Risk Of Major Birth Defects Research Articles

Safety of diclofenac use during early pregnancy: A prospective observational cohort study

Diclofenac is a widely used analgesic so that exposure during pregnancy may frequently occur. Most publications have evaluated the safety of NSAIDs on pregnancy outcome as a group of substances. Specific data on diclofenac are rare. This observational cohort study used the German Embryotox pharmacovigilance database to assess the risk of major birth defects and spontaneous abortion after first trimester exposure to diclofenac. A group of 260 women who took diclofenac during first trimester was compared to 778 non-exposed pregnancies. In the diclofenac exposed cohort 4 major birth defects were observed among 220 live-born infants and 25 spontaneous abortions occurred. Neither the rate of major birth defects (1.8% vs. 3.1%; OR adjusted 0.59; 95% CI 0.17–2.08) nor the risk of spontaneous abortion (HR adjusted 0.90; 95% CI 0.56–1.46) was increased. The study results do not indicate that diclofenac exposure during first trimester is associated with a teratogenic risk.

Insulin analogues use in pregnancy among women with pregestational diabetes mellitus and risk of congenital anomaly: a retrospective population-based cohort study

ObjectivesTo evaluate the risk of major congenital anomaly associated with first-trimester exposure to insulin analogues compared with human insulin in offspring of women with pregestational diabetes.Design and settingA population-based cohort...

Metformin in the first trimester and risks for specific birth defects in the National Birth Defects Prevention Study.

We assessed associations between first-trimester metformin use for pregestational diabetes and specific major birth defects. We compared risks associated with first-trimester metformin use by diabetic women to nondiabetic women on no diabetes medication; we calculated crude odds ratios by exact logistic regression and adjusted by inverse probability weighting. Confounding by diabetes was assessed by comparing risks for metformin-exposed diabetic women to those for insulin-exposed diabetics and nondiabetics treated with metformin for subfertililty. Among 9,279 nonmalformed controls and 24,375 malformed cases, diabetics who used metformin (with or without insulin) had increased adjusted odds ratios (aORs) for several birth defects associated with diabetes. However, women treated with metformin for subfertility had aORs similar to or lower than those for diabetic metformin users, and many approximated the null. For atrial septal defect secundum, anorectal defects, and limb reduction defects, the estimates for metformin when used for subfertility were 2-3-fold. While metformin use for diabetes was associated with an increased risk of many birth defects, when metformin was used for subfertility most defects had aORs that approximated the null, while only three defects had modestly increased aORs, two of which had lower confidence bounds that included the null. Our study does not suggest that metformin poses an appreciable risk for major birth defects, but further studies are necessary.

What is the risk of major congenital abnormalities among women on antiretroviral therapy?

What is the risk of major congenital abnormalities among women on antiretroviral therapy?

Pregnancy outcomes in women on metformin for diabetes or other indications among those seeking teratology information services.

Metformin is used to treat type 2 diabetes, polycystic ovary syndrome associated infertility, and gestational diabetes. This study aims to evaluate the safety of metformin in early pregnancy. We evaluated the risk of major birth defects and pregnancy losses in a cohort of pregnant women exposed to metformin during the first trimester for different indications relative to a matched unexposed reference group. The risk of major birth defects was 5.1% (20/392) in pregnancies exposed to metformin during the first trimester and 2.1% (9/431) in the reference group [adjusted odds ratio (OR) 1.70; 95% CI 0.70-4.38]. Among metformin users, this risk was 7.8% (17/219) in patients with pre-gestational diabetes and 1.7% (3/173) in those without this diagnosis. Compared to the unexposed reference, the OR for metformin user with diabetes was 3.95 (95% CI 1.77-9.41) and for metformin with other indications it was 0.83 (95% CI 0.18-2.81). The risk of pregnancy losses (spontaneous abortions and stillbirths) was 20.8% in women on metformin during the first trimester and 10.8% in the reference group [adjusted hazard ratio (HR) 1.57; 95% CI 0.90-2.74]. The risks for women on metformin with and without pre-gestational diabetes were 24.0% and 16.8% respectively, with adjusted HR of 2.51 (95% CI 1.44-4.36) and 1.38 (95% CI 0.74-2.59) when compared to the reference. Pregnant women with pre-gestational diabetes on metformin are at a higher risk for adverse pregnancy outcomes than the general population. This appears to be due to the underlying diabetes since women on metformin for other indications do not present meaningfully increased risks.

