Effects of Fetal Substance Exposure on Offspring Substance Use

Introduction

The National Institutes of Health have identified substance use disorders (SUDs) as a major public health problem and noted that the prevalence of these disorders, which typically emerge during adolescence or young adulthood, is increasing. By the time they graduate high school, 70% of adolescents will have tried alcohol, 50% an illegal drug, and ~40% smoked cigarettes.¹ Illegal drug use, including marijuana, exceeds smoking, which has been declining in high schoolers over the last 2 decades, as public disapproval for smoking has increased. Many factors have been identified that appear to influence whether an adolescent experiments with drugs. Adolescents with impulse control problems, depression, anxiety, and attention deficit/hyperactivity disorder (ADHD) are more likely to use drugs. Availability of drugs within the community, peer drug use, and household violence, physical or emotional abuse, mental illness, or drug use —also increase the risk of SUDs.²

Early initiation of drug use also is an important predictor of SUDs. Most individuals with an SUD initiated substance use before age 18.³ Whereas 15% who start drinking by age 14 eventually develop an alcohol use disorder, only 2.1% of those who wait until they are 21 do so.⁴ Thus, adolescence is a critical period for development of SUDs.

The effects of environmental factors, such as parental substance use/abuse, peer exposure, and socioeconomic factors on adolescent substance use are well-documented; however, the impact of more distal factors, such as prenatal substance exposure, are less well understood. Further complicating the relation between prenatal exposure and offspring use is the fact that prenatal exposure is highly correlated with many of the same environmental factors commonly associated with adolescent substance use, thus making it difficult to separate the influence of prenatal vs. postnatal risks on offspring. Additionally, the mechanism by which prenatal substance exposure influences offspring substance use is not well understood. Data from animal studies have shown that prenatal exposure can sensitize offspring to the effects of alcohol and drugs and increase their preference for alcohol and drugs.^5–7 Prenatal substance exposure is also associated with a wide range of offspring behavior problems, such as aggression and delinquency, factors that are commonly found to be associated with adolescent substance use.

The purpose of this paper is to review the existing literature on effects of prenatal exposure to alcohol, nicotine, and drugs on offspring alcohol and drug use.

Effects of prenatal alcohol and drug exposure on offspring development

Fetal alcohol spectrum disorders (FASD) is the umbrella term used to describe the range of adverse outcomes associated with prenatal alcohol exposure (PAE),⁸ including fetal alcohol syndrome (FAS), the most severe form of FASD; partial FAS (PFAS); and alcohol-related neurodevelopmental disorder (ARND), in which individuals fail to meet criteria for FAS and PFAS but exhibit mild to moderate neurobehavioral deficits. Although many children with FAS and PFAS are intellectually disabled and often exhibit behavioral problems, some perform in the low average-average IQ range.^9–11 Many neurocognitive and behavioral deficits associated with PAE have been identified including poorer verbal learning,^12,13 number processing,^14,15 attention and executive function,¹⁶ slower cognitive processing speed,^17,18 and impaired eyeblink conditioning.¹⁹

Children prenatally exposed to alcohol exhibit parent- and teacher-reported behavioral problems,^20,21 and more internalizing and externalizing problems,^22,23 even at relatively low levels of exposure. One or more drinks/day during the 1^st trimester are associated with an increased rate of conduct disorder in adolescents.^24,25 Consistent with the neurocognitive and behavioral effects, there is evidence of structural brain abnormalities in the cerebellum, parietal lobes, corpus callosum, and caudate nucleus,^26,27 as well as compromised white matter integrity.^28–31 Additionally, functional neuroimaging studies have provided evidence of prenatal alcohol-related neural dysfunction in verbal learning,³² working memory,³³ and number processing.^34,35 However, little is known about effects of PAE on SUDs.

