Prenatal exposure to selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors and risk for persistent pulmonary hypertension of the newborn: a systematic review, meta-analysis, and network meta-analysis.

BACKGROUND: There is a marked increase in the use of selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors in the last decade. Many newborns are likely to be exposed during pregnancy and labor. OBJECTIVE: We aimed to evaluate the association between exposure to selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors during pregnancy and the risk for persistent pulmonary hypertension of the newborn. We sought to compare the risk for persistent pulmonary hypertension of the newborn between specific selective serotonin reuptake inhibitor agents. STUDY DESIGN: MEDLINE, Embase, and Cochrane were searched up to July 2017. No language restrictions were applied. Search key words included: "SSRI," "SNRI," "pregnancy," "risk," "new-born," and "pulmonary hypertension." Retrospective cohort studies and case-control studies reporting the risk for persistent pulmonary hypertension of the newborn in the offspring of women exposed to selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors during pregnancy, were extracted. Two independent researchers identified relevant data. Random effects meta-analysis was used to pool results. Odds ratios were calculated with subsequent 95% confidence intervals. Network meta-analysis was conducted, incorporating direct and indirect comparisons among different selective serotonin reuptake inhibitors. The primary outcome was risk for persistent pulmonary hypertension of the newborn after exposure to selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors during pregnancy. RESULTS: A total of 11 studies were identified. A total of 156,978 women and their offspring were exposed to selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors during pregnancy. Persistent pulmonary hypertension of the newborn was detected among 452 exposed offspring, representing an incidence rate of 2.9 cases per 1000 live births and a number needed to harm of 1000. The risk for persistent pulmonary hypertension of the newborn was significantly increased in the analysis of exposure to selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor in any trimester (odds ratio, 1.82; 95% confidence interval, 1.31-2.54; I2 = 72%), as well as in analysis restricted to exposure week >20 (odds ratio, 2.08; 95% confidence interval, 1.44-3.01; I2 = 76%). In network meta-analysis, sertraline was ranked most likely to have the lowest risk for persistent pulmonary hypertension of the newborn among the different selective serotonin reuptake inhibitors (P = .83). CONCLUSION: Exposure to selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors during pregnancy is associated with an increased risk for persistent pulmonary hypertension of the newborn. According to our findings, sertraline ranked as most likely to have the lowest risk for persistent pulmonary hypertension of the newborn compared to other selective serotonin reuptake inhibitors, suggesting it may have the best safety profile for use in pregnancy in this regard. Further studies are needed to fully establish these results.

SSRI and SNRI use during pregnancy and the risk of persistent pulmonary hypertension of the newborn.

AIM: The use of selective serotonin reuptake inhibitors (SSRIs) in late pregnancy may be associated with an increased risk of persistent pulmonary hypertension of the newborn (PPHN). Limited data are available on the risk of PPHN associated with serotonin norepinephrine reuptake inhibitors (SNRIs). We aimed to quantify both associations. METHODS: Using data from the Quebec Pregnancy Cohort between 1998 and 2009, we included women covered by the provincial drug plan who had a singleton live birth. Exposure categories were SSRI, SNRI and other antidepressant use; non-users were considered as the reference category. Generalized estimating equation models were used to obtain risk estimates and 95% confidence intervals (CIs). Confounding by indication was minimized by adjusting for history of maternal depression/anxiety before pregnancy. RESULTS: Overall, 143 281 pregnancies were included; PPHN was identified in 0.2% of newborns. Adjusting for maternal depression, and other potential confounders, SSRI use during the second half of pregnancy was associated with an increased risk of PPHN [adjusted odds ratio (aOR) 4.29, 95% CI 1.34, 13.77] compared with non-use of antidepressants; SNRI use during the same time window was not statistically associated with the risk of PPHN (aOR 0.59, 95% CI 0.06, 5.62). Use of SSRIs and SNRIs before the 20th week of gestation was not associated with the risk of PPHN. CONCLUSIONS: Use of SSRIs in the second half of pregnancy was associated with the risk of PPHN. Given our results on SNRIs and the lack of statistical power for these analyses, it is unclear whether SNRI use during pregnancy also increases the risk of PPHN.

