A. ZAWIEJSKA1, E. WENDER - OZEGOWSKA1, J.BRAZERT1, K. SODOWSKI2

COMPONENTS OF METABOLIC SYNDROME AND THEIR IMPACTON FETAL GROWTH IN WOMEN WITH GESTATIONAL DIABETESMELLITUS1Department of Obstetrics and Women Diseases, Karol Marcinkowski University

of Medical Sciences, Poznan; 2Department of Obstetrics and Gynecology, Medical University of Silesia, Katowice, Poland

Gestational diabetes mellitus (GDM) is associated with increased maternal insulinresistance. Maternal hyperglycemia is a well known risk factor for fetal overgrowth.However, despite improved glycemia control, macrosomia complicates a significantproportion of diabetic pregnancies, resulting in increased perinatal risk. The aim ofour retrospective study was to investigate the association between fetal growth anddifferent maternal metabolic characteristics in women with GDM. The study groupincluded 357 women (singleton pregnancy, and GDM diagnosed following WHOcriteria). The following parameters were studied: maternal pre-pregnancy BMI, 75gOGTT results, HbA1c, triglycerides (TAG), total, HDL- and LDL-cholesterol levelsat admission. Neonatal birth weight and the prevalence of being large for gestationalage birth weight (LGA) was an end-point. We found a significant associationbetween birth weight and HbA1c, TAG, fasting OGTT glycemia, BMI and a birthweight of a large child born previously. BMI and birth weight of a large child wasthe strongest independent predictors for LGA. A significant increase in birth weightand the prevalence of LGA (from 10.5% to 83.3%) was related to a number of alteredmaternal metabolic features. Conclusions: Fetal growth in a diabetic pregnancy is acomplex process and maternal metabolic parameters other than glucose levels shouldbe addressed to reduce the risk of macrosomia in these groups of patients.K e y w o r d s : gestational diabetes, diabetic pregnancy, LGA, macrosomia, lipoproteins,

insulin resistance, metabolic syndrome

JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2008, 59, Suppl 4, 5–18www.jpp.krakow.pl

INTRODUCTIONPregnancy is commonly recognized as a state of physiological, and temporaryinsulin resistance. This condition is driven by high concentrations of steroidhormones such as progesterone, estrogens, prolactin, cortisol and by placentaderived human placental lactogen – all of them having a diabetogenic action –combined with a decreased sensitivity of insulin receptors within target tissues (1,2). The main reason for all these changes is to provide a preferential supply ofnutrients (mainly glucose) to the fetus. Usually, in maternal compartment lowlevels of glucose (even lower than these in non-pregnant women) are maintaineddue to increased maternal production of insulin and accelerated “drainage” ofglucose by uteroplacental unit to cover fetal needs (“accelerated starvation”).However, in some percentage of pregnant population (3% up to 9%, according topopulation and diagnostic methods) a transient form of glucose intolerancedevelops if a degree of gestational insulin resistance is beyond the compensatorycapability of the pancreas (3-5).Gestational diabetes mellitus (GDM) is defined as a glucose intolerance of anydegree diagnosed or first recognized during pregnancy. In most of the cases it isa gestation-related disease and patient’s normal carbohydrates metabolism isrestored within a couple of weeks after a delivery. However, a GDM-complicatedpregnancy is still associated with a high perinatal risk with increased neonatalmortality and morbidity, mainly as a result of fetal macrosomia as well asoperative and instrumental deliveries, birth trauma and metabolic abnormalitiesin newborn (6). In this group of pregnant women there is still increased incidenceof intrauterine fetal death in term pregnancy. Moreover, a history of gestationaldiabetes is a strong risk factor for serious maternal complications in later life,including metabolic syndrome, type 2 diabetes and cardiovascular diseases thatare considered a leading cause of death in the female population (7).The major reason for poor perinatal outcome is fetal macrosomia (defined aslarge for gestational age, with a birth weight above the 90th percentile; LGA).Fetal overgrowth induced by fetal hyperinsulinemia can develop as a response toincreased placental glucose transfer to the fetus which is secondary to maternalhyperglycemia. Fetal hyperinsulinemia and accelerated fetal growth is alsoassociated with a cluster of abnormalities usually referred to as “diabeticfetopathy” that may be grounds for serious neonatal complications, includinghypoglycemia and respiratory distress (6-9).In recent decades, significant improvements in perinatal care, diagnostic andtreatment of GDM complicated pregnancies has been made. Despite that,macrosomia still remains a serious problem, which may complicate up to 30% ofdiabetic pregnancies (10, 11). Interestingly, the certain percentage of newbornswith macrosomia remains high even in women with proper carbohydrate controls,measured using commonly available parameters (fasting and 2-hrs postprandialglycemia, HbA1c concentration) (12, 13). Therefore, further studies are necessary