Asymmetrically enlarged parietal foramina in a rare case of Goldenhar syndrome with a possible etiopathogenesis.

Goldenhar´s syndrome (GS) also known as oculo-auriculo-vertebral spectrum (OAVS) is a relatively rare condition. GS is of multifactorial etiology that includes environmental and/or genetic factors, in addition to teratogens that disturb the blastogenesis. A 5-year-old girl from Saudi Arabia, was a member of dizygotic twins conceived by assisted reproductive technology (ART), and born with features of GS. She had asymmetrical face, cleft lip and palate, right microphthalmia and microtia. Radiological imaging showed right maxillary and mandibular bone hypoplasia, asymmetrically enlarged parietal foramina, a persistent midline occipital foramen, abnormal bone arising from occipital bone, extending along tentorium cerebelli, and a lipoma at the right tentorium cerebelli. A rudimentary right eye with dermoid cyst and pseudotumor as well as bilateral atresia of external auditory canals were present. Karyotyping was normal. ART and the risk of manipulation of ovum/embryo, was shown to be associated with multiple gestation and an increased risk of major birth defects. Given that our patient was from Eastern-province close to the South of Iraq, where Gulf wars took place and the reported incidence of birth defects, including orofacial malformation, jumped there to about seven-folds, after war, thus, environmental contamination, and the possible teratogenic effect of depleted uranium could not be excluded. In conclusion, our case of GS, disclosed a rare radiological finding in calvarial anatomy, and asserted that, careful clinical evaluation is recommended in cases of GS. ART fertilization risk along with the possible parental environmental exposure were regarded as the potential cooperators of multifactorial etiology in our case.

Selective serotonin reuptake inhibitors and risk of major congenital anomalies for pregnancies in Japan: A nationwide birth cohort study of the Japan Environment and Children's Study.

We analyzed data from the Japan Environment and Children's Study (JECS), on the association between selective serotonin reuptake inhibitors (SSRI) use during pregnancy and the risk of developing of major congenital anomalies in Japan. JECS is an ongoing nationwide birth cohort study. The study includes 95994 single pregnant women and their offspring. Among them, 172 used any SSRI up to the 12th gestational week. Crude analyses show a significantly increased incidence of upper limb, abdominal, and urogenital abnormalities. In particular, the incidence of microcephaly, hydrencephalus, esophageal atresia, small intestinal atresia, and achondroplasia was significantly higher with than without exposure to these substances. On multivariate analyses, urogenital abnormality was significant (odds ratio 3.227; 95% confidence interval: 1.460-7.134). This Japanese nationwide birth cohort survey clarified that the use of any SSRI until the 12th gestational week was associated with urogenital abnormality in children. The survey for association with minor classification abnormality needs further examination in Japan.

Fetal Exposure to Montelukast and Congenital Anomalies: A Population Based Study in Denmark.