The use of antidepressant medication in pregnancy.

The use of antidepressant medications during pregnancy has stimulated much professional and public debate. As a consequence, considerable data on the reproductive safety of antidepressants has been generated that exceeds the available information for most, if not all, other classes of medications that may be used in the perinatal period. Despite progress to date, definitive conclusions are limited by the methodological issues inherent to clinical research involving illness versus treatment effects in pregnancy. A notable shortcoming is the limited discussion of statistically significant (a mathematical determination) versus clinically significant (incorporation of incidence and effect sizes into practical relevance). Research emphasises completing an individualised 'risk-benefit' assessment, which is a laudable goal but falls short in providing succinct practical guidelines that includes the key educational points for patients. In this chapter, we focus on areas in which the preponderance of data are consistent, and there is concordance with the preclinical literature to generate a practical approach for antidepressant use in pregnancy.

Maternal use of cyclobenzaprine (Flexeril) may induce ductal closure and persistent pulmonary hypertension in neonates.

A full-term male infant presented shortly after birth with respiratory distress. An echocardiogram done within the first hour of life showed an elevated pulmonary artery pressure, an associated right ventricular hypertrophy without a patent ductus arteriosus. The patient was treated for persistent pulmonary hypertension with favorable response. Maternal history was unremarkable except for chronic low back pain treated with cyclobenzaprine (Flexeril®). A proposed mechanism for cyclobenzaprine includes inhibition of norepinephrine and serotonin reuptake, factors known to inhibit prostaglandin and nitric oxide. These two factors are the leading causes of in-utero ductal closure. This report is the first to indicate that cyclobenzaprine use during late pregnancy should be considered a potential cause of early ductal closure.

The effect of perinatal exposures on the infant: antidepressants and depression.

Depression, anxiety, or both, during pregnancy are common complications during the perinatal period, with 15-20% of women experiencing depression at some point during their pregnancy. Considerable evidence suggests that untreated or undertreated maternal Axis I mood disorders can increase the risk for preterm birth, low birth weight, and alter neurobehavioral development in utero. Serotonin reuptake inhibitor antidepressants are often considered for antenatal therapy, with the goal of improving maternal mental health during pregnancy. Treatment with a serotonin-reuptake inhibitor, however, does not guarantee remission of depression, and in-utero serotonin reuptake inhibitor exposure has also been linked to increased risks for adverse infant outcomes. In this chapter, evidence linking serotonin reuptake inhibitor use with an increased risk for postnatal adaptation syndrome, congenital heart defects, and neonatal persistent pulmonary hypertension is reviewed. Management decisions should include attention to the continuum of depression symptoms, from subclinical to severe major depressive disorder and the long-term developmental risks that might also be associated with pre- and postnatal exposure.

Drug exposure: inclusion of dispensed drugs before pregnancy may lead to underestimation of risk associations.

OBJECTIVES: To assess the impact of exposure misclassification on risk associations when using prescription databases as the source for drug exposure in pregnancy by applying results from a validation analysis of exposure classification. STUDY DESIGN AND SETTING: Linkage of data on 27,656 participants in the Norwegian Mother and Child Cohort Study (MoBa) with the Norwegian Prescription Database (NorPD). Exposure to selective serotonin reuptake inhibitors (SSRIs) was defined by dispensed drugs during pregnancy including different time windows before pregnancy. The validity of NorPD data was estimated using self-reported use in MoBa as the reference standard. We applied the results from the validation analysis on data from a Nordic study on SSRI use in pregnancy and risk of persistent pulmonary hypertension in the newborn. RESULTS: Sensitivity increased and specificity decreased when the time window in NorPD was expanded before pregnancy. Using the same time window as in the Nordic study (+90 days before pregnancy), for use in early pregnancy, the odds ratio (OR) corrected for misclassification was 2.6 compared with the OR of 1.6 in the Nordic study. CONCLUSION: Expansion of the time window to include intervals before pregnancy can lead to lower specificity and underestimation of risk associations.

