Determinants of birth weight in boys and girls

Transcription

1 human_ ontogenetic s O r i g i n a l A r t i c l e HUM ONTOGENET 3(1), 2009, 7 12 doi /huon in boys and girls A r t i c l e H i s t o r y received December 18, 2008 accepted January 29, 2009 published online March 18, 2009 A f f i l i a t i o n : 1 Dept. of Obstetrics and Gynecology, Rikshospitalet Medical Centre; 2 Dept. of N a n n a V o l d n e r 1, K a t h r i n e F r e y F r ø s l i e 1, 2, K r i s t i n G o d a n g 3, J e n s B o l l e r s l e v 3, T o r e 1 Biostatistics, Institute of Basic Medical Science; 3 Dept. of Medicine, Rikshospitalet University Hospital; University of Oslo, Oslo, Norway Abstract Boys are heavier at birth than girls, but girls have higher fat mass at birth than boys. Insulin action may play an important role of this different distribution. Animal models have shown that female offspring are more sensitive to maternal feeding and glucose values during pregnancy and weaning than male offspring. Newborn girls have higher insulin and proinsulin concentrations and total proinsulin-to-insulin ratios in cord blood than boys, despite lighter birth weight. In a cohort of 522 newborn above 37 gestational weeks we split between the sexes and studied associations between birth weights, parental anthropometrics and fasting maternal plasma glucose and insulin levels. Boys weighed 184g more than girls, they were 1.1 cm longer and head circumference differed by 0.86 (all p values <0.01). Multiple linear regressions showed that parity, maternal body mass index, gestational age and maternal birth weight were associated with birth weight for both sexes, whereas maternal weight gain in pregnancy and maternal fasting plasma glucose at week were significantly associated with birth weight for girls only. The effect of fasting plasma glucose on birth weight in girls was twice as high as in boys (B=162, 95% CI , p=0.01). Paternal birth weight was significantly associated with birth weight of boys, but no such association was seen for girls. This supports the notion that there is a genetic regulation along the male line. Girls may be more sensitive to intrauterine environment and maternal glucose values, as these have a stronger influence on birth weight of girls. Introduction Males and females may differ in the pathogenic pathways leading to diabetes mellitus and insulin resistance (Mittendorfer 2005). The current insight into insulin action is largely based on studies of male subjects. More recently, along with the increasing prevalence of obesity, the female population has been subjected to more studies. It seems that adult obese women are more insulin sensitive compared with obese adult men (Vistisen et al. 2008), and the prevalence of diabetes is two to three times higher in men than in women, respective of weight categories (Kuhl et al. 2005). Sheep models show that restriction of fetal growth induced by chronic restriction of placental growth results in features of the metabolic syndrome in adult male offspring, particularly impaired insulin action (Owens et al. 2007). These authors suggested that ewes small at birth also will develop the syndrome, but later than males (Owens et al. 2007). The prevalence of insulin resistance has shown to vary between the sexes throughout puberty. Rat offspring of mothers fed a junk food diet throughout pregnancy and lactation period, combined with feeding the offspring a junk food diet post-weaning, show that male and female offspring were affected differently in terms of plasma glucose and insulin levels. Increased adiposity was more enhanced in female than male rat offspring (Bayol et al. 2001). Boys at 19 years of age have a higher lean body mass than girls at the same age, but they also have higher prevalence of insulin resistance (Moran et al. 2006). Among children at the age of five, girls have higher insulin resistance C o r r e s p o n d e n c e Nanna Voldner, Reg. Midwife, Candidate in Nursing Science Dept. of Obstetrics and Gynecology Rikshospitalet Medical Centre University of Oslo 0027 Oslo, Norway Tel: / Fax: nanna.voldner@rikshospitalet.no K e y w o r d s Birth weight, sex differences, paternal birth weight, intrauterine environment, fasting glucose A b b r e v i a t i o n s BMI body mass index FPG fasting plasma glucose FPI fasting plasma insulin Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2 than boys. These girls also have more subcutaneous fat than boys, despite similar body weights (Murphy et al. 2004). This might be because prepubertal girls are intrinsically more insulin resistant than