Drugs, Mother, and Child—An Integrative Review of Substance-Related Obstetric Challenges and Long-Term Offspring Effects

Abstract

Substance use during pregnancy is an increasingly important yet under-recognized threat to maternal and child health. This narrative review synthesizes the current evidence available on the epidemiology, pathophysiology, clinical management, and policy landscape of prenatal exposure to alcohol, tobacco, opioids, benzodiazepines, cocaine, cannabis, methamphetamines, and other synthetic drugs. All major psychoactive substances readily cross the placenta and can remain detectable in breast milk, leading to a shared cascade of obstetric complications (hypertensive disorders, placental abruption, pre-term labor), fetal consequences (growth restriction, structural malformations), and neonatal morbidities such as neonatal abstinence syndrome and sudden infant death. Mechanistically, trans-placental diffusion, oxidative stress, inflammatory signaling, and placental vascular dysfunction converge to disrupt critical neuro- and cardiovascular developmental windows. Early identification hinges on the combined use of validated screening questionnaires (4 P’s Plus, CRAFFT, T-ACE, AUDIT-C, TWEAK) and matrix-specific biomarkers (PEth, EtG, FAEE, CDT), while effective treatment requires integrated obstetric, addiction, and mental health services. Medication for opioid use disorders, particularly buprenorphine, alone or with naloxone, confers superior neonatal outcomes compared to methadone and underscores the value of harm-reducing non-punitive care models. Public-health strategies, such as Mexico’s “first 1 000 days” framework, wrap-around clinics, and home-visiting programs, demonstrate the potential of multisectoral interventions, but are hampered by structural inequities and punitive legislation that deter care-seeking. Research gaps persist in polysubstance exposure, culturally tailored therapies, and long-term neurodevelopmental trajectories. Multigenerational, omics-enabled cohorts, and digital longitudinal-care platforms represent promising avenues for closing these gaps and informing truly preventive perinatal health policies.

1. Introduction

Prenatal care (PNC), defined as the structured healthcare provided by skilled professionals to pregnant women, is designed to optimize maternal and fetal health outcomes. Its core components include the early identification and management of pregnancy-related complications, disease prevention, health promotion, nutritional guidance, and birth preparedness [1]. Effective antenatal care significantly reduces maternal and neonatal morbidity and mortality, promotes informed decision-making, and enhances the pregnancy experience [2]. Nutrition and metabolic health are fundamental pillars of prenatal care. Adequate intake of nutrients such as iron, folic acid, calcium, and vitamins is essential to reduce risks of anemia, preeclampsia, and fetal growth restriction [1,3]. Simultaneously, the metabolic and cardiovascular changes that occur during pregnancy may predispose women to complications like gestational diabetes mellitus (GDM), which affects 5–25% of pregnancies globally and increases the risk of macrosomia, preeclampsia, and neonatal hypoglycemia [4,5]. Timely screening and individualized management are crucial to mitigate short- and long-term sequelae [5].

Antenatal screening and perinatal medicine work in tandem to identify and manage complications throughout pregnancy. Routine evaluations—including OGTT, blood pressure monitoring, and fetal ultrasonography—are critical tools that guide clinical decision-making [6]. Additionally, structured protocols and midwife-led care models contribute to improved outcomes, reduced perinatal morbidity, and enhanced maternal experiences [3,7].

Grangé et al. described that 32.4% of pregnant women reported smoking at the beginning of gestation, while 18.1% continued smoking until delivery. Most women who managed to quit did so during the first trimester, indicating that early recognition of pregnancy may serve as a key window of opportunity for cessation [8]. During the COVID-19 pandemic, among pregnant and postpartum women aged 35–44 years, the drug overdose mortality rate more than tripled—from 4.9 (95% CI, 3.0–8.0) per 100,000 mothers with a live birth in the first half of 2018 to 15.8 (95% CI, 12.3–20.4) in the second half of 2021—highlighting an alarming and accelerating trend [9].