Antidepressant use in pregnancy: a critical review focused on risks and controversies.

OBJECTIVE: Conflicting data have led to controversy regarding antidepressant use during pregnancy. The objectives of this study are to i) review the risks of untreated depression and anxiety, ii) review the literature on risks of exposure to antidepressants during pregnancy, iii) discuss the strengths and weaknesses of the different study designs used to evaluate those risks, and iv) provide clinical recommendations. METHOD: MEDLINE/PubMed was searched for reports and studies on the risk of first-trimester teratogenicity, postnatal adaptation syndrome (PNAS), and persistent pulmonary hypertension (PPHN) with in utero antidepressant exposure. RESULTS: While some individual studies suggest associations between some specific major malformations, the findings are inconsistent. Therefore, the absolute risks appear small. PNAS occurs in up to 30% of neonates exposed to antidepressants. In some studies, PPHN has been weakly associated with in utero antidepressant exposure, while in other studies, there has been no association. CONCLUSION: Exposures of concern include that of untreated maternal illness as well as medication exposure. It is vital to have a careful discussion, tailored to each patient, which incorporates the evidence to date and considers methodological and statistical limitations. Past medication trials, previous success with symptom remission, and women's preference should guide treatment decisions.

Prenatal exposure to selective serotonin reuptake inhibitors and infant outcome.

BACKGROUND: The selective serotonin reuptake inhibitors are prescribed increasingly also during pregnancy. Although a number of studies have assessed their safety, data concerning congenital malformations and adverse perinatal outcome are conflicting. METHODS: Literature search in PubMed until March 31, 2012, including original research articles, meta-analyses, and reviews. RESULTS: Fluoxetine and paroxetine use in early pregnancy has been associated with a small increased risk for specific cardiovascular malformations in some studies, fluoxetine with ventricular septal defects and paroxetine with right ventricular outflow tract defects. The observed absolute risk for these specific malformations is small. Data on preterm birth, low birth weight, and being small for gestational age have been conflicting; and mother's underlying depression is obviously an important confounder. Respiratory distress and neonatal adaptation problems are common in prenatally exposed infants, and an increased risk for persistent pulmonary hypertension of the newborn has been observed in several studies. Although several studies have not confirmed an increased risk for adverse neurodevelopment, a recent study observed an increased risk for autism spectrum disorders in prenatally exposed offspring. CONCLUSIONS: Causality cannot be confirmed in observational study settings. However, parallel results in individual studies regarding the cardiac malformations and pulmonary hypertension of the newborn, together with an existing biologically plausible mechanism behind these events may support causality. Considering the important role of serotonin in central nervous system development, more studies are needed to assess the possible adverse effects on long-term neurodevelopment.

Further findings linking SSRIs during pregnancy and persistent pulmonary hypertension of the newborn: clinical implications.

Persistent pulmonary hypertension of the newborn (PPHN) is a rare but potentially life-threatening neonatal condition. Several authors have suggested that late pregnancy exposure to selective serotonin reuptake inhibitors (SSRIs) may increase the risk of PPHN. This association has been investigated in seven published studies that have shown mixed findings based on diverse methods. Several methodological limitations may account for the diversity of findings, which include, in some studies, a lack of control for well established risk factors for PPHN. The methodological improvement in the most recent study tentatively suggests that infants prenatally exposed to SSRIs are approximately twice as likely to suffer PPHN. Further research on the biological mechanisms involved is required. Clinicians should consider late pregnancy exposure to SSRIs as one of several possible risks for PPHN, which has implications for both prescribing SSRIs to pregnant women and for neonatal care of SSRI-exposed infants.

Antidepressant use in pregnancy and persistent pulmonary hypertension of the newborn (PPHN): a systematic review.

