Elena Di Gianantonio

Methimazole embryopathy: Delineation of the phenotype

We report on a further case of congenital anomalies in a child exposed to methimazole during the first trimester of pregnancy (from first to seventh gestational week), and define a specific malformation pattern related to prenatal methimazole exposure and consisting of choanal and esophageal atresia, scalp defects, minor facial anomalies and psychomotor delay.

Paroxetine and fluoxetine in pregnancy: a prospective, multicentre, controlled, observational study

AIMS Recent studies have suggested a possible association between maternal use of selective serotonin reuptake inhibitors (SSRIs) in early pregnancy and cardiovascular anomalies. The aim of the present study was to evaluate the teratogenic risk of paroxetine and fluoxetine. METHODS This multicentre, prospective, controlled study evaluated the rate of major congenital anomalies after first-trimester gestational exposure to paroxetine, fluoxetine or nonteratogens. RESULTS We followed up 410 paroxetine, 314 fluoxetine first-trimester exposed pregnancies and 1467 controls. After exclusion of genetic and cytogenetic anomalies, there was a higher rate of major anomalies in the SSRI groups compared with the controls [paroxetine 18/348 (5.2%), fluoxetine 12/253 (4.7%) and controls 34/1359 (2.5%)]. The main risk applied to cardiovascular anomalies [paroxetine 7/348 (2.0%), crude odds ratio (OR) 3.47, 95% confidence interval (CI) 1.13, 10.58; fluoxetine 7/253 (2.8%), crude OR, 4.81 95% CI 1.56, 14.71; and controls 8/1359 (0.6%)]. On logistic regression analysis only cigarette smoking of >or=10 cigarettes day(-1) and fluoxetine exposure were significant variables for cardiovascular anomalies. The adjusted ORs for paroxetine and fluoxetine were 2.66 (95% CI 0.80, 8.90) and 4.47 (95% CI 1.31, 15.27), respectively. CONCLUSION This study suggests a possible association between cardiovascular anomalies and first-trimester exposure to fluoxetine.

Treatment of Hyperthyroidism in Pregnancy and Birth Defects

CONTEXT Clinical hyperthyroidism is not uncommon in pregnancy, with a reported prevalence of 0.1 to 0.4%. The available antithyroid drugs are propylthiouracil and methimazole/carbimazole. OBJECTIVES In this report we examined the association of both drugs with congenital malformations using data from the International Clearinghouse for Birth Defects Surveillance and Research. DESIGN The study used a case-affected control analysis and included 18,131 cases with malformations and reported first-trimester exposure to medication. A total of 127 subjects were born to mothers with known first-trimester antithyroid drug exposure. RESULTS Among the 52 groups of malformations that were analyzed, situs inversus ± dextrocardia, isolated unilateral kidney a/dysgenesis, and cardiac outflow tract defects were associated with prenatal exposure to propylthiouracil based on three, two, and five cases, respectively. Prenatal exposure to methimazole/carbimazole was significantly associated with choanal atresia, omphalocele, and total situs inversus ± dextrocardia (P < 0.01). CONCLUSIONS Further studies are required to exhaustively evaluate the associations between propylthiouracil and birth defects because of the low number, the lack of biological plausibility, and the possibility of underdiagnosis. Association between methimazole/carbimazole exposure and omphalocele and choanal atresia is consistent with previous reports and definitely suggests that these malformations could be part of a specific, even if rare, embryopathy.

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

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Pregnancy outcome after in utero exposure to angiotensin converting enzyme inhibitors or angiotensin receptor blockers.

OBJECTIVE To examine first trimester safety of angiotensin-converting-enzyme-inhibitors (ACEIs) or angiotensin-receptor-blockers (ARBs). STUDY DESIGN Prospective observational cohort regarding pregnancy ACEI/ARBs-exposure including contacts to two Teratology Information Services in Israel (1994-2007) and Italy (1990-2008), with two comparison groups: (1) exposed to other antihypertensives (OAH) (2) after non-teratogenic exposure (NTE) in similar time frames. RESULTS 252 ACEI/ARBs-exposed, 256 OAH-exposed and 495 NTE-exposed pregnancies were followed-up. The rate of major congenital anomalies was comparable between the groups (8/190, 4.2%, ACEI/ARB; 9/212, 4.2%, OAH; 18/471, 3.8% NTE; p = 0.954) among first trimester exposed pregnancies. The median gestational age at delivery was two weeks earlier, rate of preterm deliveries more than 2-fold higher, and median birth weight more than 200 g lower in the ACEI/ARB and OAH groups compared to the NTE group. CONCLUSION The present study suggests that ACEI/ARBs are not major teratogens when used in the first trimester, and can reassure women with similar exposures.

