Maternal Prenatal Exposures in Pregnancy and Autism Spectrum Disorder: An Insight into the Epigenetics of Drugs and Diet as Key Environmental Influences.

Autism spectrum disorder (ASD) is a rapidly growing global pandemic that affects an estimated 1 in 59-68 children. It is a complex disease with both genetic and environmental etiologies. Due to the rapid increase in the incidence of ASD, environmental causes for ASD are gaining attention. Efforts to probe several environmental exposures that could contribute to causing ASD are underway. In this regard, this chapter is directed towards understanding prenatal exposure to key environmental factors i.e., drugs and dietary nutrients that may act via the same molecular pathway - epigenetics as a potential etiological factor for ASD. Epigenetic regulation is a molecular mechanism known to be a significant contributor to neurodevelopmental disorders. It also offers a means to explain how environmental exposures can impact genetics. We discuss the impact of maternal exposures to certain drugs, and dietary intake, on the developing fetus during pregnancy. Maternal Exposure to some drugs during gestation are associated with a higher risk of ASD, while exposure to other dietary compounds may offer promise to rescue epigenetic regulatory insults related to ASD. However, more work in this important area is still required, nevertheless preliminary research already has important implications in the understanding, prevention and treatment of ASD.

Safety of Selective Serotonin Reuptake Inhibitors in Pregnancy: A Review of Current Evidence.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressant medications worldwide. However, over the past decade, their use during pregnancy, a period of extreme vulnerability to the onset of depression, has become highly concerning to patients and their healthcare providers in terms of safety to the developing fetus. Exposure to SSRIs in pregnancy has been associated with miscarriage, premature delivery, neonatal complications, birth defects-specifically cardiac defects-and, more recently, neurodevelopmental disorders in childhood, specifically autism spectrum disorders. Studies addressing the effect of individual SSRIs indicate a small but higher risk for birth defects with maternal fluoxetine and paroxetine use. Though the excess in absolute risk is small, it may still be of concern to some patients. Meanwhile, antenatal depression itself is associated with adverse perinatal outcomes, and discontinuing antidepressant treatment during pregnancy is associated with a high risk of relapse of depression. Whether the observed adverse fetal effects are related to the mother's medication use or her underlying maternal illness remains difficult to determine. It is important that every pregnant woman being treated with an SSRI (or considering such treatment) carefully weighs the risks of treatment against the risk of untreated depression for both herself and her child. The importance of recognizing a higher risk for the development of adverse outcomes lies in the potential for surveillance and possibly a timely intervention. Therefore, we recommend that pregnant women exposed to any SSRI in early pregnancy be offered options for prenatal diagnosis through ultrasound examinations and fetal echocardiography to detect the presence of birth defects. Tapering off or switching to other therapy in early pregnancy, if appropriate for the individual, may also be considered on a case-by-case basis.

Findings from the National Birth Defects Prevention Study: Interpretation and translation for the clinician.

BACKGROUND: The National Birth Defects Prevention Study (NBDPS) is a large U.S. multi-site case-control study first established in 1996 to identify potentially preventable environmental causes and genetic risk factors for more than 30 selected categories of major birth defects. METHODS: Numerous reports with both positive and negative findings have been produced by the NBDPS, and many have influenced clinical practice. Many NBDPS reports have included novel findings, and in some cases these findings could only be considered hypothesis-generating. Other reports have met criteria for causality such as replication of findings in other studies, biological plausibility, and coherence. RESULTS: However, translation of even strongly supported associations, in some cases, has required clinicians to learn to communicate information to patients about small and uncertain absolute risks in the context of the potential effects of under- or poorly treated maternal conditions. CONCLUSION: The NBDPS has continued to play an important role as a rich U.S. data source that can advance the understanding of maternal conditions and their treatments in relation to birth defects.

The need for a disease-specific prospective pregnancy registry for multiple sclerosis (MS).

Multiple sclerosis (MS) is the most commonly acquired neurological disorder affecting young adults of reproductive age with an approximately 3:1 female to male ratio. Although pregnancy is not contraindicated in MS, data are limited regarding pregnancy outcome among MS patients, and the safety or risk to the fetus associated with most maternal MS treatments, such as disease modifying therapies (DMTs), during pregnancy is unknown. We review available epidemiological and registry data on MS and pregnancy and discuss the need to initiate a North American Multiple Sclerosis Pregnancy Registry that will prospectively identify pregnancies in women with MS, obtain information on the disease, and its treatment during gestation and lactation and follow the children to determine their health status.

Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review.

