Human teratogens and genetic phenocopies. Understanding pathogenesis through human genes mutation.

Exposure to teratogenic drugs during pregnancy is associated with a wide range of embryo-fetal anomalies and sometimes results in recurrent and recognizable patterns of malformations; however, the comprehension of the mechanisms underlying the pathogenesis of drug-induced birth defects is difficult, since teratogenesis is a multifactorial process which is always the result of a complex interaction between several environmental factors and the genetic background of both the mother and the fetus. Animal models have been extensively used to assess the teratogenic potential of pharmacological agents and to study their teratogenic mechanisms; however, a still open issue concerns how the information gained through animal models can be translated to humans. Instead, significant information can be obtained by the identification and analysis of human genetic syndromes characterized by clinical features overlapping with those observed in drug-induced embryopathies.

Pregnancy outcome in women exposed to antiepileptic drugs: teratogenic role of maternal epilepsy and its pharmacologic treatment.

Infants born to epileptic women treated with antiepileptic drugs (AEDs) have an increased risk of major congenital malformations (MCMs). In order to determine the role of maternal epilepsy we conducted a prospective cohort study on three cohorts of pregnant women: (i) 385 epileptic women treated with AEDs, (ii) 310 non-epileptic women treated with AEDs, (iii) 867 healthy women not exposed to AEDs (control group). The rate of MCMs in the epileptic group (7.

The outcomes of pregnancy in women exposed to the new macrolides in the first trimester: a prospective, multicentre, observational study.

Background: Macrolides are a group of commonly prescribed antibiotics. There is some doubt surrounding the use of the newer macrolides in pregnancy.

Objective: The present study aimed to compare outcomes of pregnancies exposed to the new macrolides clarithromycin, azithromycin and roxithromycin with non-teratogenic preparations.

Genetic susceptibility to teratogens: state of the art.

There is evidence that the susceptibility to the teratogenic effect of drugs within human populations varies extremely from one individual to another, even after identical exposures. One of the factors that may explain these interindividual differences is the genetic makeup in the pharmacokinetics and pharmacodynamics of the respective drugs. In fact, both maternal and embryonic/fetal genotypes can affect placental transport, absorption, metabolism, distribution and receptor binding of an agent, influencing its teratogenicity.

Pharmacologic treatment of hyperthyroidism during pregnancy.

Clinical hyperthyroidism has been associated with an increased risk of maternal, fetal, and neonatal complications. The available antithyroid drugs are methimazole/carbimazole and propylthiouracil. Several case reports and some epidemiologic studies suggest that methimazole/carbimazole exposure during the first trimester of pregnancy is associated with an increased risk of congenital malformations, including ectodermal anomalies, choanal atresia, esophageal atresia, and omphalocele.

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.

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%.

Migraine therapy during pregnancy and lactation.

Importance Of The Field: Migraine affects about 25% of women during childbearing years but few data are available about the risks connected with most antimigraine drugs during pregnancy.

Areas Covered In This Review: In this report, we review the available data, mainly obtained from published studies, toxicology databases and clinical guidelines, on migraine treatment during pregnancy and lactation.

What The Reader Will Gain: The following drugs should be preferred for the treatment of acute migraine attacks in pregnant women: paracetamol, NSAIDs and sumatriptan.

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.

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.

Is CFTR 621+3 A>G a cystic fibrosis causing mutation?

The 621+3 A>G variant of the CFTR gene was initially detected in four Greek patients with a severe form of cystic fibrosis, and it is reported to impair CFTR mRNA splicing. We present three lines of evidence that argue against the pathogenicity of this variant. First, its allelic frequency in the Italian population was 0.

Therapy of inflammatory bowel diseases in pregnancy and lactation.

Inflammatory bowel diseases (IBDs) are a group of disorders characterised by chronic or relapsing inflammation within the gastrointestinal tract of variable severity. A chronic medication is often needed and management of fertile women is a crucial point because of the possible adverse effects associated with the administered drugs and the disease itself. The risk of pregnancy-related complications and the disease behaviour during pregnancy depends mainly on disease activity at time of conception.

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

Background: 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.

Iodine status in pregnancy: role of dietary habits and geographical origin.

Objectives: A study was conducted on iodine status during pregnancy and its dependence on dietary habits, racial and geographical origin, and time since arrival in Italy.

Design And Methods: We enrolled 322 consecutive pregnant women: 217 Italians, 62 Eastern Europeans and 43 from Northern and Central Africa. All women completed a food frequency questionnaire on their dietary habits.

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.

Pregnancy outcome of women exposed to azathioprine during pregnancy.

Background: Azathioprine (AZP) interferes with nucleic acid synthesis and is teratogenic in animals. In view of the paucity of information on the use of AZP during pregnancy we investigated this subject in a prospective, controlled, multicenter study. Our objective was too determine whether exposure to AZP during pregnancy increases the risk for major malformations and to determine the effect on pregnancy outcome.

Inheritance of hyperbilirubinemia: evidence for a major autosomal recessive gene.

Background And Aim: To clarify the precise mode of inheritance of Gilbert syndrome, an unconjugated familial hyperbilirubinemia, where impaired bilirubin conjugation is caused by reduced UGT1A1 activity determined by a defective function of the A(TA)6TAA promoter region of the UGT1A1 gene.

Subjects And Methods: Serum bilirubin levels were measured in a large, homogeneous resident population from North-Eastern Italy, consisting of 1.639 males (age 44.

Are congenital anorectal malformations more frequent in newborns conceived with assisted reproductive techniques?

One of the major concerns about ART is the risk of birth defects in children born after in vitro fertilization. We report on a cohort of consecutive children affected with anorectal malformation (ARM) requiring surgical correction in which we found a significantly high proportion (Odds ratio 13.31, 95% confidence limits 4.

Inherited and acquired thrombophilia: pregnancy outcome and treatment.

Maternal thrombophilias increases the risk of an adverse pregnancy outcome. An extensive literature review highlights the role of inherited and acquired thrombophilic disorders in spontaneous abortion, both early and late, recurrent or isolate, in intrauterine growth retardation, in placenta abruption, in pre-eclampsia and in venous thromboembolism. We have particularly focused attention on the following factors: antithrombin III (ATIII), proteins C (PC) and S (PS) deficiencies, genetic mutations particularly factor V Leiden (FVL), prothrombin gene G20210A (PTM) and the thermolabile variant of the methylene tetrahydrofolate reductase C677T (MTHFR) gene, lupus anticoagulant (LAC) and anticardiolipin antibodies, VIIIc factor, hyperhomocysteinemia and acquired activated protein C resistance.

Pregnancy outcome after genetic counselling for prenatal diagnosis of unexpected chromosomal anomaly.

Objectives: Couples undergoing invasive prenatal diagnosis (PD) are informed and concerned mainly about autosomal trisomies. However, unexpected chromosomal abnormalities (UCA) are a frequent finding at PD. We have analysed the psychological and practical consequences in the couples counselled in our centre because of the identification of foetal UCA at PD.

Genetic susceptibility to infectious diseases.

The clinical outcome of infectious disease (ID) is determined by a complex interaction between microorganism, host genetic factors and environment. Epidemiological studies have revealed differences within and between populations exposed to the same infectious agent, and in the prevalence or severity of the disease, underlying the relevance of the genetic background. Population genetic studies have estimated the genetic component (susceptibility) in the ID determination and have identified some susceptibility gene(s)/polymorphism(s).