By contrast to PAE, for which extensive research has demonstrated cognitive impairment even at low levels of exposure, prenatal drug exposure has been linked primarily to problems in arousal and behavior.^36,37 Cognitive and executive function (EF) deficits have been detected only in children exposed at high levels.^38–41 Offspring exposed prenatally to cigarette smoking are more likely to be irritable and have a difficult temperament during infancy and poor self-regulation during childhood,⁴² as well as increased risk for ADHD⁴³ and difficulties in self-regulation, such as aggressive behavior,^44,45 antisocial behavior,⁴⁶ and conduct problems^47,48 during adolescence. Prenatal marijuana exposure is related to deficits in attention and memory, increases in impulsivity, and delinquent behavior in adolescence.^49–51 Prenatal cocaine exposure affects attention, working memory, inhibitory control, and emotion regulation.^52,53 It also is related to fussy and difficult temperament during infancy,⁵⁴ internalizing problems and depressive symptoms through age 15,^55,56 and externalizing problems in childhood and aggressive behaviors in adolescence.⁵⁷

Prenatal alcohol, smoking, and drug exposure effects on offspring substance use

In Table 1 we have summarized findings from several major studies that were the only ones, to our knowledge, to examine the impact of prenatal substance exposure on alcohol and drug use beginning in adolescence.

Table 1.

Impact of prenatal substance exposure on alcohol and drug use beginning in adolescence

Author	Age (yr)	Prenatal Exposure	Findings
Baer et al 1998	14	Alcohol	PAE more predictive of adolescent alcohol use and its negative consequences than family history of alcoholism. PAE effect remained significant after control for family history and other prenatal and environmental covariates.
Cornelius et al 2000	16	Alcohol	1st trimester alcohol exposure had direct effect on alcohol consumption in 16-year offspring.
Cornelius et al 2000	10	Tobacco	Offspring exposed to >1/2 pack cigarettes/day had 5.5-fold increased risk for early tobacco use.
Baer et al 2003	21	Alcohol	PAE related to alcohol use problems in young adults and persisted after control for other prenatal exposures and environmental covariates. PAE not related to amount of alcohol use after control for covariates.
Porath and Fried 2005	16–21	Tobacco and marijuana	Offspring exposed to cigarettes >2 times as likely to initiate cigarette smoking. Prenatal marijuana exposed offspring at increased risk for both tobacco and marijuana initiation.
Cornelius et al 2005	14	Tobacco	3rd trimester cigarette exposure associated with increased adolescent smoking; effect did not persist after control for current maternal smoking.
Day et al. 2006	14	Marijuana	Prenatal marijuana exposure predicted onset and frequency of marijuana use in 14-year offspring. Effects persisted after control for family history, current alcohol and tobacco use, pubertal stage, sexual activity, and home environment.
Lundahl et al. 2007	14	Alcohol	Pre- and not postnatal alcohol exposure predicted adolescent use of alcohol and marijuana.
Alati et al 2008	14	Alcohol	Offspring of mothers who consumed >3 glasses of alcohol prenatally at increased risk of reporting drinking >3 glasses of alcohol.
Dodge et al 2009	19	Alcohol	Prenatal alcohol predicted alcohol consumption in 19-year-old offspring.
Frank et al 2011	16	Cocaine	Heavier intrauterine cocaine exposure related to greater likelihood to initiate use of any illicit substance, including alcohol and marijuana.
Delaney-Black et al 2011	14	Cocaine	Pre- and postnatal cocaine predicted cocaine use at 14 years.
Goldschmidt et al 2012	16	Alcohol, tobacco, marijuana	Prenatal cigarette exposure related to early initiation of alcohol, marijuana, and tobacco use after control for other prenatal exposures. Prenatal alcohol and marijuana not associated with initiation of use.
Cornelius et al 2012	22	Tobacco	Prenatal cigarette exposure associated with higher rates of smoking and self-reported nicotine dependence symptoms, independent of current maternal smoking.
Rando et al 2013	14–17	Cocaine	Lower gray matter volume in superior frontal gyrus and precuneus in prenatal cocaine exposed. Lower gray matter volumes in these regions increased probability of substance use.
Richardson et al 2013	15	Cocaine	1st trimester cocaine exposure predicted earlier adolescent marijuana and alcohol initiation.
Min et al 2014	15	Cocaine	Adolescents with prenatal cocaine exposure 2.8 times more likely to have SUDs.
Minnes et al 2014	15	Cocaine	Prenatal cocaine exposed adolescents twice as likely to use tobacco, 2.2 times more likely to use alcohol and 1.8 times more likely to use marijuana.
O’Brien and Hill 2015	13–22	Alcohol and tobacco	PAE associated with increased risk of cigarette use and substance use disorders. Prenatal cigarettes associated with increased adolescent cigarette use.
Sonon et al 2015	22	Marijuana	Offspring exposed to marijuana more likely to be frequent marijuana users after control for prenatal alcohol, offspring race, sex, and age.
Richardson et al 2019	21	Cocaine	Prenatal cocaine associated with early initiation of marijuana.
Goldschmidt et al 2019	22	Alcohol	1st trimester alcohol exposure associated with increased offspring alcohol use.