The objective was to study pregnancy outcomes between groups of Danish women, with pregnancy ending between 1998 and 2009, according to their exposure to montelukast. Cross-sectional observational study in Danish women, selecting live births and stillbirths (Birth Registry) and spontaneous abortions and induced terminations (Patient Registry). Montelukast exposure was obtained from the Prescription Registry (ATC code R03DC03). Exposure period was from 3 months before the last menstrual period until the end of the first trimester. Four groups were studied: (1) women with prescription for montelukast, (2) women with prescription for montelukast and other anti-asthmatic medications, (3) women with prescription for other anti-asthmatic medications, (4) women without prescription for any anti-asthmatic medications. A total of 754,300 singleton pregnancies (> 12 weeks) were identified: 401 pregnancies in group 1, 426 pregnancies in group 2, 24878 in group 3 and 728,595 in group 4. Risk of preterm birth, maternal preeclampsia and gestational diabetes was increased for pregnancies exposed to montelukast. No significant differences were found for the risk of major congenital anomalies (CA). Adjusted odds ratio for CA was 1.4 (95% CI 0.9-2.3) for the group 1 and 1.0 (95% CI 0.6-1.8) for group 2. Pregnant women with prescriptions for montelukast had a higher risk of preterm birth and maternal complications. These risks are known to be associated with maternal asthma, no increased risk of CA was found. Further analysis including more exposed pregnancies will be needed to determine the risk of specific CA. Birth Defects Research 109:452-459, 2017. © 2017 Wiley Periodicals, Inc.

No increased risk of major congenital anomalies or adverse pregnancy or neonatal outcomes following letrozole use in assisted reproductive technology.

Does letrozole use increase the risk of major congenital anomalies and adverse pregnancy and neonatal outcomes in fresh, single-embryo transfer? Letrozole significantly decreases the risk of miscarriage and does not increase the risk of major congenital anomalies or adverse pregnancy or neonatal outcomes compared with natural cycles in patients undergoing ART. Letrozole is the most commonly used aromatase inhibitor for mild ovarian stimulation in ART. However, its safety in terms of pregnancy and neonatal outcomes is unclear. This retrospective cohort study used data from the Japanese national ART registry from 2011 to 2013. A total of 3136 natural cycles and 792 letrozole-induced cycles associated with fresh, single-embryo transfer and resulting in a clinical pregnancy were included in the analysis. The main pregnancy outcomes were miscarriage, ectopic pregnancy and still birth, and the neonatal outcomes were preterm delivery, low birth weight, small/large for gestational age and major congenital anomalies. Terminated pregnancies were included in the analysis of major congenital anomalies. Odds ratios (ORs) and 95% CIs were calculated using multivariate logistic regression analysis adjusted for maternal age and calendar year. The risk of miscarriage was significantly lower in women administered letrozole (adjusted OR [aOR], 0.37, 95% CI, 0.30-0.47, P < 0.001). There was no significant difference in the overall risk of major congenital anomalies between the two groups (natural cycle 1.5%vs letrozole 1.9%, aOR, 1.24, 95% CI, 0.64-2.40, P = 0.52), and no increased risk for any specific organ system. Subgroup analysis demonstrated that the risk of major congenital anomalies was not increased in patients who underwent eitherin vitro fertilization or ICSI, or in those who received early cleavage stage or blastocyst embryo transfer. All other pregnancy and neonatal outcomes were comparable between the two groups. Despite the large sample size, we were only able to rule out the possibility that letrozole might cause large increases in birth-defect risks in ART patients. The results suggest that letrozole stimulation reduces the risk of miscarriage, with no increase in the risk of major congenital anomalies or adverse pregnancy or neonatal outcomes compared with natural cycles in women undergoing ART. Letrozole may thus be a safe option for mild ovarian stimulation. None. Not applicable.

Advanced Maternal Age and the Risk of Major Congenital Anomalies.

Objective This study aims to determine if advanced maternal age (AMA) is a risk factor for major congenital anomalies, in the absence of aneuploidy. Study Design Retrospective cohort study of all patients with a singleton gestation presenting for second trimester anatomic survey over a 19-year study period. Aneuploid fetuses were excluded. Study groups were defined by maternal age ≤ 34 and ≥ 35 years. The primary outcome was the presence of one or more major anomalies diagnosed at the second trimester ultrasound. Univariable and multivariable logistic regression analyses were used to estimate the risk of major anomalies in AMA patients. Results Of 76,156 euploid fetuses, 2.4% (n = 1,804) were diagnosed with a major anomaly. There was a significant decrease in the incidence of major fetal anomalies with increasing maternal age until the threshold of age 35 (p < 0.001). Being AMA was significantly associated with an overall decreased risk for major fetal anomalies (adjusted odds ratio: 0.59, 95% confidence interval: 0.52-0.66). The subgroup analysis demonstrated similar results for women ≥ 40 years of age. Conclusion AMA is associated with an overall decreased risk for major anomalies. These findings may suggest that the "all or nothing" phenomenon plays a more robust role in embryonic development with advancing oocyte age, with anatomically normal fetuses being more likely to survive.