BACKGROUND: An association between PPHN and antidepressant use in pregnancy has been reported. PURPOSE: We sought to examine this relationship. METHODS: A review of the literature was performed, to evaluate this association. RESULTS: Six published studies fulfilled our criteria for inclusion, with only three studies large enough to have the power to detect an association. There appears to be a small but significantly, increased risk of late pregnancy SSRI exposure associated with PPHN in one case-control study; OR 5.1 (95% CI, 1.9-13.3) and two large cohort studies; RR 2.56; (95% CI, 1.17-4.85) and OR 2.1 (95% CI, 1.5-3.0) The other three studies did not find an association. CONCLUSION: the absolute risk cannot be determined, but it is very small, probably less than 1%. If a pregnant woman requires pharmacological treatment, this information does not support discontinuation or lowering the dose of the antidepressant.

Clinical features of the complete closure of the ductus arteriosus prenatally.

OBJECTIVE: Prenatal constriction of the ductus arteriosus associated with maternal drug ingestion was reported several decades ago. There are fewer reports of the complete closure of the ductus arteriosus; therefore, the clinical features of the latter are poorly understood. The aim of this study is to clarify the clinical features of complete ductal closure and postnatal pulmonary hypertension by performing echocardiography of the fetus. PATIENTS: We diagnosed four fetuses with complete ductal closure by performing fetal echocardiography and reviewed the prenatal and postnatal medical records of the mother and fetus. RESULTS: One mother each had bronchial asthma, ulcerative colitis, and idiopathic thrombocytopenic purpura, and they had received nonsteroidal anti-inflammatory drugs and/or corticosteroids during pregnancy. The fourth mother did not have basal disease and had not ingested any drugs. Fetal diagnosis was performed at 32-38 weeks of gestation. All fetuses had right heart dilatation with tricuspid regurgitation in the absence of any cardiac defects, and Doppler echocardiography indicated that the right ventricular pressure was elevated. Two of the fetuses had fetal hydrops, which suggested severe right heart dysfunction. All fetuses were delivered by emergent cesarean delivery. After birth, all the infants developed persistent pulmonary hypertension and required oxygen inhalation. Of these, three required mechanical ventilation, and two, nitric oxide inhalation. All infants improved within 2 weeks, and they had no neurological and cardiac complications after discharge. CONCLUSION: Right heart dilatation and severe tricuspid regurgitation in the absence of a cardiac defect in the fetus strongly suggested ductal dysfunction. Careful evaluation of ductal patency and right ventricular function can lead to precise early diagnosis and good prognosis.

Fetal pulmonary vascular remodeling in a rat model induced by hypoxia and indomethacin.

OBJECTIVE: This study sought to determine the effect of combined treatment of hypoxia plus indomethacin on pulmonary vascular remodeling in fetal rats. METHODS: Hypoxia and indomethacin were used to treat pregnant rats during 19-21 days of gestation. The adventitia, media, and intima of pulmonary arteries from fetal rats were assessed. Western blots were used for determining the abundance of smooth muscle specific alpha-actin protein (α-SMA), elastin, and endothelial nitric oxide synthase (eNOS) in lung tissues. Plasma brain-type natriuretic peptide (BNP) levels, reflecting the increased right ventricular load or pulmonary arterial pressure, were detected. RESULTS: The ratio of left ventricular free wall plus septum to right ventricular weight significantly increased in hypoxia plus indomethacin-treated group. The medial thickness percentage of pulmonary arteries of < 100 µm and ≥100 µm in diameter from hypoxia plus indomethacin-treated group was higher than that from control or single treatment group. Vascular elastin area percentage and immunostaining density of eNOS from the combined-treated group were higher than other groups. The relative abundance of α-SMA, elastin, and eNOS and plasma BNP levels in hypoxia plus indomethacin-treated group also significantly increased compared with other groups. CONCLUSIONS: Hypoxia and indomethacin had synergistic effect on fetal pulmonary vascular remodeling. This rat model induced by combined treatments can mimic human persistent pulmonary hypertension of the newborn.

[Non-steroidal anti-inflammatory drugs in pregnancy]. / Nesteroidní protizánetlivé léky v gravidite.

Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, antipyretic (lowering an elevated body temperature and relieving pain without impairing consciousness) and, in higher doses, with anti-inflammatory effects (reducing inflammation). As inhibitors of cyclooxygenase NSAIDs given during pregnancy have the potential to cause adverse maternal and fetal effects. Maternal effects include prolongation of pregnancy and labour, whereas constriction of the ductus arteriosus, renal dysfunction and haemostatic abnormalities can occur in the fetus and neonate. As weak acids, NSAIDs are excreted in small amounts into human breast milk with little risk for adverse effects in the suckling infant.

Hipertensión pulmonar neonatal grave tras ingestión de antiinflamatorios no esteroideos durante el embarazo / Persistent pulmonary hypertension of the newborn following ingestion of nonsteroidal anti-inflammatory drugs during pregnancy

Los antiinflamatorios no esteroideos inhiben la síntesis de prostaglandinas y producen una vasoconstricción del conducto arterioso fetal durante la gestación. Presentamos los casos de dos recién nacidos con hipertensión pulmonar grave secundaria a cierre ductal. En las semanas previas al parto, una de las madres había recibido tratamiento con ácido acetilsalicílico y la otra, con ácido niflúmico. Éste es el segundo caso descrito en la literatura médica de cierre ductal intraútero tras administración de ácido niflúmico. La ingestión de antiinflamatorios no esteroideos durante el embarazo está desaconsejado. No obstante, en las gestantes tratadas se debe realizar una monitorización continua, y la ecocardiografía fetal es de gran utilidad (AU)

Nonsteroidal anti-inflammatory drugs induce the inhibition of prostaglandin synthesis, which can cause constriction of the fetal ductus arteriosus in the pregnancy. We report two cases of antenatal closure of ductus arteriosus with severe pulmonary hypertension following maternal ingestion of nonsteroidal anti-inflammatory drugs (niflumic acid and acetylsalicylic acid) in the last days before delivery. To our knowledge, this is only the second case in literature describing antenatal closure of ductus arteriosus after the administration of niflúmic acid. Prescription of nonsteroidal anti-inflammatory drugs must be avoided during pregnancy. Fetal echocardiography must be monitored in those women treated with nonsteroidal anti-inflammatory drugs (AU)

Maternal use of selective serotonin re-uptake inhibitors and persistent pulmonary hypertension of the newborn.

In order to evaluate the previously published association between maternal use of selective serotonin re-uptake inhibitors (SSRI) and persistent pulmonary hypertension in the neonate (PPHN), we used data from the Swedish Medical Birth Register for the years 1997-2005. Infants were identified from discharge diagnoses, and maternal exposure to drugs from interviews performed in early pregnancy and from prescriptions from the antenatal care service. Putative confounders were studied: an increased risk for PPHN was indicated for high maternal age, for first parity, for maternal BMI, and possibly for maternal smoking. Adjusting for these variables and year of birth, an association between maternal use of SSRI and PPHN in births after 34 completed weeks was identified with a risk ratio of 2.4, 95%CI 1.2-4.3 when based on women who reported the drug use in early pregnancy. When a subgroup of the women were studied who also had prescriptions for SSRI from the antenatal care later in pregnancy, the risk estimate was 3.6, 95%CI 1.2-8.3. The risk estimates were lower than that described previously in the literature, but both estimates could come from the same about 4-5 times increased risk. The mechanism behind the association between SSRI and PPHN is unclear but an increased risk for respiratory problems after maternal use of SSRI is well known, and PPHN could be a rare part of this association.

SSRI antidepressants and persistent pulmonary hypertension in newborns.

(1) The list of adverse effects of selective serotonin reuptake inhibitor (SSRI) antidepressants in pregnant women and their newborns continues to grow; (2) It was already known that, when taken towards the end of pregnancy, SSRIs could cause spontaneously resolving neonatal disorders, particularly neurological problems; (3) A case-control study has shown an association between maternal exposure to SSRI antidepressants after the 20th week of pregnancy and neonatal persistent pulmonary hypertension, with a 6-fold increase in the risk. Another study has provided similar results; (4) Diagnosis of depression must be made with care during pregnancy, and it should be remembered that not all patients with depression require drug therapy.