Assessing the Causal Relationship of Maternal Height on Birth Size and Gestational Age at Birth: A Mendelian Randomization Analysis

Background

Observational epidemiological studies indicate that maternal height is associated with gestational age at birth and fetal growth measures (i.e., shorter mothers deliver infants at earlier gestational ages with lower birth weight and birth length). Different mechanisms have been postulated to explain these associations. This study aimed to investigate the casual relationships behind the strong association of maternal height with fetal growth measures (i.e., birth length and birth weight) and gestational age by a Mendelian randomization approach.

Methods and Findings

We conducted a Mendelian randomization analysis using phenotype and genome-wide single nucleotide polymorphism (SNP) data of 3,485 mother/infant pairs from birth cohorts collected from three Nordic countries (Finland, Denmark, and Norway). We constructed a genetic score based on 697 SNPs known to be associated with adult height to index maternal height. To avoid confounding due to genetic sharing between mother and infant, we inferred parental transmission of the height-associated SNPs and utilized the haplotype genetic score derived from nontransmitted alleles as a valid genetic instrument for maternal height. In observational analysis, maternal height was significantly associated with birth length (p = 6.31 × 10⁻⁹), birth weight (p = 2.19 × 10⁻¹⁵), and gestational age (p = 1.51 × 10⁻⁷). Our parental-specific haplotype score association analysis revealed that birth length and birth weight were significantly associated with the maternal transmitted haplotype score as well as the paternal transmitted haplotype score. Their association with the maternal nontransmitted haplotype score was far less significant, indicating a major fetal genetic influence on these fetal growth measures. In contrast, gestational age was significantly associated with the nontransmitted haplotype score (p = 0.0424) and demonstrated a significant (p = 0.0234) causal effect of every 1 cm increase in maternal height resulting in ~0.4 more gestational d. Limitations of this study include potential influences in causal inference by biological pleiotropy, assortative mating, and the nonrandom sampling of study subjects.

Conclusions

Our results demonstrate that the observed association between maternal height and fetal growth measures (i.e., birth length and birth weight) is mainly defined by fetal genetics. In contrast, the association between maternal height and gestational age is more likely to be causal. In addition, our approach that utilizes the genetic score derived from the nontransmitted maternal haplotype as a genetic instrument is a novel extension to the Mendelian randomization methodology in casual inference between parental phenotype (or exposure) and outcomes in offspring.     

Genome-wide linkage analysis assessing parent-of-origin effects in the inheritance of birth weight

Family studies suggest that genetic variation may influence birth weight. We have assessed linkage of birth weight in a genome-wide scan in 269 Pima Indian siblings (334 sibling pairs, 92 families). As imprinting (expression of only a single copy of a gene depending on parent-of-origin), is commonly found in genes that affect fetal growth, we used a recently described modification of standard multipoint variance-component methods of linkage analysis of quantitative traits. This technique allows for comparison of linkage models that incorporate imprinting effects (in which the strength of linkage is expressed as LOD(IMP)) and models where parent-of-origin effects are not included (LOD(EQ)). Where significant evidence of linkage was present, separate contributions of alleles derived from father (LOD(FA)) or mother (LOD(MO)) to the imprinting model were estimated. Significant evidence of linkage was found on chromosome 11 (at map position 88 cM, LOD(IMP)=3.4) with evidence for imprinting (imprinting model superior, P<0.001). In this region, birth weight was linked predominantly to paternally derived alleles (LOD(FA)=4.1, LOD(MO)=0.0). An imprinted gene on chromosome 11 may influence birth weight in the Pima population. This chromosome contains one of the two major known clusters of imprinted genes in the human genome, lending biological plausibility to our findings.     

LIVE BIRTH CERTIFICATES—Evaluation of Medical and Health Data in California

In a study of 1,609 single live births occurring in San Francisco County, the information on the birth certificate was compared with that on the hospital record to determine completeness and accuracy of the items reported on the certificate.Items such as color or race of mother, age of mother, birth weight and birth length of child were well recorded on the certificate and agreed with information found in the hospital record.Medical conditions were grossly underreported on the birth certificate. Conditions relating to the mother were more frequently recorded than those relating to the infant, but the birth certificates recorded less than one-fifth of all medical conditions of both mother and infant that were entered in the hospital records.Methods suggested for improving the quality of maternal and newborn morbidity information include revision of the medical section of the present certificates of live birth and fetal death and use of a precoded hospital record.     

Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals

The role of genes in normal birth-weight variation is poorly understood, and it has been suggested that the genetic component of fetal growth is small. Type 2 diabetes genes may influence birth weight through maternal genotype, by increasing maternal glycemia in pregnancy, or through fetal genotype, by altering fetal insulin secretion. We aimed to assess the role of the recently described type 2 diabetes gene TCF7L2 in birth weight. We genotyped the polymorphism rs7903146 in 15,709 individuals whose birth weight was available from six studies and in 8,344 mothers from three studies. Each fetal copy of the predisposing allele was associated with an 18-g (95% confidence interval [CI] 7-29 g) increase in birth weight (P=.001) and each maternal copy with a 30-g (95% CI 15-45 g) increase in offspring birth weight (P=2.8x10-5). Stratification by fetal genotype suggested that the association was driven by maternal genotype (31-g [95% CI 9-48 g] increase per allele; corrected P=.003). Analysis of diabetes-related traits in 10,314 nondiabetic individuals suggested the most likely mechanism is that the risk allele reduces maternal insulin secretion (disposition index reduced by ~0.15 standard deviation; P=1x10-4), which results in increased maternal glycemia in pregnancy and hence increased offspring birth weight. We combined information with the other common variant known to alter fetal growth, the -30G-->A polymorphism of glucokinase (rs1799884). The 4% of offspring born to mothers carrying three or four risk alleles were 119 g (95% CI 62-172 g) heavier than were the 32% born to mothers with none (for overall trend, P=2x10-7), comparable to the impact of maternal smoking during pregnancy. In conclusion, we have identified the first type 2 diabetes-susceptibility allele to be reproducibly associated with birth weight. Common gene variants can substantially influence normal birth-weight variation.     

Human fetal growth in Costa Rica, 1970-1975

Costa Rica has experienced a marked reduction in infant mortality--both in the neonatal and post-neonatal components--in the last decade. The decline could be related to improvements in the pattern of fetal growth. The present report analyses the birth weight of newborns from a random sample of all births in the Republic of Costa Rica during 1970 and 1975. While the average birth weight in that period was 3100 grams, the prevalence of low birth weight neonates decreased from 9 to 7 per cent in five years. The provinces of Limon and San Jose exhibited the highest frequency of low birth weight. Women 20 to 29 years old had babies with better or optimal body weight. Age, marital status and occupation of the mother appeared correlated with birth weight. A relationship between changes in fetal growth and changes in maternal, perinatal and neonatal mortality is apparent. The present situation of birth weight places Costa Rica among the countries in transition with a clearer perspective to attain an even higher infant survival in the near future. In this regard, several measures oriented toward prevention of low birth weight are recommended.     

Relationships between fetal biometry, maternal factors and birth weight of purebred domestic cat kittens

The goal of this study was to evaluate the relation between kittens' birth weights and biometrical factors from the kittens and the mother during pregnancy. Knowing fetal birth weight could help in detecting abnormalities before parturition. A Caesarean-section or a postnatal management plan could be scheduled. Consequently, the neonatal mortality rate should be decreased. We used ultrasonographic measurements of femur length (FL) or fetal biparietal diameter (BPD), pregnancies, and maternal factors to obtain a model of prediction. For this purpose, linear mixed-effects models were used because of random effects (several fetuses for one queen and a few paired measurements) and fixed effects (litter size, pregnancy rank, weight, wither height, and age of the queen). This study was performed in 24 purebred queens with normal pregnancies and normal body conditions. Queens were scanned in the second half of pregnancy, using a micro-convex probe. They gave birth to 140 healthy kittens whose mean birth weight was 104 g (ranged 65 to 165 g). No correlation between the birth weight and the age of the queen, as a maternal factor alone, was observed. But the birth weight was found to be inversely proportional to the pregnancy rank and the litter size. Moreover, birth weight increased when the weight and wither height of queen increased. BPD and FL increased linearly during pregnancy so a model was used to estimate mean birth weight. Using this model, we found a correlation between mean birth weights and an association of parameters: maternal factors (wither height and age), and litter size.     

