A critical review of the reproductive safety of Leflunomide.

Leflunomide, an inhibitor of pyrimidine synthesis, is used for the treatment of rheumatic diseases, which are prevalent in women of childbearing age. Due to the very long half-life of the active metabolite, its mechanism of action and the teratogenicity observed in animal studies at doses similar to or lower than human therapeutic doses on a weight basis, it is recommended that women stop the treatment before conception and a drug elimination procedure be performed. However, unintended gestational exposures may occur, posing challenges in risk assessment. In order to address the safety of leflunomide in unintended exposures in pregnancy, we performed a critical review of human studies. We located 13 publications in Medline and Embase, which reported on 222 pregnancies with known outcomes exposed to leflunomide preconception and/or during pregnancy. Among the 169 live births, there were eight congenital malformations with no consistent pattern of anomalies. These studies collectively showed no significant difference in the rates of malformations between exposed and unexposed pregnancies. At present, accumulating human data do not point toward leflunomide as a potent human teratogen, which may inform risk assessment of unintended gestational exposure to leflunomide.

The new biologics in pregnancy.

Growing numbers of women of reproductive age are prescribed new biological agents. This is resulting in more pregnancies exposed to these drugs. What are the new biologics (also referred to as biologicals) and what are their indications? How are they currently used in pregnant women? What are the concerns when treating pregnant women with biologics? What do we know about the reproductive safety of these agents? Current and future research is discussed.

Safety of tacrolimus in pregnancy.

QUESTION: I have a 30-year-old patient who had a kidney transplant 2 years ago. She is now planning a pregnancy. She has been treated with tacrolimus since her transplant. Will it be safe for the fetus if she continues to take it during the pregnancy or should she switch to a different antirejection medication? ANSWER: If your patient is stable while taking tacrolimus, there is no reason to switch. The current available information does not suggest that tacrolimus increases the risk of major congenital malformations above the baseline risk in the general population. Premature birth and low birth weight are often reported in this population; however, these effects are frequently reported in pregnant transplant patients treated with other immunosuppressant agents and probably reflect the effects of the maternal condition. As there are some reports of hyperkalemia and renal impairment in infants exposed to tacrolimus in utero, kidney function and electrolytes should be monitored in exposed neonates.

Safety of the newer class of opioid antagonists in pregnancy.

QUESTION: I have a patient recently confirmed to be 6 weeks pregnant. For the past 6 months she has been treated for an opioid addiction with buprenorphine-naloxone combination. Should I be concerned about her exposure to this drug combination up to this point of the pregnancy? Should I switch her medication to methadone now that she is pregnant? ANSWER: The limited data on buprenorphine exposure during pregnancy show no increased risk of adverse outcomes in the newborn. There are limited data on naloxone exposure during pregnancy; however, oral use is not expected to be associated with an increased risk of adverse pregnancy outcomes. Physicians treating pregnant women or women who become pregnant while they are stable taking buprenorphine-naloxone treatment are advised to continue this treatment but to consider transition to buprenorphine monotherapy.

Pregnancy outcome after methotrexate treatment for rheumatic disease prior to or during early pregnancy: a prospective multicenter cohort study.

OBJECTIVE: 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. METHODS: Pregnancy outcome in women taking MTX (≤30 mg/week) either after conception or within the 12 weeks before conception was evaluated in a prospective observational multicenter cohort study. Pregnancy outcomes in the MTX group were compared to outcomes in a group of disease-matched women and a group of women without autoimmune diseases (neither group was exposed to MTX). RESULTS: The study sample included 324 MTX-exposed pregnancies (188 exposed post-conception, 136 exposed pre-conception), 459 disease-matched comparison women, and 1,107 comparison women without autoimmune diseases. In the post-conception cohort, the cumulative incidence of spontaneous abortion was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was significantly higher than the incidence of spontaneous abortion in either comparison group. The risk of major birth defects (7 of 106 [6.6%]) was elevated compared to both the cohort of women without autoimmune diseases (29 of 1,001 [2.9%]) (adjusted odds ratio [OR] 3.1 [95% CI 1.03-9.5]) and the disease-matched cohort (14 of 393 [3.6%]) (adjusted OR 1.8 [95% CI 0.6-5.7]). None of the malformations were clearly consistent with MTX embryopathy. Neither the cumulative incidence of spontaneous abortion (14.4% [95% CI 8.0-25.3]) nor the risk of major birth defects (4 of 114 [3.5%]) was increased in the pre-conception cohort. Elective termination rates were increased in both of the MTX-exposed cohorts. There were no other significant differences among groups in other study end points. CONCLUSION: Post-conception administration of MTX at dosages typically used in the treatment of rheumatic diseases was associated with an increased risk of major birth defects and spontaneous abortion. Such evidence was not found among women in our pre-conception cohort.

