text: WHITE PLAINS, N.Y., Aug. 18, 2015 - Shorter mothers have shorter pregnancies, smaller babies, and higher risk for a preterm birth. New research has found that a mother's height directly influences her risk for preterm birth. 
   
   Investigators at the March of Dimes Prematurity Research Center Ohio Collaborative looked at 3,485 Nordic women and their babies, and found that maternal height, which is determined by genetic factors, helped shape the fetal environment, influencing the length of pregnancy and frequency of prematurity. In contrast, birth length and birth weight are mainly influenced by transmitted genes. Preterm birth is the number one killer of newborns in the United States and serious gaps exist between racial and ethnic groups. 
   
   More than 450,000 babies are born too soon in the U.S. and the national preterm birth rate is worse than many other high-resource countries, the March of Dimes says. Worldwide, 15 million babies are born preterm, and more than one million die due to complications of an early birth. Babies who survive an early birth face serious and lifelong health problems, including breathing problems, jaundice, vision loss, cerebral palsy and intellectual delays. 
   
   "A major goal of the nationwide network of March of Dimes prematurity research centers is identifying genes that govern fetal growth and length of pregnancy. That a woman's height influences gestational length, independent of the genes she passes on that determine fetal size, is a major finding by our research networks, and the first of what we expect to be many genetic contributions," said Joe Leigh Simpson, MD, March of Dimes senior vice president for Research and Global Programs. 
   
   "The innovative, team-based model of our prematurity research centers is critical to understanding the unknown causes or preterm birth. This new finding adds one small piece toward solving the much larger puzzle of preterm birth," says Dr. Jennifer L. Howse, president of the March of Dimes. 
   
   The March of Dimes is raising $75 million to support its five prematurity research centers. These unique, transdisciplinary centers bring together the brightest minds from many diverse disciplines -- geneticists, molecular biologists, epidemiologists, engineers, computer scientists, and others -- to work together to find answers to prevent premature birth. In addition to the Ohio Collaborative, the March of Dimes has established research centers at Stanford University School of Medicine in California, at the University of Pennsylvania, at Washington University in St. Louis, and at the University of Chicago, Northwestern University and Duke University. 
   
   "Our finding shows that a mother's height has a direct impact on how long her pregnancy lasts," said Louis Muglia, MD, PhD, the primary investigator of the Ohio Collaborative, and co-director of the Perinatal Institute at Cincinnati Children's Hospital Medical Center. "The explanation for why this happens is unclear but could depend not only on unknown genes but also on woman's lifetime of nutrition and her environment." 
   
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   The research paper, "Assessing the Causal Relationship of Maternal Height on Birth Size and Gestational Age at Birth: A Mendelian Randomization Analysis," was published online Aug. 18 by PLoS Medicine. 
   
   The March of Dimes works to improve the health of babies by preventing birth defects, premature birth and infant mortality. The March of Dimes is the leading nonprofit organization for pregnancy and baby health. For the latest resources and information, visit marchofdimes.org or nacersano.org. Visit prematurityresearch.org for more information about the research centers. Find us on Facebook and Twitter. ||||| Summary of Major Findings 
   
   While the extremes of birth size, particularly birth weight, and gestational age at birth are important global contributors to infant mortality, more modest deviations in these parameters have been repeatedly linked to risk for adult disorders such as type 2 diabetes mellitus, hypertension, and cardiovascular disease [58–60]. Thus, understanding the determinants of fetal growth and the duration of pregnancy are essential to improve both newborn and later-in-life health. Epidemiological evidence has suggested that these birth outcomes are shaped by intrauterine environment, but the relative contribution of maternal genetic, fetal genetic, and nongenetic factors that may drive epigenetic physiological adaptations remains incompletely understood. Moreover, should fetal genetics shape these outcomes, their direct involvement in the risk for the adult diseases, as well, is an intriguing possibility. Recently, to better understand normal fetal growth in healthy pregnancy, a multinational longitudinal assessment has been reported [61]. These data demonstrate similar average growth profiles across geographic populations but do not define the mechanisms for variability within a given population. 
   