Inheritance of Astigmatism: Evidence for a Major Autosomal Dominant Locus

Although astigmatism is a frequent refractive error, its mode of inheritance remains uncertain. Complex segregation analysis was performed, by the POINTER and COMDS programs, with data from a geographically well-defined sample of 125 nuclear families of individuals affected by astigmatism. POINTER could not distinguish between alternative genetic models, and only the hypothesis of no familial transmission could be rejected. After inclusion of the severity parameter, COMDS results defined a genetic model for corneal astigmatism and provided evidence for single-major-locus inheritance. These results suggest that genetic linkage studies could be implemented and that they should be limited to multiplex families with severely affected individuals.

First-trimester itraconazole exposure and pregnancy outcome: a prospective cohort study of women contacting teratology information services in Italy.

AbstractBackground: Itraconazole is an effective fungal treatment; however, there are few human data on prenatal exposure. Objectives: To evaluate the major malformation rate in itraconazole prenatally exposed infants. The secondary objective includes evaluation of the pregnancy outcome. Methods: A prospective cohort study was conducted from January 2002 to October 2006 in women who called two Italian Teratology Information Services (TIS). Pregnant women who were exposed to itraconazole during the first trimester and gave informed consent were matched with a contemporary group of pregnant women who contacted the TIS because they had undergone a non-teratogenic drug exposure during the first trimester. Information was obtained via a structured questionnaire at the time of the initial call to the TIS and no earlier than 1 month after delivery. A trained operator conducted the interview. The main outcome measure was information about major congenital anomalies, type of delivery, birth weight, and any pregnancy or neonatal complications. Results: Data were collected on 206 women who called the TIS because of first-trimester exposure to itraconazole, and 207 controls. There were no significant differences in terms of major congenital anomalies in the exposed group versus the control group (3/163 [1.8%] vs 4/190 [2.1%], respectively). There was no statistical difference in the rate of vaginal delivery between the exposed and control groups (101/162 [62.3%] vs 102/190 [53.8%]), premature birth (11/162 [6.8%] vs 15/190 [7.9%]), low birth weight (1/152 [0.7%] vs 4/175 [2.3%]) and high birth weight (10/152 [6.5%] vs 7/175 [4.0%], respectively). The rates of live births (163/206 [79.1%] vs 190/207 [91.8%]), spontaneous abortion (23/206 [11.2%] vs 10/207 [4.8%]) and termination of pregnancy (19/206 [9.2%] vs 7/207 [3.4%] in the exposed and control groups, respectively) were significantly different (p<0.05). Conclusion: First-trimester itraconazole-exposed infants were not at increased risk of major congenital anomalies, but the rates of spontaneous and induced abortion were higher in the exposed group versus the control group. Larger studies are warranted to confirm these observations.

Teratology Information Services in Europe and Their Contribution to the Prevention of Congenital Anomalies

Objectives: To inform on Teratology Information Services (TIS) in Europe, their history, function and activity in preventing congenital malformations. Conclusions: Clinical teratology tries to identify human teratogens. TIS play an important role in public health by providing counsel on known reproductive risks and conducting specific research. This has led to a reduction in unnecessary fears of pregnant women and pregnancy terminations, as well as to better, more appropriate drug selection to treat acute or chronic disease. In addition, TIS units also conduct prospective studies and inform the public and physicians of the possible effects of environmental agents on the developing embryo and fetus.

Bisphosphonates in patients with autoimmune rheumatic diseases: Can they be used in women of childbearing age?

Autoimmune rheumatic diseases (ARD) are prevalent in women during their childbearing age. For their treatment, high doses of corticosteroid (CS) for long-term periods are often required, increasing the risk of bone loss. According to recent guidelines, bisphosphonates (BP) should be used as first line treatment to prevent CS induced osteoporosis. However, due to their long-term release from bone and their ability to cross the placenta, it has been suggested to avoid BP in women during their fertile years. BP seem to decrease foetus bone length in pregnant animals, but not in humans, at least, when they are administered at therapeutic dosage. BP are embryo toxic in animals when used at high dosage. In a systematic literature review, we found 58 women treated with BP close before or during pregnancy, showing no related congenital malformations. However, the Unit of Clinical and Epidemiological Genetics in University of Padova collected ten cases of women treated with BP during pregnancy, reporting 20% of congenital malformations. Thus, we suggest to avoid BP during pregnancy and caution with their use in fertile women. When they have to be given before pregnancy, specific affinities of the BP have to be considered to plan the washout period beforehand.

First trimester diclofenac exposure and pregnancy outcome

OBJECTIVE To assess the safety of diclofenac during pregnancy. METHODS A prospective observational cohort study, evaluating follow-up data of women who contacted Teratology Information Services to get counseling. The exposed group included 145 pregnant women who were exposed to diclofenac between the 5th and the 14th gestational week. A contemporary control group (501 women) was randomly selected from among patients who contacted Teratology Information Services with regard to exposures to agents known not to be teratogenic during a similar period of pregnancy. RESULTS Major birth malformations were not more common in the study group than in the control group (p=0.07). CONCLUSION Our study suggests that the use of diclofenac is relatively safe during the first trimester of pregnancy and the studied sample size makes it possible to exclude a risk of congenital malformation higher than 3.3, with a power of 80%.