Children exposed to antiepileptic drugs in utero : clinical and epidemiological aspects on growth, development and occurrence of malformations

Antiepileptic drugs (AED) are known teratogenic substances. Major congenital malformations, minor anomalies, retarded intrauterine growth and delayed psychomotor development have been reported after exposure to AED in utero. Results from previous studies are inconclusive due to different study designs, therapeutic traditions, genetic and environmental factors. Aims of the study: A) To investigate the incidence of minor anomalies and psychomotor development in children born to women with epilepsy on AED treatment during pregnancy. B) To investigate foetal growth and the incidence of major congenital malformations in children exposed to AED in utero in Sweden between 1973 and 1997 by using the Swedish health registries. One hundred prospectively collected infants, born to 136 women with carefully monitored epilepsy during pregnancy were included in the study of minor anomalies. Based on gestational age, sex and mode of delivery, each infant was matched with infants not exposed to AED in utero. The infants were examined at birth for the occurrence of minor anomalies according to a special protocol. The investigator was unaware of the exposure status of the child. The results showed a significant increase in the incidence of minor anomalies but no special dysmorphic syndromes were observed. The tests from the routinely performed neonatal screening for hypothyreosis and congenital adrenal hyperplasia were re-analysed for 34 of the matched pairs of exposed and unexposed infants. The results showed no differences between the groups. The psychomotor development was assessed with the Griffiths' test at 9 months and at 4.5-5 years of age in the children born to the women on strict treatment strategy during pregnancy (data set 11). The test psychologist performed the evaluation without prior knowledge of the history of exposure status. Between the groups there was no difference in psychomotor development at 9 months of age. A subtle but significant difference in locomotor development in the children exposed to phenytoin (PHT) was observed at the 4.5-5 years follow-up. The influence on body dimensions was investigated in three different data sets collected 1973-1997. Data set I (1973-1980) consisted of 354 children exposed to AED in utero identified retrospectively by record linkage between the Medical Birth Registry and the Hospital Discharge Registry in Sweden. Data set II (1985-1995) is the above-described data set, but here 123 of the eligible infants are included. Data set III (1995-1997) consists of 500 infants exposed to AED in utero, identified prospectively in the Medical Birth Registry. A total of 963 singleton deliveries was included. The mean values for birth weight, body length, head circumference, and pregnancy duration for the infants in the three data sets were compared with the general population (2.5 million births) after stratification for year of birth, maternal age, parity, and maternal educational level or smoking habits. The number of women with monotherapy treatment increased from 40 to 90 % over the study period. A reduction in body dimensions was observed, more marked after exposure to polytherapy. This reduction decreased over the 25-year study period. The incidence of major congenital malformations was investigated using the same three cohorts. In addition, data from the Swedish Registry of Congenital Malformations, the Child Cardiology Registry and the Hospital Discharge Registry were added. A total of 977 infants was included. There was a significant increase in the number of major congenital malformations (OR: 1.5 95%CI: 1.1-2.0). Conclusions: There may be an association between exposure to AED in utero and a) impaired foetal growth, b) a subtle delay in motor development, c) an increased risk of major congenital malformations and d) minor anomalies in the children. Maternal treatment with monotherapy in low doses seems to have the least negative influence on the infants. The methods used in the present study do not distinguish between the effects of maternal AED treatment and genetic or environmental factors. Further follow-up studies are warranted to study subtle influences on growth and psychomotor development

School performance at age 16 in children exposed to antiepileptic drugs in utero-A population-based study.

Purpose: In order to evaluate long-term effects on neurodevelopment in children born to women with epilepsy during pregnancy we studied the children's school grades at age 16. Methods: We used the Patient Register, the Medical Birth Register, and a local study at South Hospital, Stockholm, to identify women with epilepsy in Sweden who had given birth between 1973 and 1986. The Swedish School Mark Registry was used to obtain information about school grades from the last year of compulsory school, at age 16. Exposed children were compared to all other children born in Sweden between 1973 and 1986. Key Findings: Medical records were analyzed for 1,235 children. Six hundred forty-one children had been exposed in utero to antiepileptic drugs (AEDs) in monotherapy, 429 in polytherapy, and 165 to no known AED. Children exposed to polytherapy had an increased risk of not receiving a final grade-odds ratio (OR) 2.99 [95% confidence interval (CI) 2.14-4.17]. Children exposed to monotherapy, mainly carbamazepine or phenytoin, did not have a significantly increased risk of not receiving a final grade-OR 1.19 (95% CI 0.79-1.80). Children born to women with epilepsy had a decreased chance of getting a "pass with excellence." Significance: Exposure to several AEDs in utero may have negative effects on neurodevelopment, and polytherapy should, if possible, be avoided in pregnant women

Neonatal adaptation in infants prenatally exposed to antidepressants--clinical monitoring using Neonatal Abstinence Score.

