What is any agent that can cause harm to a developing fetus during prenatal development when the mother is exposed?

Teratogen Exposures

Teratogens include substances such as alcohol, a multitude of medications, and even infectious agents. Ingestion of significant amounts of alcohol during fetal development can lead to fetal alcohol syndrome, mentioned previously. This condition was first described by Lemoine et al. [1968], and again by Jones et al. [1973]. This syndrome is a recognized constellation of physical features including short palpebral fissures, a hypoplastic philtrum, and thin upper lip. Over time, additional features, such as poor growth [leading to short stature and microcephaly] and neurocognitive deficits were recognized. Behavior issues, such as attention deficit hyperactivity disorder [ADHD] are seen more frequently in children exposed in utero to alcohol than those who were not. Due to variability in the phenotypes of children exposed in utero, the condition is now more appropriately known as FASD [Fetal Alcohol Spectrum Disorders]. Revised clinical guidelines were published in 2016 by Hoyme et al. These guidelines incorporate both physical and developmental criteria to distinguish between fetal alcohol syndrome [FAS], partial fetal alcohol syndrome [PFAS], alcohol-related neurodevelopmental disorder [ARND], and alcohol-related birth defects [ARBD].

Medications that are known to cause birth defects are myriad. Various authors have reviewed the effects of antihypertensive medications [Fischer et al., 2018] and medications to treat ADHD [Anderson et al., 2018], thyroid dysfunction [Howley et al., 2017], cancer [Selig et al., 2012], and psychiatric disease [Vitale et al., 2016].

Teratogens

A teratogen is an agent that may cause embryonic or fetal malformations. While identification of maternal teratogen exposure before or during pregnancy would be ideal, this is not always possible and infant testing is necessary. Currently, there are no federally mandated guidelines on infant teratogen and drug-exposure testing. The decision rests with the doctor and hospital. Teratogen levels are easily detected in the newborn period by blood, urine, meconium, or hair testing.

The use of illicit drugs [marijuana, cocaine, amphetamines, heroin, methadone, lysergic acid diethylamide [LSD], opioids, among others] and licit drugs [nicotine, alcohol, caffeine] during pregnancy may influence maternal and infant outcomes. Prenatal drug exposure has been associated with placental abruption, premature labor, microcephaly, congenital anomalies including cardiac and genito-urinary abnormalities, necrotizing enterocolitis, cognitive disabilities, and central nervous system stroke and hemorrhage. Withdrawal symptoms, such as sweating, irritability, hypertonia, jitteriness, diarrhea, and seizures are often seen in infants after in utero exposure to drugs. The 2004 National Survey on Drug Use and Health, based solely on self-report of randomly sampled pregnant American women, estimated that 4.6% used illicit drugs during pregnancy. When a child is found to have been exposed to drugs in utero, healthcare providers are often required to notify social services for a discharge placement decision and family court determination of custody. However separation of mother and child in the newborn period has lasting implications for the mother–infant relationship and long-term development.

Lead exposure is an additional potent neurotoxin with primary effects on the nervous, hematopoietic, and renal systems. Lead inhibits enzymes in many biochemical pathways; high levels of lead exposure are associated with poor attention, aggression, lowered cognitive abilities, somatic complaints, antisocial behaviors, seizures, coma, and death. Adverse neurodevelopmental sequelae associated with even mildly elevated levels include reduction in auditory threshold, abnormal balance, poor eye-hand coordination, slowed reaction times, sleep disturbances, and impaired cognition.

Lead is readily transmitted through the placenta from the mother to the fetus. Maternal exposure to high environmental lead levels may be associated with spontaneous abortion, premature rupture of membranes [PROM], and preterm delivery. Children absorb lead more readily than adults; children’s developing nervous systems are more susceptible to the toxic effects of lead. Even with treatment, it remains unclear to what extent the effects of lead exposure are reversible.

Currently, the primary sources of lead exposure are deteriorated lead paint, and the soil and dust it contaminates. The AAP recommends blood lead screening as part of routine health supervision for children between 9 to 12 months of age and re-screening at 24 months. It also recommends that children, pregnant women, and families be screened routinely by healthcare providers with community-specific risk-assessment questionnaires, which evaluate chances for lead exposure.

An estimated 890 000 children aged 1–5 years, or 4.4% of the US population in that age range, have elevated blood lead levels. Successful prenatal identification of lead-exposed women would allow for removal of lead, and a lead-free environment for newborns. Once exposed, treatment includes nutritional interventions [iron and calcium supplementation], a reduced-fat diet, and frequent meals. Use of chelating agents, which competitively bind lead and remove it from the body, may be necessary. Timely intervention prevents progression and improves outcome.

