Serotonin reuptake inhibitors in pregnancy and the risk of major malformations: a systematic review

OBJECTIVE: To review studies conducted to establish the risk of major congenital malformations in women exposed to serotonin reuptake inhibitors (SRIs) during the first trimester of pregnancy. METHODS: A literature search [corrected] was conducted within PsycINFO [corrected] EMBASE, MEDLINE and Cochrane databases from 1966 to October 2006, to identify studies assessing the risk of major malformations in infants whose mother was taking SRIs (SSRIs and SNRIs) during the first trimester of pregnancy. RESULTS: Fifteen studies were selected for the analysis: seven adopted a prospective cohort design and seven a retrospective design, of these one was a case-control study. DATA SYNTHESIS AND CONCLUSIONS: The reviewed studies suggest that exposure to fluoxetine, sertraline, citalopram and venlafaxine in early pregnancy is not associated with an increased risk of major congenital malformations. For paroxetine, recent data call for caution in prescribing such a drug in early pregnancy. For the other SRIs, the risk remains substantially undetermined, as data are so far scanty. Given this background, large prospective cohort studies are urgently needed to better assess the risk/benefit ratio of SRIs-treatment during pregnancy.     

Meta-analysis finds use of inhaled corticosteroids during pregnancy safe: a systematic meta-analysis review

Inhaled corticosteroids (ICs) are the drug of choice for asthmatic women during pregnancy, but the results on the effects of these medications on obstetrical and perinatal outcomes are not conclusive. Meta-analysis is the statistical analysis of a collection of analysis results from individual studies for the purpose of integrating the findings. Meta-analysis techniques are necessary because only summary statistics are available in the literature. In order to determine the risk of exposure to ICs, we pooled data from all clinical studies that evaluated the pregnancy and perinatal outcomes in women exposed to this group of drugs during pregnancy by the meta-analytic technique. PUBMED, OVID, EMBASE and SCOPUS databases were searched for studies that investigated birth outcome following exposure to ICs during pregnancy. Data were collected from 1997 to 2005 (up to 31 December). Types of outcome investigated were major malformations, preterm delivery, low birth weight and pregnancy-induced hypertension. The criteria for inclusion of studies in this meta-analysis were exposure of women to any therapeutic dosage of any ICs (fluticasone, beclomethasone, budesonide, triamcinolone and flunisolide) during pregnancy. The results showed that ICs do not increase the risk of major malformations, preterm delivery, low birth weight and pregnancy-induced hypertension. In conclusion, ICs do not increase the rates of any obstetrical outcomes investigated in the present study and interestingly improve the symptoms and are helpful in the management of asthma and thus can be used comfortably during pregnancy.     

The teratogenic effect of carbamazepine: a meta-analysis of 1255 exposures

Maternal use of antiepileptic drugs during pregnancy has been associated with an increased risk of major congenital abnormalities in the fetus. Carbamazepine (CBZ) is an antiepileptic drug that was developed and marketed mainly for the treatment of epileptic seizures. Some investigators described an increased rate of major congenital anomalies following treatment with CBZ during pregnancy while others found no such increase. In order to quantify better the risks of exposure to CBZ during pregnancy, we pooled data from prospective studies known to us. We found in prospective studies involving 1255 cases of exposure that CBZ therapy increased the rate of congenital anomalies, mainly neural tube defects, cardiovascular and urinary tract anomalies, and cleft palate. CBZ may also induce a pattern of minor congenital anomalies and developmental retardation, but our study did not address these endpoints. CBZ also appears to reduce gestational age at delivery. A combination of CBZ with other antiepileptic drugs is more teratogenic than CBZ monotherapy. Children born to untreated epileptic women do not appear to have an increased rate of major birth defects. In light of these results, we recommend performing a level 2 ultrasound and fetal echocardiography in women treated with CBZ during pregnancy.     

