Rate Of Major Anomalies Research Articles

Screening of multi-endocrine disruptors in zebrafish

The objective of the study was to evaluate the rate of major congenital anomalies after first trimester exposure to ondansetron for nausea and vomiting of pregnancy (NVP). The design is a prospective, comparative, observational cohort study, performed at the Israeli Teratology Information Service between 2010 and 2014. Follow-up was obtained for 195 ondansetron-exposed, 110 metoclopramide-exposed, and 778 pregnancies with non-teratogenic exposure (NTE). The overall rate of major anomalies did not significantly differ between the groups [4/200 = 2.0 % (ondansetron), 1/109 = 0.9 % (metoclopramide), and 13/731 = 1.8 % (NTE)]. All the anomalies in both the ondansetron and metoclopramide groups, and 6/13 anomalies in the NTE group, were cardiac septal defects most of which spontaneously resolved. Both ondansetron (adjHR = 0.29, 95 % CI 0.10−0.80) and metoclopramide (adjHR = 0.27, 95 % CI 0.08−0.86) were associated with lower miscarriage rate compared to NTE. Based on the present study, ondansetron during pregnancy is not associated with an increased risk for overall major anomalies, nor for clinically important cardiac defects. It may be a reasonable alternative for women with severe NVP who do not respond to first line medications.

Pregnancy outcome following in-utero exposure to ondansetron: A prospective comparative observational study

The objective of the study was to evaluate the rate of major congenital anomalies after first trimester exposure to ondansetron for nausea and vomiting of pregnancy (NVP). The design is a prospective, comparative, observational cohort study, performed at the Israeli Teratology Information Service between 2010 and 2014. Follow-up was obtained for 195 ondansetron-exposed, 110 metoclopramide-exposed, and 778 pregnancies with non-teratogenic exposure (NTE). The overall rate of major anomalies did not significantly differ between the groups [4/200 = 2.0 % (ondansetron), 1/109 = 0.9 % (metoclopramide), and 13/731 = 1.8 % (NTE)]. All the anomalies in both the ondansetron and metoclopramide groups, and 6/13 anomalies in the NTE group, were cardiac septal defects most of which spontaneously resolved. Both ondansetron (adjHR = 0.29, 95 % CI 0.10−0.80) and metoclopramide (adjHR = 0.27, 95 % CI 0.08−0.86) were associated with lower miscarriage rate compared to NTE. Based on the present study, ondansetron during pregnancy is not associated with an increased risk for overall major anomalies, nor for clinically important cardiac defects. It may be a reasonable alternative for women with severe NVP who do not respond to first line medications.

Antidepressants, Antipsychotics, and Mood Stabilizers in Pregnancy: What Do We Know and How Should We Treat Pregnant Women with Depression.

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.

Selective Serotonin Reuptake Inhibitors during Pregnancy: Do We Have Now More Definite Answers Related to Prenatal Exposure?

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 <1%, less than twice that observed in nonexposed newborns. Poor neonatal adaptation was described in up to 25% of exposed neonates. However, newer population-based studies have also shown similarly high rates among offspring of women with untreated depression. There is a higher risk for psychiatric problems possibly related to the maternal psychiatric disease for which SSRIs were prescribed. Judging from the new population registry-based studies with comparison to disease controls, there seems to be no demonstrable increase in the rate of major anomalies, prematurity, small for gestational age, or miscarriage. Therefore, the risk associated with treatment discontinuation (e.g., higher frequency of relapse, and postpartum depression) appears to outweigh the fetal and neonatal risks of maternal treatment. Thus, following appropriate explanation regarding possible risks, treatment should continue during pregnancy with minimal effective doses. Birth Defects Research 109:898-908, 2017. © 2017 Wiley Periodicals, Inc.

First-trimester exposure to metformin and risk of birth defects: a systematic review and meta-analysis.