Teratogens

A teratogen is an agent that may cause embryonic or fetal malformations. While identification of maternal teratogen exposure before or during pregnancy would be ideal, this is not always possible and infant testing is necessary. Currently, there are no federally mandated guidelines on infant teratogen and drug exposure testing. The decision rests with the doctor and hospital. Teratogen levels are easily detected in the newborn period by blood, urine, meconium, or hair testing.

The use of illicit drugs [marijuana, cocaine, amphetamines, heroin, methadone, lysergic acid diethylamide [LSD], and opioids, among others] and licit drugs [nicotine, alcohol, caffeine] during pregnancy may influence maternal and infant outcomes. Prenatal drug exposure has been associated with placental abruption, premature labor, microcephaly, congenital anomalies, including cardiac and genito-urinary abnormalities, necrotizing enterocolitis, cognitive disabilities, and central nervous system stroke and hemorrhage. Withdrawal symptoms, such as sweating, irritability, hypertonia, jitteriness, diarrhea, and seizures, are often seen in infants after in utero exposure to drugs. SAMHSA [Substance Abuse and Mental Health Services Administration] reports that among pregnant women in the US, 5.4% were current illicit drug users between 2012 and 2013. This is lower than the rate among women who were not pregnant [11.4%]. When a child is found to have been exposed to drugs in utero, healthcare providers are often required to notify social services for a discharge placement decision and family court determination of custody. However, separation of mother and child in the newborn period has lasting implications for the mother–infant relationship and long-term development, often leading to difficult decision-making.

Lead exposure is an additional potent neurotoxin with primary effects on the nervous, hematopoietic, and renal systems. Lead inhibits enzymes in many biochemical pathways; high levels of lead exposure are associated with poor attention, aggression, lowered cognitive abilities, somatic complaints, antisocial behaviors, seizures, coma, and death. Adverse neurodevelopmental sequelae associated with even mildly elevated levels include reduction in auditory threshold, abnormal balance, poor eye–hand coordination, slowed reaction times, sleep disturbances, and impaired cognition.

Lead is readily transmitted through the placenta from the mother to the fetus. Maternal exposure to high environmental lead levels may be associated with spontaneous abortion, premature rupture of membranes [PROM], and preterm delivery. Children absorb lead more readily than adults; children's developing nervous systems are more susceptible to the toxic effects of lead. Even with treatment, it remains unclear to what extent the effects of lead exposure are reversible.

Currently, the primary sources of lead exposure are deteriorated lead paint, and the soil and dust it contaminates. The AAP recommends blood lead screening as part of routine health supervision for children between 9 and 12 months of age and rescreening at 24 months. It also recommends that children, pregnant women, and families be screened routinely by healthcare providers with community-specific risk-assessment questionnaires, which evaluate chances for lead exposure.

According to the CDC, an estimated 310,000 children aged 1–5 years in the United States have elevated blood lead levels. From 2002 to 2010, lead screening rates in children aged 1–2 years increased from 21.5% in 2002 to 33.4% in 2010. Successful prenatal identification of lead-exposed women would allow for removal of lead, and a lead-free environment for newborns. Once exposed, treatment includes nutritional interventions [iron and calcium supplementation], a reduced-fat diet, and frequent meals. Use of chelating agents, which competitively bind lead and remove it from the body, may be necessary. Timely intervention prevents progression and improves outcome.

V.B Teratogens, Toxins, and Viruses

Specific teratogens, toxins, or viruses have not been shown to account for any substantial subset of the autism population, although clearly in each category there are known members capable of producing developmental brain damage, including damage to regions commonly affected in autism. For example, in humans, prenatal and neonatal exposure to alcohol causes Purkinje cell loss in the cerebellum. Prenatal exposure to the anticonvulsant medication valproic acid has been linked to cases of autism in one family and causes significant reduction of cerebellar Purkinje neuron numbers in rats. Prenatal exposure to sedatives such as thalidomide has been linked to autism in some individuals, and an animal model using rats to study treatment for opiate and cocaine addiction using the indole alkaloids ibogaine and harmaline found degeneration of a subset of Purkinje cells in the vermis.

Cells of the early developing brain are in a state of rapid proliferation and differentiation in the fetus and neonate—conditions ideal for viruses that replicate best in dividing cells. This in turn can lead to severe or lethal birth defects. Lymphocytic choriomeningitis virus infection of 1- to 7-day-old rats interferes with cerebellar development, resulting in cerebellar hypoplasia and permanent ataxia. After developing rats are exposed to Borna virus, affected animals show similar cerebellar pathology as well as abnormal play and other social behavior.