Pregnancy outcome in women with inflammatory bowel disease following exposure to 5-aminosalicylic acid drugs: a meta-analysis

5-ASA drugs are commonly used for management of inflammatory bowel disease (IBD) during pregnancy. The safety of drug therapy for IBD during pregnancy is an important clinical concern. The present meta-analysis was performed to explore the risk of adverse pregnancy outcomes in women with IBD following exposure to 5-ASA drugs (mesalazine, sulfasalazine, balsalazide, and olsalazine). Bibliographic databases were searched upto June 2007 for studies investigating pregnancy outcomes in women with IBD following exposure to any 5-ASA drugs. The outcomes of interest were congenital abnormalities, stillbirth, spontaneous abortion, preterm delivery, and low birth weight. The odds ratios (OR) and confidence interval (CI) for the individual studies were pooled and heterogeneity analysis was performed. Seven studies with a total of 2200 pregnant women with IBD were included; 642 received 5-ASA drugs (mesalazine, sulfasalazine or olsalazine) and 1158 received no medication. The OR was found 1.16 (95% CI: 0.76–1.77, P = 0.57) for congenital abnormalities, 2.38 (95% CI: 0.65–8.72, P = 0.32) for stillbirth, 1.14 (95% CI: 0.65–2.01, P = 0.74) for spontaneous abortion, 1.35 (95% CI: 0.85–2.13, P = 0.26) for preterm delivery, and 0.93 (95% CI: 0.46–1.85, P = 0.96) for low birth weight.

In conclusion, this meta-analysis suggest that there is no more than an 1.16-fold increase in congenital malformations, an 2.38-fold increase in stillbirth, an 1.14-fold increase in spontaneous abortion, an 1.35-fold increase in preterm delivery, and an 0.93-fold increase in low birth weight.     

Assessing the safety of drugs in pregnancy: the role of prospective cohort studies.

Since, for obvious reasons, systematic testing of the teratogenic properties of drugs in humans is not possible in the premarketing phase, the epidemiological approaches to postmarketing risk evaluation are of major importance. Cohort studies, with their prospective exposure assessment, their ability to study even exposure to drugs not commonly used in pregnancy, and their ability to monitor both adverse and beneficial fetal outcomes, seem to be the most promising study type from a methodological viewpoint. Although there are numerous cohort studies on the harmful effects of drug use in pregnant women, only a few have been able to demonstrate a risk in terms of an increase in the prevalence of malformations. Most studies with significant findings were those investigating the risk potential of one group of drugs, the anticonvulsants. The lack of cohort studies showing a risk for drug use in pregnancy, however, is not necessarily indicative of some methodological deficiency. Rather, it may suggest that, for the majority of drugs, their use in pregnancy is not associated with an increased risk of congenital malformations.     

Drug treatment in pregnancy

When considering drug therapy in pregnancy, the risk of treatment for the embryo/fetus has to be weighed against the risk to the mother and the child of carrying out no treatment. This is of particular relevance in certain conditions like diabetes, epilepsy or AIDS, where the risk of embryopathy is increased when no treatment is carried out and the available drugs are potentially teratogenic. However, carefully selected drugs and close meshed monitoring may even decrease the risk for the child. In many instances, unintentional drug exposure occurs in the period before the pregnancy has been diagnosed. This may lead to additional diagnostic measures or even abortion of an otherwise wanted child. In both situations, planned and unintentional drug exposure during pregnancy, insufficient information is available on the clinical conditions relevant here and the specific drugs involved. Identification of potential teratogenic effects of a new drug takes place during the early development phase. However, animal models may not be representative of specifically human characteristics, e.g. deficiences in enzymes. Since drug treatment is generally best avoided during pregnancy, pharmacokinetic studies in this population are rare. However, physiological changes, known to be relevant for some drugs do occur during pregnancy. In order to improve knowledge on the pharmacokinetics of drugs in pregnancy, population pharmacokinetic approaches may represent a solution. Intensive efforts to investigate the efficacy and safety of drugs during pregnancy are necessary. Since controlled clinical trials are usually not feasible due to ethical reasons, intensified collection of case reports as well as epidemiological studies are warranted to gain sufficient information for the counselling of pregnant women.     

HPV vaccines and pregnancy: the situation in early 2012

Vaccines against human papillomavirus (HPV) types 6/11/16/18 (Gardasil) and 16/18 (Cervarix) are non-viable vaccines composed of recombinant HPV proteins. As a precaution, they should not be given during pregnancy. However, some women are vaccinated shortly before conceiving or early during an undiagnosed pregnancy. What are the risks for the unborn child exposed in utero to these vaccines? We examined data available in late 2011. After in utero exposure to the HPV 6/11/16/18 vaccine during the first trimester, animal studies, only conducted in rats, showed no increase in the risk of malformations. Five clinical trials and the latest annual update of the Pregnancy Registry for Gardasil, released in 2010 and including more than 1000 vaccinated pregnant women, showed no particular pattern of malformations with the quadrivalent vaccine. A few reports of very rare abnormalities are troubling, but they do not clearly implicate the vaccine. Most data on the HPV 16/18 vaccine come from two clinical trials comparing this vaccine with hepatitis A vaccine or placebo vaccination. Fewer than 400 pregnancies exposed to the HPV 16/18 vaccine have been studied. The rate of congenital malformations was similar to that in the control population. In practice, there are few data on exposure to HPV vaccines during the first trimester of pregnancy. There are more, relatively reassuring, data on the HPV 6/11/16/18 vaccine. Women who are vaccinated just before conceiving or early in pregnancy should receive appropriate information. Active pharmacovigilance must continue.     