Metformin is generally considered a non-teratogenic drug; however, only a few studies specifically designed to assess the rate of congenital anomalies after metformin use have been published in the literature. The objects of the present study were to review all of the prospective and retrospective studies reporting on women treated with metformin at least during the first trimester of their pregnancy and to estimate the overall rate of major birth defects. Databases were searched for English language articles until December 2013. Inclusion criteria for the meta-analysis were: a case group of women with PCOS or pre-pregnancy type 2 diabetes and first-trimester exposure to metformin; a disease-matched control group which was not exposed to metformin or other oral anti-diabetic agents; and a list of the major anomalies in both the study and the control groups. A random effects model was used for the meta-analysis of data, using odds ratios. Studies not fulfilling the inclusion criteria for the meta-analysis but reporting relevant data on major malformations in women diagnosed with PCOS were then used to estimate the overall birth defects rate. Meta-analysis of nine controlled studies with women affected by PCOS detected that the rate of major birth defects in the metformin-exposed group was not statistically increased compared with the disease-matched control group and that there was no significant heterogeneity among the studies. The metformin-exposed sample was composed of 351 pregnancies and the OR of major birth defects was 0.86 (95% confidence interval: 0.18-4.08; Pheterogeneity = 0.71). By evaluating all of the non-overlapping PCOS studies reported in the literature, even those without an appropriate control group, the overall rate of major anomalies was 0.6% in the sample of 517 women who discontinued the therapy upon conception or confirmation of pregnancy and 0.5% in the sample of 634 women who were treated with metformin throughout the first trimester of their pregnancy. Regarding type 2 diabetic women, we did not identify a sufficient number of studies with metformin exposure during the first trimester to proceed with the meta-analysis. There is currently no evidence that metformin is associated with an increased risk of major birth defects in women affected by PCOS and treated during the first trimester. However larger ad hoc studies are warranted in order to definitely confirm the safety and efficacy of this drug in pregnancy.

Treatment of Graves' Disease with Antithyroid Drugs in the First Trimester of Pregnancy and the Prevalence of Congenital Malformation

Several reports have suggested that propylthiouracil (PTU) may be safer than methimazole (MMI) for treating thyrotoxicosis during pregnancy because congenital malformations have been associated with the use of MMI during pregnancy. We investigated whether in utero exposure to antithyroid drugs resulted in a higher rate of major malformations than among the infants born to a control group of pregnant women. We reviewed the cases of women with Graves' disease who became pregnant. The pregnancy outcomes of 6744 women were known, and there were 5967 live births. MMI alone had been used to treat 1426 of the women, and 1578 women had been treated with PTU alone. The 2065 women who had received no medication for the treatment of Graves' disease during the first trimester served as the control group. The remaining women had been treated with potassium iodide, levothyroxine, or more than one drug during the first trimester. The antithyroid drugs were evaluated for associations with congenital malformations. The overall rate of major anomalies in the MMI group was 4.1% (50 of 1231), and it was significantly higher than the 2.1% (40 of 1906) in the control group (P = 0.002), but there was no increase in the overall rate of major anomalies in the PTU group in comparison with the control group (1.9%; 21 of 1399; P = 0.709). Seven of the 1231 newborns in the MMI group had aplasia cutis congenita, six had an omphalocele, seven had a symptomatic omphalomesenteric duct anomaly, and one had esophageal atresia. Hyperthyroidism in the first trimester of pregnancy did not increase the rate of congenital malformation. In utero exposure to MMI during the first trimester of pregnancy increased the rate of congenital malformations, and it significantly increased the rate of aplasia cutis congenita, omphalocele, and a symptomatic omphalomesenteric duct anomaly.

Premières données épidémiologiques sur le phloroglucinol et exposition au cours du premier trimestre de grossesse

Objective Phloroglucinol is used to prevent gastric, intestine or urogenital spasms. In France, many pregnant women are exposed to phloroglucinol for which no data are available about its use in pregnancy. The present study, using EFEMERIS database, investigates potential teratogenic risk of phloroglucinol in pregnancy. Materials and methods EFEMERIS is a database including prescribed and delivered drugs during pregnancy (data from Caisse Primaire d’Assurance Maladie of Haute-Garonne) and outcomes (data from Maternal and Infant Protection Service and from Antenatal diagnostic Centre). Women delivered from July 1st 2004 to June 30th 2008 in Haute-Garonne and registered in the French Health Insurance Service were included into EFEMERIS database. We compared pregnancy outcomes and newborn health between women exposed to phloroglucinol during organogenesis and non-exposed women. Malformations were classified according to Eurocat classification. Results Five thousand one hundred and thirty-two newborns (12.7%) exposed during organogenesis to phloroglucinol were compared to 35,223 controls (non exposed newborns). The mean number of different drugs prescribed during the first trimester of pregnancy per woman was higher in women exposed to phloroglucinol than in non-exposed women (6.4 ± 4.3 versus 2.4 ± 3.3, P < 10 −4). Among newborns, 126 (2.5%) had a malformation versus 804 (2.3%) in control newborns (OR = 1.1, [0.9–1.3]). The present study was powered to find a 1.3 fold increase in the overall rate of major anomalies. Discussion and conclusion This first epidemiologic study about phloroglucinol in pregnancy does not support evidence of a teratogenic risk for phloroglucinol in humans.

