Liew, Z., Luo, J., Nohr, E. A., Bech, B. H., Bossi, R., Arah, O. A., & Olsen, J. (2020). Maternal Plasma Perfluoroalkyl Substances and Miscarriage: A Nested Case-Control Study in the Danish National Birth Cohort. Environmental health perspectives, 128(4), 47007. https://doi.org/10.1289/EHP6202
Liew Z, Luo J, Nohr EA, Bech BH, Bossi R, Arah OA, Olsen J. Maternal Plasma Perfluoroalkyl Substances and Miscarriage: A Nested Case-Control Study in the Danish National Birth Cohort. Environmental health perspectives. 2020;128(4):47007. doi:10.1289/EHP6202
Liew, Z., et al. "Maternal Plasma Perfluoroalkyl Substances and Miscarriage: A Nested Case-Control Study in the Danish National Birth Cohort." Environmental health perspectives, vol. 128, no. 4, 2020, pp. 47007.
Per- and polyfluoroalkyl substances (PFAS) are widespread persistent organic pollutants and endocrine disruptors. High doses of perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) exposure can cause pregnancy loss and infant deaths in animals, but the associations between PFAS exposures and risk of miscarriage in humans are not well studied.
Methods
Using a case-control study nested within the Danish National Birth Cohort (DNBC, 1996-2002), we compared 220 pregnancies ending in miscarriage during weeks 12-22 of gestation, with 218 pregnancies resulting in live births. Levels of seven types of PFAS [PFOS, PFOA, perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluorooctanesulfonic acid (PFOSA)] were measured in maternal plasma collected in early gestation (mean gestational week 8). We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) for miscarriage and each PFAS as a continuous variable or in quartiles, controlling for maternal age, parity, socio-occupational status, smoking and alcohol intake, gestational week of blood sampling, and maternal history of miscarriage. Stratification by parity and PFAS mixture analyses using weighted quantile sum (WQS) regression were also conducted.
Results
We observed a monotonic increase in odds for miscarriage associated with increasing PFOA and PFHpS levels. The ORs comparing the highest PFOA or PFHpS quartile to the lowest were 2.2 (95% CI: 1.2, 3.9) and 1.8 (95% CI: 1.0, 3.2). The ORs were also elevated for the second or third quartile of PFHxS or PFOS, but no consistent exposure-outcome pattern emerged. An interquartile range (IQR) increment in the WQS index of seven PFAS was associated with 64% higher odds for miscarriage (95% CI: 1.15, 2.34). The associations were stronger in parous women, while findings were inconsistent among nulliparous women.
Conclusion
Maternal exposures to higher levels of PFOA, PFHpS, and PFAS mixtures were associated with the risk of miscarriage and particularly among parous women. Larger replication studies among nulliparous women are needed to allay concerns about confounding by reproductive history. https://doi.org/10.1289/EHP6202.
Bauer AZ et al., 2021·Nature reviews. Endocrinology·Free full text on PubMed Central
Paracetamol (N-acetyl-p-aminophenol (APAP), otherwise known as acetaminophen) is the active ingredient in more than 600 medications used to relieve mild to moderate pain and reduce fever. APAP is widely used by pregnant women as governmental agencies, including the FDA and EMA, have long considered APAP appropriate for use during pregnancy when used as directed. However, increasing experimental and epidemiological research suggests that prenatal exposure to APAP might alter fetal development, which could increase the risks of some neurodevelopmental, reproductive and urogenital disorders. Here we summarize this evidence and call for precautionary action through a focused research effort and by increasing awareness among health professionals and pregnant women. APAP is an important medication and alternatives for treatment of high fever and severe pain are limited. We recommend that pregnant women should be cautioned at the beginning of pregnancy to: forego APAP unless its use is medically indicated; consult with a physician or pharmacist if they are uncertain whether use is indicated and before using on a long-term basis; and minimize exposure by using the lowest effective dose for the shortest possible time. We suggest specific actions to implement these recommendations. This Consensus Statement reflects our concerns and is currently supported by 91 scientists, clinicians and public health professionals from across the globe.
