Background and aim: Diminished ovarian reserve (DOR) is one of the most frequent pathology diagnosed in women consulting for infertility. Animal studies have reported impacts of some heavy metals on the ovarian function but research on the ovarian reserve in humans is limited.
Methods: We included 139 cases and 153 controls between 2016-2020. The participants were aged 18-40 and consulted for couple infertility in one of four fertility centres in western France. Cases of DOR were defined as women with an antral follicle count < 7 and/or anti-müllerian hormone (AMH) levels ≤ 1.1 ng/ml. Controls were frequency matched on age and centre and were women with normal ovarian reserve evaluations, no malformations, and regular menstrual cycles. Four heavy metals (lead, mercury, cadmium and chromium) were measured in whole blood at inclusion. Single-exposure associations were examined with multivariable logistic regressions adjusted on potential confounders. Mixture effects were investigated with quantile g-computation and bayesian kernel machine regression (BKMR).
Results: All metals were detected in over 85% of control samples. We observed non-significant increased risks of DOR for chromium (OR = 1.24 [0.65 - 2.39] for the second tercile of exposure and OR = 1.77 [0.84 - 3.70] for the tercile) and cadmium (OR = 1.89 [0.98 - 3.67] for the second tercile of exposure and OR = 1.18 [0.55 - 2.52] for the tercile). Quantile g-computation and BKMR both yielded a non-significant increased risk of DOR for the mixture of metals, with no evidence of interaction.
Conclusions: We detected weak signals that some heavy metals could be associated with DOR. These findings should be replicated in other studies.
Keywords: Reproductive outcomes, Female fertility, Heavy metals, Chemical exposures, Mixtures, Environmental epidemiology.

Background and aim: Solar and geomagnetic activity have been previously shown to suppress melatonin, which is an important hormone for fetal development. We explored whether solar and geomagnetic activity were associated with fetal growth.

Methods: We included singleton births with routine ultrasounds at an academic medical center in Eastern Massachusetts from 2011 through 2016. Sunspot number (SSN), interplanetary magnetic field (IMF), and Kp index were obtained from the NASA Goddard Space Flight Center. Three exposure windows were considered, including the first 16 weeks of pregnancy, one month prior to fetal growth measurement, and conception until fetal growth measurement (cumulative). Ultrasound scans from which we extracted biparietal diameter (BPD), head circumference (HC), femur length (FL), and abdominal circumference measurements were categorized as anatomic (<24 weeks’ gestation) or growth scans (≥24 weeks’ gestation). Ultrasound parameters and birth weight were standardized, and linear mixed models adjusted for seasonality, long-term trends, meteorological factors, and maternal characteristics were fitted.

Results: Among 9,428 pregnancies, prenatal exposure was negatively associated with ultrasound parameters among growth scans. Associations varied by exposure window, solar metric, and fetal growth parameter. Cumulative exposure to solar and geomagnetic activity was important across exposure metrics, where an interquartile range (IQR) increase in SSN was associated with a -0.20 (95% CI: -0.30, -0.11), -0.28 (95% CI: -0.39, -0.17), and -0.16 (95% CI: -0.26, -0.06) difference in average BDP, HC, and FL z-scores, respectively. Cumulative IMF and Kp index were also associated with reduced average HC, -0.23 (95% CI: -0.36, -0.10) and -0.14 (95% CI: -0.24, -0.03) z-score difference per IQR increase, respectively.

Conclusions: Solar and geomagnetic activity were associated with reduced fetal growth. Future studies are needed to better understand the impact of these natural phenomena on clinical endpoints.

Keywords: fetal growth, solar activity, pregnancy

Background and Aim: Although uterine fibroids are common, etiology of these smooth muscle tumors remains unclear. Mounting data suggest genetic mutations are an early event in fibroid development, with hormonal signaling promoting tumor growth. Cadmium exhibits mutagenic and hormonal properties, yet prior human studies of cadmium and fibroids have yielded discrepant results, and none were prospective investigations.

Methods: The Study of Environment, Lifestyle & Fibroids is a cohort study of 1,693 Black women ages 23-35 years, based in Detroit, Michigan. Participants underwent transvaginal ultrasound at baseline and every 20 months for 5 years to detect fibroids ≥0.5 cm in diameter. Among 1,123 fibroid-free participants at baseline, we quantified baseline whole blood and creatinine-corrected urinary cadmium concentrations in 1,027 and 1,119 participants, respectively. We conducted Cox regression to estimate adjusted hazard ratios (aHRs), and 95% CIs for the association between cadmium and fibroid incidence, adjusting for urinary creatinine and time-varying factors of parity, years since last birth, years since last depot medroxyprogesterone acetate use, body mass index, smoking, and education.

Results: Urinary cadmium was not associated with fibroid incidence. However, we observed elevated incidence estimates with blood cadmium (quartile 3 vs. 1: aHR 1.49, 95% CI: 1.07,2.08; quartile 4 vs. 1: 1.17, 95% CI: 0.75,1.84). Considering the short half-life of cadmium in blood (3 months), we repeated the analyses restricting follow-up to 20 months and observed a stronger association (quartile 3 vs. 1: aHR 1.79, 95% CI: 1.03,3.10; quartile 4 vs. 1: aHR 1.42, 95% CI: 0.67,2.99).

Conclusion: We found suggestive evidence of an association between blood cadmium concentrations and fibroid incidence. While urinary cadmium represents long-term exposure over prior decades, urinary excretion may come directly from kidney storage rather than blood circulation, which is the component available to the uterus. Future analyses will examine blood cadmium and fibroid growth.