   In this study, we observed the consistent associations between maternal height and birth length, birth weight, and gestational age in each of the three study cohorts. The estimated effect sizes of the observed associations were respectively ~0.05 cm/cm for birth length, ~10 g/cm for birth weight, and ~0.34 d/cm for gestational age per 1 cm change in maternal height, which are in the same range as previous reports for fetal growth [20] and gestational age [15]. We then disentangled causal relationships underlying these observational associations. 
   
   Based on an extensive list of height-associated SNPs (n = 697) reported by a recent large GWA meta-analysis [40], we constructed a height genetic score as a powerful genetic instrument for maternal height. In our study samples, the genotype-based genetic score explained a substantial fraction (~20%) of variance in maternal height. This percentage was even larger than that (~16%) reported in the original study [40], which is likely due to the homogeneity of our samples (i.e., all females with northern European origin and a more restricted age distribution). Our previous studies have shown that the height genetic score explained larger variance in females than males [62,63]. 
   
   We observed significant associations of maternal height genetic score with birth length, with birth weight, and, to a lesser extent, with gestational age. As the genetic score captures the genetic variation in maternal height, these significant associations suggested either direct causal influence (Fig 1A) of maternal height or fetal genetic effect (Fig 1C) rather than confounding effects (Fig 1B), although the latter mechanism could not be excluded. It should be emphasized that maternal genetic score is not a valid instrument for maternal height, unless adjusted for fetal genotype; thus, it cannot be used to differentiate the causal effect of maternal height (Fig 1A) from fetal genetic effect (Fig 1C). 
   
   We further probed the causal impacts of maternal height using genetic instruments either based on maternal genetic score without or with adjustment for fetal genetic score (method 1 and 2) and maternal nontransmitted haplotype score (method 3). The results strongly suggested that the observed correlations between maternal height and birth length or birth weight were mainly due to fetal genetic effects but not due to nongenetic intrauterine effect (i.e., maternal height as an environmental factor that casually influences fetal growth). Multiple lines of evidence consistently supported this conclusion. 
   
   First, we observed significant association of fetal genetic score with birth length and birth weight, and after controlling for fetal genetic score, the associations between maternal genetic score with birth length and weight were no longer significant, which suggests substantial fetal genetic influence. This observation was in line with previous studies, which showed that the magnitudes of associations between paternal height with either birth length or birth weight were comparable to maternal height [20,21,64]. Genetic analyses of parent-offspring data [6,11] also suggested fetal genetics explain more variation in birth size. 
   
   Second, our haplotype-based genetic score analysis showed that both maternal transmitted genetic score and paternal transmitted genetic score were highly significantly associated with birth length and birth weight, but the nontransmitted score was not (particularly for birth weight), which again indicated that maternal height has relatively minimal effect on birth length or birth weight if not transmitted genetically. The nontransmitted score was marginally associated with birth length, which suggests some direct causal effect of maternal height on birth length, and the estimated causal effect size was similar to the observational effect (~0.05 cm change in birth length per 1 cm change in maternal height). 
   
   Thirdly, our single marker analysis indicated that those adult height-associated SNPs were excessively associated with birth length and birth weight in fetus, but the estimated effect sizes of these SNPs on birth length and birth weight were not well correlated with their effect on maternal height, which indicated direct but different functional effects of these SNPs on fetal growth rather than a common causal effect mediated through maternal height. The inference of the parental transmission in mother-child pairs also allows us to examine parent-of-origin effects of those height-associated SNPs on birth length and weight. Our results showed excessive differences between the maternal and paternal transmitted alleles. For birth weight, the effect sizes of the maternal transmitted alleles were generally larger than paternal transmitted ones. 
   