Pregnancy outcome after exposure to antidepressants and the role of maternal depression: results from the Norwegian Mother and Child Cohort Study

Results of previous studies on the safety of antidepressants during pregnancy have been conflicting. The primary objective of this study was to investigate whether first-trimester exposure to antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs), was associated with increased risk of congenital malformations. The secondary objective was to examine the effects of exposure to antidepressants during pregnancy on birth weight and gestational age.We included 63,395 women from the Norwegian Mother and Child Cohort Study. The women had completed 2 self-administered questionnaires at gestational weeks 17 and 30 on medication use and medical, sociodemographic, and psychological factors. Data on pregnancy outcome were retrieved from the Medical Birth Registry of Norway.Of the 63,395 women, 699 (1.1%) reported using antidepressants during pregnancy, most frequently SSRIs (0.9%). Exposure to SSRIs during the first trimester was not associated with increased risk of congenital malformations in general (adjusted odds ratio [OR], 1.22; 95% confidence interval [CI], 0.81-1.84) or cardiovascular malformations (adjusted OR, 1.51; 95% CI, 0.67-3.43). Exposure to antidepressants during pregnancy was not associated with increased risk of preterm birth (adjusted OR, 1.21; 95% CI, 0.87-1.69) or low birth weight (adjusted OR, 0.62; 95% CI, 0.33-1.16).This study does not suggest a strongly increased risk of malformations, preterm birth, or low birth weight following prenatal exposure to antidepressants. Without adjustments for level of maternal depression and various sociodemographic and lifestyle factors, antidepressant use during pregnancy would wrongly have been associated with an increased risk of preterm birth.     

First trimester exposure to cefuroxime: a prospective cohort study

AIMS: There are no published studies on the safety of cefuroxime use during pregnancy. We therefore investigated prospectively the possible teratogenic effect of intrauterine exposure to cefuroxime. METHODS: One hundred and six women who received cefuroxime during the first trimester of pregnancy were recruited from three teratogen information centres in Israel. Exposed women were paired for age, smoking habits and alcohol consumption with references being exposed to nonteratogenic antibiotics administered for the same indications. RESULTS: Maternal history, birthweight, gestational age at delivery, rates of live births, spontaneous abortions and fetal distress were comparable among the two groups. Rates of major malformations in the cefuroxime group (3.2%) did not differ from references (2%) (P = 0. 61, relative risk = 1.56, 95% confidence interval 0.27-9.15). There was a significantly higher rate of induced abortions among the cefuroxime exposed women as compared to the references (P = 0.04, relative risk = 3.33, 95% confidence interval 0.94-11.77). CONCLUSIONS: Our data may suggest that exposure to cefuroxime during the first trimester is probably not associated with an increased risk for malformations or spontaneous abortions; however, in light of the small sample size and the broad confidence limits, larger studies are needed to confirm these findings.     

First-trimester exposure to amoxycillin/clavulanic acid: a prospective, controlled study

AIMS: The number of published studies on the use of amoxycillin/clavulanic acid during pregnancy is small and so is the number of pregnancies investigated in those studies. In this study we wished to investigate prospectively the safety of intrauterine exposure to amoxycillin/clavulanic acid in a relatively large cohort of women. METHODS: Women treated (n = 191) with amoxycillin/clavulanic acid during the first trimester of pregnancy were recruited from two teratogen information centres in Israel. Exposed women were matched for age, smoking habits and alcohol consumption with 191 controls exposed to amoxycillin only for similar medical indications. RESULTS: Maternal age, birth weight, gestational age at delivery, rates of live births and abortions were comparable between the two groups. Rates of major malformations in the amoxycillin/clavulanic acid group (3/158, 1.9%) did not differ significantly from controls (5/163, 3%) (P = 0.49, relative risk = 0.62, 95% confidence interval 0.15, 2.55), and were within the expected baseline risk for the general population. CONCLUSION: These data suggest that exposure to amoxycillin/clavulanic acid during pregnancy is unlikely to be associated with an increased risk of malformations.     