OBJECTIVE: To examine the evidence guiding management of multiple sclerosis (MS) in reproductive-aged women. DATA SOURCES: We conducted an electronic literature search using PubMed, ClinicalTrials.gov, and other available resources. The following keywords were used: "multiple sclerosis" and "pregnancy." We manually searched the reference lists of identified studies. METHODS OF STUDY SELECTION: Two reviewers categorized all studies identified in the search by management topic, including effect of pregnancy on MS course, fetal risks associated with disease-modifying treatments during pregnancy, and management of patients off disease-modifying treatment. We categorized studies by strength of evidence and included prior meta-analyses and systematic studies. These studies were then summarized and discussed by an expert multidisciplinary team. TABULATION, INTEGRATION, AND RESULTS: The risk of MS relapses is decreased during pregnancy and increased postpartum. Data are lacking regarding the risks of disease-modifying treatments during pregnancy. There may be an increased risk of MS relapses after use of assisted reproductive techniques. There does not appear to be a major increase in adverse outcomes in newborns of mothers with MS. CONCLUSION: Although there are many unmet research needs, the reviewed data support the conclusion that in the majority of cases, women with MS can safely choose to become pregnant, give birth, and breastfeed children. Clinical management should be individualized to optimize both the mother's reproductive outcomes and MS course.

A review of safety-related pregnancy data surrounding the oral disease-modifying drugs for multiple sclerosis.

The recent approval of several oral disease-modifying drugs (DMDs) for multiple sclerosis (MS) brings promise of improved clinical effectiveness as well as greater drug compliance compared to the existing non-oral DMDs, and substantially increases patient choice and therapeutic options in the effective management of MS. However, for men and women with MS of childbearing age, concerns about the effect of oral DMDs on pregnancy and the fetus may arise. Some limited data from animal reproductive studies of oral DMDs suggest a potential increased risk of early pregnancy loss, impaired growth and birth defects. Although active surveillance mechanisms exist, there is limited data to inform clinical practice. Using existing information from published clinical trials and drug monographs, as well as recent conference proceedings, this review summarizes the mechanism of action (in relation to embryogenesis and pregnancy) and existing animal or human pregnancy-related data for approved (fingolimod, teriflunomide and dimethyl fumarate) and investigational (laquinimod and firategrast) oral DMDs for MS.

Multiple sclerosis and pregnancy: a comparison study.

OBJECTIVE: To determine whether different health care systems may affect reproductive decision-making among patients with Multiple Sclerosis (MS), we describe the reproductive practices and attitudes of Canadian MS patients ascertained from the multidisciplinary MS Clinic at Hôpital Notre-Dame in Montreal, Quebec (NDMSC), in comparison to those of matched American self-registrants from the database of the North American Research Committee on Multiple Sclerosis (NARCOMS). METHODS: A total of 665 self-administered questionnaires on reproductive practices were sent out to eligible attendees attending the NDMSC. The short questionnaires were completed and returned to the authors in an anonymous format for analysis. RESULTS: A total of 459 completed questionnaires were returned. The majority of NDMSC respondents (72.5%) and NARCOMS subset (75.2% females), did not encounter a pregnancy following diagnosis of MS. The most common MS-related reason for this decision was "symptoms interfering with parenting" (75.0% for the NDMSC, 72.6% for the NARCOMS). The most commonly reported non-MS-related reason was "a completed family" by the time of diagnosis in both the NDMSC and NARCOMS subset (58.0%, 40.4%, respectively). Concerns about financial issues both related and unrelated to MS were also commonly reported by males and females in both cohorts but significantly more so among the NARCOMS participants. CONCLUSION: These results indicate that reproductive decisions of MS patients are highly affected by their illness and its associated disability, regardless of the available health care program. Health care providers should discuss their patients' reproductive needs and perceptions to help them make more informed decisions.

Multiple sclerosis and pregnancy: maternal considerations.

Multiple sclerosis (MS) is the most commonly acquired neurological disorder affecting young adults of reproductive age with approximately a 3:1 female-to-male ratio. Pregnancy is not contraindicated in MS but remains to be an issue that raises many questions. Although relapse rates tend to increase in the first 3 months postpartum, pregnancy does not seem to be a detriment to the long-term progression of MS and has a protective effect on reducing relapses, especially during the third trimester. MS does not appear to affect fertility or increase the risk of congenital anomalies or pregnancy complications. There has been some evidence that maternal treatment with ß interferons, the most commonly used disease-modifying therapies in MS, may cause adverse reproductive outcomes, prompting the US FDA to issue warnings about their use at conception and during pregnancy.

Patterns of antidepressant medication use among pregnant women in a United States population.

This article describes the pattern of reported antidepressant use around the time of pregnancy in a population-based sample of women who delivered live-born babies without birth defects. Data were used from the National Birth Defects Prevention Study, an ongoing case-control study of risk factors for birth defects covering 10 US states. Mothers of live-born infants without birth defects (controls) born between 1998 and 2005 were randomly selected from each site. Information on the mother's characteristics and exposure to antidepressants was collected via a standardized telephone interview. Among 6582 mothers included in the study, 298 (4.5%) reported use of an antidepressant in the period of 3 months before through the end of pregnancy. Use of selective serotonin-reuptake inhibitors was reported most often (3.8%), followed by bupropion (0.7%). A statistically significant decline was observed, from 3.1% to 2.3% (P < .001), in reported use of antidepressants between the first and second month after conception. The frequency of reported antidepressant use at any time during pregnancy increased from 2.5% in 1998 to 8.1% in 2005 (P < .001) in 4 states. The findings show an increase in reported antidepressant use over a 9-year period and a substantial decrease in use around the usual time of pregnancy recognition.

