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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.

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.

Use of selective serotonin reuptake inhibitors (SSRIs) in late pregnancy has been associated with persistent pulmonary hypertension of the newborn (PPHN), a rare condition with substantial infant mortality and morbidity. Although the increase in absolute risk is small on a population level, it may be of concern to many patients. It remains unclear the extent to which the increased risks reported for PPHN are explained by the underlying maternal illness rather than the use of SSRIs.

At least one in ten women is exposed to a psychotropic medication in the perinatal period, and the rate has increased tremendously over the past two decades. Pregnancy is a period of extreme vulnerability to the onset of depression and other mental illnesses, and the use of pharmacological treatment has become highly concerning to patients and their healthcare providers with limited data available to assess their effectiveness to the pregnant woman and safety to her developing fetus. This has been demonstrated by the high rates of discontinuation of many psychotropic medications upon recognition of pregnancy, thereby posing a risk of relapse of the underlying condition in women with severe form of psychiatric disease, which may have adverse effects on the pregnancy and possibly on the health of the fetus as well. Antidepressants account for the majority of prescribed psychotropic medications for women in the perinatal period and are indicated for a variety of conditions, other than depression. Other commonly reported psychotropic medications among perinatal women include anxiety medications and atypical antipsychotics. Both geographical and temporal factors are important in understanding prescription trends of these medications over the perinatal period.

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. Birth Defects Research (Part A) 103:721–728, 2015. © 2015 Wiley Periodicals, Inc.

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.

All patients with multiple sclerosis (MS) should be offered and have access to medications that have been well studied, and these patients should receive counseling with regard to the risks and benefits of using these medications. Women with MS who are pregnant or planning a pregnancy, however, are usually at a disadvantage because of the limited data available on the safety of medications indicated for MS. Collection of post-marketing data on the effects of disease-modifying therapies (DMTs) during pregnancy can be achieved through the use of pregnancy exposure and/or disease registries that collect information on MS treatments. However, there is a need for a specific pregnancy registry for MS that would encompass a large multicenter prospective observational study, designed to collect longitudinal data on medication exposure and outcomes in exposed and unexposed MS pregnancies and provide relevant information and counseling to women with MS who are pregnant or of childbearing age.

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.

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.

Consanguineous marriages are respected and practiced among more than one billion of the world’s population with consanguinity rates reaching 20–50%. Sociocultural factors, such as the maintenance of family structure and property, ease of marital arrangements, better relationships with in-laws, and financial advantages relating to dowry, seem to be strong contributory factors in the preference for consanguineous unions. In countries with civil unrest, consanguineous marriages are preferred because close-kin marriage is regarded as safeguarding for personal and family. It is suggested that marriage dissolution and divorce is lower among cousin couples. Studies have indicated that women in first-cousin marriages are protected against intimate partner violence. Consanguineous marriages are associated with earlier age at marriage and lower levels education and employment in females. Evidence-based social research in defining the various influences and outcomes of consanguinity is recommended.

Angiotensin II (A-II) is the main effector of the renin-angiotensin system. A-II functions by binding its type 1 (AT1) receptors to cause vasoconstriction and retention of sodium and fluid. Several AT1 receptor antagonists-a group of drugs collectively called "sartans"-have been marketed during the past few years for treatment of hypertension and heart failure. At least 15 case reports describe oligohydramnios, fetal growth retardation, pulmonary hypoplasia, limb contractures, and calvarial hypoplasia in various combinations in association with maternal losartan, candesartan, valsartan, or telmisartan treatment during the second or third trimester of pregnancy. Stillbirth or neonatal death is frequent in these reports, and surviving infants may exhibit renal damage. The fetal abnormalities, which are strikingly similar to those produced by maternal treatment with angiotensin-converting enzyme (ACE) inhibitors during the second and third trimesters of pregnancy, are probably related to extreme sensitivity of the fetus to the hypotensive action of these drugs. Very little information is available regarding the outcome of human pregnancies in which the mother was treated with an AT1 receptor antagonist during the first trimester, but animal studies have not demonstrated teratogenic effects after maternal treatment with large doses of AT1 receptor antagonists during organogenesis. We conclude that pharmacological suppression of the fetal renin-angiotensin system through ACE inhibition or AT1 receptor blockade seems to disrupt fetal vascular perfusion and renal function. We recommend that maternal treatment with AT1 receptor antagonists be avoided during the second and third trimesters of pregnancy and that women who become pregnant while taking one of these medications be changed to an antihypertensive drug of a different class as soon as the pregnancy is recognized.