A systematic review was conducted to evaluate the relationship between ART and the risk of urogenital tract malformations, especially hypospadias and cryptorchidism. Thirty-three papers were selected. Meta-analysis showed that ART was correlated with an increased risk of urogenital tract malformation in offspring (odds ratio (OR) = 1.61, 95% confidence interval (CI): 1.41-1.85), hypospadias (OR = 1.87, 95% CI: 1.47-2.40) and cryptorchidism (OR = 1.83, 95% CI: 1.54-2.18). Among offspring conceived by ART, multiple pregnancies appeared to result in a higher risk of urogenital tract malformation than singleton pregnancies (OR = 1.42, 95% CI: 0.99-2.04; P = 0.058). No significant difference in the risk of urogenital tract malformation was found between in vitro fertilization and intracytoplasmic sperm injection technologies. A sensitivity analysis showed that the above conclusions were relatively consistent. ART is correlated with an increased risk of urogenital tract malformations in offspring, especially hypospadias and cryptorchidism. Among ART offspring, multiple pregnancies may lead to a higher risk of urogenital tract malformations than singleton pregnancies, but more studies are needed for confirmation.
Sun Y et al., 2007·Human reproduction (Oxford, England)
Only few studies have addressed the long-term neurological outcomes of children born by subfertile couples. We studied the risk of epilepsy and febrile seizures in children of treated and untreated subfertile couples. The study included 83 194 live singletons born by mothers who took part in the Danish National Birth Cohort (DNBC). Information on time to pregnancy (TTP) and infertility treatment was reported by the mothers in computer-assisted telephone interviews. Data on epilepsy and febrile seizures were extracted from the Danish National Hospital Register. Overall, children of subfertile couples (TTP > 12 months) had a 51% higher risk of epilepsy [incidence rate ratio (IRR): 1.51; 95% confidence interval (95% CI): 1.17-1.94] compared with children of couples with a TTP of 0-5 months. The corresponding estimates were 1.71 (95% CI: 1.21-2.42) if the couples had received infertility treatment and 1.38 (95% CI: 1.00-1.89) if they conceived spontaneously. Children of subfertile couples did not have a higher risk of febrile seizures except for those who received hormonal treatment (HT) with or without intrauterine insemination (IRR = 1.37; 95% CI: 1.14-1.66). Children of subfertile couples had a slightly increased risk of epilepsy, and the risk tended to be higher for children of couples who received infertility treatment. Whether this reflects side effects of treatment or severity of subfecundity is not known.
Zhu JL et al., 2006·BMJ (Clinical research ed.)·Free full text on PubMed Central
To examine whether infertile couples (with a time to pregnancy of > 12 months), who conceive naturally or after treatment, give birth to children with an increased prevalence of congenital malformations. Longitudinal study. Danish national birth cohort. Three groups of liveborn children and their mothers: 50,897 singletons and 1366 twins born of fertile couples (time to pregnancy < or = 12 months), 5764 singletons and 100 twins born of infertile couples who conceived naturally (time to pregnancy > 12 months), and 4588 singletons and 1690 twins born after infertility treatment. Prevalence of congenital malformations determined from hospital discharge diagnoses. Compared with singletons born of fertile couples, singletons born of infertile couples who conceived naturally or after treatment had a higher prevalence of congenital malformations-hazard ratios 1.20 (95% confidence interval 1.07 to 1.35) and 1.39 (1.23 to 1.57). The overall prevalence of congenital malformations increased with increasing time to pregnancy. When the analysis was restricted to singletons born of infertile couples, babies born after treatment had an increased prevalence of genital organ malformations (hazard ratio 2.32, 1.24 to 4.35) compared with babies conceived naturally. No significant differences existed in the overall prevalence of congenital malformations among twins. Hormonal treatment for infertility may be related to the occurrence of malformations of genital organs, but our results suggest that the reported increased prevalence of congenital malformations seen in singletons born after assisted reproductive technology is partly due to the underlying infertility or its determinants. The association between untreated infertility and congenital malformations warrants further examination.
