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Background Existing data on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) during late pregnancy is well established, providing assurance. However, the use of NSAIDs during early pregnancy remains inconclusive owing to conflicting findings on adverse neonatal outcomes as well as the limited data on adverse maternal outcomes. Therefore, we sought to investigate whether early prenatal exposure to NSAIDs was associated with neonatal and maternal adverse outcomes. Methods and findings We conducted a nationwide, population-based cohort study using Korea's National Health Insurance Service (NHIS) database with a mother-offspring cohort constructed and validated by the NHIS to include all live births in women aged 18 to 44 years between 2010 and 2018. We defined exposure to NSAIDs as at least two records of NSAID prescriptions during early pregnancy (first 90 days of pregnancy for congenital malformations and first 19 weeks for nonmalformation outcomes) and compared against three distinct referent groups of (1) unexposed, no NSAID prescription during the 3 months before pregnancy start to end of early pregnancy; (2) acetaminophen-exposed, at least two acetaminophen prescriptions during early pregnancy (i.e., active comparator); and (3) past users, at least two NSAID prescriptions before the start of pregnancy but no relevant prescriptions during pregnancy. Outcomes of interest were adverse birth outcomes of major congenital malformations and low birth weight and adverse maternal outcomes of antepartum hemorrhage and oligohydramnios. We estimated relative risks (RRs) with 95% CIs using generalized linear models within a propensity score (PS) fine stratification weighted cohort that accounted for various potential confounders of maternal sociodemographic characteristics, comorbidities, co-medication use, and general markers of burden of illness. Of 1.8 million pregnancies in the PS weighted analyses, exposure to NSAIDs during early pregnancy was associated with slightly increased risks for neonatal outcomes of major congenital malformations (PS-adjusted RR, 1.14 [CI, 1.10 to 1.18]) and low birth weight (1.29 [1.25 to 1.33]), and for maternal outcome of oligohydramnios (1.09 [1.01 to 1.19]) but not antepartum hemorrhage (1.05 [0.99 to 1.12]). The risks of overall congenital malformations, low birth weight, and oligohydramnios remained significantly elevated despite comparing NSAIDs against acetaminophen or past users. Risks of adverse neonatal and maternal outcomes were higher with cyclooxygenase-2 selective inhibitors or use of NSAIDs for more than 10 days, whereas generally similar effects were observed across the three most frequently used individual NSAIDs. Point estimates were largely consistent across all sensitivity analyses, including the sibling-matched analysis. Main limitations of this study are residual confounding by indication and from unmeasured factors. Conclusions This large-scale, nationwide cohort study found that exposure to NSAIDs during early pregnancy was associated with slightly higher risks of neonatal and maternal adverse outcomes. Clinicians should therefore carefully weigh the benefits of prescribing NSAIDs in early pregnancy against its modest, but possible, risk of neonatal and maternal outcomes, where if possible, consider prescribing nonselective NSAIDs for, Author(s): Eun-Young Choi 1, Han Eol Jeong 1,2, Yunha Noh 1,2, Ahhyung Choi 1, Dong Keon Yon 3,4, Jung Yeol Han 5, Ji-Hee Sung 6, Seung-Ah Choe 7, Ju-Young Shin [...]

Abstract Background Preeclampsia is a major cause of maternal and perinatal mortality and morbidity. The etiology of preeclampsia remains unclear. Recently, it was shown that misregulation of fms-like tyrosine kinase-1 (Flt-1) in the peripheral blood mononuclear cells of pregnant women results in over-expression of the soluble splice variant of Flt-1, sFlt-1, producing an additional (extra-placental) source of sFlt-1 that can contribute to the etiology of preeclampsia. The aim of this study was to investigate the relationship between preeclampsia and a dinucleotide (threonine-glycine; TG)n repeat polymorphism in the 3' non-coding region of the Flt-1 gene. Methods The number of the d(TG)n repeats was analyzed in 170 patients with preeclampsia and in 202 normotensive pregnancies. The region containing the dinucleotide repeat polymorphism of the Flt-1 gene was amplified by polymerase chain reaction (PCR) from the DNA samples and was analyzed by direct PCR sequencing. Results We found 10 alleles of the dinucleotide repeat polymorphism and designated these as allele*12 (A1) through allele*23 (A12) according to the number of the TG repeats, from 12 to 23. The frequency of the 14-repeat allele (A3) was most abundant (63.82% in preeclampsia and 69.06% in controls), followed by the 21-repeat allele (A10; 28.53% in preeclampsia and 23.76% in controls). There was no significant difference in the allele frequency between patients with preeclampsia and normal controls. The most common genotype in preeclamptic and normotensive pregnancies was heterozygous (TG)14/(TG)21 (41.76%) and homozygous (TG)14/(TG)14 (45.05%), respectively. However, the genotype frequencies were not significantly different between preeclamptic patients and controls. Conclusion This is the first study to characterize the dinucleotide repeat polymorphism of the Flt-1 gene in patients with preeclampsia. We found no differences in the allele or genotype frequencies between patients with preeclampsia and normal pregnancies. Although limited by a relatively small sample size, our study suggests that the d(TG)n repeat polymorphism of the Flt-1 gene is not associated with the development of preeclampsia in Korean pregnant women.

Objectives: The aim was to investigate the effect of -maternal smoking exposure assessed by urinary tobacco-specific nitrosamine metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-a1-butanol (NNAL) with adverse pregnancy outcomes.Methods: A total of 251 pregnant women were recruited. Urinary cotinine and NNAL were measured. Participants' sociodemographics were obtained by questionnaire and pregnancy outcomes were collected by charts review after delivery.Results: The prevalence of smoking was 8.4% (21 of 249), 1.2% (3 of 241), and 3.7% (9 of 241) in pregnant women according to questionnaire, cotinine, and NNAL, respectively. As compared with questionnaire positivity and cotinine levels, women with positive NNAL were independent determinants for spontaneous abortion (adjusted OR 12.357, 95% CI 2.053-74.368), preterm birth (adjusted OR 22.239, 95% CI 3.737-132.357), and small for gestational age (adjusted OR 6.915, 95% CI 1.385-34.524).Conclusions: Urinary NNAL might be a useful biomarker in detection of maternal smoking status in association with adverse pregnancy outcomes. Use of this marker in preconception and pregnancy counselling before planning pregnancy may allow prevention of several adverse pregnancy outcomes. [ABSTRACT FROM AUTHOR]