pregnancy is critical.

A systematic review by Larson and Yousafzai [78] that in-

cluded 10 prenatal trials that evaluated a variety of nutrition

interventions (macro- and/or micronutrients) did not find a

significant impact on young child mental development. Most

of these studies were conducted in low- to middle-income

countries in Asia and Africa, but important limitations includ-

ed sample size/power and sensitivity of tests to assess men-

tal development in children under 2 years. Findings from the

PRECONCEPT trial showed that children in the IFA group had

improved motor development assessed by the Bayley Scales

of Infant Development (BSID), especially fine motor develop-

ment (IFA vs FA: 0.41; 95% CI: 0.05, 0.77), but there were no

significant differences in Bayley mental or language scores

[62] . Both early nutritional status and home learning environ-

ment were also associated with child development in this

sample [79] . Preliminary results

from the most recent follow-up

that was conducted when the

offspring were aged 6–7 years

show promising differences by

treatment group. The Wechsler

Intelligence Scale for Children

IVth edition (WISC-IV ® ) was

used to measure global intelli-

gence, verbal comprehension,

memory, and executive func-

tioning and compared to the FA group; offspring in the MM

group had higher IQ scores as well as working memory and

processing speed. These differences were also stronger

among the subgroup of children born to women who re-

ceived the preconception intervention for at least 6 months,

and there is also evidence of effect modification by baseline

socioeconomic status (SES), indicating that MM attenuated

the effects of SES on perceptual reasoning and IQ [80] . Im-

portant strengths of this study include the low rates of attri-

tion (< 10%) and that the groups were balanced on several

baseline characteristics including SES and maternal educa-

tion.

Two large studies, from Nepal and Indonesia, have also

documented the impact of maternal micronutrient supple-

mentation on cognitive functioning in school-age children

[81, 82] . In Nepal, working memory, inhibitory control, and

fine motor functioning at age 7–9 years were positively as-

sociated with prenatal IFA supplementation [81] . In Indonesia,

MM supplementation that began early in pregnancy had long-

term benefits for cognitive development at age 9–12 years

compared to IFA, including positive associations with proce-

dural memory and general intellectual ability (for children of

anemic mothers) [82] . This study also noted the importance

of measuring socio-environmental determinants, such as

home environment and maternal depression, which were

strongly associated with school-age cognitive, motor, and

socio-emotional scores. However, concerns about the limit-

ed findings and null results from follow-up studies in other

settings like China and Tanzania have been raised, and further

As women may not realize

they are pregnant during the

first 1–2 months, optimal

nutrition prior to pregnancy is

critical



research is needed to better understand the long-term health

effects on maternal and child health [60, 83] .

Finally, long-term studies from Guatemala have demon-

strated the benefits of nutritional supplementation during the

first 1,000 days of life on cognitive outcomes in later child-

hood and adolescence, effects which were considerably larg-

er than those seen in early childhood [84–88] . At ages 3–7

years, there was only a small effect (< 0.2 standard deviation)

of the Atole-Fresco differences compared to medium to large

effects (0.6 standard deviation) during adolescence/young

adulthood (11–26 years). Although the findings are mixed for

the influence of prenatal docosahexaenoic acid (DHA) on

cognitive outcomes, especially during the first 2 years of life

[89] , there is evidence of a small but significant effect of pre-

natal DHA on measures of attention in the offspring at age 5

years in Mexico, and higher global scores of intelligence

among those from poorer home environments when com-

pared to those in the placebo group [90] . Results from the

MAL-ED longitudinal cohort corroborate the importance of a

nurturing home environment, adequate micronutrient status,

and maternal reasoning on child cognitive function at age 5

years [91] . These studies highlight the importance of assessing

the impact of maternal nutrition interventions on cognitive

outcomes in later childhood and adolescence.

Priority Areas and Research Gaps for Improving Women’s Nutrition before and during Pregnancy

Despite recent progress and shifts in global agenda, women’s

nutrition has historically not received sufficient political or

program prioritization. Furthermore, narrowing the focus of

women’s nutrition to the pregnancy window may limit the ef-

fectiveness of interventions. This is particularly critical in set-

tings of severe food insecurity with high rates of anemia, mi-

cronutrient deficiencies, and undernutrition and where wom-

en may not enter antenatal care until into the second or third

trimester. Simply put, maternal nutrition interventions in these

settings may be too little, too late . Table 2 outlines several

program priorities areas and research gaps for improving

women’s nutrition. While efforts to improve timely and qual-

ity antenatal care that includes interventions that effectively

address the nutrient gaps during pregnancy need strengthen-

ing, greater program prioritization is needed to reach women

earlier to provide preconception care and family planning ser-

vices. Programs focused on school-age or adolescent girls

have also been identified as promising strategies for reaching

women earlier. A notable gap in the field includes research

examining the long-term effects of periconceptional nutri-

tional supplementation on later cognitive outcomes, includ-

ing aspects of intellectual functioning, executive function, and

academic achievement. Examining these effects during early

adolescence is particularly important as effects of early-life

experiences may become more pronounced at later ages.

Further, the role of improving maternal nutrition right before

and during the periconceptional period, along with the home

environment, on later cognitive outcomes can provide much

needed information on the relative importance of early nutri-

tion and socio-environmental factors on cognitive outcomes.

During pregnancy, we have several evidence-based ma-

ternal nutrition interventions. However, while it is clear we

know what to do , challenges remain in knowing how to do it

at scale? Research and program focus on implementation sci-

ence is required to develop effective strategies to scale up

Table 2. Program priority areas and research gaps for improving women’s nutrition before and during pregnancy

Key priority areas for research and programs

⚫ Program prioritization is needed to improve access and counseling on family planning (delayed age at first pregnancy, inter-pregnancy interval) and preconception care

⚫ Additional research is required to understand the long-term effects of periconceptional nutritional supplementation on later cognitive outcomes, including aspects of intellectual functioning, executive function, and academic achievement

⚫ Greater research and program focus on implementation science is required to develop effective strategies to scale up evidence-based maternal nutrition interventions

⚫ Political and program support is needed for the promotion and scale up of multiple micronutrient supplement programs among women

⚫ Research on long-term impact of multiple micronutrient supplementation during pregnancy⚫ Strong formative research is needed to contextualize and develop multiple micronutrient supplementation

programs to help overcome prior barriers with iron and folic acid programs⚫ An enhanced program focus on equity is required to ensure programs are reaching vulnerable and marginalized

communities in order to decrease global maternal undernutrition disparities


50

DOI: 10.1159/000510595

evidence-based maternal nutrition interventions. For exam-

ple, providing MM supplements during pregnancy is a highly

effective strategy for improving birth outcomes; however,

there is limited national policy adoption and evidence of im-

pact at scale. Further political and program advocacy is need-

ed for the promotion and scale up of multiple micronutrient

supplement programs among women. In addition, strong for-

mative research is needed to contextualize and develop MM

supplementation programs to help overcome prior barriers

with IFA programs. Finally, an enhanced focus on equity is re-

quired to ensure programs are reaching vulnerable and mar-

ginalized communities in order to decrease global maternal

undernutrition disparities.


The writing of this article was supported by Nestlé Nutrition Institute and the authors declare no other conflicts of interest.

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