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Possible negative effects of selective serotonin reuptake inhibitors (SSRIs) in pregnancy relate to congenital anomalies, negative perinatal events and neurodevelopmental outcome. Many studies are confounded by the underlying maternal disease and by pharmacogenetic and pharmacokinetic differences of these drugs. Areas covered: The possible interactions of SSRIs and serotonin and norepinephrine reuptake inhibitors with other drugs and the known effects of SSRIs on congenital anomalies, perinatal and neurodevelopmental outcome. Expert opinion: SSRIs should be given with caution when combined with other drugs that are metabolized by cytochrome P450 enzymes. SSRIs apparently increase the rate of severe cardiac malformations, induce neonatal adaptation problems in up to 30% of the offspring, increase the rate of persistent pulmonary hypertension of the newborn and possibly slightly increase the rate of prematurity and low birth weight. Most neurodevelopmental follow up studies did not find significant cognitive impairments except some transient gross motor delay, slight impairment of language abilities and possibly behavioral changes. The literature on the possible association of SSRIs with autism spectrum disorder is inconsistent; if an association exists, it is apparently throughout pregnancy. The risk associated with treatment discontinuation seems to outweigh the risk of treatment, as severe maternal depression may negatively affect the child's development. If needed, treatment should continue in pregnancy with the minimal effective dose.

It was assumed for decades that the human placenta serves as a barrier, protecting the fetus from exposure to xenobiotics circulating in the mother. The thalidomide disaster completely reversed this concept. The study of the human placenta is therefore critical to understanding the mechanisms by which xenobiotics reach the fetus and exert their effects. Areas covered: This review describes mechanisms by which drugs interact with the human placenta, and experimental methods to study these interactions in humans. We have selected three areas of current clinical interest, where the placenta exhibits critical role in drug transport: The ABC transporters, the placental handling of cancer therapeutic drugs and the interaction between the placenta and immunoglobulins. Expert commentary: The optimal model to predict drug transfer and transport from the mother to the fetus is the isolated human placental lobule perfused in vitro. Unlike subcellular preparations or tissue homogenates, data obtained from a perfused intact tissue, where structural integrity and cell-cell organization are maintained, more closely reflect the in vivo situation. Moreover, confounding metabolic and physiologic influences are minimized and the experimental conditions can be controlled. It is important to remember that due to significant differences in the function of the placenta in the first two months (histiotrophic nutrition) and later in pregnancy (hemotrophic nutrition) there might be differences in the transplacental transfer of drugs. While most of our knowledge comes from studies on term placentae, we are in need of studies on young placenta that functions during the period of organogenesis.

During the last twenty years, in spite of extensive literature regarding the use of SSRIs in pregnancy, confusion still exists as to possible long-term risks of these drugs on the offspring. Possible negative effects relate to neurodevelopmental outcome and association with Autism Spectrum Disorder (ASD). Most neurodevelopmental follow up studies did not find significant cognitive impairment except from some apparently transient, gross motor delay and slight impairment of language abilities. The literature on the possible association of SSRIs with ASD is inconsistent, and if an association exists it is apparently throughout pregnancy. There is a higher risk for psychiatric problems which might be related to the maternal psychiatric disease for which SSRIs were prescribed. Most animal studies did not demonstrate teratogenicity, and the observed neurodevelopmental problems are of models with depression induced during pregnancy. Depression seems to be associated with up regulation of hypothalamic pituitary adrenal (HPA) axis and prenatal SSRIs also seem to affect the HPA axis in animals and man, but the possible long-term outcome has yet to be established. SSRIs might apparently also induce epigenetic changes. There is, however, little proof for significant damaging effects of SSRIs in pregnancy. When evaluating the risk/benefit ratio of SSRI treatment in pregnancy, the risk associated with treatment discontinuation e.g. higher frequency of relapse and postpartum depression appears to outweigh the potential risks of treatment. Moreover, maternal depression may negatively affect the child's development, emphasizing the importance of prevention by appropriate treatment during pregnancy with the least minimal effective dose.

Depression is generally treated with antidepressants, but may often need antipsychotics and mood stabilizers. We discuss the updated data regarding the safety in pregnancy of antidepressants and antipsychotics, except selective serotonin reuptake inhibitors, and their possible impact on the long-term development of the offspring. Several earlier studies demonstrated a slight increase in the rate of major anomalies following maternal tricyclic antidepressant treatment, but most current literature shows their relative safety in pregnancy. Data on the development of the offspring are also reassuring. The antipsychotic drugs are also safe for the developing fetus and do not seem to induce developmental delay. Both groups of drugs may cause perinatal withdrawal symptoms and difficulties in neonatal adaptation. The mood stabilizers, lithium, and several anti-epileptic drugs, may adversely affect the developing embryo and fetus. While valproic acid, carbamazepine, and topiramate are teratogenic and may also affect postnatal development, the newer antiepileptic and mood stabilizers, lamotrigine and levetiracetam, seem to be safe in pregnancy and apparently have no long-term neurodevelopmental damage. Lithium may increase the rate of cardiac anomalies, especially of Ebstein's anomaly, and may warrant a mid-trimester fetal echocardiography. Although data on the development of the offspring are reassuring, we should remember that most studies were carried out during early childhood, at a time when inattention, learning difficulties, behavioral and psychiatric problems are not yet identifiable. When considering medical treatment for depression in women at child-bearing age, we have to weigh the severity of the symptoms and their impact on the developing fetus and child. Birth Defects Research 109:933-956, 2017.© 2017 Wiley Periodicals, Inc.

Despite extensive studies, there still seems to be uncertainty as to the possible reproductive risk of selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine reuptake inhibitors (SNRIs) in pregnancy. We, therefore, assess the current data on the risk/benefit of SSRI use in pregnancy. As the neurodevelopmental effects of SSRIs are discussed in another paper in this issue, we will not address the possible neurodevelopmental effects. Special emphasis is given to the newer, large population-based studies. Most studies have shown that the overall risk of major malformations is similar to that in unexposed children, except for some small increased risk for cardiac anomalies. Persistent pulmonary hypertension of the newborn has also been described with a low absolute risk of

Background Lamotrigine is a second-generation antiepileptic drug, also used as a mood stabilizer. Published data on its use in human pregnancy are largely derived from pregnancy registries. Pregnancy experience in most studies has been reassuring. However, data from the North American Antiepileptic Drug Pregnancy Registry suggested an increased risk for oral clefts. The primary objective of the study was to evaluate the rate of major anomalies after lamotrigine exposure during pregnancy compared with pregnancies of women counseled for nonteratogenic exposure (NTE). Methods Callers who contacted the Israeli Teratology Information Service regarding lamotrigine treatment or NTE during pregnancy between 1997 and 2008 were prospectively followed-up. Results The rate of major congenital anomalies was similar between 218 lamotrigine exposed pregnancies (208 in the first trimester) and 865 NTE-pregnancies. There was no case of oral cleft in the lamotrigine-exposed group. The median lamotrigine dose in the beginning of pregnancy was 200 mg/d. The dose was increased during pregnancy in 29%. The majority of women in the cohort (82%) were treated for neurologic indications, while 18% for psychiatric disorders. Monotherapy was taken by 72%. Conclusion The data available, thus far, on lamotrigine monotherpy-exposed pregnancies are encouraging. However, further studies are needed to determine with greater certainty the overall risk for major anomalies, as well as the specific risk for oral clefts. Based on the current and previously published data, lamotrigine, seems a reasonable alternative for pregnant women when clinically indicated. Birth Defects Research 109:1196-1203, 2017. © 2017 Wiley Periodicals, Inc.

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