Alcohol

In one of the first studies of prenatal alcohol on offspring drinking behaviors, Baer and colleagues⁵⁸ reported that prenatal alcohol exposure predicted a composite measure of alcohol consumption and alcohol-related problems at age 14, while family history of alcohol problems did not. This effect persisted after control for family history, prenatal smoking, current parental drinking, and environmental potential confounders. At 21 years, prenatal alcohol exposure continued to predict offspring drinking problems, even after control for family history, other prenatal exposures, postnatal parental drinking and other sociodemographic factors.⁵⁹ However, quantity and frequency of drinking at 21 years were not related to prenatal alcohol exposure.

Data from the Mater University Study of Pregnancy, a large prospectively recruited population-based birth cohort, showed that maternal consumption of >3 glasses of alcohol a few times/month in early pregnancy was related to a 3-fold increase in the risk for early- (13–17 years of age) and late-onset (18–21 years) alcohol use disorders.⁶⁰ Postnatal maternal alcohol consumption of ≥3 drinks was also associated with a 1.5-fold increase in the risk of late-onset alcohol use disorders. No significant effects were seen in offspring of mothers who consumed alcohol in late pregnancy. Offspring born to mothers who consumed ≥3 glasses of alcohol during pregnancy were 2.7 times more likely to have reported drinking ≥3 drinks at age 14 years, after controlling for pre- and post-pregnancy drinking.⁶¹

The Maternal Health Practices and Child Development (MHPCD) project is a large prospectively-recruited cohort based in Pittsburgh.⁴⁹ In the MHPCD cohort, detailed interviews of maternal alcohol, cigarette, and drug use were obtained from the pregnant mothers, and offspring were followed-up multiple times through 22 years. Heavy 1^st trimester PAE had a direct effect on alcohol consumption in the offspring at 16 years, which was not mediated by childhood externalizing problems.⁶² Similarly, at 22 years, 1^st trimester alcohol exposure was related to increased offspring alcohol use.⁶³ The Detroit Longitudinal Prenatal Alcohol Cohort¹¹ is another large, prospectively-recruited cohort that assessed effects of PAE on offspring development. Data from the 14-year follow-up⁶⁴ showed that PAE and not postnatal maternal alcohol use was associated with increased alcohol and marijuana use among the 14-year-olds (Table 2). Adolescent alcohol use at 14 years subsequently predicted alcohol and drug use in these offspring at 19 years, indicating that the vulnerability of adolescent alcohol and drug use to PAE predicts greater use as the offspring reach young adulthood.⁶⁵

Table 2.

Relation of pre- and postnatal alcohol exposure to adolescent substance use in the Detroit Longitudinal Prenatal Alcohol Cohort Study

	Prenatal						Postnatal
	oz AA/day		oz AA/drinking day		Frequency		oz AA/day
	r	β	r	β	r	β	r	β
Alcohol (oz AA)
Lifetime	.08	.06	.14*	.14*	.07	.06	−.00	−.01
Year	.09	.09	.13*	.14*	.11†	.13†	−.02	−.03
Month	.09	.09	.02	.03	.13*	.14*	−.02	−.04
Week	.08	.05	.07	.06	.08	.07	−.18	−.13†
Cigarettes
Month	.08	.03	.14*	.12	.07	.04	−.01	−.03
Week	.07	.03	.14*	.12	.07	.04	−.01	−.03
Marijuana (occasions)
Lifetime	.05	.00	.12†	.08	.01	−.03	−.00	.01
Year	.01	−.03	.11†	.08	−.01	−.03	−.01	.01
Month	.08	.05	.15*	.14*	.07	.07	−.07	−.07

Values are Pearson r’s and standardized regression coefficients (β), adjusted for confounding variables.