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.

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.

To examine the evidence guiding management of multiple sclerosis (MS) in reproductive-aged women.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.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.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.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.

Objective: This study aimed to determine reproductive practices and attitudes of North Americans diagnosed with multiple sclerosis (MS) and the reasons for their reproductive decision making. Methods: A self-administered questionnaire on reproductive practices was mailed to 13,312 registrants of the North American Research Committee on Multiple Sclerosis (NARCOMS) database who met inclusion criteria for the study. Completed questionnaires were then returned to the authors in an anonymous format for analysis. Results: Among 5949 participants, the majority of respondents (79.1%) did not become pregnant following diagnosis of MS. Of these, 34.5% cited MS-related reasons for this decision. The most common MS-related reasons were symptoms interfering with parenting (71.2%), followed by concerns of burdening partner (50.7%) and of children inheriting MS (34.7%). The most common reason unrelated to MS for not having children was that they already have a “completed family” (55.6%). Of the 20.9% of participants who decided to become pregnant (or father a pregnancy) following a diagnosis of MS, 49.5% had two or more pregnancies. Conclusion: This study indicates that an MS diagnosis does not completely deter the consideration of childbearing in MS patients of both genders.

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 β 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.

We sought to determine if maternal bupropion treatment in early pregnancy is associated with congenital heart defects in the infant.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.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).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.

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.

Estimates of the lifetime risk of major depression in women range from 10% to 25%, peaking during the reproductive years. Today, selective serotonin-reuptake inhibitors (SSRIs) are the most commonly used type of antidepressant medication. Recent studies suggest that taking these drugs while pregnant may be associated with birth defects in general and with congenital heart defects in particular. The investigators have analyzed data from 9622 case infants having major birth defects and 4092 control infants who were born in the years 1997 to 2002 and enrolled in the National Birth Defects Prevention Study. Both cases and controls were chosen through birth defects surveillance systems in 8 states. The mothers took part in a standardized phone interview dealing with exposure to potential risk factors, including medications, before and during pregnancy. Exposure was defined as taking any SSRI from 1 month before to 3 months after conception. Combining cases and control subjects, 3% of study participants reported having used a SSRI at some time before or during pregnancy, and 2.3% during the designated 4-month interval. No significant association was found between the maternal use of SSRIs during early pregnancy and congenital heart defects. There were, however, 3 conditions associated with maternal use of SSRIs. They included anencephaly (adjusted odds ratio [OR], 2.4; 95% confidence interval [CI], 1.1-5.1); craniosynostosis (OR, 2.5; 95% CI, 1.5-4.0); and omphalocele (OR, 2.8; 95% CI, 1.3-5.7). None of the mothers of case infants having defects associated with SSRI use were found to have been exposed at the same time to medications known to have teratogenic effects. This study failed to establish any association between the maternal use of SSRIs during early pregnancy and an elevated risk of congenital heart defects-or of several other classes of birth defects. Three associations were observed, but the absolute risks were small in view of the baseline risk of birth defects inherent in all pregnancies. At the same time, maternal stress and depression during pregnancy have been implicated in adverse reproductive outcomes, and discontinuing antidepressant therapy in pregnant women who are seriously depressed may negatively affect both the mother and infant.