   We also performed the analysis using gestation-adjusted birthweight percentiles (converted to z-scores) as the outcome and obtained similar results (S8 Table). This evidence collectively suggests that birth weight and birth length are mainly defined by fetal genetics. Therefore, it is difficult to define abnormality of fetal growth in a general term (e.g., by deviation from population mean) without taking genetic variance into account. It should be noted that the samples of the current study were collected from high-resource northern European countries, with presumably good nutrition throughout childhood, adolescence, and pregnancy, enabling the mothers and their infants to grow to their full genetic potential. This fact might account for why we observed a predominant influence of genetic factors on birth size in this study. The conclusion may not be directly transferrable to low- or middle-income countries, where malnutrition may substantially constrain one’s growth and significantly change the association between maternal height and fetal growth [24,25]. 
   
   In contrast with the findings in birth length and birth weight, we observed evidence that suggested gestational age at birth might be causally influenced by maternal height, in which case maternal height might operate as an important factor that shapes the intrauterine environment and influence the gestational age. Again, this conclusion was supported by multiple lines of evidence: (i) gestational age was (marginally) associated with maternal height genetic score but not with fetal height genetic score, and after adjustment for fetal genetics, the association between gestational age and maternal height genetic score were still significant; (ii) gestational age was associated with maternal nontransmitted haplotype genetic score, which indicated the effect of maternal height on gestational age was transmitted through phenotypic causal mechanism rather than genetic inheritance (i.e., transmission of alleles); (iii) the estimated causal effect of 0.4 d/cm of maternal height on gestational age was similar to the size from observational association; and (iv) single-marker analysis indicated that those adult height SNPs were excessively associated with gestational age, and the estimated effect sizes of these SNPs (in mothers) on gestational age, although relatively low, were correlated with their effect on maternal height, which suggested the effect of these SNPs is projected through a common intermediate (i.e., maternal height) rather than through SNP-specific pathways (biological pleiotropy). 
   
   We also performed analysis using preterm status as a dichotomous outcome, and the results (S9 Table) indicated that shorter maternal height is a risk factor for preterm birth (observational association p = 3.77 × 10−6, with an estimated 3% increase in risk if the mothers are 1 cm shorter). This result was consistent with a recent epidemiology study [18]. Genetic score analysis also showed significant association between preterm birth risk and the nontransmitted haplotype score (p = 0.0456), which suggests that maternal height causally influences preterm birth risk. 
   
   We recognize that the association between maternal non-transmitted haplotype score and gestational age was only modestly significant (meta p = 0.0424), and it was mainly driven by the DNBC cohort (p = 0.018) and was not significant in the other two cohorts. Also, gestational age in the DNBC cohort was estimated by combining information from self-reported data and gestational age reported in birth registry, while it was estimated by ultrasound in the other two cohorts. However, our meta-analysis did not reveal any sign of inconsistency—the confidence intervals of the estimates from different cohorts overlap and the p-value for the heterogeneity test was not significant. Nevertheless, the error-free validity of this association needs to be confirmed by further replication studies in independent cohorts.
target: – The height and weight of a newborn baby is largely governed by his or her own genes, but it's the height of the mother that's giving researchers a telltale sign, reports the Telegraph. Specifically, shorter women have shorter pregnancies and thus more premature babies, report investigators at the March of Dimes Prematurity Research Center Ohio Collaborative in the journal PLOS Medicine. The team analyzed 3,485 Nordic women and their babies, and found that a woman's height actually shapes the fetal environment, thereby influencing the length of her pregnancy. This has broad health implications around the world, where 15 million babies are born prematurely every year and more than 1 million of them die due to complications of early birth—which include breathing problems, vision loss, and intellectual delays, report researchers in a press release. "That a woman's height influences gestational length, independent of the genes she passes on that determine fetal size, is a major finding by our research networks, and the first of what we expect to be many genetic contributions," one researcher says. (Premature birth is now the world's top killer of children under 5.)