Update on antidepressant use during breastfeeding.

QUESTION: Many of my patients who are diagnosed with postpartum depression want to continue breastfeeding. How safe are the newer antidepressant medications during breastfeeding? ANSWER: The newer antidepressants transfer into breast milk in low amounts and have not been associated with serious adverse events. Therefore, the antidepressant most effective for the woman should be considered.

Tdap vaccination during pregnancy to reduce pertussis infection in young infants.

QUESTION: What is the basis for the new recommendations to vaccinate pregnant women against pertussis after the first trimester? ANSWER: There have been outbreaks of epidemic proportions of pertussis, mostly among young infants who have not received sufficient passive immunity from their mothers. This strategy of vaccination during pregnancy aims at stopping these life-threatening epidemics.

The fetal safety of fluoxetine: a systematic review and meta-analysis.

OBJECTIVE: Fluoxetine is the selective serotonin reuptake inhibitor (SSRI) with the longest clinical use. Published reports regarding its fetal safety are contradictory. We aimed to establish the fetal safety of the drug. METHODS: We performed a systematic review of the literature, searching PubMed, Medline, and Embase from inception to August 31, 2012, for cohort and case-control studies in which women were exposed to fluoxetine during the first trimester and compared outcomes with those of unexposed control subjects. RESULTS: Twenty-one studies met the inclusion criteria. The odds ratio for major malformations associated with maternal fluoxetine use in cohort studies was 1.12 (95% CI 0.98 to 1.28). The studies included were homogeneous. Fifteen cohort studies evaluated cardiac malformations and yielded an overall odds ratio of 1.6 (95% CI 1.31 to 1.95). These studies also were homogeneous. In contrast, two case-control studies assessing cardiac malformations yielded a combined odds ratio of 0.63 (95% CI 0.39 to 1.03). CONCLUSION: The apparent increased risk of fetal cardiac malformations associated with maternal use of fluoxetine has recently been shown also in depressed women who deferred SSRI therapy in pregnancy, and therefore most probably reflects an ascertainment bias. Overall, women who are treated with fluoxetine during the first trimester of pregnancy do not appear to have an increased risk of major fetal malformations.

Objectif : La fluoxétine est l'inhibiteur spécifique du recaptage de la sérotonine (ISRS) qui compte la plus longue période d'utilisation clinique. Les rapports publiés qui traitent de son innocuité fœtale sont contradictoires. Nous avons cherché à établir son innocuité fœtale. Méthodes : Nous avons mené une analyse systématique de la littérature en menant des recherches dans PubMed, Medline et Embase, des débuts jusqu'au 31 août 2012, afin d'en tirer les études de cohorte et les études cas-témoins dans le cadre desquelles des femmes ont été exposées à la fluoxétine au cours du premier trimestre; nous avons par la suite comparé les issues constatées chez ces femmes aux issues qu'ont connues les témoins non exposés. Résultats : Vingt et une études ont satisfait aux critères d'inclusion. Dans le cadre des études de cohorte, le rapport de cotes en ce qui concerne les malformations majeures qui sont associées à l'utilisation maternelle de fluoxétine était de 1,12 (IC à 95 %, 0,98 - 1,28). Les études incluses étaient homogènes. Quinze études de cohorte ont évalué les malformations cardiaques et ont généré un rapport de cotes global de 1,6 (IC à 95 %, 1,31 - 1,95). Ces études ont également été homogènes. En revanche, deux études cas-témoins évaluant les malformations cardiaques ont généré un rapport de cotes combiné de 0,63 (IC à 95 %, 0,39 - 1,03). Conclusion : La hausse apparente du risque de malformations cardiaques fœtales qui est associée à l'utilisation maternelle de fluoxétine a récemment été également démontrée chez les femmes déprimées qui ont suspendu leur traitement aux ISRS pendant la grossesse, ce qui reflète fort probablement la présence d'un biais de constatation. Règle générale, les femmes qui sont traitées à la fluoxétine au cours du premier trimestre de grossesse ne semblent pas être exposées à un risque accru de malformations fœtales majeures.