boys, and that sex-linked genes may explain this difference. Girls have lower birth weight than boys, but the underlying reasons have not been thoroughly investigated (Alexander et al. 1999, Skjaerven et al. 2000). Despite being lighter, newborn girls display a lower proportion of fat-free mass and have a higher percent of body fat than newborn boys (Catalano et al. 1995). Fetal insulin is strongly related to intrauterine growth, and can be considered the true fetal growth hormone. Insulin does not pass through the placenta, and appears to have no substantial effect on transplacental glucose transport. It acts indirectly by changing the transplacental glucose concentration gradient. Glucose appears to be one of the major physiological regulators of insulin release in utero (Fowden 1989). Fetal hyperglycaemia accelerates the developments of insulin secretory mechanisms (Langer 2000). Measurements of cord insulin and insulin-related peptides in newborns have shown that girls have higher insulin and proinsulin concentrations and total proinsulin-to-insulin ratios in cord blood than boys, despite lighter birth weight. No difference in cord glucose concentrations was found between newborn girls and boys (Shields et al. 2007). The aim of the present study was to examine whether parental anthropometric values and fasting maternal plasma glucose and insulin levels influence birth weight differently in the two sexes. Material and methods The population of the cohort that consists of 553 women and their newborn infants has been described in detail elsewhere (Voldner et al. 2008). Healthy women with Scandinavian heritage were invited to participate. Exclusion criteria were multiple pregnancies, known diabetes, fetal malformation or other severe maternal illnesses. The women came for four antenatal visits during pregnancy. At gestational weeks and fasting plasma glucose values (FPG) were measured. Fasting plasma insulin values (FPI) were measured at weeks 14-16, 22-24, and Weight was measured on a digital scale at the first visit and height was self reported. Information of maternal and paternal birth weight was obtained at the same time, both self reported. Independent variables Glucose was measured immediately in EDTA blood, by Accu Check glucose test strips and glucometer (Roche Diagnostics, Basel, Switzerland). Samples were collected in 7 ml Vaccutainer tubes, centrifuged at room temperature at 3000 RCF in 10 min. and serum aliquoted and stored at -80 ºC until analyzed. Samples for insulin were assayed in duplicate (RIA, DPC, Los Angeles, CA, USA) and the intra- and inter-assay CV were 4.9% and 5.4%, respectively. All blood samples were drawn an after overnight fast (from midnight until 8.00 am). Maternal and paternal birth weight and maternal height was self-reported. Weight was measured on a digital scale at the first visit (week 14-16). Statistical methods Descriptive statistics are presented as mean and standard deviations (SD), or median and quartiles for skewed data. Comparisons of boys and girls were done by two-sample t-tests. The effects of predictor variables on birth weight were explored in univariate and multiple linear regression analyses. Also, logistic regression analyses with birth weight above 4200 g as the response variable were done. Due to the low sample sizes (n=26 cases among girls and n=58 cases among boys), the results presented from logistic regression analysis were restricted to the univariate analyses. All models were checked for violations from the model assumptions. A p value less than 0.05 was considered statistically significant. All analyses were done by SPSS Ethics The study was approved by the Regional Ethic Committee and performed according to the Declaration of Helsinki and written informed consent obtained. Results Of the 553 children in the cohort, 522 were born after 37 gestational weeks (ultrasound based between weeks 17-19). Of these, 248 were female newborns (47.5 %). Table 1 shows the distribution of maternal anthropometrics and fasting plasma glucose and insulin values at weeks and The only significant differences between boys and girls were gestational age, the size, boys weighing 184g more, they were 1.21 cm 8