Relationships between fetal biometry,maternal factors and birth weight of purebred domestic cat kittens

The goal of this study was to evaluate the relation between kittens' birth weights and biometrical factors from the kittens and the mother during pregnancy. Knowing fetal birth weight could help in detecting abnormalities before parturition. A Caesarean-section or a postnatal management plan could be scheduled. Consequently, the neonatal mortality rate should be decreased. We used ultrasonographic measurements of femur length (FL) or fetal biparietal diameter (BPD), pregnancies, and maternal factors to obtain a model of prediction. For this purpose, linear mixed-effects models were used because of random effects (several fetuses for one queen and a few paired measurements) and fixed effects (litter size, pregnancy rank, weight, wither height, and age of the queen). This study was performed in 24 purebred queens with normal pregnancies and normal body conditions. Queens were scanned in the second half of pregnancy, using a micro-convex probe. They gave birth to 140 healthy kittens whose mean birth weight was 104 g (ranged 65 to 165 g). No correlation between the birth weight and the age of the queen, as a maternal factor alone, was observed. But the birth weight was found to be inversely proportional to the pregnancy rank and the litter size. Moreover, birth weight increased when the weight and wither height of queen increased. BPD and FL increased linearly during pregnancy so a model was used to estimate mean birth weight. Using this model, we found a correlation between mean birth weights and an association of parameters: maternal factors (wither height and age), and litter size.     

Teratogenic alleles and neurodevelopmental disorders

The genetic interaction between mother and fetus during pregnancy is discussed, focusing on teratogenic alleles that act in the mother to alter fetal development and contribute to a neurodevelopmental disorder. For these alleles, the mother is the genetic patient. Teratogenic alleles interact with modifying and specificity alleles that act in the fetus and with environmental factors. Based on examples of the model, two candidate mechanisms emerge as contributors to neurodevelopmental disorders, folate-homocysteine pathways and immune/inflammatory mechanisms. Both, acting in mothers, affect fetal development and contain many polymorphic genes. These two systems interact with each other. Common functional polymorphisms of mild effect in these two systems of interacting genes are good candidates for teratogenic alleles. The presence of teratogenic alleles complicates gene identification for neurodevelopmental disorders. However, using the special methods required to identify teratogenic alleles is important because this could lead to new approaches to prevention and improved therapy of these disorders.     

Relationships between some maternal factors and pregnancy outcome

This study, carried out on mother-infant pairs in obstetric hospitals in Istanbul, was designed to investigate the impact of some maternal parameters on pregnancy outcome as well as to provide information on birth weight, and incidence of low birth weight, preterm birth, and small for gestational age birth. Low birth weight, preterm birth, and fetal malnutrition are among major risk factors influencing perinatal, neonatal, and postneonatal mortality and morbidity. Reported values for prepregnancy body weight and postpartum measurements of stature, weight, mid-upper arm circumference showed that the women in this series did not have caloric undernutrition, while nearly 9% were of low stature. Maternal stature, postpartum body weight, and postpartum weight and height values were found to be important determinants of birth weight. The frequency of preterm births in this series corresponds fairly well with that found in another group of Turkish mother-infant pairs in which gestational age was determined by Dubowitz scoring. In agreement with many previous studies, maternal stature and body weight stood out as important influences on the outcome of pregnancy in this series. Overall, the nutritional state of the mother prior to pregnancy is the most important determinant of birth weight.     