BACKGROUND: Intrauterine exposure to antidepressants may lead to neonatal symptoms from the central nervous system, respiratory system and gastrointestinal system. Finnegan score (Neonatal Abstinence Score, NAS) has routinely been used to assess infants exposed to antidepressants in utero. AIM: The purpose was to study neonatal maladaptation syndrome in infants exposed to selective serotonin reuptake inhibitors (SSRI) or serotonin-norepinephrine reuptake inhibitors (SNRI) in utero. METHOD: Retrospective cohort study of women using antidepressants during pregnancy and their infants. Patients were identified from the electronic health record system at Karolinska University Hospital Huddinge containing pre-, peri- and postnatal information. Information was collected on maternal and infant health, social factors and pregnancy. NAS sheets were scrutinized. RESULTS: 220 women with reported 3rd trimester exposure to SSRIs or SNRIs and who gave birth between January 2007 and June 2009 were included. Seventy seven women (35%) used citalopram, 76 used (35%) sertraline, 34 (15%) fluoxetine and 33 (15%) other SSRI/SNRI. Twenty-nine infants (13%) were admitted to the neonatal ward, 19 were born prematurely. NAS was analyzed in 205 patients. Severe abstinence was defined as eight points or higher on at least two occasions (on a scale with maximum 40 points), mild abstinence as 4 points or higher on at least two occasions. Seven infants expressed signs of severe abstinence and 46 (22%) had mild abstinence symptoms. Hypoglycemia (plasma glucose <2.6 mmol/L) was found in 42 infants (19%). CONCLUSION: Severe abstinence in infants prenatally exposed to antidepressants was found to be rare (3%) in this study population, a slightly lower prevalence than reported in previous studies. Neonatal hypoglycemia in infants prenatally exposed to antidepressant may however be more common than previously described

Antipsychotic Use During Pregnancy and Risk for Gestational Diabetes : A National Register-Based Cohort Study in Sweden

Objective: We aimed to study whether antipsychotic use during pregnancy is associated with gestational diabetes. Methods: This was a Swedish national register‐based cohort study on the Medical Birth Register and the Prescribed Drug Register including all 1,307,487 singleton births between July 2006 and December 2017. Antipsychotics were divided into first-generation antipsychotics (n = 728), high-risk metabolic second-generation antipsychotics including olanzapine, clozapine and quetiapine (n = 1710), and other second-generation antipsychotics (n = 541). The risks for gestational diabetes, foetal growth disturbances, pre-eclampsia, caesarean section and preterm labour were assessed. Women treated during pregnancy were compared to women not treated during pregnancy and to women who used antipsychotics before/after but not during pregnancy. Results: The crude risk ratio for gestational diabetes for women treated with high-risk metabolic second-generation antipsychotics during pregnancy was 2.2 (95% confidence interval [CI] 1.6–2.9) compared to untreated pregnant women (n = 1,296,539) and 1.8 (95% CI 1.4–2.5) compared to women treated before/after pregnancy (n = 34,492). After adjustment for maternal factors including body mass index, the risk ratios were 1.8 (95% CI 1.3–2.4) and 1.6 (95% CI 1.2–2.1). Exposed infants had an increased risk of being large for gestational age: adjusted risk ratios 1.6 (95% CI 1.3–1.9) and 1.3 (95% CI 1.1–1.6) compared to no maternal antipsychotic use during pregnancy and maternal use before/after the pregnancy. Other antipsychotics were not associated with metabolic risks. Conclusions: Olanzapine, clozapine and quetiapine used during pregnancy were associated with increased risks for gestational diabetes and the infant being large for gestational age. Enhanced metabolic monitoring should be considered for pregnant women using these drugs

Neonatal morbidity after fetal exposure to antipsychotics : a national register-based study

