maternal vegetarianism and neurodevelopment of children enrolled in the danish national birth cohort

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This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/apa.12761 This article is protected by copyright. All rights reserved.

Received Date : 19-Feb-2014

Revision Date : 15-May-2013

Accepted Date : 23-Jul-2014

Article type : Short Communication

Type of manuscript: Short communication

Maternal vegetarianism and neurodevelopment of children enrolled

in The Danish National Birth Cohort

Authors’ full name: Pernille Stemann Larsen1,MSc, Anne-Marie Nybo Andersen1,MD, PhD

Peter Uldall2, MD, PhD, Bodil Hammer Bech3, MD PhD, Jørn Olsen3, MD, PhD, Anne Vinkel

Hansen1, MSc, Katrine Strandberg-Larsen1, MSc, PhD

Author affiliations:1Section of Social Medicine, Department of Public Health, University of

Copenhagen, Denmark; 2Paediatric Clinic, The Juliane Marie Centre, Rigshospitalet,

Copenhagen University Hospital, Copenhagen, Denmark; 3Department of Public Health,

Section for Epidemiology, Aarhus University, Denmark

Address correspondence to: Pernille Stemann Larsen, Section of Social Medicine,

Department of Public Health, University of Copenhagen, Øster Farimagsgade 5, P.O. Box

2099, DK-1014 Copenhagen K, Denmark, Tel. +45 35 32 79 98, E-mail:

[email protected]

Short title: Maternal vegetarianism and child neurodevelopment

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This article is protected by copyright. All rights reserved.

Clinical observations suggest that children born to vegan mothers may be at risk of severe

neurodevelopmental impairments due to vitamin B12 (1-3), which is to be expected, as this

vitamin is exclusively found in food of animal origin (4). Thus, children born to all

vegetarians, not just vegans, may be at increased risk of impaired neurodevelopment if they

have an insufficient intake of dietary supplements (5). As a result, it has been suggested that

mothers should be warned about the impact of vegetarianism, in particular a vegan diet,

during childbearing. The aim of this study was to use an existing large-scale population-

based cohort to examine the association between maternal vegetarianism and the risk of

impaired neurodevelopment, including more subtle impairments, in children. We initiated the

present study based on the clinical observations described in Text Box 1 in order to improve

the evidence for dietary counselling of pregnant vegetarians.

Our study, which was approved by The Danish Protection Agency, was based on

pregnancies enrolled in The Danish National Birth Cohort (DNBC) between 1996 and 2002

(6) and further details of the study can be found at www.dnbc.dk. We used data from 80,743

mother-child dyads of singleton pregnancies with a minimum gestational age of 154 days

and information from two pregnancy interviews completed around gestational weeks 16 and

30. The study population was further restricted to observations with either information on

impaired neurodevelopment from national registers (n=77,968), parental reports on the age,

in months, when their child sat and walked (n=55,185) or parental reports on Strengths and

Difficulties Questionnaire (SDQ) (n=47,176). Information on age at sitting and walking and

SDQ were collected when the children were 18-months and seven-years-of-age,

respectively.

The cohort was linked to the Danish National Patient Register (7) and the Danish Psychiatric

Central Research Register (8). These two registers include information on all somatic and

psychiatric in and outpatient hospital contacts.

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Impaired neurodevelopment was defined using the following 10th revision of the International

Classification of Diseases codes: seizure disorders/epilepsy (G40-G41), retarded

psychomotor development (R62.0), mental retardation (F70-F79), autism spectrum disorder

(F84.0, F84.1, F84.5, F84.8, F84.9), developmental disorder of motor function (F82) and

attention deficit/hyperactivity disorder (F90.0, F90.1, F90.8, F90.9). We derived information

on head circumference at birth, in centimetres, from the Danish Medical Birth Registry (9)

and on cerebral palsy from the Danish Cerebral Palsy Registry, a research register of cases

that have been validated by a neuropaediatrician (10). All the children were followed in the

registers from birth until the age of seven years and only diagnoses occurring before this age

were included.

Information on maternal vegetarianism and intake of multivitamins, folic acid and iron were

obtained during pregnancy. The women were asked if they were vegetarians and those who

answered yes were asked to state what kind of vegetarian diet they followed. This

information was recorded as one of three predefined sub-types of vegetarianism by the

interviewer: pesco-vegetarians (unfortunately the predefined response category did not

distinguish between fish and poultry), lacto-ovo-vegetarians, and vegans. The observations

were grouped into non-vegetarians and these three subtypes of vegetarianism. Intake of

multivitamins, folic acid and iron were categorised based on yes versus no responses. Three

combined variables of maternal vegetarianism - non-vegetarian versus vegetarian - were

constructed with, and without, the intake of each type of dietary supplement: multivitamins,

folic acid and iron. They were then categorised as: non-vegetarian plus dietary supplements,

non-vegetarian minus dietary supplements, vegetarian plus dietary supplements and

vegetarian minus dietary supplements.

