Ondansetron is an effective antiemetic that is being widely used as a second‐line treatment option for severe nausea and vomiting of pregnancy in accordance with clinical guidelines. The safety of ...ondansetron during pregnancy has—following publication of controversial and seemingly contradictory results—been subject to considerable academic turmoil, specifically with respect to the risk of congenital cardiac malformations and oral cleft. In July 2019, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) released an updated, comprehensive assessment report on the use of ondansetron in the first trimester. The ensuing Summary of Product Characteristics (SmPC) was updated in November 2019 with important changes to section on “Fertility, pregnancy and lactation.” The SmPC now states that ondansetron should not be used in the first trimester of pregnancy. ENTIS, The European Network of Teratology Information Services, believes that the implementation of this regulatory step—which has important clinical consequences—is insufficiently substantiated and is not serving the interest of pregnant women with severe nausea and vomiting. Herein, we discuss the underlying evidence and argue the case against the EMA decision.
Background
The objective of this study was to collect outcome after vortioxetine exposure during the first trimester of pregnancy in a case series.
Methods
Callers who were counseled by the Israeli ...Teratology Information Service (TIS) regarding vortioxetine exposure during pregnancy were prospectively collected and followed‐up by telephone using a structured questionnaire. Outcomes were confirmed by a pediatrician with medical records in the neonatal period.
Results
Between 2016 and 2019, a total of 19 women were included in the TIS database after first trimester exposure to vortioxetine. Seventeen pregnancy follow‐ups were obtained, while two pregnancies were lost to follow‐up. Eleven pregnancies resulted in 12 live births with no malformations including one set of twins; there were three miscarriages, two terminations, and one stillbirth in week 22. One termination was performed due to prenatal diagnosis of acrania (the woman also took carbamazepine, folic acid and dipyrone), and the second due to fear of abnormalities after cystic hygroma was suspected at week 12 with nuchal translucency of 8.1 mm and no further cytogenetic testing. The twins were born in week 35. Two women continued using the medication until delivery; one of these women reported nursing her baby from birth to up to 1 year, while she continued taking vortioxetine.
Discussion
This case series provides preliminary outcome data on vortioxetine exposure in pregnancy. However, the small sample size calls for caution in the interpretation of results. Denominator‐based studies are needed before conclusions can be drawn.
•Pregnancy use of anti-TNF-α medications was not associated with a teratogenic risk in 65 live-born infants.•There were no cases of VATER/VACTERL association.
To evaluate pregnancy safety of ...anti-TNF-α medications.
Prospective, comparative, observational study done at the Israeli Teratology Information Service between 2002 and 2011.
83 anti-TNF-α-exposed-pregnancies (97.6% in the first trimester, T1) were followed-up and compared with 86 disease-matched (DM) and 341 non-teratogenic-exposed (NTE) pregnancies. The anti-TNF-α group consisted of 35 infliximab-, 25 etanercept-, and 23 adalimumab-exposed pregnancies. The rate of major congenital anomalies did not significantly differ between the three groups 3/65 (4.6%) (anti-TNF-α, T1), 5/79 (6.3%) (DM), 8/336 (2.4%) (NTE), even after excluding genetic or cytogenetic anomalies 3/65 (4.6%) (anti-TNF-α, T1), 4/79 (5.1%) (DM), 6/336 (1.8%) (NTE). There were no cases of VATER/VACTERL association.
The present study suggests that anti-TNF-α treatment does not pose a major teratogenic risk in humans. This conclusion is based on relatively small numbers of exposed pregnancies and should be interpreted with caution. Larger studies are needed to establish anti-TNF-α pregnancy safety.
The authors conducted a prospective, comparative observational study to evaluate the risk of major anomalies following exposure to lithium during pregnancy.
A total of 183 lithium-exposed pregnancies ...of women who contacted the Israeli Teratology Information Service were followed up (90.2% in the first trimester) and compared with 72 disease-matched and 748 nonteratogenic-exposed pregnancies.
There were significantly more miscarriages (adjusted odds ratio=1.94, 95% CI=1.08-3.48) and elective terminations of pregnancy (17/183 9.3% compared with 15/748 2.0%) in the lithium-exposed group compared with the nonteratogenic exposure group. The rate of major congenital anomalies after exclusion of genetic or cytogenetic anomalies was not significantly different between the three groups (lithium-exposed in the first trimester: 8/123 6.5%; bipolar: 2/61 3.3%; nonteratogenic: 19/711 2.7%). Cardiovascular anomalies occurred more frequently in the lithium group exposed during the first trimester when compared with the nonteratogenic exposure group (5/123 4.1% compared with 4/711 0.6%) but not after excluding anomalies that spontaneously resolved (3/123 2.4% compared with 2/711 0.3%). Ebstein's anomaly was diagnosed in one lithium-exposed fetus and in two retrospective lithium cases that were not included because contact with the information service was made after the prenatal diagnosis by ultrasound. The rate of noncardiovascular anomalies was not significantly different between the groups. The rate of preterm deliveries was higher in the lithium group compared with the nonteratogenic exposure group (18/131 13.7% compared with 41/683 6.0%).