Qin XD et al., 2023·Environmental health perspectives·Free full text on PubMed Central
Estrogens play a critical role in parturition, and poly- and perfluoroalkyl substances (PFAS), which have estrogenic effects, have been associated with preterm birth. However, the impact of estrogens on the association between PFAS and preterm birth is unknown. The objective of this study is to investigate if estrogens modified the association between PFAS and preterm birth, using a nested case-control study design. A total of 371 preterm births and 508 controls were selected from a birth cohort study in China between 2016 and 2018. Perfluorobutanoic acid (PFBA), perfluorohexanesulfonic acid (PFHxS) and its branched isomer, perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS) and its branched isomer, and perfluorononanoic acid (PFNA) were quantified in maternal serum (mean gestational age of 32 wk). Estradiol and estriol were quantified in cord serum. Preterm birth was defined as live delivery at <37 gestational weeks. Causal mediation analysis was used to estimate the mediation and interaction effects of estrogen on the association between PFAS and preterm birth. Latent profile analysis was used to identify important estrogen profiles. Multiple linear regression was used to estimate associations between PFAS and preterm birth and interactions between PFAS and estrogens on preterm birth. Overall, higher odds ratios (ORs) of preterm birth were associated with each 1 ln-unit PFAS increase: PFBA [1.20, 95% confidence interval (CI): 1.14, 1.26], PFNA (1.30, 95% CI: 1.21, 1.39), PFOA (1.98, 95% CI: 1.54, 2.55), and PFOS (1.91, 95% CI: 1.76, 2.07) and its branched isomer (1.91, 95% CI: 1.90, 1.92). We detected statistically significant interactions between cord estradiol and PFAS on preterm birth, while no mediation effects of cord estrogen were observed. The ORs of PFOS (4.29, 95% CI: 1.31, 8.25), its branched isomer (6.71, 95% CI: 1.06, 11.91), and preterm birth were greater for participants with high cord estrogen levels than for participants with low cord estrogen levels. Our findings suggest that estrogen modified the association between maternal PFAS exposure and preterm birth. Further studies on maternal PFAS exposure and preterm birth, taking interaction effects of cord estrogens into account, are warranted. https://doi.org/10.1289/EHP11377.
Louis GMB et al., 2012·Epidemiology·Free full text on PubMed Central
Environmental chemicals may be associated with endometriosis. No published research has focused on the possible role of perfluorochemicals (PFCs) despite their widespread presence in human tissues. We formulated two samples. The first was an operative sample comprising 495 women aged 18-44 years scheduled for laparoscopy/laparotomy at one of 14 participating clinical sites in the Salt Lake City or San Francisco area, 2007-2009. The second was a population-based sample comprising 131 women matched to the operative sample on age and residence within a 50-mile radius of participating clinics. Interviews and anthropometric assessments were conducted at enrollment, along with blood collection for the analysis of nine PFCs, which were quantified using liquid chromatography-tandem mass spectrometry. Endometriosis was defined based on surgical visualization (in the operative sample) or magnetic resonance imaging (in the population sample). Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for each PFC (log-transformed), adjusting for age and body mass index, and then parity. Serum perfluorooctanoic acid (PFOA; OR = 1.89 [95% CI = 1.17-3.06]) and perfluorononanoic acid (2.20 [1.02-4.75]) were associated with endometriosis in the operative sample; findings were moderately attenuated with parity adjustment (1.62 [0.99-2.66] and 1.99 [0.91-4.33], respectively). Perfluorooctane sulfonic acid (1.86 [1.05-3.30]) and PFOA (2.58 [1.18-5.64]) increased the odds for moderate/severe endometriosis, although the odds were similarly attenuated with parity adjustment (OR = 1.50 and 1.86, respectively). Select PFCs were associated with an endometriosis diagnosis. These associations await corroboration.