Spontaneous loss of a co-twin and the risk of birth defects after assisted conception

The study of very early pregnancy loss is impractical in the general population, but possible amongst infertility patients receiving carefully monitored treatments. We examined the association between fetal loss and the risk of birth defects in the surviving co-twin in a retrospective cohort study of infertility patients within an infertility clinic in South Australia from January 1986 to December 2002, linked to population registries for births, terminations and birth defects. The study population consisted of a total of 5683 births. Births from singleton pregnancies without loss were compared with survivors from (1) pregnancies with an empty fetal sac at 6-8 weeks after embryo transfer, (2) fetal loss subsequent to 8-week ultrasound and (3) multiple pregnancy continuing to birth. Odds ratios (OR) for birth defects were calculated with adjustment for confounders. Amongst infertility patients, the prevalence of birth defects was 7.9% for all twin pregnancies without fetal loss compared with 14.6% in pregnancies in which there had been an empty sac at ultrasound, and 11.6% for pregnancies with fetal loss after 6-8 weeks. Compared with singleton pregnancies without loss, the presence of an empty sac was associated with an increased risk of any defect (OR=1.90, 95% confidence intervals (CI)=1.09-3.30) and with multiple defects (OR=2.87, 95% CI=1.31-6.28). Twin pregnancies continuing to birth without loss were not associated with an overall increased prevalence of defects. We conclude that the observed loss of a co-twin by 6-8 weeks of pregnancy is related to the risk of major birth defects in the survivor.

Adalimumab long-term safety: infections, vaccination response and pregnancy outcomes in patients with rheumatoid arthritis

BackgroundAdalimumab has been used in patients with moderately to severely active rheumatoid arthritis (RA) for over 10 years and has a well-established safety profile across multiple indications.ObjectiveTo update adverse events...

Pregabalin Exposure During First Trimester of Pregnancy May Raise Risk of Major Birth Defects

Pregabalin Exposure During First Trimester of Pregnancy May Raise Risk of Major Birth Defects

Pregnancy outcome following maternal exposure to pregabalin may call for concern.

To investigate pregnancy outcomes following maternal use of pregabalin. This multicenter, observational prospective cohort study compared pregnancy outcomes in women exposed to pregabalin with those of matched controls (not exposed to any medications known to be teratogenic or to any antiepileptic drugs). Teratology Information Services systematically collected data between 2004 and 2013. Data were collected from 164 exposed pregnancies and 656 controls. A significantly higher major birth defect rate in the pregabalin group was observed after exclusion of chromosomal aberration syndromes, and when cases with exposure during first trimester of pregnancy were analyzed separately (7/116 [6.0%] vs 12/580 [2.1%]; odds ratio 3.0, 95% confidence interval 1.2-7.9, p = 0.03). The rate of live births was lower in the pregabalin group (71.9% vs 85.2%, p < 0.001), primarily due to a higher rate of both elective (9.8% vs 5.0%, p = 0.02) and medically indicated (5.5% vs 1.8%, p = 0.008) pregnancy terminations. In the Cox proportional cause specific hazards model, pregabalin exposure was not associated with a significantly higher risk of spontaneous abortion. This study demonstrated a signal for increased risk of major birth defects after first trimester exposure to pregabalin. However, several limitations such as the small sample size, differences across groups in maternal conditions, and concomitant medication exposure exclude definitive conclusions, so these results call for confirmation through independent studies.