Cox regression analyses were used to compare continuous measures of the ages, across

the different exposure groups, when the children sat and walked. The children were followed

from birth to the age when they sat/walked, died or were censored at time of interview,

whichever occurred first. Hazard ratios (HR) of less than one indicated delayed achievement

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of sitting or walking. Linear regression analyses were used to compare continuous measures

of head circumference and total SDQ scores without the pro-social scale (11). The analyses

were adjusted for maternal age at birth, occupational status, smoking, alcohol consumption

during pregnancy and lifetime eating disorders. Information on covariates was obtained from

the national registers and from self-reports during pregnancy.

A total of 986 (1.2%) women reported vegetarianism during pregnancy and, of these, only 21

(2.1%) women reported being vegan. The majority of women took multivitamins during

pregnancy (90.9 %) and no statistically significant difference was observed between the sub-

types of vegetarianism (Table 1). When we looked at the vegetarians, we found that the

vegans were younger, more likely to be unemployed, underweight, heavy smokers and non-

drinkers. In addition, they reported lifetime anaemia and eating disorders more frequently

(data not shown).

The number of children with a diagnosis of impaired neurodevelopment among the lacto-

ovo-vegetarian and vegan groups was too low to perform statistical tests. However, the raw

distributions of diagnoses according to subtypes of maternal vegetarianism did not indicate

marked differences (data not shown). No clinically relevant differences in head

circumference, age when the children sat and walked or SDQ scores were observed among

the different types of vegetarians (Table 2). If anything, compared to the children of the non-

vegetarians, children born to vegetarians walked earlier and had slightly decreased SDQ

scores, with a mean difference of 0.1. The mothers’ intake of multivitamins, folic acid, and

iron did not alter the findings (Supplementary Table 1). Furthermore, adjustment for maternal

age, occupational status, smoking, alcohol consumption during pregnancy and lifetime

eating disorders did not have a major impact on the results.

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The findings from one of the largest birth cohorts, which provided information on

vegetarianism collected during pregnancy, did not support the clinical suspicion that children

born to vegetarians may be at increased risk of impaired neurodevelopment. In addition to

the prospective collection of data on maternal vegetarianism, the major strengths of our

study include the almost complete follow-up in the Danish national health registers and the

opportunities for including a broad range of diseases as well as less severe parental-

reported indicators of impaired neurodevelopment. Our study was limited by the low number

of vegetarians and the lack of information on the micronutrient status of both the mothers

and their children. Maternal vegetarianism only serves as a proxy for the dietary intake of

essential micronutrients and potential vitamin B12 deficiency. Moreover, it is likely that the

generally healthier lifestyle in vegetarians, and the high frequency of dietary supplements in

the DNBC, may explain the low incidence of impaired neurodevelopment in children born to

vegetarians. Finally, mothers who had children who walked at the age of 16 months or later,

were more likely to be lost to follow-up. Selection bias is possible if loss to follow-up also

depended on vegetarianism during pregnancy.

In conclusion, our findings from a large and wealthy population with ample access to healthy

food and dietary supplements did not support previous clinical suspicion of impaired

neurodevelopment in children of vegetarian mothers.

FUNDING

The Danish National Research Foundation has established the Danish Epidemiology of

Science Centre that initiated and created the DNBC. The cohort is furthermore a result of a

major grant from this foundation. Additional support for the DNBC is obtained from The

Pharmacy Foundation, The Egmont Foundation, The March of Dimes Birth Defect

Foundation, The Agustinus Foundation, and The Health Foundation. The DNBC 7-year

follow-up is supported by The Lundbeck Foundation (195/04) and The Danish Medical

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Research Council (SSFV 0646). Katrine Strandberg-Larsen was funded by The Danish

Council for Independent Research | Medical Sciences (grant identifier number: 09-066049),

and Pernille Stemann Larsen was funded by a strategic grant from The Department of Public

Health.

AKNOWLEDGEMENT

The authors thank Dr Allan Meldgaard Lund MD, Department of Clinical Genetic,

Rigshospitalet, for diagnostic assistance on the clinical observations reported in Text Box 1.

REFERENCES

1. Roed C, Skovby F, Lund AM. [Severe vitamin B12 deficiency in infants breastfed by vegans]. Ugeskr Laeger 2009;171:3099-3101.

2. von SU, Bender-Gotze C, Koletzko B. Persistence of neurological damage induced by dietary vitamin B-12 deficiency in infancy. Arch Dis Child 1997;77:137-139.

3. Graham SM, Arvela OM, Wise GA. Long-term neurologic consequences of nutritional vitamin B12 deficiency in infants. J Pediatr 1992;121:710-714.

4. Johntson PK, Sabaté J. Nutritional implications of vegetarian diets. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern nutrition in health and disease. 10th ed. Lippincott Williams & Wilkins; 2006;1638-1654.