Objective To investigate the admission rate to neonatal care and neonatal morbidity after maternal use of antipsychotics during pregnancy. Design A population-based register study. Setting Information on all singleton births between July 2006 and December 2017 in Sweden including data on prescription drugs, deliveries and infants' health was obtained from the Swedish Medical Birth Register, the Prescribed Drug Register and the Swedish Neonatal Quality Register. Exposed infants were compared with unexposed infants and with infants to mothers treated with antipsychotics before or after but not during pregnancy. Participants The cohort comprised a total of 1 307 487 infants, of whom 2677 (0.2%) were exposed to antipsychotics during pregnancy and 34 492 (2.6%) had mothers who were treated before/after the pregnancy. Outcome measures The primary outcome was admission rate to neonatal care. Secondary outcomes were the separate neonatal morbidities. Results Of the exposed infants, 516 (19.3%) were admitted to neonatal care compared with 98 976 (7.8%) of the unexposed infants (adjusted risk ratio (aRR): 1.7; 95% CI: 1.6 to 1.8), with a further increased risk after exposure in late pregnancy. The highest relative risks were seen for withdrawal symptoms (aRR: 17.7; 95% CI: 9.6 to 32.6), neurological disorders (aRR: 3.4; 95% CI: 2.4 to 5.7) and persistent pulmonary hypertension (aRR: 2.1; 95% CI: 1.4 to 3.1) when compared with unexposed infants. The absolute risks for these outcomes were however low among the exposed infants, 1.3%, 1.8% and 1.0%, respectively, and the relative risks were lower when compared with infants to mothers treated before/after the pregnancy. Conclusion Fetal exposure to antipsychotics was associated with an increased risk of neonatal morbidity. The effects in the exposed infants seem transient and predominantly mild, and these findings do not warrant discontinuation of a necessary treatment but rather increased monitoring of these infants. The increased risk of persistent pulmonary hypertension requires further studies

Neonatal morbidity after maternal use of antidepressant drugs during pregnancy

OBJECTIVES: To estimate the rate of admissions to NICUs, as well as infants' morbidity and abs neonatal interventions, after exposure to antidepressant drugs in utero. METHODS: Data on pregnancies, deliveries, prescription drug use, and health status of the newborn infants were obtained from the Swedish Medical Birth Register, the Prescribed Drug Register, and the Swedish Neonatal Quality Register. We included 741 040 singletons, born between July 1, 2006, and December 31, 2012. Of the infants, 17 736 (2.4%) had mothers who used selective serotonin reuptake inhibitors (SSRIs) during pregnancy. Infants exposed to an SSRI were compared with nonexposed infants, and infants exposed during late pregnancy were compared with those exposed during early pregnancy only. The results were analyzed with logistic regression analysis. RESULTS: After maternal use of an SSRI, 13.7% of the infants were admitted to the NICU compared with 8.2% in the population (adjusted odds ratio: 1.5 [95% confidence interval: 1.4-1.5]). The admission rate to the NICU after treatment during late pregnancy was 16.5% compared with 10.8% after treatment during early pregnancy only (adjusted odds ratio: 1.6 [95% confidence interval: 1.5-1.8]). Respiratory and central nervous system disorders and hypoglycemia were more common after maternal use of an SSRI. Infants exposed to SSRIs in late pregnancy compared with early pregnancy had a higher risk of persistent pulmonary hypertension (number needed to harm: 285). CONCLUSIONS: Maternal use of antidepressants during pregnancy was associated with increased neonatal morbidity and a higher rate of admissions to the NICU. The absolute risk for severe disease was low, however

Neonatal Abstinance Score.

<p>Modified from Finnegan to Swedish, (Sarman 2000) here re-translated.</p

Neonatal characteristics of infants exposed to antidepressants in utero, born 1 Jan 2007 to 30 June 2009 at Karolinska University Hospital.

<p>*gestational age <37+0.</p><p>**other antidepressants (n = 33): escitalopram (13 patients), venlafaxine (11), paroxetine (8) and duloxetine (1).</p>†<p>p 0.02, statistical test (logistic regression, adjusting for gestational age, maternal tobacco use, infant sex and 5 min Apgar).</p><p>Neonatal characteristics of infants exposed to antidepressants in utero, born 1 Jan 2007 to 30 June 2009 at Karolinska University Hospital.</p

Characteristics of study population, women with antidepressant treatment and delivery at Karolinska University Hospital Huddinge Jan 2007 to June 2009.

≠<p>one patient can have more than one diagnosis.</p>≠≠<p>other psychiatric diagnoses, all antidepressants (n): Phobia (4), Post-traumatic stress disorder (4), Eating disorder (9), Personality disorder (6), Obsessive compulsive disorder (7), Bipolar disorder type II (1), Attention deficit hyperactivity disorder (3).</p><p>*stated by mother at interview with midwife in prenatal care center, gestational week 10–14.</p><p>**other antidepressants (n = 33): escitalopram (13 patients), venlafaxine (11), paroxetine (8) and duloxetine (1).</p><p>***Highest dose in maternal care records during third trimester.</p><p>NA  =  not applicable.</p><p>Characteristics of study population, women with antidepressant treatment and delivery at Karolinska University Hospital Huddinge Jan 2007 to June 2009.</p