Safety of Haloperidol and Penfluridol in Pregnancy

To assess the safety of the butyrophenone neuroleptics haloperidol and penfluridol in pregnancy. The rate of major anomalies was compared between a cohort of pregnant women counseled for gestational exposure to haloperidol or penfluridol and a control group counseled for nonteratogen exposure. This multicenter, prospective, controlled study was conducted within the European Network of Teratology Information Services (ENTIS) and included women who contacted 1 of 4 teratology information services for counseling between January 1989 and December 2001. We followed up on the outcomes of 215 pregnancies exposed to haloperidol (N = 188) or penfluridol (N = 27)-78.2% (of 206) were in the first trimester-and compared to outcomes of 631 ENTIS controls. The rate of congenital anomalies did not differ between the haloperidol/penfluridol-exposed group and the control group (6/179 = 3.4% vs. 22/581 = 3.8%, p = .787). No difference was found by limiting the analysis to those exposed to butyrophenones during the first trimester. There were 2 cases of limb defects in the butyrophenone-exposed group (1 after haloperidol and 1 after penfluridol exposure) and none in the controls. A higher rate of elective terminations of pregnancy (8.8% vs. 3.8%, p = .004), a higher rate of preterm birth (13.9% vs. 6.9%, p = .006), a lower median birth weight (3155 g vs. 3370 g, p < .001), and a lower median birth weight of full-term infants (3250 g vs. 3415 g, p = .004) were found in the butyrophenone-exposed group compared to the controls. This study suggests that haloperidol and penfluridol do not represent a major teratogenic risk. Since a possible association between butyrophenone exposure and limb defects cannot be ruled out with this sample size, a level II ultrasound with emphasis on the limbs should be considered in pregnancies with first trimester exposure.

Pregnancy outcome following gestational exposure to montelukast: A prospective cotrolled study

Background Asthma is the most common respiratory crisis complicating pregnancy. Montelukast is prescribed orally for chronic treatment of asthma. Although animal reproductive studies show no evidence of teratogenic effects, there are no human studies assessing possible effects on the developing fetus with in utero exposure. Despite known risks associated with poorly controlled asthma, lack of safety data prevents women from using montelukast in pregnancy. Our aim is to evaluate pregnancy outcomes following gestational exposure to montelukast. Methods This prospective controlled study enrolls pregnant women who contact Motherisk about exposure to montelukast. These women are followed up using standardized data collection forms. Montelukast-exposed women are compared to a disease-matched group using inhalers for similar indications and a group of women exposed to known non-teratogens. Rates of major anomalies and other adverse outcomes are compared between groups. Results To date, 64 women exposed to montelukast during 1st trimester have been enrolled, of which 24 have used it throughout pregnancy. Outcomes of this group include: 62 (96.9%) live births, 2 (3.1%) SA and 2 (3.1%) major malformations. Upon comparison to controls, no statistical differences are apparent in these or any other endpoints of interest. Conclusions Data collected thus far in this ongoing study appear to suggest no increased risk for major malformations above baseline of 1–3%, following use of montelukast in pregnancy. Clinical Pharmacology & Therapeutics (2005) 77, P30–P30; doi: 10.1016/j.clpt.2004.12.005

The safety of proton pump inhibitors in pregnancy: a multicentre prospective controlled study

