Heli Malm

Paroxetine and congenital malformations: meta-analysis and consideration of potential confounding factors

BACKGROUND Antidepressants have been commonly used by women of childbearing age. Recent studies suggest that paroxetine, a selective serotonin reuptake inhibitor (SSRI), might specifically increase teratogenic risk. OBJECTIVES The purpose of this study was to quantify first-trimester exposure to paroxetine and birth defects and examine potential sources of bias in the in utero or postnatal detection of more congenital malformations among women with depression. We also sought to examine whether paroxetine was used for the same indications as other SSRIs among pregnant women. METHODS This meta-analysis was designed to quantify malformation rates associated with the use of paroxetine. A search of the literature from 1985 to 2006 (English language) found in MEDLINE, EMBASE, REPROTOX, Scopus, and Biological Abstracts was conducted using the following terms: pregnancy outcome, congenital or fetal AND anomalies, malformations, cardiac/heart defects, AND selective serotonin reuptake inhibitors, paroxetine, and Paxil. Administrative databases of medication and medical services use in the Province of Quebec, Canada, were used to calculate the rates of ultrasound and echocardiogram in pregnancy and infancy in women/infants exposed to SSRIs and to compare the indications for general SSRI use versus paroxetine use. RESULTS Based on the studies analyzed, first-trimester paroxetine exposure was associated with a significant increase in the risk for cardiac malformation (odds ratio [OR], 1.72; 95% CI, 1.22-2.42). Women using antidepressants in pregnancy had a 30% higher rate of utilization of ultrasound in pregnancy. Infants of women who received SSRIs underwent approximately twice as many echocardiograms in the first year of life compared with children of women who used nothing. Significantly more women receiving paroxetine used the drug for anxiety or panic than women receiving other SSRIs (OR, 4.11; 95% CI, 2.39-7.08). CONCLUSIONS Based on the results of this metaanalysis, first-trimester exposure to paroxetine appears to be associated with a significant increase in the risk for cardiac malformation. However, a detection bias cannot be ruled out as contributing to the apparent increased detection of cardiovascular malformation of children exposed in utero to paroxetine. A significantly greater number of women were using paroxetine for anxiety or panic when compared with women using other SSRIs.

Risks associated with selective serotonin reuptake inhibitors in pregnancy.

OBJECTIVE: To study the effects of selective serotonin reuptake inhibitors (SSRIs) on pregnancy outcome. METHODS: We performed a population-based study of women exposed to SSRIs during pregnancy (n = 1782). Data were derived from a national project in Finland, established by 3 governmental organizations. In that project, the Drug Reimbursement Register, the Medical Birth Register, the Register of Congenital Malformations, and the Register of Induced Abortions have been linked. Comparisons were made between women with SSRI purchases to matched controls and between women with purchases in different trimesters. Only singleton pregnancies were included. Primary outcomes were major malformations, preterm birth, small for gestational age, low birth weight, and treatment in neonatal special or intensive care unit. Analyses were based on logistic models. RESULTS: Major malformations were not more common in infants or fetuses of women with first trimester SSRI purchases (n = 1,398) when compared with controls with no drug purchases (P = .4). Of infants born to mothers with SSRI purchases in the 3rd trimester, 15.7% were treated in special or intensive care unit compared with 11.2% of infants exposed only during the 1st trimester (P = .009, adjusted odds ratio 1.6, 95% confidence interval 1.1–2.2). We found no increased risk of preterm birth (< 37 weeks), birth 32 weeks of gestation or less, small for gestational age, or low birth weight in women with purchases in each trimester or during the 2nd and 3rd trimesters when compared with women with only 1st trimester purchases CONCLUSION: Use of SSRIs during pregnancy is not independently associated with increased risk of adverse perinatal outcome other than need for treatment in neonatal special or intensive care unit. LEVEL OF EVIDENCE: II-2

Evaluation of the Risk of Congenital Cardiovascular Defects Associated With Use of Paroxetine During Pregnancy