Maternal use of bupropion and risk for congenital heart defects.

OBJECTIVE: We sought to determine if maternal bupropion treatment in early pregnancy is associated with congenital heart defects in the infant. STUDY DESIGN: We conducted a retrospective case-control study of birth defects risk factors. Data on 6853 infants with major heart defects were compared with 5869 control infants born in 1997-2004. Bupropion exposure was defined as any reported use between 1 month before and 3 months after conception. RESULTS: Mothers of infants with left outflow tract heart defects were more likely to have reported taking bupropion than mothers of control infants (adjusted odds ratio, 2.6; 95% confidence interval, 1.2-5.7; P = .01). CONCLUSION: We identified a positive association between early pregnancy bupropion use and left outflow tract heart defects; however, the magnitude of the observed increased risk was small. Nevertheless, further studies are needed to confirm these results.

Safety of selective serotonin reuptake inhibitors in pregnancy.

Selective serotonin reuptake inhibitors (SSRIs) are among the most commonly used medications, with a prescription frequency of 2.3% in pregnant women. Although most babies born to women who take SSRIs during pregnancy are normal, there is accumulating evidence that maternal SSRI treatment during pregnancy may cause adverse reproductive outcomes. Maternal SSRI treatment during the first trimester has been implicated in increased risks of birth defects, specifically cardiac abnormalities, in the infant, whereas third-trimester treatment has been linked to various neonatal complications, including symptoms of neonatal withdrawal and toxicity, prematurity, low birth weight and persistent pulmonary hypertension of the newborn. Although data on neurobehavioural and long-term cognitive problems among children of women who were treated with SSRIs during pregnancy remain limited, the possibility of such functional abnormalities is an additional concern. On the other hand, untreated maternal depression also carries serious risks for both the mother and the baby, and SSRIs are one of the best available treatments. Thus, pregnant women who require treatment for depression and their physicians often face a difficult choice regarding the use of SSRIs.

Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects.

BACKGROUND: Information regarding the safety of selective serotonin-reuptake inhibitors (SSRIs) in human pregnancy is sparse. Concern has been raised about the risk of congenital heart defects associated with the use of SSRIs in pregnancy. METHODS: We obtained data on 9622 case infants with major birth defects and 4092 control infants born from 1997 through 2002 from the National Birth Defects Prevention Study. Case infants were ascertained through birth-defects surveillance systems in eight U.S. states; controls were selected randomly from the same geographic areas. Mothers completed a standardized telephone interview regarding exposure to potential risk factors, including medications, before and during pregnancy. Exposure to SSRIs was defined as treatment with any SSRI from 1 month before to 3 months after conception. Birth defects were assigned to 26 categories and subcategories. RESULTS: There were no significant associations between maternal use of SSRIs overall during early pregnancy and congenital heart defects or most other categories or subcategories of birth defects. Maternal SSRI use was associated with anencephaly (214 infants, 9 exposed; adjusted odds ratio, 2.4; 95% confidence interval [CI], 1.1 to 5.1), craniosynostosis (432 infants, 24 exposed; adjusted odds ratio, 2.5; 95% CI, 1.5 to 4.0), and omphalocele (181 infants, 11 exposed; adjusted odds ratio, 2.8; 95% CI, 1.3 to 5.7). CONCLUSIONS: Maternal use of SSRIs during early pregnancy was not associated with significantly increased risks of congenital heart defects or of most other categories of birth defects. Associations were observed between SSRI use and three types of birth defects, but the absolute risks were small, and these observations require confirmation by other studies.

Mutations in the TMPRSS3 gene are a rare cause of childhood nonsyndromic deafness in Caucasian patients.

Two loci for nonsyndromic recessive deafness located on chromosome 21q22.3 have previously been reported, DFNB8 and DFNB10. Recently a gene which encodes a transmembrane serine protease, TMPRSS3 or ECHOS1, was found to be responsible for both the DFNB8 and DFNB10 phenotypes. To determine the contribution of TMPRSS3 mutations in the general congenital/childhood nonsyndromic deaf population we performed mutation analysis of the TMPRSS3 gene in 448 unrelated deaf patients from Spain, Italy, Greece, and Australia who did not have the common 35delG GJB2 mutation. From the 896 chromosomes studied we identified two novel pathogenic mutations accounting for four mutant alleles and at least 16 nonpathogenic sequence variants. The pathogenic mutations were a 1-bp deletion resulting in a frameshift and an amino acid substitution in the LDLRA domain of TMPRSS3. From this and another study we estimate the frequency of TMPRSS3 mutations in our sample as 0.45%, and approximately 0.38% in the general Caucasian childhood deaf population. However, TMPRSS3 is still an important contributor to genetic deafness in populations with large consanguineous families.