For instance, a recent study conducted in Guadalajara, Mexico, analyzed hair samples from 300 pregnant women who acknowledged illicit drug use at some point during their pregnancy, and found that 127 (42.3%) tested positive for at least one psychoactive substance. Specifically, 45 (15%) tested positive for cannabis only, 24 (8%) for methamphetamines only, 13 (4.3%) for cocaine only, 1 (0.3%) for heroin only, 1 (0.3%) for N,N-dimethyltryptamine only, 1 (0.3%) for ketamine only, and 35 (11.6%) for more than one psychoactive substance [10]. Additionally, a recent U.S. population-based analysis reported 2083 drug overdose deaths among approximately 10,715 pregnancy-associated deaths between 2018 and 2022, corresponding to a rate as high as 36 per 100,000 live births. This data highlights the lethal impact of illicit drug exposure during pregnancy and postpartum periods [11]. Global data cited in the UNODC World Drug Report (2019) and synthesized in a 2020 review show that the average prevalence of illicit drug use during pregnancy varies significantly depending on the method of data collection—from 1.65% by self-report to 12.28% via toxicological testing—revealing substantial underestimation when relying solely on maternal declarations; additionally, a 190% increase in maternal mortality due to opioid abuse has been reported over the last five years [12].

In this context, it is imperative to recognize the growing challenge posed by substance use among pregnant women. Substance use disorders during pregnancy, including alcohol, tobacco, opioids, and other illicit drugs, are associated with significant adverse maternal and fetal outcomes such as miscarriage, preterm birth, intrauterine growth restriction, placental abruption, neonatal abstinence syndrome, and long-term neurodevelopmental impairments in the offspring [12,13]. These risks are compounded by polysubstance use, late prenatal care initiation, and coexisting psychiatric or social vulnerabilities [12]. However, the prevalence of illicit drug use in pregnant women can be underreported due to stigma and limitations in self-disclosure during clinical encounters; toxicological analyses have consistently revealed higher true prevalence rates than self-reporting measures [12]. Effective detection requires validated tools, interprofessional coordination, and a nonjudgmental clinical approach to build trust and enhance disclosure [13]. Beyond the clinical implications, the societal burden of substance use during pregnancy places a significant strain on public health systems due to increased healthcare costs, long-term developmental support for affected children, and intergenerational cycles of disadvantage and disease [12,14].

2. Types of Substances and Its Effects

Prenatal substance use is a significant public health concern with serious implications for both maternal and child health. Tobacco, alcohol, cannabis, and other illicit substances are commonly used during pregnancy, often in combination, which can amplify harmful effects (Figure 1) [13]. Substance use during this critical period is associated with a range of adverse outcomes, including increased risks of stillbirth, preterm birth, low birth weight, small-for-gestational-age infants, and neonatal complications such as abstinence syndrome and sudden infant death [15]. Long-term consequences for exposed offspring include neurocognitive, behavioral, and emotional dysfunctions, with evidence linking prenatal exposure to tobacco and alcohol to higher rates of conduct problems and attention deficit hyperactivity disorder. Socioeconomic disadvantages, psychiatric comorbidities, and limited access to prenatal care further compound these risks [7]. Despite the severity of these outcomes, effective treatment options remain limited, highlighting the urgent need for comprehensive prevention and intervention strategies targeting substance use among women of childbearing age and during pregnancy [16].

2.1. Benzodiazepines

Benzodiazepine use during pregnancy remains a clinical concern because of its documented fetal and neonatal adverse effects. In utero exposure has been linked to a higher incidence of major congenital anomalies—including cardiac defects and central nervous-system malformations—as well as an increased risk of ectopic pregnancy [17]. Women who take these agents in the first trimester show higher rates of stillbirth, pre-term delivery, and fetal-growth restriction [18]. A greater likelihood of spontaneous abortion has also been reported, underscoring the importance of early risk identification and targeted interventions to mitigate harm [19]. Exposure to benzodiazepines during pregnancy is often stems from pre-existing psychiatric conditions or those that arise during gestation, with anxiety disorders—affecting approximately 20% of pregnant women—being among the most common indications. This diagnosis frequently leads to the initiation of benzodiazepine therapy [20,21]. However, in settings where the sale and distribution of psychoactive medications are poorly regulated, many pregnant women may continue using these drugs without medical supervision or a valid prescription. Multiple-cohort studies confirm that first-trimester exposure elevates the overall burden of congenital malformations, a risk that appears to persist throughout gestation [22,23]. These findings highlight the need for individualized, multidisciplinary risk–benefit assessments in pregnant patients; whenever feasible, clinicians should prioritize non-benzodiazepine alternatives, balancing maternal symptom control against potential fetal harm and ensuring the equitable protection of both mother and child.