OBJECTIVE In 2005-2006, several studies noted an increased risk of cardiovascular birth defects associated with maternal use of paroxetine compared with other antidepressants in the same class. In this study, the authors sought to determine whether paroxetine was associated with an increased risk of cardiovascular defects in infants of women exposed to the drug during the first trimester of pregnancy. METHOD From teratology information services around the world, the authors collected prospectively ascertained, unpublished cases of infants exposed to paroxetine early in the first trimester of pregnancy and compared them with an unexposed cohort. The authors also contacted the authors of published database studies on antidepressants as a class to determine how many of the women in those studies had been exposed to paroxetine and the rates of cardiovascular defects in their infants. RESULTS The authors were able to ascertain the outcomes of 1,174 infants from eight services. The rates of cardiac defects in the paroxetine group and in the unexposed group were both 0.7%. The rate in the database studies (2,061 cases from four studies) was 1.5%. CONCLUSIONS Paroxetine does not appear to be associated with an increased risk of cardiovascular defects following use in early pregnancy, as the incidence in more than 3,000 infants was well within the population incidence of approximately 1%.

Selective Serotonin Reuptake Inhibitors and Risk for Major Congenital Anomalies

OBJECTIVE: To estimate the risk of major congenital anomalies after exposure to selective serotonin reuptake inhibitors during pregnancy. METHODS: A retrospective cohort study based on national population-based registers (years 1996–2006) of births, congenital anomalies, and terminations of pregnancy because of severe fetal anomalies (maintained by National Institute for Health and Welfare, source offspring population n=635,583) and drug reimbursements (Social Insurance Institution) linked by a personal identification number. Offspring exposed to selective serotonin reuptake inhibitors during the first trimester (n=6,976) were compared with unexposed referent offspring. RESULTS: Overall major congenital anomalies were not more common in selective serotonin reuptake inhibitor-exposed offspring compared with unexposed referent offspring (adjusted odds ratio [OR] 1.08, 95% confidence interval [CI] 0.96–1.22). Fluoxetine was associated with an increased risk of isolated ventricular septal defects (adjusted OR 2.03, 95% CI 1.28–3.21) and paroxetine was associated with an increased risk of right ventricular outflow tract defects (adjusted OR 4.68, 95% CI 1.48–14.74). Citalopram use was associated with neural tube defects (adjusted OR 2.46, 95% CI 1.20–5.07). Fetal alcohol spectrum disorders were 10-times more common in the selective serotonin reuptake inhibitor-exposed offspring than in unexposed referent offspring. CONCLUSION: Fluoxetine use is associated with an increased risk of isolated ventricular septal defects and paroxetine is associated with right ventricular outflow tract defects. The absolute risk for these specific cardiac anomalies is small but should guide clinicians not to consider fluoxetine or paroxetine the first option when prescribing selective serotonin reuptake inhibitors to women planning pregnancy. Special attention should be given to alcohol use in pregnant women using selective serotonin reuptake inhibitors. LEVEL OF EVIDENCE: II

Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design.

Objective To assess whether use of specific selective serotonin reuptake inhibitors (SSRIs) or venlafaxine in early pregnancy is associated with an increased risk of birth defects, with emphasis on cardiovascular birth defects even when accounting for lifestyle or other familial confounding. Design Multicountry population based cohort study, including sibling controlled design. Setting Nordic population (Denmark, Finland, Iceland, Norway, and Sweden) identified from nationwide health registers at different periods in 1996-2010. Population The full study cohort included women giving birth to 2.3 million live singletons. The sibling cohort included 2288 singleton live births. The sibling controlled analyses included sibling pairs who were discordant for exposure to SSRIs or venlafaxine and birth defects. Main outcome measure Prevalence of birth defects, including subtypes of cardiac defects. Odds ratio of birth defects from logistic and conditional logistic regression. Results Among 36 772 infants exposed to any SSRI in early pregnancy, 3.7% (n=1357) had a birth defect compared with 3.1% of 2 266 875 unexposed infants, yielding a covariate adjusted odds ratio of 1.13 (95% confidence interval 1.06 to 1.20). In the sibling controlled analysis the adjusted odds ratio decreased to 1.06 (0.91 to 1.24). The odds ratios for any cardiac birth defect with use of any SSRI or venlafaxine were 1.15 (95% confidence interval 1.05 to 1.26) in the covariate adjusted analysis and 0.92 (0.72 to 1.17) in the sibling controlled analysis. For atrial and ventricular septal defects the covariate adjusted odds ratio was 1.17 (1.05 to 1.31). Exposure to any SSRI or venlafaxine increased the prevalence of right ventricular outflow tract obstruction defects, with a covariate adjusted odds ratio of 1.48 (1.15 to 1.89). In the sibling controlled analysis the adjusted odds ratio decreased to 0.56 (0.21 to 1.49) for any exposure to SSRIs or venlafaxine and right ventricular outflow tract obstruction defects. Conclusions In this large Nordic study no substantial increase was found in prevalence of overall cardiac birth defects among infants exposed to SSRIs or venlafaxine in utero. Although the prevalence of septal defects and right ventricular outflow tract defects was higher in exposed infants, the lack of an association in the sibling controlled analyses points against a teratogenic effect of these drugs.