Bias toward the null hypothesis in pregnancy drug studies that do not include data on medical terminations of pregnancy: the folic acid antagonists

Most studies on safety/risk of drugs in pregnancy consider the proportion of births (but not pregnancy terminations) affected by the drug from all exposed infants. Lack of data on pregnancy terminations could bias results. A computerized database for medications dispensed to pregnant women in southern Israel was linked with records from the district hospital; 84 823 deliveries and 998 medical pregnancy terminations took place; 571 of the women were exposed to folic acid antagonists in the first trimester. When only births were examined, there was no association between folic acid antagonists and fetal malformations. When data on pregnancy terminations were examined and births and pregnancy terminations were combined, there was a significant risk (neural tube defects: odds ratio 18.83, 95% confidence interval 9.24-38.37; cardiovascular defects: odds ratio 3.86, 95% confidence interval 1.67-8.88; and neural tube defects: odds ratio 6.30, 95% confidence interval 3.34-9.15; cardiovascular defects: odds ratio 1.76, 95% confidence interval 1.05-2.92, respectively). Inclusion of only birth data in observational studies of drugs in pregnancy constitutes a source of bias toward the null hypothesis.     

Gestational Exposure to Serotonin Reuptake Inhibitors and Pregnancy Outcome; Exploring the Role of Bias and Confounders

There is no other example in human teratology where, after more than 40 epidemiological studies, repeated meta-analyses and thousands of pregnancies, the fetal safety or risk of an agent has not been verified and settled.The objectives of the present review were to identify and discuss sources of bias that may lead clinicians and scientists to believe that SRIs cause malformation or other adverse outcomes, where, in fact, they may not.The present study highlights sources of bias that may explain why children exposed in utero to SRI exhibit higher rates of congenital malformations, mostly cardiovascular and other complications. It appears that pregnant women treated for depression and anxiety are distinctively different from healthy women in numerous covariates, which may confound pregnancy outcomes. Acknowledging and adjusting for these sources of bias are critical before one selects to withhold therapy for moderate or severe cases of depression and anxiety in pregnancy.     

Safety of the newer antiepileptic drug oxcarbazepine during pregnancy

OBJECTIVE: Seizure control in pregnant women with epilepsy is vital, as maternal seizures may have deleterious consequences. The treatment of pregnant women with epilepsy is, however, complicated by the teratogenicity of older antiepileptic drugs (AEDs). In this review, the safety of the newer AED oxcarbazepine during pregnancy is assessed based on published pregnancy outcome data. Other relevant safety issues, such as oxcarbazepine pharmacokinetics during pregnancy and the compatibility of oxcarbazepine treatment with breastfeeding, are also discussed. METHODS: Literature searches of the following databases were performed: MEDLINE, EMBASE, eNova, NOWIMA (an internal Novartis Germany database), Derwent Drug File, SciSearch and BIOSIS. Identified publications were examined for original data reporting rates of foetal malformation following maternal exposure to oxcarbazepine as monotherapy or adjunctive therapy. RESULTS: Relevant publications reporting data from the worldwide Novartis safety database and pregnancy registries or study centres in six countries were identified. A total of 248 pregnancies involving maternal exposure to oxcarbazepine monotherapy and 61 involving adjunctive therapy were reported. There were six malformations among the monotherapy group, equating to a malformation rate of 2.4% (6/248). The malformation rate reported in the general population is 2-4%. There were four malformations associated with oxcarbazepine adjunctive therapy, equating to a malformation rate of 6.6% (4/61). CONCLUSIONS: This literature review suggests that, compared with newborns in the general population, the newborns of women receiving oxcarbazepine monotherapy during pregnancy do not appear to show an increased risk for malformations. However, the number of pregnancies involving maternal exposure to oxcarbazepine identified by this review is not sufficient to draw definitive conclusions. Additional information from large-scale pregnancy registries is required to confirm the safety profile of oxcarbazepine as monotherapy or adjunctive therapy during pregnancy.     

