Intrauterine Drug Exposure: Fetal and Postnatal Effects

Introduction

Alcohol consumption during pregnancy can cause a range of disorders, known as the fetal alcohol spectrum disorders (FASDs). FASDs include fetal alcohol syndrome (FAS), alcohol-related neurodevelopmental disorder (ARND), alcohol-related birth defects (ARBDs), partial FAS, and neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE). Intrauterine alcohol exposure also is associated with growth restriction that persists postnatally. The classic features of FAS were initially described by a French pediatrician in 1968 who observed a common pattern of birth anomalies in children born to alcoholic mothers. In the 1970s, two U.S. reports were published describing similar features in children born to women consuming alcohol while pregnant. This recognition led to the U.S. federal law placing warning labels on all alcoholic beverage containers regarding the increased risk of alcohol-related birth defects. In 2005, the Surgeon General reissued an advisory for people who are or might become pregnant, urging abstinence from alcohol to eliminate the risk for FASD.

Data from the NSDUH in 2015–2018 indicated that nearly 10% of pregnant respondents had admitted to alcohol consumption and 4.5% to binge drinking within the past 30 days. Prevalence differed, with greater consumption and binge drinking in the first trimester compared to the second and third trimesters. Overall, nearly 20% of pregnant respondents reported drinking any alcohol and using tobacco within the past 12 months. The objective set by Healthy People 2030 is to increase abstinence from alcohol among pregnant persons to 92.2%. The rate of FAS in the United States has been estimated to vary from 0.5 to 2 cases per 1000 live births, but its true prevalence is unknown and is likely underdiagnosed worldwide.

Pediatricians often do not recognize FAS in the neonatal period and do not always inquire about alcohol exposure during pregnancy. There are prenatal alcohol exposure screening instruments that are appropriate for use in pregnant persons as well as expert guidelines to clarify the diagnosis of FASD and aid in the earlier recognition and referral of affected infants and children.

Diagnosis and Classification

The Institute of Medicine defined FASD in 1996 as an umbrella term for a range of sequelae of prenatal alcohol exposure. A scientific task force led by the Centers for Disease Control (CDC) confirmed and refined the diagnostic criteria in 2004. FASD includes FAS as well as additional classifications for patients with variations on the classic FAS presentation. A diagnosis of FAS requires evidence of: (1) all three facial abnormalities (see description below), (2) growth deficits, and (3) central nervous system (CNS) abnormalities (structural, neurological, and/or functional).

Additional classifications include:

• Partial FAS (pFAS)—some, but not all of the physiologic features of FAS,

• ARND, where there are no facial deformities but features of CNS injury,

• ARBD, presenting primarily with physical malformations (cardiac, renal, bone, visual, and/or hearing),

• ND-PAE.

A diagnosis of FASD is made using maternal history, the infant’s physical findings, and neurobehavioral testing results. Although biomarkers such as fatty acid ethyl ester levels in meconium have been evaluated for use in diagnosis of prenatal alcohol exposure, no laboratory tests are available and validated for clinical use to quantify the extent of fetal alcohol exposure. There are also no clinical methods for validating maternal self-reporting of alcohol use, quantifying the level of fetal exposure, or predicting future disability after fetal exposure.

Pharmacology and Biologic Actions

Alcohol is a mood-altering substance that enhances the effects of the inhibitory neurotransmitter γ-aminobutyric acid while reducing the effects of the excitatory neurotransmitter glutamate. This results in dose-dependent depressant or sedative effects on the CNS. Alcoholic beverages contain ethanol, which is metabolized in the liver to acetaldehyde by alcohol dehydrogenase (ADH). Acetaldehyde is then metabolized to acetate by aldehyde dehydrogenase and eventually eliminated as water and CO ₂ . A small amount of oxidation in the liver is catalyzed by the cytochrome P450 enzyme CYP2E1.

Ethanol readily diffuses across the placenta and can be rapidly detected in the fetus. The placenta expresses an isoform of ADH that has a low affinity for ethanol and a reduced metabolic rate. The fetal liver expresses CYP2E1 by mid-gestation, but at lower levels and less metabolic capacity than adult liver. Despite the presence of fetal and placental metabolic activity, fetal ethanol clearance largely relies on maternal metabolism. Toxic effects of alcohol during pregnancy appear to be related to the peak and circulating alcohol concentrations. Undernutrition and alcohol exposure may interact to cause greater fetal toxicity, due to slower maternal metabolism.

Fetal and Neonatal Effects

It is unclear how much alcohol exposure is necessary to cause fetal teratogenicity and even high consumption levels do not always result in the birth of a child with FASD. The adverse effects of alcohol on the fetus are related to gestational age (GA), duration of exposure, amount of alcohol consumed, pattern of consumption (e.g., binge drinking), maternal peak blood alcohol concentrations, and maternal alcohol metabolism. Studies show that maternal blood alcohol levels are affected by body size and genetic disposition, with poor maternal nutritional status a significant risk factor for FASD. A variety of additional risk factors increase susceptibility to FASD, including increased maternal age, poverty, and socioeconomic status.