Risks associated with in utero and lactation exposure to selective serotonin reuptake inhibitors (SSRIs)

BACKGROUND Prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) may increase risk for congenital malformations and adverse perinatal outcome. OBJECTIVE This article reviews the published literature on exposure to SSRIs in utero and during lactation. METHODS Literature search in PubMed. RESULTS There is no conclusive evidence for increased risk for malformations but paroxetine and possibly fluoxetine use in early pregnancy may be associated with a small increased risk for cardiovascular malformations. Perinatal adverse effects, including respiratory distress and neonatal adaptation problems are common in exposed infants, and an increased risk for persistent pulmonary hypertension of the newborn (PPHN) has been observed. The suspected increased risk of preterm birth, low birth weight or small for gestational age has not been confirmed. It is not clear to what extent the adverse effects observed in some studies are attributable to the drug effect or related to mothers underlying disease and other possible confounders. The SSRIs are usually compatible with breastfeeding, however, individual variations in infant exposure may occur.

Pregnancy Outcome After Methotrexate Treatment for Rheumatic Disease Prior to or During Early Pregnancy: A Prospective Multicenter Cohort Study

High‐dose methotrexate (MTX) exposure during pregnancy is associated with embryopathy. The teratogenic potential of MTX at dosages typically used in the treatment of rheumatic diseases remains uncertain. The aim of this study was to evaluate the risk of spontaneous abortion, major birth defects, elective termination of pregnancy, shortened gestational age at delivery, and reduced birth weight in women exposed to MTX.

Pregnancy outcome after TNF-α inhibitor therapy during the first trimester: a prospective multicentre cohort study.

AIMS TNF-α inhibitors are considered relatively safe in pregnancy but experience is still limited. The aim of this study was to evaluate the risk of major birth defects, spontaneous abortion, preterm birth and reduced birth weight after first trimester exposure to TNF-α inhibitors. METHODS Pregnancy outcomes of women on adalimumab, infliximab, etanercept, certolizumab pegol or golimumab were evaluated in a prospective observational cohort study and compared with outcomes of a non-exposed random sample. The samples were drawn from pregnancies identified by institutes collaborating in the European Network of Teratology Information Services. RESULTS In total, 495 exposed and 1532 comparison pregnancies were contributed from nine countries. The risk of major birth defects was increased in the exposed (5.0%) compared with the non-exposed group (1.5%; adjusted odds ratio (ORadj ) 2.2, 95% CI 1.0, 4.8). The risk of preterm birth was increased (17.6%; ORadj 1.69, 95% CI 1.1, 2.5), but not the risk of spontaneous abortion (16.2%; adjusted hazard ratio [HRadj ] 1.06, 95% CI 0.7, 1.7). Birth weights adjusted for gestational age and sex were significantly lower in the exposed group compared to the non-exposed cohort (P = 0.02). As a diseased comparison group was not possible to ascertain, the influence of disease and treatment on birth weight and preterm birth could not be differentiated. CONCLUSIONS TNF-α inhibitors may carry a risk of adverse pregnancy outcome of moderate clinical relevance. Considering the impact of insufficiently controlled autoimmune disease on the mother and the unborn child, TNF-α inhibitors may nevertheless be a treatment option in women with severe disease refractory to established immunomodulatory drugs.