Lithium treatment in pregnancy is associated with a higher rate of cardiovascular anomalies. Women who are treated with lithium during organogenesis should undergo fetal echocardiography and level-2 ultrasound.
In this context, we introduce a recent Italian study by Zanetti et al1 on pregnancy outcomes after therapeutic use of MTX in women with rheumatoid arthritis (RA). Birth defects may represent the ...baseline risk rather than result from MTX, especially true for relatively common malformations such as septal defects.6 Genetic aetiology: In summary, MTX is not the cause for all malformations in offspring with intrauterine MTX exposure. ...not every malformation associated with intrauterine MTX exposure expands the phenotype of the MTX embryopathy, which, unfortunately, is neither well understood nor adequately described. Italian study on low-dose MTX and pregnancy In view of these questions and uncertainties, it is to be welcomed that the Italian Society of Rheumatology published a retrospective cohort study evaluating the impact of low-dose MTX in patients with RA on pregnancy outcomes, namely, the risks of spontaneous abortion and elective TOP, the rate of congenital anomalies and the probability of becoming pregnant.1 The study was performed using administrative healthcare data of the Record Linkage of Rheumatic Disease.
•Hydroxychloroquine use in pregnancy was not associated with a teratogenic risk.•Neonatal lupus was not reported among infants of mothers with rheumatologic diseases.•The preterm delivery rate was ...higher and birth weight lower in the exposed group.
To evaluate pregnancy safety of hydroxychloroquine (HCQ) for rheumatologic diseases.
Prospective comparative observational study done at the Israeli teratology information service between 1998 and 2006.
114 HCQ-exposed pregnancies (98.2% in the first trimester, T1) were followed-up and compared with 455 pregnancies of women counseled for non-teratogenic exposure. The difference in the rate of congenital anomalies was not statistically significant 7/97 (7.2%) vs. 15/440 (3.4%), p=0.094. The analysis was repeated among those exposed in T1 excluding genetic or cytogenetic anomalies or congenital infections 5/95 (5.3%) vs. 14/440 (3.2%), p=0.355. There were no cases of neonatal lupus erythematosus. The gestational age at delivery was earlier, rate of preterm delivery higher, and birth weight lower, in the HCQ group.
The present study suggests that HCQ treatment in pregnancy is not a major human teratogen. The earlier gestational age and lower birth weight might be associated with maternal disease.
In March 2022, the Summary of Product Characteristics for the Lyrica brand of pregabalin was updated with warnings regarding malformation risks. This literature review and critical appraisal aims to ...explore whether these Summary of Product Characteristics updates are justified and provide clarity on the risk–benefit balance for pregabalin use in early pregnancy. A literature review was conducted in May 2022 to identify English language comparative studies of any design providing data about first trimester maternal pregabalin use and malformation risk. Five observational comparative cohort studies using data from 9 distinct datasets were located. Collectively these studies described at least 5300 unique pregabalin exposed pregnancies, with 4900 exposed in at least the first trimester. Three studies investigated overall major malformation risks, and 4 investigated specific malformation risks. The available evidence was found to be conflicting and generally of low quality, probably influenced by bias and data confounding, with no clear pattern of specific malformations observed. Findings from the largest study suggested absolute risks of major malformation of 4.8–5.6%, relative to a background risk of approximately 4%. Due to study methodology limitations, the available data were judged to only provide low quality evidence suggestive of a possible and unconfirmed small increased risk that cannot be solely attributed to foetal pregabalin exposure. This literature review and critical appraisal indicates that the Lyrica product literature updates are insufficiently substantiated and could result in confusion and misinformed clinical risk–benefit decision making.
Background and Objective: An inconsistent association between exposure to SSRIs and SNRIs and the risk for ASD and ADHD in the Offspring was observed in observational studies. Some suggest that the ...reported association might be due to unmeasured confounding. We aimed to study this association and to look for sources of bias by performing a systematic review and meta-analysis.
Methods: Medline, Embase, and the Cochrane Library were searched up to June 2019 for studies reporting on ASD and ADHD in the Offspring following exposure during pregnancy. We followed the PRISMA 2009 guidelines for data selection and extraction. Outcomes were pooled using random- effects models and odds ratios (OR), and 95% confidence intervals (CI) were calculated for each outcome using the adjusted point estimate of each study.