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to investigate other factors contributing to fetal overgrowth in diabetic pregnancy.Maternal hyperglycemia is a commonly recognized classical risk factor for fetalovergrowth. However, it is still debatable whether fasting or postprandialhyperglycemia is a pivotal factor for developing fetal overgrowth (11).In recent studies fetal growth and development is considered a complexprocess where maternal characteristics, fetal potential and the intrauterineenvironment plays an important role (2, 13). This concept opens a new horizonfor further research; however, there are a limited number of tools and techniquesdesigned for investigating fetal development and the intrauterine milieu.Moreover, the list of factors influencing fetal growth both in normal and indiabetic pregnancy is expanding and still far from being complete, results ofdifferent studies are often conflicted and new areas for research emerge (14).Recently, a great deal of data has accumulated on lipid metabolism in normaland diabetic pregnancies, maternal obesity and gestational insulin resistance,however, data concerning their impact on fetal growth are limited (15-19).Pregnancy is commonly described as a condition characterized by a rapidincrease in all lipids, however, evidence concerning the relationship between lipidmetabolism and hormonal changes during fetal gestation is conflicting (20, 21).In the study performed on a small group of 9 women with GDM, Montelongo etal. reported a linear correlation between HDL-cholesterol, TAG and β-estradiol,progesterone and prolactin – a finding supported only for TAG by more recentstudy performed on a larger group by Smolarczyk et al. (20, 21). In their study,Knopp et al. reported a significant association between maternal triglyceridelevels and neonatal weight both in normal and in GDM-complicated pregnancy(22). Their results were in line with those obtained by Kitaima et al. who reportedmaternal hypertriglyceridemia as a significant predictor of LGA (23).In our study we aim to investigate different maternal metabolic characteristicscorresponding to particular features of metabolic syndrome and theircompounding influence on fetal growth and the incidence of LGA in pregnantwomen with GDM.

MATERIAL AND METHODOur study group consisted of 357 women referred to the Department of Obstetrics and Women

Diseases for a tertiary-level, specialistic antenatal care from 1993 to 2005. The protocol of our studyinvolved a retrospective analysis of patients’ records from the database of our Department. Theinclusion criteria were as follows: GDM diagnosed following WHO criteria, singleton pregnancy, livebirth and no fetal malformation suspected during gestation or detected postpartum. In our research, weinvestigated the following parameters: patients’age, pre-pregnancy body mass index (BMI), gestationalage when GDM was diagnosed, 75g oral glucose tolerance test (OGTT) (fasting and 2-hrs post-loadglycemia), total, and HDL cholesterol (HDL) at booking, triglycerides (TAG) and HbA1c concentrationat booking. We also recorded a birth weight of the largest child born in a previous pregnancy (ifapplicable). Birth weight and the proportion of LGA (defined as a birth weight >90th percentile for localpopulation after adjusting for gestational age and sex) was studied at the end-point (22).

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Patients with gestational diabetes diagnosed in primary or secondary-level centres were referredto our Department for further diagnostic and combined perinatal and diabetes-related care. In 72.8%of patients GDM was diagnosed as an abnormal blood glucose level in 2 hours after 75g glucoseadministered orally (≥140 mg/dl), whereas in remaining 27.2% of individuals GDM was diagnosedfollowing highly elevated fasting glycemia or highly abnormal result of 50g glucose screening test(1 hour glycemia ≥200 mg/dl). During their first hospitalization, having assessed metabolic statusand a daily glycemia profile (blood samples taken every two hours starting from 8.00 AM), generalobstetrical status and fetus well-being, all participants underwent personal training concerning diet(diet low in simple carbohydrates but covering special nutritional needs of pregnant woman),lifestyle and self-monitoring of glycemia. Target glucose levels were as follows: fasting glycemiabetween 60-90 mg/dl and 2-hrs postprandial glycemia <120 mg/dl. If a diet alone was not sufficientfor maintaining glucose levels within recommended values, insulin therapy in the form of multipleinjections of short- and long lasting human insulin was introduced, starting from 0.3 IU/ kg of bodyweight. The insulin doses were adjusted following meal compositions and the current blood glucoselevel, as well as patients participating in additional training concerning insulin self-administration.Then, all participants were covered with a specialized perinatal care, involving ambulatory visits inour outpatients’ clinic and hospitalization for delivery.

