The effect of maternal and paternal height and weight on antenatal, perinatal and postnatal morphology in sex‐stratified analyses

Low birthweight is associated with diseases later in life. The mechanisms for these associations are not well known. If the hypothesis concerning “maternal constraint” is correct for humans, as shown in animal experiments, we expect the maternal, not paternal, body proportions to influence antenatal growth and those of both parents to influence postnatal growth. We aimed to study the effect of maternal and paternal height and weight on fetal femur length antenatally (gestational weeks 20 and 30) and body length and weight at birth and postnatally (12 and 24 months old) in both sexes.


| INTRODUC TI ON
Poor fetal growth with subsequent low birthweight is reported to be associated with an increased risk for diseases later in life, including cardiovascular disease, diabetes mellitus, reduced bone mass and hip fractures. 1,2 The variation in fetal dimensions has a large genetic component, although environmental factors also contribute to this variation. 3 The mechanisms for these associations are not well known, but increasing the understanding of the determinants for the patterns of intrauterine growth and development may contribute to the optimization of health in adulthood.
Maternal constraint of fetal growth is considered to be the major non-genetic factor determining the size of the fetus at term, especially in young mothers, small mothers, nullipara mothers and mothers with multiple pregnancies. [4][5][6][7] Reference is made to "processes by which maternal and uteroplacental factors act to limit the growth of the fetus, presumably by limiting nutrient availability and/or the metabolic-hormonal drive to grow", 5 to enhance the mother's ability to deliver her offspring successfully and ensure her own survival. 6 Both genetic and epigenetic maternal factors expressed in the placenta may contribute to limiting fetal growth. 5 This may have long-term consequences because increasing evidence suggests that poor fetal growth resulting from maternal constraint may lead to increased risk of chronic diseases in adulthood. 1,2 There is no doubt that maternal body proportions influence fetal growth. The paternal role is less clear, as there is little data on how the paternal body proportions influence fetal growth. 8 The paternal body proportions are associated with the offspring's birthweight. [9][10][11] Although maternal weight had a greater impact on birthweight than paternal weight, this finding suggested that paternal genetic factors still influence birthweight independently of maternal factors. 10 Others have reported that paternal height had an effect on the offspring's birthweight, whereas the paternal body mass index (BMI) did not. 12 They demonstrated maternal constraint by showing that the father's height had a small effect on birthweight if the mother was short. 12 Maternal and paternal height and weight contribute similarly to postnatal weight gain. 10 The aims of this study were to determine the effect of maternal and paternal height and weight on fetal femur length (FL) in the antenatal period (gestational weeks 20 and 30) and the body length and weight at birth and in the postnatal period (12 and 24 months old) in girls and boys. We investigated a cohort from the general population in Australia with mainly Caucasian participants. We hypothesized that (1) fetal FL and neonatal length and weight are more strongly associated with maternal body proportions than paternal body proportions in both sexes due to maternal constraint and that (2) postnatal length and weight are associated similarly with maternal and paternal height and weight in both sexes after release from maternal constraint.

| Design and population
In this prospective cohort study, 399 healthy pregnant women aged

| Variables
Gestation was determined based on the last menstrual period un- HDI-5000 or a GE Voluson HDI-3000 ultrasound machine. We excluded fetuses who had major malformations detected by ultrasound scan and newborns who were delivered preterm before gestational week 37. A questionnaire about maternal lifestyle, such as current smoking and alcohol use, parity, and country of birth, to classify the mothers' ethnicity, was distributed. Of the 370 women who completed the questionnaires, 279 (75.4%) women reported that they were Caucasians, while 24.6% were of different multiethnic origins, mainly from Asian countries.
Following birth (1-7 days of age) and at 12 and 24 months of age, crown-heel length and weight were measured by 2 trained researchers. Crown-heel length was measured to the nearest 0.1 cm using a length board (Ellard Instrumentation Ltd, Seattle, WA, USA), and weight was measured on regularly calibrated scales. Parental height was measured to the nearest 0.1 cm using a Holtain stadiometer fixed on the wall, and weight was measured to the nearest 0.1 kg using an electronic scale while wearing light clothing without shoes at gestational week 30.