Recent speculation that the measles, mumps, and rubella vaccine may be an etiological factor in autism led to a thorough examination of the evidence by many medical researchers. No scientific support for the speculation was found. Nonetheless, scientists remain open to the possibility that some teratogenic, toxic, or viral exposures might serve as risk factors that add to or compound the etiological effect of genetic factors.

Environmental Exposures

Exposure to teratogens [e.g., lead, organophosphate pesticides, and certain medications] and engagement in certain activities that significantly elevate body temperature [e.g., excessive time spent in saunas and hot tubs] may result in birth defects and/or neurodevelopmental and behavioral deficits in offspring and should be avoided during pregnancy [Kilpatrick et al., 2017]. Exposure to disasters prenatally [e.g., terrorist attack, environmental/chemical disasters, and natural disasters] may lead to reduction in fetal growth among some women, but does not appear to affect gestational age at birth [Harville et al., 2010]. Additionally, severity of the exposure predicts maternal mental health problems throughout the perinatal period and may have a stronger influence on children's development than other disaster-related stress [Harville et al., 2010].

Alcohol as a Neurobehavioral Teratogen

As a neurobehavioral teratogen, alcohol interferes with normal fetal growth and CNS development through multiple actions at different sites. Alcohol is a very potent teratogen, altering the developing fetal brain and CNS largely through alcohol-induced disturbance in neurogenesis and synaptogenesis [how neurons and connections between neurons are formed]. But the impact of alcohol on the CNS is found at the cellular, hormonal, neurochemical, structural, and functional levels – with a further complex interplay of genetic and epigenetic factors. Researchers are now carefully and intensively studying the biochemical mechanisms underlying alcohol’s effects, in part because of hope that pharmacologic treatments might eventually be used to intervene with [or prevent] alcohol-related fetal injury. Researchers are also using technology such as ultrasounds, structural and functional neuroimaging, spectroscopy, and physical measures [including electroencephalograms [EEGs]] to understand more precisely how alcohol damages the brain.

Fetal effects of alcohol exposure differ depending on the amount, timing, and pattern of maternal drinking, so deficits are highly variable from one child to another. In general, the more a pregnant woman drinks, the greater the severity of persistent CNS deficits. Episodic [or binge] drinking that creates higher maternal peak blood alcohol concentrations is associated with greater fetal damage. On an individual basis, however, any amount of drinking during pregnancy can cause harm, and alcohol use at any time during gestation is associated with a higher risk of CNS dysfunction.

Signs and symptoms in the fetus

Rubella is one of the most severe teratogens, and associated with poor outcomes when acquired during organogenesis [Adams Waldorf and McAdams, 2013]. While sensorineural deafness is the most common single defect from disease, congenital rubella infection can also result in the following abnormalities: [1] ophthalmologic defects [microphthalmia, cataracts, retinopathy], [2] heart defects [patent ductus arteriosus and pulmonary artery stenosis], [3] neurologic deficits [microcephaly, developmental delay, intellectual disability, and meningoencephalitis], [4] hepatosplenomegaly and jaundice, and [5] radiolucent bone disease.

Neonates with CRS may be a threat to other infants and to susceptible adults because of the shedding of virus during early infancy. Chronic fetal nonlytic infections may affect any organ. Delayed presentation includes the extended rubella syndrome, which presents as progressive panencephalitis and type 1 diabetes, in the second or third decade of life [Webster, 1998].

Lead Exposure

Lead, ubiquitous in the environment, is the teratogen that receives the most attention from a public health perspective. Although much of the attention to lead is on postnatal exposure of children, there are prenatal exposures as well. Exposures can occur in paint, soil, and ceramics; it is a common pollutant in air as well, with gasoline being one historical source [although banned in recent years]. Lead exposure at high levels has demonstrable effects on child development. Physical health can be affected in areas as diverse as growth, fertility, hearing, and renal function [even leading to death at very high exposure levels]; effects extend to the behavioral realm as well, including intelligence, attention, memory, and self-regulation. Prenatal exposure is also associated with epigenetic changes in the IGF2 gene, which has relevance for physical growth. To combat these known effects, testing for lead levels is widespread, and therapeutic interventions to reduce levels in the body and in the environment are common when high levels are detected [Kaufman, 2001; Fraser et al., 2006].