Results: Eighteen studies were included in the meta-analysis. We found an association between SSRIs/ SNRIs prenatal use and the risk for ASD and ADHD (OR=1.42, 95% CI: 1.23–1.65, I2=58%; OR=1.26, 95% CI: 1.07-1.49, I2=48%, respectively). Similar findings were obtained in women who were exposed to SSRIs/SNRIs before pregnancy, representing statistically significant association with ASD (OR=1.39, 95% CI: 1.24-1.56, I2=33%) and ADHD (OR=1.63, 95% CI: 1.50-1.78, I2=0%) in the Offspring, although they were not exposed to those medications in utero.
Conclusions: Although we found an association between exposure to SSRIs/SNRIs during pregnancy and the risk for ASD and ADHD, an association with those disorders was also present for exposure pre-pregnancy, suggesting that the association might be due to unmeasured confounding. We are aiming to further assess the role of potential unmeasured confounding in the estimation of the association and perform a network meta-analysis.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Human pregnancy experience with propylthiouracil has not shown an increased risk of major anomalies, but its use in pregnancy has been associated with fetal ...or neonatal thyroid dysfunction with or without goitre.
• The rate of these complications has not been prospectively evaluated.
WHAT THIS PAPER ADDS
• Based on prospective data from the Israeli Teratology Information Service, propylthiouracil was not associated with an increased teratogenic risk.
• Hypothyroidism was found in 9.5% (56.8% of whom with goitre) of fetuses or neonates, whereas hyperthyroidism was detected in 10.3%.
• In most cases neonatal thyroid functions normalized without treatment.
AIMS
Propylthiouracil (PTU) is presently considered to be the treatment of choice for hyperthyroidism in pregnancy. It is known to cross the human placenta, and therefore may affect the fetus. The major aims of this study were to evaluate the rate of major anomalies and to report the rate of fetal goitre, accompanied by hypothyroidism, in fetuses/ newborns of mothers after in utero exposure to PTU.
METHODS
Prospective observational controlled cohort study of PTU‐exposed pregnancies of women counselled by the Israeli Teratology Information Service between the years 1994 and 2004 compared with women exposed to nonteratogens.
RESULTS
We followed up 115 PTU‐exposed pregnancies and 1141 controls. The rate of major anomalies was comparable between the groups PTU 1/80 (1.3%), control 34/1066 (3.2%), P= 0.507. Hypothyroidism was found in 9.5% of fetuses/neonates (56.8% of whom with goitre). Hyperthyroidism, possibly resulting from maternal disease, was found in 10.3%. Goitres prenatally diagnosed by ultrasound were successfully treated in utero by maternal dose adjustment. In most cases neonatal thyroid functions normalized during the first month of life without any treatment. Median neonatal birth weight was lower PTU 3145 g (2655–3537) vs. control 3300 g (2968–3600), P= 0.018.
CONCLUSIONS
PTU does not seem to be a major human teratogen. However, it could cause fetal/neonatal hypothyroidism with or without goitre. Fetal thyroid size monitoring and neonatal thyroid function tests are important for appropriate prevention and treatment.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• In recent years there has been concern regarding the possibility that selective serotonin reuptake inhibitors (SSRIs) cause an increased rate of congenital ...cardiovascular anomalies.
• As of today, there is still debate in the literature as to the possible effects of paroxetine and fluoxetine on the embryonic cardiovascular system.
WHAT THIS STUDY ADDS
• Based on prospective data from three Teratogen Information Services, we have demonstrated an increased rate of congenital cardiovascular anomalies among the offspring of fluoxetine‐ and paroxetine‐treated mothers.
AIMS
Recent studies have suggested a possible association between maternal use of selective serotonin reuptake inhibitors (SSRIs) in early pregnancy and cardiovascular anomalies. The aim of the present study was to evaluate the teratogenic risk of paroxetine and fluoxetine.
METHODS
This multicentre, prospective, controlled study evaluated the rate of major congenital anomalies after first‐trimester gestational exposure to paroxetine, fluoxetine or nonteratogens.
RESULTS
We followed up 410 paroxetine, 314 fluoxetine first‐trimester exposed pregnancies and 1467 controls. After exclusion of genetic and cytogenetic anomalies, there was a higher rate of major anomalies in the SSRI groups compared with the controls paroxetine 18/348 (5.2%), fluoxetine 12/253 (4.7%) and controls 34/1359 (2.5%). The main risk applied to cardiovascular anomalies paroxetine 7/348 (2.0%), crude odds ratio (OR) 3.47, 95% confidence interval (CI) 1.13, 10.58; fluoxetine 7/253 (2.8%), crude OR, 4.81 95% CI 1.56, 14.71; and controls 8/1359 (0.6%). On logistic regression analysis only cigarette smoking of ≥10 cigarettes day−1 and fluoxetine exposure were significant variables for cardiovascular anomalies. The adjusted ORs for paroxetine and fluoxetine were 2.66 (95% CI 0.80, 8.90) and 4.47 (95% CI 1.31, 15.27), respectively.
CONCLUSION
This study suggests a possible association between cardiovascular anomalies and first‐trimester exposure to fluoxetine.
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