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.
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.
Using a Mendelian randomization approach, Ge Zhang and colleagues examine the causal relationship between maternal height, birth size, and gestational age at birth.
Soon after the birth of a baby, doting parents send messages to friends and relatives or post information on social media sites to let everyone know when their new baby boy or girl was born. They may also post information about how heavy he/she was at birth and his/her length. These pregnancy outcomes, together with gestational age at birth (the length of time that a baby has spent developing in its mother’s womb), affect the baby’s immediate health and survival. Importantly, however, these pregnancy outcomes are also associated with the risk of long-term adverse health outcomes such as obesity, cardiometabolic disorders (heart disease and conditions such as diabetes that affect how the body makes energy from food), and neuropsychiatric conditions (mental disorders attributable to diseases of the nervous system, such as depression). For example, some studies have shown an association between low birth weight and an increased risk of type 2 diabetes later in life.
Why Was This Study Done?
Identification of the environmental and genetic factors that causally influence gestational age, length, and weight at birth would improve our understanding of why these pregnancy outcomes are associated with disease during adulthood and could help in the design of strategies to prevent these diseases. Epidemiological studies (investigations that examine disease patterns in populations) suggest that, compared to tall mothers, short mothers tend to deliver their babies at earlier gestational ages, with lower birth weights and lengths. Epidemiological studies cannot show, however, whether variations in maternal height cause variations in pregnancy outcomes. Other characteristics shared by tall mothers might actually determine the size and gestational age of their offspring (confounding). Here, the researchers use “Mendelian randomization” to assess the causal effect of maternal height on the size and gestational age at birth of babies. Because gene variants are inherited randomly, they are not prone to confounding. So, if maternal height actually affects gestational age and size at birth, genetic variants (instruments) that affect maternal height should be associated with differences in gestational age and size at birth, provided confounding due to the transmission of parental alleles (variant forms of genes; people have two alleles of every gene, one inherited from each parent) is avoided by adjusting for the baby’s genotype.
What Did the Researchers Do and Find?
The researchers used phenotype data (observable characteristics such as maternal height and birth weight of the baby) and single nucleotide polymorphism (SNP; a type of genetic variant) data obtained from 3,486 Nordic mother/baby pairs. Analysis of the phenotype data indicated that maternal height was significantly associated with length, weight, and gestational age at birth (a significant association is unlikely to have arisen by chance). For their Mendelian randomization analysis, the researchers constructed a genetic score based on 697 SNPs known to be associated with adult height. To avoid confounding due to genetic sharing between the mother and baby, they determined which of the height-associated alleles each baby had inherited from its mother and used the nontransmitted haplotype score as a genetic instrument for maternal height (a haplotype is a set of DNA variations that are inherited together). Birth length and weight were significantly associated with both the maternal and paternal transmitted haplotype scores but not with the maternal nontransmitted haplotype score. However, gestational age was significantly but modestly associated with the maternal nontransmitted haplotype score.
What Do These Findings Mean?
The validity of the assumptions that underlie the Mendelian randomization approach and the design of the studies supplying the data for this analysis may affect the accuracy of the findings reported here. Nevertheless, these findings suggest that the observed association between maternal height and fetal growth measurements is mainly determined by the genetics of the baby. That is, differences in maternal height do not cause differences in birth weight or length. Rather, some of the gene variants that the baby inherits from its mother determine both its size and its mother’s height. These findings also provide weak evidence that the association between maternal height and gestational age is causal. Maternal height might, for example, causally influence gestational age by limiting the space available for the baby’s growth before birth. Finally, these findings introduce an extension to the Mendelian randomization approach that can be used to investigate causal associations between parental characteristics and offspring outcomes.
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001865.
The March of Dimes, a not-for-profit organization for pregnancy and baby health, provides information about low birth weight and its consequences
Nemours, a not-for-profit organization for child health, provides information about the weight of newborn babies (in English and Spanish)
Wikipedia has pages on birth weight, gestational age, and Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
MedlinePlus provides information and links to additional resources about birth weight and a brief explanation of gestational age (in English and Spanish)