Blood samples for HbA1c and lipid assessment were taken after overnight fasting, centrifugedand assayed according to protocols used in our ISO-certified Central Hospital Laboratory. HbA1cconcentration was measured using turbidimetric immunoinhibitory method, with reference values(for nonpregnant individuals) 4.8-6.0%. Total and HDL cholesterol concentrations were measuredusing quantitative enzymatic colorimetric methods, with reference values (for nonpregnantindividuals) 0.57-2.28 and 0.4-0.8 mmol/l, respectively. TAG concentration was measured using aquantitative enzymatic colorimetric method.

For the purposes of this study, we initially investigated bivariate correlations between thematernal parameters and a birth weight, as well as features that correlated significantly with a birthweight were chosen for further calculations. We have analyzed distribution of the followingcovariates: fasting glycemia in 75g OGTT, HbA1c level, pre-pregnancy BMI, HDL and TAGconcentration. Then, we defined values above 75th percentile as altered, except from HDL that wasdescribed as altered if below the 25th percentile. As a next step, we retrospectively divided the studygroup into five subgroups according to the number of altered metabolic parameter found in eachparticipant: from 0 if all of the following: BMI, fasting glycemia, HbA1c concentration, HDLconcentration and TAG concentration were within interquartile range (i.e. between 25th and 75thpercentile) to 5 if all of them were altered. Then, the birth weight and prevalence of LGA werestudied across the subgroups.

Statistical analysis was performed using SPSS 12.0 for Windows software. Results are expressedas median (minimum-maximum value), unless otherwise stated. The significance of the differencesbetween study groups was tested using U Mann-Whitney’s test, or Kruskall-Wallis test, according toa number of groups tested. Differences in categorical variables were tested using a chi-square statistic.Associations between maternal metabolic parameters and birth weight were analysed using Spearmanrank correlation coefficients. Linear regression analysis was performed to find independent predictorsfor birth weight in the study group. p<0.05 was considered statistically significant.

RESULTSBasic characteristics of the patients enrolled into the study are given in

Table 1. Insulin therapy was necessary to achieve a proper metabolic control

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in 25.2% of individuals. Hypertension (chronic or gestational) was diagnosedin 10.9% of subjects.We found weak but significant positive linear correlations between birthweight and the following covariates (see Fig. 1A-E): maternal pre-pregnancyBMI (R=0.2, p<0.00001), birth weight of the largest offspring (R=0.34,p<0.00001), HbA1c at booking (R=0.11, p<0.05), fasting glycemia during 75gOGTT (R=0.23, p<0.00001) and TAG concentration at booking (R=0.12,p<0.05). No correlation was found for total and HDL-cholesterol and for maternalage as well as gestational age when GDM was diagnosed.To determine independent predictors of birth weight in our study group, weperformed linear multiple regression analysis with birth weight as an dependentvariable and maternal metabolic characteristics as an initial independent variable.Results of the regression analysis are summarized in Table 2. Univariate analysis

9Table 1. Characteristics of the study group

Number of patients studied N=357Age (years) 29(17-48)Proportion of individuals >30 years 42.4%Pre-pregnancy BMI (kg/m2) 24.2(16.7-46.1)Gestational age at diagnosis (week of gestation) 28(5-40)Fasting glycemia in 75g OGTT (mg/dl) 95(45-275)2hrs post-load glycemia in 75g OGTT (mg/dl) 166.5(91-310.0)HbA1c at booking (%) 5.6(2.4-11.1)Proportion of patients with Hb1c at booking ≥ 6.3% 25.5%HbA1c at term (%) 6.1(2.8-9.6)Proportion of patients with Hb1c at term ≥ 6.3% 41.3%Gestational age at delivery (week of gestation) 38(32-42)Birth weight (g) 3450(1530-6500)Proportion of LGA (%) 19.9insulin/ diet treated GDM (N) 90/267Hypertensive/ normotensive individuals (N) 35/285*)

*) There was insufficient information on hypertensive disorders in 37 patients.Data given as median (minimum-maximum value)

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Fig. 1A. Correlation between maternal BMI before pregnancy and a birth weight (p<0.00001,N=309)

Fig. 1B. Correlation between birth weight of the largest offspring and a birth weight in the studygroup (p<0.00001, N=170)

BIRTH WEIGHT [g]

BIRTH WEIGHT [g]