Maternal cocaine use during breastfeeding.

QUESTION: In my practice several patients have struggled with cocaine abuse during their pregnancies. One woman, now postpartum, wants to breastfeed her infant. Despite being abstinent for the final few months of her pregnancy, I am concerned about the potential adverse effects on her child if she happens to relapse. What is the current evidence about the risks of cocaine exposure during breastfeeding? ANSWER: Given the substantial benefits of breastfeeding for infant health and development, there is no reason for mothers who previously abused cocaine to avoid breastfeeding. It is important for the health care team to counsel patients both on the serious potential risks of cocaine exposure for babies and on the benefits of breastfeeding, to allow for an informed choice. Additionally, attempts should be made to estimate maternal commitment to breastfeeding and discontinuation of cocaine use, and to offer addiction counseling to mitigate the potential risks of infant cocaine exposure. It is paramount to minimize the risk to the infant, which would certainly include mothers ceasing use of cocaine while breastfeeding. For mothers who elect to breastfeed and use cocaine intermittently, breastfeeding should be delayed sufficiently after cocaine use to allow for drug elimination (approximately 24 hours).

Smoking cessation therapy during pregnancy.

QUESTION: Despite being highly motivated to quit, many of my patients struggle with smoking cessation during pregnancy. Can you comment on the current treatment options and discuss their safety and efficacy during pregnancy? ANSWER: Given the considerable and well-documented adverse effects of antenatal smoking on mother and fetus, pharmacotherapy for smoking cessation should be considered. Available medications include nicotine replacement therapy, sustained-release bupropion, and varenicline. Nicotine replacement therapy and bupropion do not appear to increase the risk of major malformations; however, there is currently limited evidence on the use of varenicline during pregnancy. Given that these agents are only marginally successful in smoking cessation, their use should always be accompanied by behavioural counseling and education to maximize quit rates.

Safety of azathioprine use during pregnancy.

QUESTION: Quite a few of my female patients with rheumatic diseases and inflammatory bowel disease are using azathioprine. They are afraid to take a "cancer drug" during pregnancy. What is known about the risks? ANSWER: An increasing body of evidence from prospective cohort studies suggests that azathioprine is safe for the fetus during pregnancy.

Herpes zoster during pregnancy.

QUESTION: One of my pregnant patients, a 32-year-old woman (gravida 2, para 1), has a flare up of herpes zoster (HZ) at the T11 to T12 dermatomes. This virus, the varicella-zoster virus, causes chickenpox, which can be teratogenic. Is this also true for HZ? ANSWER: Herpes zoster, unlike chickenpox, is not associated with increased fetal risk. In contrast, a nonimmune woman exposed to HZ by contact might contract chickenpox.

Safety of infliximab use during pregnancy.

Infliximab is a chimeric IgG1 monoclonal antibody to tumor necrosis factor alpha (TNF)-α used in the treatment of inflammatory bowel disease and rheumatoid arthritis. Infliximab does not actively cross the placenta during the first trimester, but undergoes efficient placental transfer during the late second and third trimesters and is detectable in the infant's serum for several months after birth. This raises concerns about immunological risks of infection and response to vaccines. Available evidence from registry studies and case reports involving more than 300 pregnancy outcomes suggest that infliximab carries low fetal risk and is compatible with use during conception and the first two trimesters of pregnancy. The long-term effects of infliximab exposure on the developing immune system are yet unknown. Based on limited data from several case reports, infants born with detectable levels of infliximab do not seem to have an increased risk of infections in their first year of life and have normal responses to nonlive vaccines. However, a fatal case of disseminated mycobacterial infection has been reported in an infant who received BCG vaccine at 3 months of age, to a mother who had been treated with infliximab throughout her pregnancy. Vaccination with live viruses should be postponed in infants exposed to infliximab in utero, until serum levels are undetectable which may require more than 6 months. Discontinuing infliximab early in the third trimester should be considered in order to minimize late fetal exposure.

Drug exposure in pregnancy and heart defects.

Being the most common group of congenital malformations, congenital heart defects have often been investigated to rule out teratogenic effects by medicinal drugs and chemicals. Yet, the use of rigorous epidemiological methods has rejected such claims in many cases. We critically evaluate drugs believed to be associated with an increased risk of causing congenital heart defects, highlighting the debate and the practical implications of such associations.