Less clear is the effect of lead at low levels [typically examined between 10 and 20 μg/dL]. It has been widely presumed that low levels of lead would have similar, albeit smaller, effects on young children – assumptions reflected in public health policies. Data supporting this assumption are far from conclusive. Many published studies identify effects on a wide variety of behavioral outcomes. Many other studies, however, have found little or no effects on the same behavioral parameters. In the case of IQ, for example, some argue that small effect sizes [3 IQ points or less] are both of limited practical significance and conceptually suspect in the context of numerous methodological difficulties noted in the extant literature; such limitations include poor inclusion of confounding variables, lack of attention to parental IQ, little control for multiple statistical comparisons, examination of extreme groups, and poor quality-control in data collection [Kaufman, 2001]. This set of arguments [which indeed can be applied to all areas of behavioral teratology] has been refuted, noting that the corpus of studies on lead exposure is commensurate in quality with those in the human development literature in general.

Meta-analysis, often useful in resolving uncertainty in the face of conflicting findings has generated as much debate as the corpus of original empirical studies. Indeed, Kaufman's [2001] commentary in presents aggregate evidence in the domain of IQ, arriving at a relatively non-controversial estimate of effect size of about 2–3 IQ points for the increase from 10 to 20 μg/dL. What becomes controversial, however, is the non-quantitative portion of meta-analytic procedures. High quality meta analyses examine not only the specific estimates of associations or group differences, but also examine variance associated with various study characteristics, including quality. It is at this point that disagreements often occur [as is true for the literature on low lead levels] as the criteria are inherently more subjective. Despite these uncertainties, the American Academy of Pediatrics and Centers for Disease Control have lowered the recommended surveillance level to 5 μg/dL.

Lead Exposure

Lead, which is ubiquitous in the environment, is the teratogen that receives the most attention from a public health perspective. Although much of the attention with regard to lead is on postnatal exposure of children, there are prenatal exposures as well. Exposures can occur in paint, soil, and ceramics; it is a common pollutant in air as well, with gasoline being one historical source [although banned in recent years]. Lead exposure at high levels has demonstrable effects on child development. Physical health can be affected in areas as diverse as growth, fertility, hearing, and renal function [even leading to death at very high exposure levels]; effects extend to the behavioral realm as well, including intelligence, attention, memory, and self-regulation. To combat these known effects, testing for lead levels is widespread, and therapeutic interventions to reduce levels in the body and in the environment are common when high levels are detected.

The effects of low levels of lead [typically examined between 10 and 20 μg dl−1] are less clear. It has been widely presumed that low levels of lead would have similar, albeit smaller, effects on young children – assumptions reflected in public health policies. Data supporting this assumption are far from conclusive. A large number of published studies identify effects on a wide variety of behavioral outcomes. Many other studies, however, have found little or no effects on the same behavioral parameters. In the case of intelligence quotient [IQ], for example, some argue that small effect sizes [3 IQ points or less] are both of limited practical significance and conceptually suspect in the context of numerous methodological difficulties noted in the extant literature; such limitations include poor inclusion of confounding variables, lack of attention to parental IQ, little control for multiple statistical comparisons, examination of extreme groups, and poor quality control in data collection. This set of arguments [which indeed can be applied to all areas of behavioral teratology] has been refuted, noting that the corpus of studies on lead exposure is commensurate in quality with those in the human development literature in general.

Meta-analysis, often useful in resolving uncertainty in the face of conflicting findings, has generated as much debate as the corpus of original empirical studies. Indeed, Kaufman’s commentary in 2001 presents aggregate evidence in the domain of IQ, arriving at a relatively noncontroversial estimate of effect size of about 2–3 IQ points for the increase from 10 to 20 μg dl−1. What becomes controversial, however, is the nonquantitative portion of meta-analytic procedures. High-quality meta-analyses examine not only the specific estimates of associations or group differences, but also examine variance associated with various study characteristics, including quality. It is at this point that disagreements often occur [as is true for the literature on low lead levels] as the criteria are inherently more subjective.

Abstract

Historically, research has revealed the pervasive effects of prenatal exposure to maternal health conditions and potential teratogens during pregnancy on risk for poor birth outcomes and other maternal-fetal/child morbidities and mortality. However, recent research has elucidated maternally mediated exposures ranging from health conditions such as gestational diabetes mellitus to prenatal cannabis exposure can result in changes in fetal brain development and downstream effects on postnatal neurodevelopment. In this chapter, we will summarize several potential prenatal maternally mediated exposures, their mechanisms of action, and their effect on brain development from infancy through early childhood.