Pregabalin: increased risk of major birth defects?

Pregabalin: increased risk of major birth defects?

Oral contraceptive exposure in newly pregnant women not linked to birth defects

University of California, San Francisco School of Pharmacy, told Pharmacy Today. “If a woman mistakenly continued using oral contraceptives during the early part of pregnancy, it didn’t increase the risk of birth defects.” Using Danish health registries, the researchers studied four exposure groups and found that prevalence of major birth defects—about 25 per 1,000 births—was consistent across each group. Nearly 70% of the mothers stopped using oral contraceptives more than 3 months before pregnancy; 21% never used oral contraceptives; 8% used oral contraceptives until 0 to 3 months

Maternal use of oral contraceptives and risk of birth defects in Denmark: prospective, nationwide cohort study

Study question Is oral contraceptive use around the time of pregnancy onset associated with an increased risk of major birth defects? Methods In a prospective observational cohort study, data on...

Fluconazole use and birth defects in the National Birth Defects Prevention Study

Low-dose fluconazole is used commonly to treat vulvovaginal candidiasis, a condition occurring frequently during pregnancy. Conflicting information exists on the association between low-dose fluconazole use among pregnant women and the risk of major birth defects. We used data from the National Birth Defects Prevention Study to examine this association. The National Birth Defects Prevention Study is a multisite, population-based, case-control study that includes pregnancies with estimated delivery dates from 1997 to 2011. Information on fluconazole use in early pregnancy was collected by self-report from 31,645 mothers of birth defect cases and 11,612 mothers of unaffected controls. Adjusted odds ratios and 95% confidence intervals were estimated for birth defects with 5 or more exposed cases; crude odds ratios and exact 95% confidence intervals were estimated for birth defects with 3-4 exposed cases. Of the 43,257 mothers analyzed, 44 case mothers and 6 control mothers reported using fluconazole. Six exposed infants had cleft lip with cleft palate, 4 had an atrial septal defect, and each of the following defects had 3 exposed cases: hypospadias, tetralogy of Fallot, d-transposition of the great arteries, and pulmonary valve stenosis. Fluconazole use was associated with cleft lip with cleft palate (odds ratio= 5.53; confidence interval= 1.68-18.24) and d-transposition of the great arteries (odds ratio= 7.56; confidence interval= 1.22-35.45). The associations between fluconazole and both cleft lip with cleft palate and d-transposition of the great arteries are consistent with earlier published case reports but not recent epidemiologic studies. Despite the larger sample size of the National Birth Defects Prevention Study, fluconazole use was rare. Further investigation is needed in large studies, with particular emphasis on oral clefts and conotruncal heart defects.

Chemotherapy in pregnancy

Cancer diagnosed during pregnancy is uncommon, complicating between 0.02% and 0.1% of all pregnancies. Nonetheless, due to increasing age of childbearing, the incidence of cancer during pregnancy is likely to increase due to higher incidence of several age-dependent malignancies. The most common malignancies include breast cancer, cervical cancer, malignant melanoma and lymphoma. One of the key challenges in the management of cancer in pregnancy is treating the women with standard chemotherapy regimen, without compromising the safety of the developing foetus. Exposure of chemotherapy in the first trimester is associated with an increased risk of major birth defects, whereas use in the second and third trimesters is associated with intrauterine growth restriction, low birthweight and stillbirth. In this article, we review available data regarding the use of chemotherapeutic agents in pregnancy, and we summarise the neonatal outcomes, including malformations, perinatal complications and long-term follow-up. In addition, the management plan during pregnancy is also discussed.

Risk of Major Congenital Anomalies in Children Born to Women Prescribed Anti-epileptic Drugs with and without Periconceptional Folic Acid Supplementation: A United Kingdom Population-based Cohort Study.

Risk of Major Congenital Anomalies in Children Born to Women Prescribed Anti-epileptic Drugs with and without Periconceptional Folic Acid Supplementation: A United Kingdom Population-based Cohort Study.