Early Determinants of Child Health

There has been long-standing concern, from couples and health care providers, that children conceived using fertility treatment grow and develop differently than children not conceived by these technologies. Some of the concern stems from observations that children conceived by assisted reproductive technologies (ART) have lower birthweight and gestational age (even after accounting for multiples), known risk factors for many later health outcomes. The increased risk that these perinatal outcomes confer for heart disease, along with elevated blood pressure, has been particularly consistent across different populations. Mechanisms specific to ART include the potential for epigenetic changes during the implementation of these technologies, including culture media. Using the Upstate KIDS cohort, we previously evaluated the long-term cardio-metabolic risk of children conceived by fertility treatment, both by ART and by fertility drugs, finding no differences [Yeung et al. Fertil Steril 2022;121:793].

Nevertheless, conflicting evidence regarding blood pressure elevations arose from different studies, and our evaluation had been from one specific cohort. Hence, we undertook a systematic review and meta-analysis, which included thousands of children from studies worldwide [Reference 1]. Meta-analyzing unadjusted results from 34 reports, we observed no differences in systolic or diastolic blood pressure among children conceived by ART (N = 5,229) compared with those not conceived by ART (N = 8,509, reference). Meta-analysis of results that were adjusted for covariates (for instance maternal age and body-mass index) were similar. In subgroup analyses type of treatment (IVF vs. ICSI), birth year, age of the children at blood pressure measurement, and the like, did not change the results. This quantitative study presents the most comprehensive evidence to date on the topic and reassurance that there is no evidence for vascular “reprogramming” on account of these technologies. The review also summarized the few studies that have been published on other types of fertility treatment (e.g., by ovulation-induction drugs or injections), and some studies indicating that parental subfertility is more directly related to offspring blood pressure in childhood.

In collaboration with international researchers in the Pregnancy And Childhood Epigenetics (PACE) consortium, we led an examination of the association between parental age at delivery on newborn and childhood DNA methylation [Reference 2]. Evidence suggests that older parental age (among males and females) is associated with adverse offspring outcomes. While epigenetics is a suspected mechanism, few studies have examined DNA methylation. Our study analyzed data from blood samples of over 9,500 newborns and 2,200 children. Maternal age was associated with newborn DNA methylation at 33 sites, the most prominent of which was located in/near MTNR1B (encoding a melatonin receptor). Associations were also found with RTEL1-TNFRSF6B, which is involved in maintaining telomere length (RTEL1), and inflammatory processes through a tumor necrosis factor receptor (TNFRSF6B). Evidence suggested that these differences in blood DNA methylation persist when children were older (5–10 years). There were, however, no associations with paternal age at delivery. The association with parental age is next being interrogated, as part of the consortium, using placental samples. We also contributed to other PACE investigations, including prenatal exposures related to smoking, vitamin D, shift work, and others. These studies point to possible pathways to interrogate further and in which to intervene.

Place-based social determinants of health are environmental factors in the places people inhabit and that have the potential to impact their development, health, and well-being. Examples of place-based social determinants include neighborhood resources such as access to quality education, healthy food, air quality, and safe play spaces. We leveraged the large, longitudinal Upstate KIDS Study to assess the impact of place-based social determinants of health on various child outcomes using the Child Opportunity Index 2.0 (COI), a national, place-based measure of social determinants of healthy child development. The COI includes 11 education indicators covering high quality preschools through post-secondary enrollment, 10 health and environment indicators assessing healthy environments, toxic exposures, health insurance coverage, and eight social and economic indicators such as adult employment, poverty and income, public assistance rate, and single-headed households. The COI is scored from 1 to 100 on a national level and can also be categorized into quintiles from very low to very high.

In one study using the COI as the exposure in the Upstate KIDS cohort, after adjusting for family-level confounding variables, for each ten-point increase in the COI at birth, children had a slightly lower odds of a developmental delay on a developmental screening instrument from age 4–36 months. A subsample of children tested at age 4 also had better scores on selected subscales of a developmental test with increasing COI scores [Reference 3]. Two other Upstate KIDS Studies explored associations between the COI measured in quintile groups and child-health outcomes. In the first study, compared with children in very high COI tracts, children who lived in very low, low, and moderate COI tracts at birth had lower odds of attending well-child visits from 4–36 months [Reference 4]. In the second study, children who lived in very high COI tracts at birth had lower odds of experiencing recurrent episodes of wheezing from 4–36 months than did children who lived in moderate COI census tracts. Furthermore, children who moved into census tracts with a lower COI quintile by age 3 were more likely to be diagnosed with asthma by a physician from 18–36 months, even when adjusting for covariates such as child sex and parental asthma, but the association attenuated when additionally adjusting for medical insurance status [Reference 5].

We continued to recruit couples into the Study of Pregnancy and Neonatal Health (SPAN) at four study sites, in order to investigate paternal contributions to the developmental origins of health and disease. While much research has been devoted to maternal exposures, information on paternal factors is greatly lacking, despite evidence of potential epigenetic pathways in animal models. Data collected will uniquely answer important questions about how paternal obesity and other cardio-metabolic risk factors affect the fetal growth, placental factors, and neonatal outcomes.