Proton pump inhibitors are used to treat gastro-oesophageal reflux and peptic ulcers. Gastro-oesophageal reflux is a common condition in pregnancy. Human pregnancy experience with lansoprazole or pantoprazole is very limited. More data exist on the safety of omeprazole in pregnancy. To assess the safety of proton pump inhibitors in pregnancy. The rate of major anomalies was compared between pregnant women exposed to omeprazole, lanzoprazole, or pantoprazole and a control group counselled for non-teratogens. The study design is a multicentre (n = 8), prospective, controlled study of the European Network of Teratology Information Services. We followed up 295 pregnancies exposed to omeprazole [233 in the first trimester (T1)], 62 to lansoprazole (55 in T1) and 53 to pantoprazole (47 in T1), and compared pregnancy outcome to that of 868 European Network of Teratology Information Services controls. The rate of major congenital anomalies did not differ between the exposed and control groups [omeprazole nine of 249 (3.6%), lansoprazole two of 51 (3.9%) and pantoprazole one of 48 (2.1%) vs. controls 30 of 792 = 3.8%]. No differences were found when exposure was limited to the first trimester after exclusion of genetic, cytogenetic or infectious anomalies. This study suggests that proton pump inhibitors do not represent a major teratogenic risk in humans.

Pregnancy outcome following gestational exposure to Azithromycin: a prospective controlled study

Introduction Azithromycin is an azalide antibiotic with an extensive range of indications including upper/lower respiratory tract ailments, skin, genitourinary infections etc. It is a popular treatment option due to its convenient dosing regimen and therapeutic advantages. Available human studies addressing gestational use of azithromycin have primarily focused on efficacy, rather than fetal safety. Objective: To evaluate pregnancy outcome following gestational exposure to azithromycin. Methods: This prospective controlled study consists of an azithromycin-exposed group compared to: 1) women receiving non-teratogenic antibiotics for similar indications and 2) exposed to non-teratogenic agents. The three groups were matched for gestational age at time of call, maternal age, smoking/alcohol status. Rates of major anomalies and secondary endpoints of interest were compared. Results: Pregnancy outcome was ascertained from a total of 123 women enrolled in each group. In the exposed group, 88 pregnancies occurred in the first trimester. Statistical analysis did not show any significant differences between the three groups in the rates of major malformations; 3.4% versus 2.3% and 3.4% (P=0.9) or any other endpoints that were examined. Conclusion: To date, results do not appear suggest an increased risk above baseline with gestational azithromycin exposure, providing an evidence-based option for health professionals caring for non-compliant populations with Chlamydia. Clinical Pharmacology & Therapeutics (2004) 75, P75–P75; doi: 10.1016/j.clpt.2003.11.283

Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study

Objective: To evaluate the safety of glucocorticosteroids (GCS) in pregnancy. Study design: The Israeli Teratogen Information Service (TIS) prospectively collected and followed 311 pregnancies counseled regarding systemic use of different GCS in the first trimester. The rate of major congenital anomalies was compared to that of 790 controls who were counseled for non-teratogenic exposure. Results: The rate of major anomalies did not significantly differ between the groups [12/262=4.6% (GCS), 19/728=2.6% (control), P=0.116]. There was no case of oral cleft and no pattern of anomalies among the GCS exposed group. Higher rates of miscarriages (11.5% versus 7.0%, P=0.013) and preterm births (22.7% versus 10.8%, P<0.001) were observed among the GCS exposed group compared to the controls. GCS exposed infants had a lower median birth weight [3080 g versus 3290 g, P<0.001] and were born at an earlier median gestational age [39 weeks versus 40, P<0.001] compared to the control. Conclusions: The present study supports that GCS do not represent a major teratogenic risk in humans. The study was powered to find a 2.5-fold increase in the overall rate of major anomalies.