AA=absolute alcohol. 1 standard drink is equivalent to 0.5 oz of absolute alcohol.

^†p<0.10

^*p<0.05

Tobacco

In the MHPCD cohort prenatal cigarette exposure increased the risk of early cigarette experimentation in 10-year-olds.⁶⁶ Offspring exposed to ≥1/2 a pack of cigarettes/day during pregnancy had a 5.5-fold increased risk for early tobacco experimentation. Effects of prenatal cigarette exposure on early experimentation had both a significant direct effect and an indirect effect through child behavior and peer tobacco use. At 14 years, 3^rd trimester cigarette exposure was associated with adolescent smoking after control for other prenatal exposures, demographic variables, and maternal and child psychopathology.⁶⁷ However, after controlling for current maternal cigarette use and peer smoking, effects of prenatal cigarette exposure no longer predicted adolescent smoking at age 14. At age 16, adolescents exposed to tobacco during the 1^st trimester were 1.4 times more likely to initiate use of multiple substances (cigarettes, alcohol, and/or marijuana) by age 16, while prenatal alcohol and marijuana exposure were not associated with early initiation of cigarettes, alcohol, and marijuana.⁶⁸ At 22 years, prenatal cigarette exposure was associated with higher rates of smoking and self-reported nicotine dependence symptoms, an effect that was independent of current maternal smoking.⁶⁹ Prenatal cigarette exposure was also associated with externalizing and internalizing problems and a history of criminal arrests. Prenatal alcohol and marijuana exposures were not associated with rates of smoking and self-reported nicotine dependence.⁶⁹

The Ottawa Prenatal Prospective Study (OPPS) was a prospectively-recruited longitudinal cohort designed to assess effects of maternal drug use in a low-risk, white, middle- class sample.⁷⁰ Adolescent cigarette and marijuana use was assessed in 152 16- to 21-year-olds. Offspring born to mothers who smoked during pregnancy were more than twice as likely to have initiated cigarette use; however, prenatal smoking was not related to adolescent cigarettes smoked/day or to initiation of marijuana use or amount of daily use.

Marijuana

In the MHPCD project, prenatal marijuana exposure was associated with an earlier age of onset and frequency of marijuana use among 14-year-olds.⁷¹ Those exposed to one joint/day of marijuana during gestation were 1.3 times more likely to have a higher frequency of marijuana use at age 14 than those not exposed to marijuana, effects which persisted after control for current adolescent alcohol and tobacco use and peer drug use. Of note, the effect of prenatal marijuana exposure was specific to adolescent marijuana use and not related to adolescent smoking or alcohol use. At 22 years, offspring exposed to marijuana were more likely to be frequent marijuana users, after controlling for prenatal alcohol, offspring race, sex, and age,⁷² whereas family history of substance use problems did not predict offspring marijuana use.

In the OPPS cohort, adolescents born to mothers who smoked marijuana during pregnancy were 2.5 times as likely to have initiated cigarette use and more than twice as likely to engage in daily cigarette use.⁷⁰ Those born to mothers who smoked marijuana were almost three times as likely to have initiated marijuana use, and joints/day of prenatal marijuana exposure were directly associated with the adolescent’s report of joints/day.