Per- and polyfluoroalkyl substances (PFAS) is persistent endocrine disrupting chemicals. Previous evidence suggests that exposure to PFAS is associated with reproductive hormone levels, but the results of relevant studies are inconsistent. The objective of our study is to determine the association between exposure to PFAS and reproductive hormone levels in gender-specific general population. Based on scientific search strategies, we systematically searched PubMed, Web of Science, Embase, Medline, and Scopus to obtain the eligible studies published before January 21, 2023. The quality of the included articles was assessed using the Office of Health Assessment and Translation (OHAT) Risk of Bias tool. We combined the β coefficient and 95% confidence intervals (CI) using Stata.17 with random-effect model or fixed-effect model. We also performed subgroup analysis, sensitivity analysis, and Begger's and Egger's tests. Eleven studies involving 7714 participants were included. Meta-analysis showed that PFHxS exposure was positively associated with estradiol (E2) levels in female [β = 0.030, 95% CI: (0.013, 0.046), P = 0.000]. A negative association was found between PFOA [β = -0.012, 95% CI: (-0.023, -0.002), P = 0.017] and PFOS [β = -0.011; 95% CI: (-0.021, -0.000), P = 0.042] exposure with male testosterone (TT) levels. In the subgroup analysis, there were stronger associations in children than in adults. And the high heterogeneity was mainly due to the cross-sectional studies. Publication bias was not found in most of the analyses. Our study showed that PFAS exposure was significantly associated with reproductive hormone levels. Further related studies are needed to identify the association and potential mechanism in the future.
González N et al., 2025·Arch Toxicol·Free full text on PubMed Central
Abstract Per- and polyfluoroalkyl substances (PFAS), previously known as perfluorinated compounds (PFC), are a group of synthetic chemicals widely used over the past decades. Their extensive application, combined with their environmental persistence, has contributed to their ubiquitous presence in the environment and the associated toxicological risks. Regarding humans, blood serum testing remains the primary method for biomonitoring PFAS exposure, while breast milk has also been used due to the transfer of these substances from mothers to infants during lactation. This paper aims to review the scientific literature (using PubMed and Scopus databases) on PFAS concentrations in the breast milk of non-occupationally exposed women. Where available, the estimated daily intake of these compounds by breastfeeding infants is also examined. The reviewed studies are categorized by continent and country/region, revealing a significant lack of data for many countries, including both developed and developing nations. The findings indicate substantial variability in PFAS concentrations, influenced by factors such as geographic location, sampling year, and the specific PFAS analyzed. Among the identified compounds, perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are most commonly detected, along with perfluorohexanesulfonic acid (PFHxS) and perfluorononanoic acid (PFNA), being the only PFAS with regulated maximum levels in certain foodstuffs. Most studies were conducted before the implementation of the current (updated) tolerable weekly intake (TWI) values for these substances. Consequently, the majority reported a low health risk for breastfeeding infants, even in high-intake scenarios. Nevertheless, biomonitoring studies are urgently needed in countries with limited or no data, and new investigations should assess whether current estimated intakes exceed the updated TWI. Special focus should be given to rural and industrial areas where exposure levels remain poorly understood.
Lifestyle and Environment › Environmental Exposures › Persistent Organic Pollutants · Pregnancy › Pregnancy Complications › Premature Rupture of Membranes · Birth and Delivery › Birth Outcomes › Maternal Morbidity
PMID 32319790 32319790 DOI 10.1289/EHP6202 10.1289/EHP6202 Liew et al. 2020, Liew 2020
Cite this article
Liew, Z., Luo, J., Nohr, E. A., Bech, B. H., Bossi, R., Arah, O. A., & Olsen, J. (2020). Maternal Plasma Perfluoroalkyl Substances and Miscarriage: A Nested Case-Control Study in the Danish National Birth Cohort. Environmental health perspectives, 128(4), 47007. https://doi.org/10.1289/EHP6202
Liew Z, Luo J, Nohr EA, Bech BH, Bossi R, Arah OA, Olsen J. Maternal Plasma Perfluoroalkyl Substances and Miscarriage: A Nested Case-Control Study in the Danish National Birth Cohort. Environmental health perspectives. 2020;128(4):47007. doi:10.1289/EHP6202
Liew, Z., et al. "Maternal Plasma Perfluoroalkyl Substances and Miscarriage: A Nested Case-Control Study in the Danish National Birth Cohort." Environmental health perspectives, vol. 128, no. 4, 2020, pp. 47007.
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