Pregnancy outcome after gestational exposure to loratadine or antihistamines: A prospective controlled cohort study

Background: Loratadine is a second-generation histamine H1-receptor antagonist, used in the treatment of allergic conditions. No prospective controlled trials on loratadine in human pregnancy have been published to date. Objective: To determine whether the use of loratadine or other antihistamines (OAH) is associated with an increased risk of major anomalies. Methods: Callers who were counseled by the Israeli Teratogen Information Service in regard to loratadine or OAH exposure during pregnancy were prospectively collected and followed up. Pregnancy outcome was compared among three exposure groups: loratadine, OAH, and a control group of patients who were counseled for nonteratogenic exposure, nonteratogenic controls (NTC). The OAH included astemizole, chlorpheniramine, terfenadine, hydroxyzine, promethazine, and dimetindene. Results: We followed up 210 pregnancies exposed to loratadine (77.9% in the first trimester) and 267 pregnancies exposed to OAH (64.6% in the first trimester) and compared pregnancy outcome with that of 929 NTC. The rate of congenital anomalies did not differ among the groups [loratadine: 4/175 (2.3%), OAH: 10/247 (4.0%), NTC: 25/844 (3.0%), P = .553, relative risk (RR), 0.77; 95% confidence interval (CI), 0.27 to 2.19, (loratadine vs NTC); RR, 0.56; 95% CI, 0.18 to 1.77, (loratadine vs OAH)]. The rate did not differ between those exposed to antihistamines in the first trimester and the control patients [loratadine: 1/126 (0.8%), OAH: 7/146 (4.8%), NTC: 25/844 (3.0%), P = .152, RR, 0.27; 95% CI, 0.04 to 1.94, (loratadine vs NTC); RR, 0.17; 95% CI, 0.02 to 1.33, (loratadine vs OAH)]. Conclusions: This study on the use of loratadine in human pregnancy suggests that this agent does not represent a major teratogenic risk. The study was powered to find a 3-fold increase in the overall rate of major anomalies. (J Allergy Clin Immunol 2003;111:1239-43.)

Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies.

Corticosteroids are first-line drugs for the treatment of a variety of conditions in women of childbearing age. Information regarding human pregnancy outcome with corticosteroids is limited. We collected prospectively and followed up 184 women exposed to prednisone in pregnancy and 188 pregnant women who were counseled by Motherisk for nonteratogenic exposure. The primary outcome was the rate of major birth defects. A meta-analysis of all epidemiological studies was conducted. The Mantel-Haenszel summary odds ratio was calculated for the pooled studies with 95% confidence intervals. A cumulative summary odds ratio was also calculated by combining studies in chronological order. Chi-squared for homogeneity was determined to establish the comparability of the studies. In our prospective study, there was no statistical difference in the rate of major anomalies between the corticosteroid-exposed and control groups. In the meta-analysis, the Mantel-Haenszel summary odds ratio for major malformations with all cohort studies was 1.45 [95% CI 0.80, 2.60] and 3.03 [95% CI 1.08, 8. 54] when Heinonen et al. ('77) was removed. This suggests a marginally increased risk of major malformations after first-trimester exposure to corticosteroids. In addition, summary odds ratio for case-control studies examining oral clefts was significant (3.35 [95% CI 1.97, 5.69]). Although prednisone does not represent a major teratogenic risk in humans at therapeutic doses, it does increase by an order of 3.4-fold the risk of oral cleft, which is consistent with the existing animal studies.

Outcome of children born to epileptic mothers treated with carbamazepine during pregnancy.

The purpose of the study was to assess whether there was an increased rate of congenital anomalies or significant developmental delay in infants of women with epilepsy who had been treated with carbamazepine during pregnancy. 47 children were studied, aged 6 months-6 years, who were born to 37 epileptic mothers on carbamazepine monotherapy (group A). All children had a complete physical and neurodevelopmental assessment by a developmental paediatrician, and 41 a complete psychological evaluation. They were compared with 47 children of similar socioeconomic status (group B). Six of the 47 children in group A had typical facial features of 'carbamazepine syndrome'. The average cognitive score of children in group A was significantly lower than in group B. This was mainly because all six children with carbamazepine syndrome had a development quotient or intelligence quotient below 90. There were no differences between the two groups in physical growth or in the rate of major anomalies. Two children in group A had cleft palate but in each case this was found in a parent as well. In utero exposure to carbamazepine may result in 'carbamazepine syndrome' characterised by facial dysmorphic features and mild mental retardation. Prevalence of carbamazepine syndrome does not seem to be related to the dose of carbamazepine or the presence of maternal convulsions. It may depend upon heredofamilial factors that have yet to be defined. One possible factor is decreased activity of the enzyme epoxide hydrolase with resulting increased concentrations of carbamazepine epoxide which may be teratogenic.