Nicole McPhersonMale Reproductive Health, University of Adelaide
- University of Adelaide
We thank the authors for their interest in our paper, and their support on the importance of a couple’s-based approach to pre-conception health care. In addition we thank them for the emphasis on the need for future studies to ensure adequate assessment of both partners biological and lifestyle factors when determining associations between parental factors and infant birthweights and child outcomes.
We agree with Yisahak et al. (1) comments that birthweight can be suboptimal at either end of the spectrum, which is why it was originally addressed in the first drafted submission of our manuscript. However due to peer review request we ended up analysing our data using a different statistical design (linear regression) which is currently presented in the published manuscript. The impact of paternal and maternal BMI on infant birthweight at either end of the spectrum was originally assessed using quantile regressions, adjusting for baby sex (male or female), gestational age, delivery method (caesarean or vaginal), transfer method (IVF or ICSI), maternal age, paternal age, and parental SEIFA score. Non-linear associations using restricted cubic splines were included for gestational age and maternal BMI. An interaction between the maternal and paternal BMI factors (both as linear) was also included. Associations with the 5th and 10th birthweight percentiles were estimated to assess small for gestational age (SGA) and associations with 90th and 95th for large for gestational age (LGA) outcomes, and contrasted against associations with median birthweights. Figure 1 presents the data from this original statistical analysis. In this model, maternal weight was associated with increased risk of extreme LGA (95th percentile: β=25.1, 95%CI=[5.07, 45.1], p=0.01), while there was no detectable effect of increasing paternal BMI on LGA or extreme LGA. In the 5th and 10th percentile regressions there was a strong non-linear association between maternal BMI and infant birthweight (p=0.002 and p=0.03). Infant birthweight decreased with maternal BMI below 25kg/m2 indicating increased risk of SGA, while for maternal BMI in the obese range (>30kg/m2), the 5th percentile of infant birthweight plateaued, indicating a greater divergence from the median infant weight which continued to increase. Again we found no effect of paternal BMI on risk of SGA infants in this cohort. These, results mirror what was found in our mean infant birthweight data, with maternal overweight/obesity having an increased risk of extreme infant LGA and SGA for maternal weight extremes. The attenuation due to paternal overweight/obesity was similar in both median and mean regressions, but not for the SGA and LGA quantile regressions, albeit it is likely that there was low power to detect interactions at extremes. However we believe that these data, further highlight the impact of the female and male genetic and epigenetic contributions to fetal growth, which has been previously reported (2, 3).
We also agree with the authors that future work needs to be done to determine how the individual contributions of mothers and fathers at conception are both independently and synergistically working together to control the growth and development of offspring and how lifestyle/biological factors contribute to or change this growth trajectory. Further, understanding how in the in-utero (including gestational weight gain/nutrition) and post-natal environments (i.e. nutrition) including offspring sex interplay with this process to either reverse or enhance childhood growth and chronic disease risk is of importance. Without this information the establishment of evidenced based clinical guidelines and effective interventions will be limited.
- Yisahak, S.F and Mumford, S.L. Association of parental obesity with infant birthweight: weighing the evidence. (2021). Fertility and Sterility Reports
- Rice, F and Thapar, A. Estimating the relative contributions of maternal genetic, paternal genetic and intrauterine factors to offspring birth weight and head circumference. (2010). Early Hum Dev Jul;86(7):425-32
- Juliusdottir, T. et al. Distinction between the effects of parental and fetal genomes on fetal growth. (2021) Nat. Genet. 53, pages 1135–1142
Figure 1: Joint association of parental BMI on infant birthweight. Box link: https://universityofadelaide.box.com/s/w6yv1vbnla4ayxndlv4bnlq6d9y07j88
The effect of the interaction is illustrated by varying maternal (A & B) and paternal BMI (C & D) with the other parental BMI set at 20 and 35 kg/m2 respectively. Grey circles are observed birth weights. Solid red lines are the median model estimates, dashed lines are 10th and 90th percentiles and dotted lines are the 5th and 95th percentile models. 95% confidence intervals (blue bars) are presented for parental BMIs of 20 kg/m2, 27.5 kg/m2 and 35 kg/m2. These estimates are for IVF insemination, vaginal births and female babies and have other continuous covariates set at their median values.