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Fig. 1C. Correlation between HbA1c concentrations at booking and a birth weight (p<0.05, N=317)

Fig. 1D. Correlation between fasting glycemia during 75g OGTT and a birth weight (p<0.00001,N=282)

BIRTH WEIGHT [g]

BIRTH WEIGHT [g]

demonstrated that birth weight of the largest offspring was the strongestindependent predictor of a birth weight in our group, accounting for around 19%of the variation. Maternal BMI and fasting glycemia alone predicted 7.5% and7.7% of the variation in the dependent variable, respectively. Other predictorsexplained small proportion of the variation in the studied parameter (less than5%). All predictors, except from TAG concentrations, remained significant whengestational age at diagnosis was entered into models.Our research also involved an investigation of the combined influence ofmultiple metabolic alterations on birth weight and the prevalence of macrosomia.

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Fig. 1E. Correlation between maternal TAG concentrations at booking and a birth weight (p<0.05,N=319)

Table 2. Independent predictors of birth weight in the study groupcovariate R2 F pMaternal BMI prior the pregnancy 0.075 17.92 ***Birth weight of the largest offspring 0.193 37.55 ***HbA1c at booking 0.03 6.73 *Fasting glycemia during 75g OGTT 0.077 27.20 ***TAG concentrations at booking 0.02 9.43 **

*** p<0.0001; ** p<0.01; * p<0.05

BIRTH WEIGHT [g]

There was no association between HDL concentrations and birth weight in ourstudy, however, as a separate analysis showed that HDL-cholesterolconcentrations were a significant predictor for LGA (study in progress, dataunpublished), we decided to include this parameter in a further analysis.Distribution of maternal metabolic parameters is given in Table 3. Finally, weanalysed birth weight and the proportion of LGA newborns in subgroups ofindividuals with different numbers of altered parameters (i.e. values for particularmetabolic characteristics given in Table 3 above 75th percentile/ below 25thpercentile for HDL). Results are given in Table 4 and Fig. 2. We found a highlysignificant difference in birth weight and the prevalence of LGA when comparingpregnant women with the different numbers of altered metabolic features (i.e.values within the highest or the lowest quartile). Proportion of macrosomicnewborns varied from approximately10% in individuals with no abnormalities ortwo altered values to over 80% in patients with 5 out of 6 parameters changed.

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Table 3. Metabolic characteristics in the study groupvariable 25th 50th 75th

percentile percentile percentileMaternal BMI prior to pregnancy (kg/m2) 21.4 24.1 28.6Birth weight of the largest offspring (g) 3250 3645 4000Fasting glycemia at 75g OGTT (mg/dl) 85 95 111HbA1c at booking (%) 5.1 5.6 6.4TAG concentration at booking (mmol/l) 2.45 3.22 4.24HDL-cholesterol concentration at booking (mmol/l) 1.59 1.87 2.26

Table 4. Birth weight and % of LGA newborns in relation to maternal metabolic alterationsNumber of altered maternal N Birth weight (g) % of LGAmetabolic characteristics0 92 3340±470 10.91 65 3500±490 16.92 38 3360±570 10.53 31 3530±560 35.64 14 4000±670 71.45 6 4760±1130 83.3p <0.0001*) <0.0001†)

*) Kruskal-Wallis test; †) Chi2 test;Maternal metabolic characteristics defined as altered: pre-pregnancy BMI above 75th percentile,TAG concentration above 75th percentile, fasting glycemia above 75th percentile, HbA1c at booking(during first hospitalisation) above 75th percentile, HDL concentration below 25th percentile.

DISCUSIONPregnancy is commonly recognised as a period of very intense changes inmaternal metabolism. Apart from vast literature regarding gestational diabetes,there is much evidence available on maternal insulin resistance or shifts in lipids/lipoproteins profiles (18, 19, 25- 27).In their study, Piechota et al. reported all lipids significantly elevated duringuncomplicated gestation in healthy women, with a 2.7-fold increase in the TAGlevel, 56% increase in total cholesterol and 25% increase in HDL-cholesterol(28). Comparing data from their study with our population, our patients hadhigher TAG concentrations [95th percentile for our study group: 6.03 mmol/l vs

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Fig. 2. Birth weight in relation to maternal metabolic alterations (p<0.0001)

BIRT

H WE

IGHT

[g]