2.2. Opioids

Opioid consumption is associated with a spectrum of obstetric and neonatal complications, notably neonatal abstinence syndrome (NAS), pre-term birth, and low birth weight. Medicines for opioid use disorder (MOUD)—such as methadone or buprenorphine—improve maternal and perinatal outcomes, particularly when maintained throughout pregnancy [24]. Nevertheless, uptake of MOUD among pregnant and postpartum women remains suboptimal; up to half of patients voice concerns about appropriate dosing and possible neonatal effects, indicating the need for more effective educational strategies [25]. Access disparities are pronounced: non-Hispanic Black, Hispanic, and rural-dwelling pregnant women are less likely to receive MOUD than their non-Hispanic White counterparts, regardless of educational attainment [26]. Nutritional status also modulates risk: class II/III obesity and low serum folate, iron, or transferrin saturation may potentiate adverse fetal outcomes [27]. Obstetric pain management demands individualized plans; divergences exist between patient and provider perceptions of analgesic adequacy, with patients often fearing restricted options and clinicians at times underestimating pain severity [28]. Although overt opioid poisoning in pregnancy is uncommon, it has been linked to intrauterine hypoxia, hypoxic–ischemic encephalopathy, and neonatal seizures [29].

Opioid dependence remains a major public health challenge due to the high risk of overdose and severe withdrawal associated with full μ-opioid agonists such as heroin. Maintenance therapy with methadone and buprenorphine has proven to be safer: methadone shows a lower overdose risk and fewer arrhythmogenic effects (e.g., QT prolongation), while buprenorphine, as a partial agonist, confers even less overdose potential and adverse events [30,31]. These agents differ pharmacodynamically from illicit opioids by offering more stable serum concentrations, longer half-lives, and reduced euphoric effects, thereby minimizing intoxication–withdrawal cycles and enabling safer neurodevelopmental environments for the fetus [31]. Both treatments reduce overdose mortality, improve social integration, and decrease criminal behavior compared to illicit heroin use. Moreover, buprenorphine is linked to superior neonatal outcomes, including higher birth weight and reduced preterm delivery, relative to methadone [32]. Moreover, maintenance therapy has been associated with reduced transmission of blood-borne infections such as HIV and hepatitis C by decreasing risky injection practices and promoting access to harm-reduction services [33]. Thus, the therapeutic goal of MOUD extends beyond symptom control to encompass broader maternal–fetal protection, public health improvement, and reintegration into stable social structures.

2.3. Cocaine

Cocaine use in pregnancy constitutes a persistent public health challenge. In Mexico, despite low overall illicit drug prevalence among pregnant women, cocaine remains one of the most frequently detected substances, suggesting ongoing use within vulnerable groups [10]. Similar biomarker studies in Argentina (hair analysis) confirm intrauterine exposure and underline the need for robust surveillance and prevention strategies [34]. U.S. data show that pregnant women with substance use disorders, including cocaine, have markedly higher risks of severe obstetric morbidity—with preeclampsia, placental abruption, and postpartum hemorrhage being among them [35]. Concomitant use with opioids or amphetamines further elevates postpartum rehospitalization rates [36]. Effective interventions must couple epidemiologic monitoring and health education with efforts to dismantle stigma and deliver multidisciplinary care models tailored to high-risk populations.

2.4. Alcohol

Prenatal alcohol exposure carries considerable maternal, fetal, and neonatal repercussions. Alcohol disrupts placental structure and function, impairing nutrient and oxygen transfer and altering endocrine activity—mechanisms linked to preeclampsia, placental abruption, pre-term birth, low birth weight, and postpartum hemorrhage [37]. A large Danish cohort revealed that heavy maternal alcohol intake increases the risk of significant morbidity during and after pregnancy, including cardiovascular and metabolic disorders [38]. Alcohol can also modify the maternal hormonal milieu; altered endogenous sex steroid levels have been documented, with potential ramifications for pregnancy progression and maternal health [39]. These data mandate comprehensive interventions that address both fetal safety and maternal well-being.

2.5. Cannabis

Rising prenatal cannabis use has prompted heightened scrutiny. Recent evidence associates consumption with gestational hypertension, aberrant gestational -weight gain, placental abruption, pre-term birth, and low birth weight [40]. Psychosocial factors strongly influence use: women with depression, anxiety, or trauma histories are more likely to consume cannabis during pregnancy [41]. Adverse childhood experiences further predict higher usage, often mediated by concurrent health problems [41]. Effective prevention requires multidimensional, culturally sensitive approaches that incorporate social and psychological determinants while emphasizing harm-reduction strategies [42].