Cocaine

Prenatal cocaine exposure has been found to be associated with earlier initiation of any substance, more than any other prenatal exposure. Intrauterine cocaine exposure was associated with earlier initiation of a licit or illicit substance at age 16 years.⁷³ These findings persisted after control for demographic background and other prenatal and postnatal exposures. Similarly, in the Pittsburgh longitudinal cohort, 1^st trimester cocaine exposure was related to earlier initiation of marijuana and alcohol in 15-year-olds.⁵⁵ By 21 years, prenatal cocaine exposure was a significant predictor of marijuana use initiation and amount of marijuana used in the past year⁷⁴; it was also associated with higher odds of ever having been arrested and poorer inhibitory control. In a large Detroit longitudinal cohort, both pre- and postnatal cocaine exposure were found to be independently associated with adolescent cocaine use at age 14 years.⁷⁵ In a Cleveland cohort, 15-year-olds with prenatal cocaine exposure were more likely to have externalizing problems and were 2.8 times more likely to have substance use related problems⁷⁶ and twice as likely to have used alcohol, cigarettes or cocaine.⁴¹

Summary/Discussion

These studies show that prenatal exposure to alcohol and/or drugs can affect the risk of alcohol and drug use among exposed offspring. There is ample evidence that these more distal prenatal effects persist after controlling for other more proximal environmental factors, including current parental use and the home environment, suggesting that they are independent of the effects of the postnatal environment. Two possible mechanisms for how prenatal alcohol/drug exposure affect offspring use of alcohol and drugs are:

• Prenatal exposures may sensitize offspring to the rewarding effects of alcohol and drugs.

• Prenatal exposures increase the risk of offspring substance use, possibly through behavioral mediators such as childhood and adolescent behavior problems.

Data from animal models have shown a relation between gestational exposure to alcohol and drugs and increased preference for alcohol and drugs in offspring. Rodents prenatally exposed to alcohol consume more alcohol than unexposed controls,^5,77,78 and these results are consistent with those seen in humans. Among humans, young adults prenatally exposed to alcohol were more likely to rate alcohol as having a pleasant odor.⁷⁹ This enhanced alcohol preference, which is present in rat pups and persists into adolescence,^77,80 may be related to sensitization in the reward system since sucrose-intake was also increased in the prenatally exposed rodents. Prenatal nicotine exposure is associated with increased nicotine self-administration⁶ and increases the number of nicotine-binding sites in the brain.⁸¹ Prenatal cocaine exposure has been shown to increase cocaine self-administration in rats,⁷ and in mice, increasing dose of gestational cocaine increases the probability of acquiring cocaine self-administration.⁸² Cocaine-exposed mice are also more sensitive to the locomotor effects of acute cocaine administration.⁸³ The increased preference and sensitization found in prenatally-exposed rodents is likely driven by changes in the brain reward system. Morphological and neurochemical changes to the midbrain areas mediating reward have been detected in prenatal alcohol, cigarette, and cocaine exposure.^84,85

Prenatal exposure to alcohol and drugs is also associated with behavior problems that are associated with adolescent and young adult substance use. A consistent finding among prenatal alcohol, cocaine, and cigarette smoke exposure is increased externalizing behaviors and impulsivity in childhood and adolescence.^{22,23,43,76,86–88} These behavioral problems in childhood and adolescence are also predictive of initiation of substance use and increased risk of substance-related problems. Thus, the relation between prenatal exposures and offspring substance use may also be mediated through behavior problems.

In summary, there is evidence that the fetal environment has an important impact on the development of SUDs in adolescence and adulthood. Longitudinal studies that extend well into adulthood are needed to determine the persistence, severity, and consequences of substance use problems in humans prenatally exposed to alcohol and/or drugs.

Key Points:

1. Prenatal exposure to alcohol, cigarettes, and illicit drugs is associated with physical, cognitive, and behavioral problems in offspring.

2. Prenatal exposure to alcohol, cigarettes, and illicit drugs of abuse is also related to increased risk of offspring substance use and abuse in adolescence and young adulthood.

3. Effects of prenatal exposure on offspring substance use may occur independently of postnatal exposure through parental/familial use.

4. Effects of prenatal exposures on offspring substance use may be mediated by behavior problems in childhood and adolescence.

Synopsis.

Prenatal exposure to alcohol and drugs is associated with physical, cognitive, and behavioral problems across the offspring’s lifespan and to an increased risk of alcohol and drug use in adolescent and young adult offspring. These prenatal effects continue to be evident after control for demographic background and parental alcohol and drug use. Behavior problems in childhood and adolescence associated with prenatal exposures may serve as a mediator of the prenatal exposure effects to offspring substance use.