5. Dwyer JT. Nutritional consequences of vegetarianism. Annu Rev Nutr 1991;11:61-91.

6. Olsen J, Melbye M, Olsen SF et al. The Danish National Birth Cohort--its background, structure and aim. Scand J Public Health 2001;29:300-307.

7. Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Register. Scand J Public Health 2011;39:30-33.

8. Mors O, Perto GP, Mortensen PB. The Danish Psychiatric Central Research Register. Scand J Public Health 2011;39:54-57.

9. Knudsen LB, Olsen J. The Danish Medical Birth Registry. Dan Med Bull 1998;45:320-323.

10. Uldall P, Michelsen SI, Topp M, Madsen M. The Danish Cerebral Palsy Registry. A registry on a specific impairment. Dan Med Bull 2001;48:161-163.

11. Goodman R. The Strengths and Difficulties Questionnaire: A Research Note. Journal of Child Psychology and Psychiatry 1997;38:581-586.

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Table 1. Maternal intake of dietary supplements according to maternal vegetarianism in pregnancy. The Danish National Birth Cohort 1996-2002.

Maternal characteristics

Maternal vegetarianism

Non-vegetarians Pesco-vegetarians Lacto-ovo-vegetarians Vegans

n=80,743 n=79,757 n=763 n=202 n=21

% % % % %

Intake of multivitamins during pregnancy

No 9.1 9.0 10.0 8.9 4.8

Yes 90.9 90.9 90.0 91.1 95.2

Missing <0.1 <0.1 _ _ _

Intake of iron supplement during pregnancy

No 21.6 21.6 25.7 27.2 42.9

Yes 78.3 78.4 74.3 72.7 57.1

Missing <0.1 <0.1 _ _ _

Intake of folic acid during pregnancy

No 74.4 74.5 69.1 66.3 71.4

Yes 25.5 25.4 30.5 33.7 28.6

Missing 0.1 0.1 0.4 _ _

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Table 2. Impaired neurodevelopment according to maternal vegetarianism. The Danish National Birth Cohort, 1996-2002. Head circumference

(cm) Age at sitting

(months) Age at walking

(months) Total SDQ score*

n (77,968

)

Mean

95% CI n (55,185

)

HR 95% CI

n (55,158

)

HR 95% CI

n (47,176

)

Mean

95% CI

Non-vegetarians

77,026 35.50

35.48 - 35.53

54,553 1.00

Ref. 54,553 1.00

Ref. 46,574 1.63 1.62 - 1.64

Pesco-vegetarians

780 -0.10 -0.21 - 0.02

483 1.08

1.00 -

1.17

483 1.17

1.08 -

1.28

468 -0.10 -0.17 - -0.03

Lacto-ovo-vegetarians

193 -0.11 -0.34 -0.12

137 1.01

0.89 -

1.14

137 1.16

0.99 -

1.34

123 -0.09 -0.21 - 0.04

Vegans 19 -0.17 -0.86 - 0.52

12 0.95

0.64 -

1.42

12 1.25

0.86 -

1.81

11 -0.11 -0.45 - 0.24

Adjusted for maternal age at birth, occupational status, smoking, alcohol consumption, and eating disorders.

*Total SDQ (Strengths and Difficulties Questionnaire) scores ranging from 0-40 (pro-social scale excluded)

HR: hazard ratio. HR <1 indicates delayed sitting /walking status

Due to lack of proportional hazards the cox regression analyses for age at sitting were stratified on age at birth, occupational status, smoking, and eating disorders.

The analyses for age at walking were stratified on all these variables.

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Text Box 1. Clinical observations of neurodevelopmental impairments in a child born

to a vegan mother. This child was not included in the Danish National Birth Cohort.

An otherwise healthy seven-month-old boy was referred to a paediatric clinic in Denmark

with a suspected metabolic disorder. After two weeks with a fever and ear infection, the boy

slowly became hypotonic, with insufficient eye contact and constant dyskinetic movements.

Routine blood tests and spinal fluid examinations were normal, except for minor anaemia.

Magnetic resonance imaging showed an increased signal on the lateral globus pallidus and

decreased diffusion of the lateral nucleus caudate. Neurometabolic blood tests showed an

increased concentration of homocystein, a very low level of cobalamin (B12) and increased

plasma methylmalonate. Macrocytic anaemia was diagnosed. The boy had been breastfed

and the mother was a vegan and had not taken vitamin B12 supplements during pregnancy

or breastfeeding. The mother suffered from vitamin B12 deficiency with megaloblastic

anaemia. The neurologic symptoms in the child decreased rapidly after vitamin B12

injections. The child had a full and lasting response following B12 treatment, as well as

normalisation of his plasma methylmalonate and homocystein, and this made it possible to

exclude methylmalonic acidemia caused by gene mutations. At follow up at the age of 15

months, the boy had improved further, but he was still not able to walk and could only sit

unsupported for a short while.

maternal vegetarianism and neurodevelopment of children enrolled in the danish national birth cohort

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