| Statistical analyses
All variables were checked for normality by visual inspection of the histograms. Royston models were fitted to the fetal and infant growth measurements to create z-scores for the size measurements during growth. 13 Linear regression models were used to explore the relation between parental height and weight (exposures) with offspring antenatal HC, AC, FL and EFW and postnatal length and weight z-scores (outcomes) in the sex-stratified analysis. Standardized regression coefficients were used to facilitate the comparison of the strength of the associations between the exposures and outcomes per standard deviation (SD) unit.
The univariate models included the maternal and paternal heights and weights alone. In multivariable models, parental height and weight, maternal age, smoking (no vs yes), alcohol intake during gestation (no vs yes), primipara (no vs yes), Caucasian ethnicity (no vs yes) and paternal age were considered as covariates. The P-value for entering covariates was P < 0.25 and that for deleting covariates was P > 0.10. The P < 0.05 was considered significant in the final model. 14 SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA) was used for data analyses.

| Ethical approval
All participants gave written informed consent. Mercy Health & Aged Care Human Research Ethics Committee approved the study (Project number R08/14).

| RE SULTS
The characteristics of the participants are shown in Table 1. The mean ± SD maternal height and weight were 164.3 ± 6.7 cm and 76.9 ± 15.5 kg, and the paternal height and weight were 177.7 ± 7.2 cm and 86.9 ± 14.1 kg, respectively. The male fetuses had larger HC and AC than the females at gestational week 20 and larger HC at gestational week 30. FL and EFW did not differ between female and male fetuses at gestational weeks 20 and 30. The boys were 0.8, 2.1 and 1.8 cm longer than the girls at birth and 12 and 24 months after birth and 0.11, 0.86 and 0.93 kg heavier than girls at birth and 12 and 24 months after birth, respectively.
In both sexes, maternal, not paternal, body proportions were associated with fetal FL (Table 2) Paternal height was associated with larger AC and EFW at gestational week 30 in female fetuses.
In girls, only paternal height was associated with birth length and with weight and length at 12 months (Table 3) All results from the above-mentioned multivariable linear regression analysis were mutually adjusted for parental height and weight and adjusted for maternal age, smoking, alcohol intake during gestation, parity, ethnicity and paternal age, and all P values were < 0.05.

| D ISCUSS I ON
We reported that maternal, not paternal, body proportions predicted antenatal growth of FL. Only paternal height predicted the birth length in girls, and only maternal height predicted the birth length in boys, both of which were independent of the other parental body proportions and potential confounders. The same pattern was found for body weight and length in girls at 12 months and body weight in boys at 12 months after birth. The body proportions of both parents influenced the body weight and length of the offspring at 24 months after birth in both sexes.
First, we confirmed that paternal height and weight were not associated with the antenatal growth measurement of fetal FL. This is in agreement with our previous report that paternal FL and kneeheel length were not associated with the corresponding fetal traits. 8 We found that maternal weight was the main independent predictor of fetal FL in both female and male fetuses, which is in agreement with the previous finding that the maternal FL and knee-heel length are associated with the corresponding fetal traits. 8 The reasons for the clear association between maternal traits and antenatal growth are probably a combination of genetic, epigenetic and environmental factors. 5 TA B L E 1 Characteristics of mothers, fathers and offspring during gestation and after birth Second, in this current study, maternal traits had the most important effect on birthweight in both sexes, which fits with the theories of maternal constraint 5 and the results of a previous report. 9 However, we did not expect to discover that paternal height predicted birth length in girls independently of maternal height, and there was no independent effect of maternal height itself on the birth length of girls. In contrast, maternal height predicted birth length in boys independently of paternal height, and there was no independent effect of paternal height itself on the birth length of boys. We do not know the reasons for these findings. We speculate that as boys have a tendency to grow faster and become larger than girls, they may need to be more "constrained" by the mother for her own survival. [15][16][17] Paternal height has been reported to be more strongly associated with bone mineral density in newborn girls than in boys, and this effect was also independent of maternal influence. 18 Male mice were reported to be more adversely affected than female mice after experiencing fetal growth restrictions by bilateral uterine vessel ligation. 19 The growth-restricted fetuses had a low birthweight for gestational age, a low cortical bone mass during early postnatal life, and low bone bending strength that remained low at 6 months of age, which may lead to a predisposition for fractures later in life. 19 The mouse model findings suggest a sex-specific programming of the outcomes, as the deficits were corrected by postnatal nutrition for females born small, but not for males. 19 Results from other studies differ from our findings. [20][21][22][23][24][25] In a retrospective multicenter study, paternal and maternal height and maternal weight were associated with fetal HC, AC and FL. 20,21 In the Intergrowth-21st study, fathers of infants born large-for-gestational-age were taller and heavier but they had similar BMI. 22 Paternal height predicted large-for-gestational-age in boys and girls, but paternal BMI was not associated with greater odds ratio

0.339
Note: Numbers are standardized beta coefficients (β) with 95% CI in a unadjusted and b multivariable linear regression models including maternal and paternal heights and weights, maternal age, primipara (no vs yes), Caucasian ethnicity (no vs yes), smoking (no vs yes) alcohol intake (no vs yes) and paternal age. We used P value < 0.25 for entering variables and P value > 0.10 for deleting variables. P < 0.05 was considered significant.