Neonatal Variables,Altitude of Residence and Aymara Ancestry in Northern Chile

Studies performed in the Andean plateau, one of the highest inhabited areas in the world, have reported that reduced availability of oxygen is associated to fetal growth retardation and lower birth weight, which are established predictors of morbidity and mortality during the first year of life. To test this hypothesis, perinatal variables of neonates born at the Juan Noé Hospital of Arica, Chile, were analyzed in relation to altitude of residence and Aymara ancestry of their mothers. The study population comprised the offspring of 5,295 mothers born between February 2004 and August 2010. Information included birth weight, height, head circumference, gestational age, altitude of residence and socioeconomic status, and was obtained from medical records. Mother´s ancestry was assessed based on surnames which were linked to percentages of Aymara admixture estimates relying on 40 selected ancestry informative markers. After correcting for the effect of multicollinearity among predictor variables, neonates born to mothers with an increased component of Aymara ancestry showed significantly higher birth weight and height at sea level, a marginally significant (p-value 0.06) decrease of birth weight and a significant decrease of height with altitude in comparison with the offspring of mothers with low Aymara ancestry. Since observed tendencies are suggestive of a possible genetic adaptation to hypoxia of the Chilean Aymara, we discuss briefly preliminary evidence related to fetal oxygen transport, particularly polymorphisms in the promoters of the HBG1 and HBG2 genes that are modulators of HbF synthesis, obtained in this ethnic group.     

Effects of sow nutrition during gestation on within-litter birth weight variation: a review

The increasing demand for efficiency in pork production requires great specialization of all sectors involved in this activity. In this context, the development of strategies that could reduce undesirable traits related with negative effects on piglet survival and postnatal growth and development are essential for the pig industry. Currently, special attention is given to variation in birth weight, as some evidences suggest an increased within-litter birth weight variation in modern sows. This variation has been shown to be associated with preweaning mortality, variable weights at weaning and deteriorated growth performance, which results in economic losses and lower efficiency. Therefore, understanding the factors that can influence the events that occur during gestation and that have an impact on the fetal growth and development are important to achieve better efficiency and also to develop strategies that can be used to achieve increased within-litter uniformity of piglet birth weight. This study concludes that even at a given placental size, fetal growth may vary because of differences in placental vascularization and efficiency. Feeding extra feed or energy during late gestation only marginally improves birth weight, and positive effects are not consistent between different studies. The detrimental effects of protein restriction on fetal growth during early gestation may be due to altered placental and endometrial angiogenesis and growth, which leads to a reduction in placental-fetal blood flow, nutrient supply from mother to the fetuses and ultimately to fetal growth retardation. The number of studies that attempted to influence within-litter birth weight variation by means of sow nutrition during gestation is limited. Therefore, more research concerning sow nutrition during gestation associated with the provision of balanced diets to meet requirements of the sows and fetuses are still required. This knowledge may subsequently provide starting points for the design of nutritional strategies that can influence within-litter birth variation.     

Polymorphism in maternal LRP8 gene is associated with fetal growth

Fetal growth restriction (FGR) affects >200,000 pregnancies in the United States annually and is associated with increased perinatal mortality and morbidity, as well as poorer long-term health for infants with FGR compared with infants without FGR. FGR appears to be a complex trait, but the role of genetic factors in the development of FGR is largely unknown. We conducted a candidate-gene association study of birth weight and FGR in two independent study samples obtained at the Boston Medical Center. We first investigated the association between maternal genotypes of 68 single-nucleotide polymorphisms (SNPs) from 41 candidate genes and fetal growth in a sample of 204 black women selected for a previous study of preeclampsia, 92 of whom had preeclampsia (characterized by high blood pressure and the presence of protein in the urine). We found significant association between SNP rs2297660 in the LRP8 gene and birth weight. Subsequently, we replicated the association in a larger independent sample of 1,094 black women; similar association between LRP8 and FGR was observed in this sample. The "A" allele at rs2297660 was associated with a higher standardized birth weight and a lower risk of FGR. Under the additive genetic model, each additional copy of the "A" allele reduced the risk of FGR by 33% (P<.05). In conclusion, results from the two independent samples of black women provide consistent evidence that SNP rs2297660 in LRP8 is associated with fetal growth.     