3 Girls Boys n Mean or SD or Range n Mean or SD or Range p 248 median a Q 1 -Q 3 * 274 median a Q 1 -Q 3 * Gestational age (weeks) <0.01 Maternal age (year) Para Maternal birth weight (g) Paternal birth weight (g) Maternal height (cm) Maternal BMI (kg/m 2 ) week Maternal weight gain (kg) week to Fasting plasma glucose week (mmol/l) Fasting plasma glucose week (mmol/l) Fasting insulin week (pmol/l) a a a a Fasting insulin week (pmol/l) a a a a Birth weight (g) <0.01 Length (cm) <0.01 Head circumference (cm) <0.01 T a b l e 1. Characteristics of girls and boys at birth. Maternal characteristics were obtained throughout pregnancy. Data are presented as means and standard deviations (SD), or medians and quartiles (Q) for skewed data. longer and head circumference differed by 0.86 cml (all p values <0.01). Table 2 shows the results from univariate linear regression analyses. Gestational age, maternal BMI in early pregnancy and maternal birth weight were significantly associated with birth weight for both girls and boys. Maternal height and weight gain throughout pregnancy was only associated with birth weight of the girls, whereas paternal birth weight were significantly associated with birth weight of the boys. We found significant differences between the sexes in term of the association between birth weight and maternal FPG and FPI. In multiple linear regression models shown in Table 3, we found that parity, maternal BMI, gestational age and maternal birth weight were associated with birth weight for both sexes, whereas maternal weight gain in pregnancy and maternal FPG at week were significantly associated with birth weight for girls only. The adjusted effect of FPG at week on birth weight in boys was positive, but not significant (B=79.4, 95% CI , p=0.21). In contrast, the ef- Girls Boys B p CI CI B p CI CI lower upper lower upper Gestational age (weeks) 198 < < Maternal age (year) Maternal birth weight (kg) 215 < < Paternal birth weight (kg) < Parity (0 1+) 256 < < Maternal BMI (week 14 16) 24 < < Weight gain week 14 to 36 (kg) 24 < Maternal height (cm) 27 < Fasting glucose weeks (mmol/l) 191 < Fasting glucose weeks (mmol/l) 297 < Fasting glucose diff. weeks to (mmol/l) Fasting insulin week (pmol/l) 6 < Fasting insulin week (pmol/l) 3 < T a b l e 2. Results from univariate linear regression analyses on birth weight. The analyses were stratified by fetal sex. For both sexes, results are given as the crude regression coefficient B, 95 % confidence intervals (CI) for B and p-values. Maternal variables considered to be relevant covariates were obtained throughout pregnancy. 9

4 Female Male B p 95% CI B p 95% CI Gestational age (weeks) 184 < < Maternal age (year) Maternal birth weight (kg) 184 < < Paternal birth weight (kg) < Parity (0 1+) 286 < < Maternal BMI week (kg/m 2 ) Weight gain week 14 to 36 (kg) 26.7 < Fasting glucose week (mmol/l) Fasting insulin week (pmol/l) T a b l e 3. Adjusted models. Results from multiple linear regression analyses on birth weight. The analyses were stratified by fetal sex. For both sexes, results are given as the adjusted regression coefficients B, 95 % confidence intervals (CI) for B and p-values. Maternal variables considered to be relevant covariates were obtained throughout pregnancy. fect of FPG on birth weight in girls was twice as high, and significant (B=162, 95% CI , p=0.01). Paternal birth weight was significantly associated with birth weight of boys, with an increase in birth weight of 180g per kg change in paternal birth weight (p<0.01), but no such association was seen for girls. Macrosomia is defined as birth weight above 4200g, this is in relation to the 90 th percentile of the Norwegian birth cohort (Skjaerven et al. 2000, Voldner et al. 2008). Of the 84 (15%) newborns in our cohort with birth weight above 4200g, 58 (69%) were boys and 26 (31%) were girls. By performing the same analyses using a univariate logistic regression model, with birth weight above 4200g as dependent variable, similar results were found (data not shown). Discussion Our findings, that gestational age, parity, maternal birth weight and BMI independently influence birth weight for both boys and girls is in accordance with previous reports (Catalano et al. 1998, Shields et al. 2006). However, after adjusting for these variables, paternal birth weight had a significant effect on birth weight of boys but not for girls. Furthermore, maternal weight gain from early to late pregnancy and FPG at weeks was independently associated with birth weight of girls but not for boys. It has previously been shown that modifiable variables like fasting glucose, pre-pregnant BMI, low level of pre-pregnant physical activity independently influence fetal macrosomia (Voldner et al. 2008). A previous Norwegian study reported that paternal birth weight contributed independently to offspring birth weight (Magnus et al. 2001). In a UK study it was found that paternal height, but not paternal BMI, independently correlated