Prescription of Hazardous Drugs During Pregnancy

AbstractBackground: Prescribing drugs to pregnant women requires the balancing of benefits and risks. Only a small proportion of drugs are known to be harmful to the fetus, but for the vast majority of drugs little evidence of fetal safety exists. Aim: To determine the prescription pattern of potentially and clearly harmful prescription drugs during pregnancy with reference to drug safety categorisation, and to define the drug groups primarily responsible for multiple drug use during pregnancy. Study design: A retrospective, register-based cohort study. Methods: Linkage of three nationwide registers in Finland. Data collection included prescription drugs purchased during the preconception period and each trimester in the pregnant cohort, and the corresponding time periods in the non-pregnant controls.The pregnancy safety categorisation was determined for each drug (Anatomic Therapeutic Chemical [ATC] code) by using the Swedish classification of approved medicinal products (Farmaceutiska Specialiteter i Sverige [FASS]) and if not available, the corresponding Australian (Australian Drug Evaluation Committee [ADEC]) or US categorisation (FDA). Groups studied: Women applying for maternity support (maternal grants) during the year 1999 (n = 43 470) plus non-pregnant control women matched by age and hospital district (n = 43 470). Results: In the pregnant cohort, 20.4% of women purchased at least one drug classified as potentially harmful during pregnancy, and 3.4% purchased at least one drug classified as clearly harmful. A significant decline occurred in the number of pregnant women purchasing potentially and clearly harmful drugs during the first trimester when compared with the preconception period, and the decline continued from the first to the second trimester. In the pregnant cohort, 107 (0.2%) women purchased at least ten different drugs during pregnancy. The drugs most commonly purchased in this group were topical corticosteroids and nasal preparations. Conclusion: The use of hazardous prescription drugs declines during pregnancy but prescriptions of known teratogens and the relatively frequent practice of polypharmacy in epilepsy place emphasis on the need for careful pre-pregnancy counselling. However, drug safety classifications give a very crude estimation of risk and should only be used as general guidelines when planning treatment. Risk assessment must always be made on an individual basis, and pregnant women with illnesses requiring treatment must be treated adequately.

Pregnancy Complications Following Prenatal Exposure to SSRIs or Maternal Psychiatric Disorders: Results From Population-Based National Register Data

OBJECTIVE Using national register data, the authors examined the relationship between prenatal selective serotonin reuptake inhibitor (SSRI) treatment and pregnancy complications, accounting for psychiatric diagnoses related to SSRI use. METHOD This was a population-based prospective birth cohort study using national register data. The sampling frame included 845,345 offspring, representing all singleton live births in Finland between 1996 and 2010. Pregnancies were classified as exposed to SSRIs (N=15,729), unexposed to SSRIs but with psychiatric diagnoses (N=9,652), and unexposed to medications and psychiatric diagnoses (N=31,394). Pregnancy outcomes in SSRI users were compared with those in the unexposed groups. RESULTS Offspring of mothers who received SSRI prescriptions during pregnancy had a lower risk for late preterm birth (odds ratio=0.84, 95% CI=0.74-0.96), for very preterm birth (odds ratio=0.52, 95% CI=0.37-0.74), and for cesarean section (odds ratio=0.70, 95% CI=0.66-0.75) compared with offspring of mothers unexposed to medications but with psychiatric disorders. In contrast, in SSRI-treated mothers, the risk was higher for offspring neonatal complications, including low Apgar score (odds ratio=1.68, 95% CI=1.34-2.12) and monitoring in a neonatal care unit (odds ratio=1.24, 95% CI=1.14-1.35). Compared with offspring of unexposed mothers, offspring of SSRI-treated mothers and mothers unexposed to medications but with psychiatric disorders were both at increased risk of many adverse pregnancy outcomes, including cesarean section and need for monitoring in a neonatal care unit. CONCLUSIONS In a large national birth cohort, treatment of maternal psychiatric disorders with SSRIs during pregnancy was related to a lower risk of preterm birth and cesarean section but a higher risk of neonatal maladaptation. The findings provide novel evidence for a protective role of SSRIs on some deleterious reproductive outcomes, possibly by reducing maternal depressive symptoms. The divergent findings suggest that clinical decisions on SSRI use during pregnancy should be individualized, taking into account the mothers psychiatric and reproductive history.