Genetics and caging type affect birth weight in captive pigtailed macaques (Macaca nemestrina)

The heritability of birth weight was estimated in 3,562 captive pigtailed macaques using 30 years of breeding and pedigree records. Based on a pedigree of over 12,000 animals, quantitative genetic analyses were performed using statistical variance decomposition methods. The model included additive genetic effects, cytoplasmic genetic effects, birth environment, shared maternal environment, and unmeasured environmental effects. The results demonstrated a strong (h(2) = 0.51) heritable component of birth weight overall, and included significant additive genetic heritability (h(2) = 0.23), and cytoplasmic heritability (h(2) = 0.09). In addition, a significant effect of birth location and cage type was identified, explaining an additional 6% of birth weight variance. The use of a nonhuman primate model for studying the effects of genes on birth weight eliminated many of the problems associated with confounding variables in human studies, and allowed for the quantification of a heritable component of birth weight.     

Genome Wide Screening of Candidate Genes for Improving Piglet Birth Weight Using High and Low Estimated Breeding Value Populations

Birth weight is an economically important trait in pig production because it directly impacts piglet growth and survival rate. In the present study, we performed a genome wide survey of candidate genes and pathways associated with individual birth weight (IBW) using the Illumina PorcineSNP60 BeadChip on 24 high (HEBV) and 24 low estimated breeding value (LEBV) animals. These animals were selected from a reference population of 522 individuals produced by three sires and six dam lines, which were crossbreds with multiple breeds. After quality-control, 43,257 SNPs (single nucleotide polymorphisms), including 42,243 autosomal SNPs and 1,014 SNPs on chromosome X, were used in the data analysis. A total of 27 differentially selected regions (DSRs), including 1 on Sus scrofa chromosome 1 (SSC1), 1 on SSC4, 2 on SSC5, 4 on SSC6, 2 on SSC7, 5 on SSC8, 3 on SSC9, 1 on SSC14, 3 on SSC18, and 5 on SSCX, were identified to show the genome wide separations between the HEBV and LEBV groups for IBW in piglets. A DSR with the most number of significant SNPs (including 7 top 0.1% and 31 top 5% SNPs) was located on SSC6, while another DSR with the largest genetic differences in F_ST was found on SSC18. These regions harbor known functionally important genes involved in growth and development, such as TNFRSF9 (tumor necrosis factor receptor superfamily member 9), CA6 (carbonic anhydrase VI) and MDFIC (MyoD family inhibitor domain containing). A DSR rich in imprinting genes appeared on SSC9, which included PEG10 (paternally expressed 10), SGCE (sarcoglycan, epsilon), PPP1R9A (protein phosphatase 1, regulatory subunit 9A) and ASB4 (ankyrin repeat and SOCS box containing 4). More importantly, our present study provided evidence to support six quantitative trait loci (QTL) regions for pig birth weight, six QTL regions for average birth weight (ABW) and three QTL regions for litter birth weight (LBW) reported previously by other groups. Furthermore, gene ontology analysis with 183 genes harbored in these 27 DSRs suggested that protein, metal, ion and ATP binding, viral process and innate immune response present important pathways for deciphering their roles in fetal growth or development. Overall, our study provides useful information on candidate genes and pathways for regulating birth weight in piglets, thus improving our understanding of the genetic mechanisms involved in porcine embryonic or fetal development.     

Fetal growth and neurobehavioral outcomes in childhood

Using a sample of sibling pairs from a nationally representative U.S. survey, we examine the effects of the fetal growth rate on a set of neurobehavioral outcomes in childhood measured by parent-reported diagnosed developmental disabilities and behavior problems. Based on models that include mother fixed effects, we find that the fetal growth rate, a marker for the fetal environment, is negatively associated with lifetime diagnosis of developmental delay. We also find that the fetal growth rate is negatively associated with disruptive behaviors among male children. These results suggest that developmental disabilities and problem behaviors may play a role in explaining the well-documented association between birth weight and human capital outcomes measured in adulthood.     