Antiepileptic drugs during pregnancy: pharmacokinetics and transplacental transfer

Epilepsy represents the most common maternal neurological disorder requiring continuous treatment during pregnancy. Maintaining optimum seizure control is an important objective in pregnancy, and the majority of women with epilepsy will need to continue antiepileptic drugs (AEDs). AEDs are frequently used to treat several other conditions, such as headaches and mood disorders. They have been associated with an increased risk of congenital malformations, minor anomalies, congenital syndrome and development disorders. This risk seems to be higher among women using polypharmacy and valproic acid. Neural tube defects are associated with valproic acid and carbamazepine exposure. New AEDs seem to have a less teratogenic effect, but human experience is still limited. The purpose of this review is to provide an update on AED exposure in pregnancy, focusing on pharmacokinetics and transplacental transport.     

妊娠期抗癫痫药物的安全性研究

妊娠期女性服用抗癫痫药物（antiepileptic drugs,AEDs）对妊娠结局有着重要的影响,如暴露于丙戊酸钠、苯妥英钠、卡马西平等AEDs中会导致新生儿先天性畸形的风险增加。越来越多的证据表明,宫内AEDs暴露可能与认知发展损害有关,会对新生儿造成神经发育方面的远期影响,多药联用及高剂量的AEDs会增加胎儿的致畸风险。本文就传统及新型AEDs妊娠期致畸性风险进行综述。     

Bupropion in pregnancy and the prevalence of congenital malformations

PURPOSE: Reports from the GlaxoSmithKline Bupropion Pregnancy Registry suggested an increase in cardiovascular defects following exposure to bupropion during pregnancy. We conducted a study of congenital malformations among infants born to women exposed to bupropion during their first trimester. METHODS: The study used data from UnitedHealthcare between January 1995 and September 2004. We calculated the prevalence of all congenital malformations and cardiovascular malformations associated with bupropion exposure in the estimated first trimester (1213 infants), compared with (1) other antidepressant exposure in the first trimester (4743 infants) and (2) bupropion exposure outside the first trimester (1049 infants). Malformation cases were confirmed through medical record abstraction. We calculated adjusted odds ratios (AORs) using the GEE form of logistic regression. RESULTS: For all congenital malformations, the prevalence associated with bupropion first trimester was 23.1 per 1000 infants. The AORs were 0.95 (95%CI 0.62-1.45) and 1.00 (95%CI 0.57-1.73) in comparison to other antidepressants (prevalence 23.2 per 1000) and bupropion outside the first trimester (prevalence 21.9 per 1000), respectively. For cardiovascular malformations, the prevalence associated with bupropion first trimester was 10.7 per 1000 infants. The AORs were 0.97 (95%CI 0.52-1.80) and 1.07 (95%CI 0.48-2.40) in comparison to other antidepressants (prevalence 10.8 per 1000) and bupropion outside the first trimester (prevalence 9.5 per 1000), respectively. CONCLUSIONS: Results do not support a hypothesis of a teratogenic effect of first trimester bupropion exposure. The prevalence of malformations associated with bupropion exposure in the first trimester was not increased relative to the comparison groups.     

Oral antihyperglycemic agents during pregnancy and lactation: a review

The treatment approach of diabetes mellitus during pregnancy requires a combination of diet, exercise, multiple home glucose determinations and intensive insulin regimens. During the last decade there was an increased interest in the use of oral antihyperglycemic agents (OAHAs) as an alternative to insulin in achieving good glycemic control. OAHAs are divided into four groups: derivatives of sulfonylurea, biguanides, glucosidase inhibitors and thiazolidinediones. This review describes the possible teratogenic effects of the use of OAHAs during pregnancy and the effects of these drugs during lactation. Animal and human studies assessing the teratogenic effects of OAHAs have yielded conflicting data because the risk of major malformations in infants of mothers with diabetes appears to be related to maternal glycemic control rather than the antidiabetic therapy. A major concern with the use of OAHAs during pregnancy is neonatal hypoglycemia, which may be severe and persist for days. Therefore, insulin is still the drug of choice because it has not been implicated as a teratogen in human pregnancies. In addition, because of the lack of data regarding the use of OAHAs in pregnancy, we cannot draw firm conclusions about all of the available drugs. However, OAHAs, especially glibenclamide (glyburide), may be beneficial in a situation where the proper use of insulin is problematic. Because there are very limited clinical data on the exposure of OAHAs to the infant via breast milk, and the potentially serious effect of neonatal hypoglycemia, the safest recommendation is not to breast feed while taking OAHAs. Well-conducted, prospective, controlled studies regarding the feasibility of OAHAs in pregnant women with diabetes and during lactation are needed.