Background and Aim: The placenta plays a key role in assuring a normal foetal development and growth. Few epidemiological studies have investigated the effects of phenols and phthalates on placental function. We aimed to explore whether maternal exposure to phenols and phthalates during the second and third pregnancy trimesters are associated with changes in placental weight at birth and placental-to-birth weight ratio (PFR).

Methods: We relied on a subsample of 357 women from the French SEPAGES cohort with placental and birth weights assessed, and for whom 8 phenols (4 parabens, 2 bisphenols, triclosan and benzophenone-3), 13 phthalate metabolites and 2 non-phthalate plasticizer metabolites were measured in within-subject pools of repeated urine samples collected at second and third pregnancy trimesters (median= 21 samples/trimester). Adjusted linear regressions were used to evaluate the associations between each compound and placental weight or PFR.

Results: Each ln-unit increase in urinary monobenzyl phthalate (MBzP) concentrations at the second and third trimesters was associated with a mean placental weight decrease of 19.67 g (95%CI: -37.94; -1.4) and 16.71 g (95%CI: -33.08; -0.33), respectively. A decrease in PFR was also observed with MBzP exposure at the second (β: -0.51; 95%CI: -0.99; -0.04) and third trimester (β: -0.46; 95%CI: -0.88; -0.03). Children born to mothers with detected/quantified bisphenol S (BPS) in the second trimester showed a significantly lower PFR compared to mothers with undetected BPS (β: -0.83, 95%CI: -1.57; -0.09). No associations were observed with the remaining compounds.

Conclusions: This is the first study exploring the effect of BPS maternal exposure on placental function in humans. Our MBzP results are consistent with a previous study that found a similar negative association on placental function in girls, whereas three other studies relying on spot urine samples reported null associations.

Keywords: placental weight, phenols, phthalates, pfr, prenatal exposure

Background and Aim: Exposure to perfluoroalkyl substances (PFAS) may affect fertility, but human studies are scarce. We assessed associations between PFAS concentrations and probability of pregnancy and live birth in women in Singapore.

Methods: In a case-control study nested within the Singapore Preconception Study of Long-Term Maternal and Child Outcomes, we measured PFAS in preconception serum from 382 women of reproductive age (328 who became pregnant and 54 who failed to conceive or miscarried). We used logistic and weighted quantile sum (WQS) regression respectively to assess the associations between concentrations of seven individual PFAS and the PFAS mixture with the odds of pregnancy or live birth. We calculated time-to-pregnancy based on the number of menstrual cycles over 12 months of follow up and used Cox regression to estimate fecundability ratios (FR). We used inverse probability weighting to account for the nested case-control design. All models were adjusted for batch, age, ethnicity, education, household income, and parity.

Results: Higher PFAS mixture exposure was associated with reduced odds of pregnancy (WQS: OR [95% CI] per PFAS quartile increase=0.67 [0.44, 1.02]) and live birth (0.71 [0.48, 1.07]), with PFOA and PFOS being the major contributors to the mixture associations. In individual PFAS analyses, the strongest associations were observed for PFOA (OR [95% CI]=0.58 [0.35, 0.96] for pregnancy and 0.62 [0.39, 1.00] for live birth) compared to other PFAS. Higher concentrations of PFOA (FR [95% CI]=0.87 [0.75, 1.02]), PFOS (0.84 [0.68, 1.03]), and PFHpA (0.76 [0.59, 0.98]) were associated with lower fecundability. Associations for PFHxS, PFDA, and PFHpS were in the same direction but more attenuated. There was no association between PFNA and the fertility outcomes.

Conclusions: Higher PFAS exposures may decrease fertility in women from Singapore. These findings need further investigation in larger populations.

Keywords: Perfluoroalkyl substances; Endocrine disrupting chemicals; Fertility; Pregnancy outcomes.

Background and Aim: Evidence suggests fluoride exposure may affect neurodevelopment among children. A portion of this effect may be operating via adverse birth outcomes, but there is a lack of research on the relationship between water fluoridation and pregnancy outcomes.

Methods: We linked California birth records from 2010-2018 to annual average fluoride levels by community water system. Fluoride levels were collected from consumer confidence reports. Births were geocoded to the address at delivery and the fluoride level in the year of pregnancy was determined, using a weighted average if the pregnancy spanned multiple years. We estimated the effects of a hypothetical intervention reducing water fluoride levels to 0.7 ppm and 0.5 ppm on birthweight and gestational age using G-computation. We used a linear regression model with a natural cubic spline to allow for non-linearity in the effects of fluoride. Individual covariates included maternal age, race/ethnicity, insurance type, educational attainment, and the month and year of conception. Area-level covariates included water system size, county-level unemployment, income inequality, temperature and urbanicity. Inference was calculated using a clustered bootstrap with Wald-type confidence intervals.

Results: There was no estimated effect of the hypothetical intervention to reduce fluoride levels to 0.7 ppm on birthweight (-1.6 g, 95% CI -4.1, 0.8). We did observe a negative association of the hypothetical intervention to reduce fluoride level to 0.5 ppm (-7.6 g, 95% CI -12.6, -2.6). We also observed no effect for either the 0.7 or 0.5 ppm intervention on gestational age (-0.007 weeks, 95% CI -0.017, 0.003 and -0.023 weeks, 95% CI -0.050, 0.003, respectively).

Conclusions: We found a negative association of a hypothetical intervention of reducing fluoride levels to 0.5 ppm on birthweight, but no association for reducing fluoride levels to 0.7 ppm. We did not observe associations for either intervention with gestational age.