Growth Restriction

Fetal growth restriction (FGR) is one of the most consistent sequelae of prenatal alcohol exposure. The diagnostic criteria for FAS require birth weight and/or length to be below the 10th percentile (adjusted for age, sex, gestational age, and race or ethnicity). Restricted growth begins in utero and continues postnatally, with high levels of alcohol exposure causing greater impact on head and body growth. Fetal and childhood growth deficits appear to be multifactorial, with etiologies including abnormal placentation, abnormal vascular development, and impaired production of insulin-like growth factors that are involved in somatic growth and placental function. Growth deficiency may persist through childhood, particularly in those children with the highest levels of intrauterine exposure.

Dysmorphology

Key features of FAS include characteristic facial dysmorphology, including a smooth philtrum (using University of Washington Lip-Philtrum Guide), a thin vermillion border, and small palpebral fissures. Characteristic features also may include midface hypoplasia, broad flat nasal bridge, and thin upper lip ( Fig. 11.2 ) . Patients with FAS also have a higher risk of microcephaly, micrognathia, and cleft palate. Genetic syndromes must be excluded because some of their dysmorphic features can overlap with FAS. The facial features and growth restriction may become less distinctive during adolescence and puberty. While skeletal anomalies, abnormal hand creases, and ophthalmologic, renal, and cardiac anomalies have been described in children with FAS, they are less frequent than the facial dysmorphology.

Central Nervous System Abnormalities

Children with FASD are at higher risk of seizure disorders as well as significant cognitive, motor, and neurobehavioral problems. A host of CNS abnormalities are associated with FASD. Table 11.1 lists some of the more common findings.

Long-Term Effects

FASDs are associated with lifelong social, behavior, intellectual, and psychological difficulties, and deficits in reading, spelling, and math are common. In a cohort of 76 children and young adults with FASD, high rates of attention deficit/hyperactivity disorder (ADHD; 62%), oppositional defiant disorder (43%), and developmental coordination disorders (41%) were noted. Visual and/or ocular abnormalities were also found in 86% of the children. Of the adults evaluated, 70% had ADHD, 52% had an anxiety disorder, 42% had experienced a depressive episode, and 24% had engaged in self-injurious behavior. Adolescents and young adults who were exposed prenatally to alcohol are at an increased risk for earlier alcohol use and subsequent abuse.

Researchers using the Canadian National FASD Database reported on a sample of 726 adolescents and adults (mean age 19.8 years [range 12 to 60]) who had prenatal alcohol exposure. Impairments in adaptive behavior, social skills, executive functioning, academic achievement, and attention were seen in approximately 2/3 of the sample, and 40% had an intelligence quotient less than 70. Difficulties included independent living needs (63%), substance misuse (46%), employment problems (37%), legal problems (30%), and housing problems (21%), with 81% experiencing at least one such difficulty at the time of assessment. Earlier recognition and intervention for children with FAS and its variants may help mitigate eventual adulthood disabilities and help to prepare affected adolescents and young adults for independent living.

Introduction

Nicotine in the form of cigarettes (including electronic cigarettes—ECIGS and electronic nicotine delivery systems—ENDS), smokeless tobacco, and nicotine replacement patches, is the most commonly used substance during pregnancy which negatively affects perinatal outcomes. Cigarette smoking in the United States has decreased significantly over the past 25 years, due to effective public health strategies. Unfortunately, these efforts have not been as effective for pregnant persons. Since the 2019 NSDUH survey revealed that 9.6% of pregnant persons used tobacco, targets set by the Healthy People 2020 initiative to decrease tobacco use to less than 2% of pregnant people have not been reached. These targets are becoming even more tenuous with the use of ECIGS steadily increasing during pregnancy, likely because they are believed to be a safer alternative than conventional cigarette smoking. Pregnant persons who use nicotine products are more likely to use opioids, alcohol, cocaine, amphetamines, and marijuana. Cigarette smoking is especially prevalent among pregnant persons with OUD (85% to 95%) and smoking cessation programs should improve both maternal and neonatal outcomes.

Pharmacology and Biological Actions

Cigarette smoke contains a mixture of approximately 4000 compounds (93 of which are considered toxic), including nicotine and carbon monoxide. Nicotine stimulates the reward center of the brain through activation of nicotinic acetylcholine receptors. It readily crosses the placenta and concentrates in fetal blood and amniotic fluid, where levels can significantly exceed maternal blood concentrations. The maternal serum concentration of cotinine (the primary metabolite of nicotine) is used to quantitate smoking and fetal exposure. Cotinine has a half-life of 15 to 20 hours with serum levels 10-fold higher than nicotine.