TA B L E 2 (Continued)
TA B L E 3 The effect of parental height and weight on neonatal birth length, and the birthweight z-scores and body length and weight zscores of the infants at 12 and 24 months of age Maternal-child BMI association has been reported to be stronger than paternal-child BMI at birth, 1 year and 7 years in both girls and boys. 24 Similar associations between maternal-child BMI and paternal-child BMI at 3 years have been reported; 25 and as others, 26 they questioned the contribution by the intrauterine environment and suggested that prevention of childhood adiposity will benefit more from postnatal than prenatal intervention. 25 The role of ethnicity is not clear, as a small effect on fetal biometry is reported in some studies, 20,21 the large Intergrowth-21st study found no effect of ethnicity after adjustment for socioeconomic confounders, 27 which supports the Barker hypothesis. 1,2 There is some disagreement about the mechanism behind mater- An alternative explanation for maternal constraint involves imprinted genes and the parent-offspring conflict theory. 15 In studies with mice, several imprinted genes were reported to play an important role in the regulation of fetal growth, and the paternally expressed genes enhanced fetal growth, while the maternally expressed genes suppressed fetal growth. 15 This is linked to the insulin and insulin-like growth factor (IGF) system. IGF-2 is expressed by a paternal gene that enhances fetal growth, whereas the maternally expressed IGF2-receptor is a suppressor of fetal growth. 15 This gives rise to the parent-offspring conflict theory, in which the mother downregulates fetal growth to avoid difficulties during parturition and wishes to reserve resources for future offspring.
On the other hand, the father extracts more resources to maximize fetal growth. Several studies have shown that a large proportion of the imprinted genes that influence fetal growth work in such an antagonistic manner. 29 The evidence is based on the following 6 points for mammalian genomic imprinting: (1)  Third, our findings that both maternal and paternal body proportions predicted the weight and length at 24 months after birth in both sexes are in agreement with a previous report that found a similar contribution of both parents on offspring weight gain after birth. 9,25 The strength of this study is the relatively large sample size and the standardized research setting for obtaining the measurements of both the parents and offspring rather than using self-reported measurements of height and weight. However, the study has some limitations. The best way to assess age in the antenatal period, based on the first day of the last menstrual period, is prone to errors because the interval from menstruation to fertilization varies from 8 to 20 days. 30 The measurement errors may dilute the true associations and lead to an underestimation of the associations, and the results must therefore be interpreted with caution. The lack of information on nutrition and food intake, which may influence postnatal growth, is another limitation. Nutrition is generally good within Australia but there are individual variations in food consumption that are not covered by this study that may affect fetal and newborn growth.

<0.001
Numbers are standardized beta coefficients (β) with 95% CI in a unadjusted and b multivariable linear regression models including maternal and paternal heights and weights, maternal age, primipara (no vs yes), Caucasian ethnicity (no vs yes), smoking (no vs yes), alcohol intake (no vs yes) and paternal age. We used P value < 0.25 for entering variables and P-value > 0.10 for deleting variables. The P value < 0.05 were considered significant. determined birth length in girls, and maternal, not paternal, height determined birth length in boys. These findings of sex-based differences, in which maternal height predicts birth length in boys, and paternal height predicts birth length in girls, need to be confirmed and further explored in other studies. We confirmed that the body proportions of both parents influenced postnatal growth. Growth is multifactorial and we have explored some factors contributing to growth. It will be of clinical interest to clarify the role of the intrauterine environment to better understand the many factors contributing to growth abnormality. Further investigation of prenatal growth and postnatal growth and how growth in these periods may prevent adult diseases is needed.

ACK N OWLED G M ENTS
We thank Professor Susan P. Walker and a team of dedicated research nurses and ancillary staff for their assistance, particularly Nafissa Akhounova at The Mercy Hospital for Women, and Kylie King and Xiaofang Wang at The Austin Health, Melbourne, Australia. We thank Tom Wilsgaard at UiT The Arctic University of Norway, Tromsø, Norway for help with the statistical analysis.

CO N FLI C T O F I NTE R E S T
The authors have stated explicitly that there are no conflicts of interest in connection with this article.