with birth weight. The authors suggested that skeletal growth is genetically regulated, while the maternal environment predominantly alters the adiposity of the fetus (Knight et al. 2005). Our finding that paternal birth weight has a significant influence on birth weight of boys, but not for girls, supports the notion that there is a genetic regulation along the male line. These genes may either be associated with the y-chromosome or subjected to sex-dependent imprinting (Hager et al. 2008). As far as we know, paternal birth weight has previously not been studied in relation to birth weight and infant sex. The present results add new information by the finding that the father s own birth weight influence that of the male offspring only. FPG in third trimester and weight gain were positively associated with birth weight of females only. Growth of the fetus is generally a result of both placental properties and inherent growth potentials of the fetus. The observed sex-specific effects may therefore be caused by sex-dependent differences in sensitivity of the placental and/or fetal tissue to fasting plasma glucose or factors associated with weight gain. Such sex-dependent differences in sensitivity may, for example, include placental transport capacity of glucose or fetal growth response to a given supply of glucose. Our findings are summarized in Figure 1. These findings are in accordance with a previous study which found girls to be intrinsically more insulin resistance than boys at birth (Shields et al. 2007). Despite weighing less at birth, the girls had significantly higher insulin and proinsulin concentrations in cord blood than boys, whereas there was no difference in cord glucose concentrations between girls and boys. The same study also found that girls had significantly more subcutaneous fat measured by triceps and subscapular skinfold thicknesses (Shields et al. 2007). 10

5 Fasting glucose week U - Fasting insulin week Maternal birth weight F i g u r e 1 Effects of paternal and maternal birth weight, maternal anthropometry, fasting plasma and glucose values on birth weight of boys and girls. Maternal weight gain Maternal BMI Paternal birth weight Associations (p < 0.05) No associations We preferred not to use relative birth weight in the present work. This is based on findings indicating that among newborn anthropometric parametres birth weight is a better predictor of adolescent fat distribution than is relative birth weight (Araujo et al. 2008). Furthermore, relative birth weight explains less of proportion of fat in newborn than does birth weight (Catalano et al. 1992). However, we have calculated relative birth weight and reanalysed the data with relative birth weight as the response in the multiple analyses. Paternal birth weight remained significantly associated with birth weight for boys, but not for girls. Conclusion It seems that paternal birth weight is associated with the birth weight of boys but not with girls, and therefore support the notion that there is a genetic regulation along the male line. Girls may be more sensitive to intrauterine environment and maternal glucose values, as these have a stronger influence on birth weight of girls. Acknowledgements The study is supported by: The Norwegian Health Association, The National Resource Centre for Women s Health, Dept. of Obstetrics and Gynecology, Rikshospitalet University Hospital, University of Oslo, Norway Faculty of Medicine, Thematic Research Area, University of Oslo, Norway References Alexander, G.R., Kogan, M.D. & Himes, J.H U.S. singleton birth weight percentiles for gestational age by race, Hispanic origin, and gender. Matern Child Health J 3: Araújo, C.L., Hallal, P.C., Nader, G.A., Neutzling, M.B., defátima Vieira, M., Menezes, A.M. & Victora, C.G Effect of birth size and proportionality on BMI and skinfold thickness in early adolescence: prospective birth cohort study. Eur J Clin Nutr epub ahead of print, doi: /ejcn Accessed Feb 13, Bayol, S.A., Simbi, B.H., Bertrand, J.A. & Stickland, N.C Offspring from mothers fed a junk food diet in pregnancy and lactation exhibit exacerbated adiposity that is more pronounced in females. J Physiol 586: Catalano, P.M., Drago, N.M. & Amini, S.B Factors affecting fetal growth and body composition. Am J Obstet Gynecol 172: Catalano, P.M., Thomas, A.J. Huston, L.P. & Fung, C.M Effect of maternal metabolism on fetal growth and body composition. Diabetes Care 21: B85-B90. Catalano, P.M., Tyzbir, E.D., Allen, S.R., McBean, J.H. & McAuliffe, T.L Evalua- 11

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