4.68 mmol/l reported by Piechota et al. (27)], lower total cholesterolconcentrations (95th percentile for our study group: 9.03 mmol/l vs 9.83 mmol/lreported by Piechota et al.) and higher HDL-cholesterol concentrations [5thpercentile for our study group: 1.20 mmol/l vs 1.04 mmol/l reported by Piechotaet al. (27)].The major difficulty we encountered during our research was the lack ofofficially recommended reference values for lipids adapted for pregnant women.Therefore, we decided to use the interquartile range to establish subgroups forfurther analysis and our approach is similar to those of past researchers (23, 25).In their study, Kitajima et al. (23) defined maternal hipertriglyceridemia as serumTAG above the 75th percentile and reported it as a significant risk factor for LGA.They also analysed the maternal fasting plasma glucose, prepregnancy BMI andgestational change in maternal body weight, however, they did not find anyassociation between these covariates and birth weight. The same methodologyconcerning TAG concentrations was also applied by Di Cianni at al. who reportedsignificant association between elevated maternal TAG levels, pregestationalBMI, weight gain during pregnancy and 2-hrs OGTT glycemia (26). The lastfinding is not supported by our results, as we found a significant associationbetween maternal fasting glycemia and LGA. It seems surprising as a mainpathomechanism of gestational diabetes is driven by impaired response tocarbohydrate loading. It should be stated that both Kitajima et al. (23) and DiCianni et al. (26) studies were performed in smaller study groups (146 and 180individuals, respectively). Some differences in results may also be attributed todifferent ethnic background (Kitajima et al. (23) investigated Japanese gravidas).There is an increasing amount of evidence from recent studies that a numberof factors appears to have an impact on fetal growth (2, 11, 12). Our findingconcerning association between maternal BMI, TAG concentrations and fetalgrowth is in accordance with results reported by Cianni et al. who investigatedpregnant women with different forms of glucose intolerance (impaired fastingglycemia or GDM) (26). Also another study, performed by Schaefer-Graf et al.described an increased incidence of LGA in obese pregnant women with GDMrather than in women with hyperglycemia alone, which is comparable to ourfindings (18).The overall proportion of LGA newborns in our study group wasapproximately 19%, which is similar to findings of past studies (19, 26).However, in our study we report a significant increase (almost eight-fold) in theprevalence of LGA, following the presence of complex, even if mild metabolicalterations. It is important to note that a proportion of LGA in pregnant womenfrom our study group with all analyzed metabolic parameters (maternal BMI,fasting glycemia, HbA1c concentration, HDL concentration and TAGconcentration) within an interquartile range is similar to that noted within thenormal population (10%). Surprisingly, the same percentage is noted in the groupof women with two altered parameters. However, upon closer analysis, we

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observed that most of these patients had a BMI below the 75th percentile (71.1%),whereas in individual with 3 or more altered metabolic features an elevated BMIwas a common finding (up to 100% in the group with 5 altered features),accompanied by a significant increase in birth weight. Our results suggest that ina population of properly controlled and treated women with GDM, fetalovergrowth seems to be driven by other factors, possibly a cluster of metabolicalterations associated with maternal obesity, as we observed an elevated maternalBMI in 36.6% of LGA in our study group. The association between gestationaldiabetes and metabolic syndrome is a subject of recent studies, and one of thesestudies reported on the influence of metabolic syndrome on fetal growth indiabetic women regardless of the degree of hyperglycemia (19). It may explainthe phenomenon of an increased prevalence of macrosomia in this group ofpatients, despite improvement in diagnostics and treatment options. However,further studies addressing a variety of factors associated with metabolicsyndrome, performed during gestation and their both individualised andcombined impact on birth weight are necessary to corroborate our findings.Clinical implications of these findings may include a more active approach toobesity among women in childbearing age as our evidence suggest that maternalobesity is a factor that deteriorates the effectiveness of hypoglycaemic treatmentin pregnancy complicated with GDM. Fetal growth in a diabetic pregnancy is acomplex process and maternal metabolic parameters other than glucose levelsshould be addressed to reduce the risk of macrosomia in this group of patients.Conflict of interest statement: None declared.

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28. Bo S, Menato G, Gallo ML et al. Mild gestational hyperglycemia, the metabolic syndrome andadverse neonatal outcomes. Acta Obstet Gynecol Scand 2004; 83: 335-340.R e c e i v e d : March 15th, 2008A c c e p t e d : August 1st, 2008Author’s address: Prof. Ewa Wender-O¿egowska, MD, PhD; Department of Obstetrics and Women

Diseases, ul. Polna 33, 60-535 Poznan, Poland; phone/ fax: +48 61 8419 641; e-mail: ewaoz@post.pl

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