Bivariate linkage confirms genetic contribution to fetal origins of childhood growth and cardiovascular disease risk in Hispanic children

Birth weight has been shown to be associated with obesity and metabolic diseases in adulthood, however, the genetic contribution is still controversial. The objective of this analysis is to explore the genetic contribution to the relationship between birth weight and later risk for obesity and metabolic diseases in Hispanic children. Subjects were 1,030 Hispanic children in the Viva La Familia Study. Phenotypes included body size, body composition, blood pressure, fasting glucose, insulin, lipids, and liver enzymes. Birth weights were obtained from Texas birth certificates. Quantitative genetic analyses were conducted using SOLAR software. Birth weight was highly heritable, as were all other phenotypes. Phenotypically, birth weight was positively correlated to childhood body size parameters. Decomposition of these phenotypic correlations into genetic and environmental components revealed significant genetic correlations, ranging from 0.30 to 0.59. Negative genetic correlations were seen between birth weight and lipids. The genome scan of birth weight mapped to a region near marker D10S537 (LOD = 2.6). The bivariate genome-wide scan of birth weight and childhood weight or total cholesterol, improved the LOD score to 3.09 and 2.85, respectively. Chromosome 10q22 harbors genes influencing both birth weight and childhood body size and cardiovascular disease risk in Hispanic children.     

The effect of maternal and cord-blood vitamin C, vitamin E and lipid peroxide levels on newborn birth weight

Background Newborn birth weight has been shown to significantly correlate with the blood levels of vitamin C. Objective This study was planned to answer the question of why vitamin C levels correlate with birth weight; does such correlation reflect a protective effect of vitamin C on fetal growth, by its antioxidant characteristics or does it correspond to the nutritional status of both the mother and the fetus. We examined the hypothesis that maternal blood levels of vitamin C, but not vitamin E influence newborn birth weight. We determined maternal and newborn blood levels of vitamin C, vitamin E, and lipid peroxides (an index of oxidative insult) and the birth weights of full-term newborns delivered at our hospital. Results Compared with maternal blood levels, newborns have higher levels of vitamin C and lipid peroxides, but lower levels of vitamin E. There was a significant correlation in levels between mothers and their newborns for blood levels of vitamin C (r = 0.82, P < 0.01) and vitamin E (r = 0.61, P < 0.02) but not for lipid peroxides (r = 0.001). This suggests that maternal vitamin C and vitamin E intake can influence fetal vitamin C and vitamin E levels. Linear regression analysis shows a significant positive relationship between newborn birth weight and maternal plasma vitamin C (r = 0.51, P < 0.02). Similarly, there was a modest but significant positive relationship between newborn birth weights and newborn vitamin C levels (r = 0.61, P < 0.05). However, there was no relationship between maternal or fetal vitamin E or lipid peroxides levels and the newborn birth weight. Conclusions This study with a small number of subjects suggests a significant association between newborn birth weight and maternal and newborn plasma vitamin C levels. Lack of relationship between birth weight and vitamin E and lipid peroxides suggest that antioxidant function of vitamin C does not appear to have a major role in the effect of vitamin C on birth weight.     

Genetic and Environmental Influences on the Tracking of Body Size from Birth to Early Adulthood

Objective: This study identified genetic and environmental influences on the tracking of body size from birth to 16 to 18.5 years of age. Research Methods and Procedures: Longitudinal information was collected from a nationally representative sample of Finnish twin adolescents (birth cohorts 1975 to 1979) and their parents through questionnaires mailed when the twins were ages 16 and 18.5 years old. The sample included 702 monozygotic, 724 same‐sex dizygotic, and 762 opposite‐sex dizygotic sets of twins. The measures used were length, weight, ponderal index (kilograms per cubic meters), and gestational age at birth, and height, weight, and body mass index (kilograms per square meters) at 16 to 18.5 years of age. The changes in genetic and environmental influences on body size from birth to early adulthood were analyzed by quantitative genetic modeling. Results: The twins who had a higher weight or ponderal index at birth were taller and heavier in early adulthood, whereas those who were longer at birth were taller, but not heavier, later in life. Adult height was affected more by the birth size than body mass index. In the genetic modeling analyses, the genetic factors accounting for the variation of body size became more apparent with age, and both genetic and environmental influences on stature had a sizable carry‐over effect from birth to late adolescence, whereas for relative weight, the influences were more age‐specific. Discussion: The genetic and environmental architecture of body size changes from birth to adulthood. Even in monozygotic twins who share their genetic background, the initially larger twin tended to remain larger, demonstrating the long‐lasting effects of fetal environment on final body size.