OBJECTIVE:To examine the effect of the bivalent human papillomavirus (HPV) vaccine on miscarriage. DESIGN:Observational long term follow-up of a randomized, double blinded trial combined with an independent unvaccinated population based cohort. SETTING:Single center study in Costa Rica. PARTICIPANTS:7466 women in the trial and 2836 women in the unvaccinated cohort enrolled at the end of the randomized trial and in parallel with the observational trial component. INTERVENTION:Women in the trial were assigned to receive three doses of bivalent HPV vaccine (n=3727) or the control hepatitis A vaccine (n=3739). Crossover bivalent HPV vaccination occurred in the hepatitis A vaccine arm at the end of the trial. Women in the unvaccinated cohort received (n=2836) no vaccination. MAIN OUTCOME MEASURE:Risk of miscarriage, defined by the US Centers for Disease Control and Prevention as fetal loss within 20 weeks of gestation, in pregnancies exposed to bivalent HPV vaccination in less than 90 days and any time from vaccination compared with pregnancies exposed to hepatitis A vaccine and pregnancies in the unvaccinated cohort. RESULTS:Of 3394 pregnancies conceived at any time since bivalent HPV vaccination, 381 pregnancies were conceived less than 90 days from vaccination. Unexposed pregnancies comprised 2507 pregnancies conceived after hepatitis A vaccination and 720 conceived in the unvaccinated cohort. Miscarriages occurred in 451 (13.3%) of all exposed pregnancies, in 50 (13.1%) of the pregnancies conceived less than 90 days from bivalent HPV vaccination, and in 414 (12.8%) of the unexposed pregnancies, of which 316 (12.6%) were in the hepatitis A vaccine group and 98 (13.6%) in the unvaccinated cohort. The relative risk of miscarriage for pregnancies conceived less than 90 days from vaccination compared with all unexposed pregnancies was 1.02 (95% confidence interval 0.78 to 1.34, one sided P=0.436) in unadjusted analyses. Results were similar after adjusting for age at vaccination (relative risk 1.15, one sided P=0.17), age at conception (1.03, P=0.422), and calendar year (1.06, P=0.358), and in stratified analyses. Among pregnancies conceived at any time from bivalent HPV vaccination, exposure was not associated with an increased risk of miscarriage overall or in subgroups, except for miscarriages at weeks 13-20 of gestation (relative risk 1.35, 95% confidence interval 1.02 to 1.77, one sided P=0.017). CONCLUSIONS:There is no evidence that bivalent HPV vaccination affects the risk of miscarriage for pregnancies conceived less than 90 days from vaccination. The increased risk estimate for miscarriages in a subgroup of pregnancies conceived any time after vaccination may be an artifact of a thorough set of sensitivity analyses, but since a genuine association cannot totally be ruled out, this signal should nevertheless be explored further in existing and future studies.Trial registration Clinicaltrials.gov NCT00128661 and NCT01086709.

Background

Phthalate exposures are ubiquitous during pregnancy and may contribute to racial and ethnic disparities in preterm birth.

Objectives

We investigated race and ethnicity in the relationship between biomarkers of phthalate exposure and preterm birth by examining: a) how hypothetical reductions in racial and ethnic disparities in phthalate metabolites might reduce the probability of preterm birth; and b) exposure-response models stratified by race and ethnicity.

Methods

We pooled individual-level data on 6,045 pregnancies from 16 U.S. cohorts. We investigated covariate-adjusted differences in nine urinary phthalate metabolite concentrations by race and ethnicity [non-Hispanic White (White, 43%), non-Hispanic Black (Black, 13%), Hispanic/Latina (38%), and Asian/Pacific Islander (3%)]. Using g-computation, we estimated changes in the probability of preterm birth under hypothetical interventions to eliminate disparities in levels of urinary phthalate metabolites by proportionally lowering average concentrations in Black and Hispanic/Latina participants to be approximately equal to the averages in White participants. We also used race and ethnicity-stratified logistic regression to characterize associations between phthalate metabolites and preterm birth.

Results

In comparison with concentrations among White participants, adjusted mean phthalate metabolite concentrations were consistently higher among Black and Hispanic/Latina participants by 23%-148% and 4%-94%, respectively. Asian/Pacific Islander participants had metabolite levels that were similar to those of White participants. Hypothetical interventions to reduce disparities in metabolite mixtures were associated with lower probabilities of preterm birth for Black [13% relative reduction; 95% confidence interval (CI): -34%, 8.6%] and Hispanic/Latina (9% relative reduction; 95% CI: -19%, 0.8%) participants. Odds ratios for preterm birth in association with phthalate metabolites demonstrated heterogeneity by race and ethnicity for two individual metabolites (mono-n-butyl and monoisobutyl phthalate), with positive associations that were larger in magnitude observed among Black or Hispanic/Latina participants.

Conclusions

Phthalate metabolite concentrations differed substantially by race and ethnicity. Our results show hypothetical interventions to reduce population-level racial and ethnic disparities in biomarkers of phthalate exposure could potentially reduce the probability of preterm birth. https://doi.org/10.1289/EHP12831.

Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10-7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for acausal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (P_Bonferroni < 1.06 x 10^-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10^-74) and BMI in pregnancy (3/914, p = 1.13x10^-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.