Smoking during pregnancy can impact fetal growth and development; nicotine and its metabolites are potent vasoconstrictors which decrease uterine and placental blood flow. Carbon monoxide crosses the placenta, forming carboxyhemoglobin in the fetus and resulting in significant hypoxemia. Serum erythropoietin levels are significantly higher in cord blood from neonates who were exposed to cigarette smoke, a finding likely reflecting fetal hypoxia. Nicotine may also act as a developmental toxin targeting the placenta as well as the brain and other organ systems in the fetus. Since the amount of nicotine delivered by ECIGS is similar to conventional cigarettes, potential toxicity would be expected to be similar.

Long-Term Effects of Perinatal Exposure to Cigarettes and Electronic Cigarettes

Maternal smoking has been shown to increase the risk of stillbirth, miscarriage, and preterm delivery. Liu et al. studied over 25 million pregnancies in the U.S. National Vital Statistics System from 2011 to 2018. They demonstrated that smoking during the first or the second trimester of pregnancy (even 1 to 2 cigarettes per day) was associated with an increased risk of preterm birth, which was in part due to increased placental abruption and placenta previa. Cigarette smoking is also well recognized to cause FGR in a dose-dependent manner. Reductions in weight, fat mass, and other anthropometric measurements occur through impaired placental blood flow, tissue hypoxia, and alterations in protein metabolism and enzyme activity in the placenta. When these children are followed to 3 years of age, body weights are increased, consistent with early childhood obesity. Although nicotine replacement therapy (NRT) and ENDS do not show clear evidence of effectiveness and safety in pregnant women, those who stopped smoking before or during early pregnancy had appropriate fetal and childhood growth.

Fetal exposure to cigarette smoke can impact lung development, putting preterm neonates at increased risk of bronchopulmonary dysplasia (BPD) and longer-term pulmonary dysfunction termed chronic pulmonary insufficiency of prematurity (CPIP). Term neonates are at increased risk of diminished lung function, altered central and peripheral respiratory chemoreception (e.g., SIDS), and asthma during childhood. Possible mechanisms also include dysregulated cytokine production, oxidative stress, and the direct effects of nicotine on lung receptors resulting in altered lung development. Genetic (upregulation of asthma susceptibility genes) and epigenetic (alterations in DNA methylation) factors have been identified that may influence the risk for long-term lung disease. Pregnant persons who smoke during pregnancy often continue to smoke postnatally, exposing their children to secondhand smoke exposure. This can further increase the risk of morbidity and mortality throughout childhood.

Finally, alterations in developmental patterning of DNA methylation and gene expression can be detected in the fetal brain following antenatal exposure to cigarette smoke. This can result in reduced mature neuronal content, fetal brain growth, and smaller volume of cortical gray matter. This may explain the increased incidence of behavioral problems and impaired executive function that can be seen later in childhood.

Introduction

Cannabis is a potent psychoactive agent used commonly during pregnancy. Between 2016 and 2019, the NSDUH reported a rate of cannabis use in pregnant persons aged 15 to 44 years ranged from 4.9% to 7.1%, with frequent use in 1.5% to 3.1%. Another analysis found increased cannabis use occurring despite cigarette and alcohol use in pregnancy declining. The majority of cannabis use is recreational and probably underreported due to recall bias. Surveys of pregnant persons and non pregnant persons indicate that 70% believe that there is slight or no risk of harm from using cannabis. The increased potency of cannabis products is of particular concern. Chandra et al. reported that mean Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC; the active component of the endocannabinoid system) concentrations have increased from 8.9% in 2008 to 17.1% in 2017 and the mean Δ ⁹ -THC: Cannabidiol (CBD) ratios from 23 to 104. The greatest reported use occurs in the first trimester, often before the person is aware of being pregnant.

Pharmacology and Biological Actions

Endocannabinoids and phytocannabinoids activate cannabinoid receptors in the endocannabinoid system. CB1 is primarily found in the central nervous system and CB2 in immune cells and the retina. Cannabinoid signaling is necessary for normal placental implantation and receptors are expressed early in the fetal brain, particularly in white matter and areas with high cellular proliferation. During pregnancy, cannabis readily crosses the placenta and the fetal blood-brain brain barrier since it is highly lipophilic, altering normal endocannabinoid signaling, synaptogenesis, development of neuronal interconnections, and developing neurotransmitter systems. All of these effects can potentially influence embryogenesis and fetal development by disrupting normal angiogenesis, increasing cellular apoptosis, and reducing cellular migration and DNA replication.

Cannabis use during the postpartum period can increase neonatal exposure through breast milk and secondhand exposure. THC may remain in breast milk up to 6 weeks after ingestion and up to eight times the maternal serum level. Recent studies have suggested that cannabis use during pregnancy is associated with placental abruption, preterm birth, fetal growth restriction, admission to a neonatal intensive care unit, and lower 5-minute Apgar scores which can significantly impact both short- and longer-term outcomes.