2.6. Methamphetamines and Other Synthetic Drugs

Prenatal exposure to methamphetamines and other synthetic drugs has expanded beyond isolated subpopulations, becoming a broader public health issue. Mexican studies detect these substances among pregnant women, linking use to social vulnerability, limited healthcare access, and sustained gestational risk [10]. Beyond pre-term delivery and intrauterine growth restriction, severe neonatal complications—respiratory distress syndrome and admission to intensive care—have been reported [43]. Experimental work shows that prenatal exposure disrupts fetal dopaminergic neuron development, raising the prospect of later neurobehavioral sequelae, and may heighten adult susceptibility to ischemic cardiac injury [44]. Psychosocially, pregnant users frequently encounter stigma and inadequate support, barriers that delay care and perpetuate maternal–infant health inequities [44,45]. Policies and interventions must, therefore, integrate medical management with social support frameworks to reduce harm and improve outcomes.

3. Pathophysiological Mechanisms

3.1. Trans-Placental Passage

The majority of lipophilic substances cross the placental barrier readily (Figure 2), subjecting the fetus to drug concentrations that mirror maternal levels and subsequently re-emerge in breast milk. High lipophilicity, low molecular weight, minimal ionization, and limited protein binding facilitate passive diffusion, while selected transporters can augment transfer. Consequently, prenatal exposure occurs throughout gestation and extends into the neonatal period, heightening the likelihood of adverse outcomes [46,47].

3.2. Effects on Fetal Development

Prenatal substance use has been linked to a broad spectrum of developmental disturbances. Exposure during gestation affects the central nervous system, leading to persistent neurocognitive, behavioral, and emotional deficits in offspring [48,49]. The cardiovascular system is also frequently compromised, manifesting as intrauterine growth restriction, low birth weight, and increased rates of preterm birth, premature rupture of membranes, and placental abruption [13,46,50]. Neonatal adaptation is affected as well, with heightened incidence of neonatal abstinence syndrome and sudden infant death syndrome [46,51,52], while, in early childhood, exposed infants often present with higher rates of respiratory infections and attention- or behavior-related disorders [50].

Importantly, the severity, type, and long-term consequences of these outcomes depend heavily on the timing of exposure during gestation. Embryogenesis and organogenesis occur primarily in the first trimester, a phase in which teratogenic insults—such as alcohol-induced oxidative damage or opioid-related hypoxia—can result in structural anomalies including neural tube defects, congenital heart malformations, and craniofacial dysmorphisms [53,54]. For instance, the central nervous system begins to form in the third gestational week, and exposure to substances such as cocaine or methamphetamine during this period can disrupt neuroepithelial proliferation or early axonal pathfinding [55,56]. Between gestational weeks 4 and 7, cardiac septation and limb development occur, rendering the embryo particularly vulnerable to vasoactive agents and GABAergic modulators like benzodiazepines [57,58].

In contrast, exposures occurring during the second and third trimesters are less likely to result in gross anatomical malformations, but can interfere with neuronal migration, synaptogenesis, glial development, and hypothalamic–pituitary–adrenal (HPA) axis programming [16,21,22]. These later disturbances often manifest as functional deficits such as cognitive delay, attention-deficit phenotypes, heightened anxiety, or impaired stress regulation in infancy and beyond [59]. Therefore, understanding the gestational timing of substance exposure is critical for predicting the organ systems most likely to be affected and for tailoring long-term clinical surveillance strategies [60].

3.3. Placental Dysfunction: Blood Flow and Nutrient Delivery

A precise appraisal of placental injury by psychoactive agents begins with its transport architecture. The trophoblast harbors two principal transporter superfamilies—ATP-binding cassette (ABC) and solute carrier (SLC)—strategically arrayed on the maternal (apical microvillous) and fetal (basal) membranes. Their coordinated activity governs the transplacental kinetics of drugs, xenobiotics, peptides, and endogenous metabolites. When these carriers are inhibited or overwhelmed, the fetal micro-environment is perturbed, predisposing to intra-uterine growth restriction, pre-eclampsia, pre-term birth, and, in severe cases, fetal demise [61].

• Hypoxia and catecholaminergic vasoconstriction: Vasoactive agents (e.g., cocaine, methamphetamines) potentiate placental hypoxia, up-regulate hypoxia-inducible factor-1 α (HIF-1α), and, consequently, overexpress P-glycoprotein (ABCB1). This blunts extravillous trophoblast invasion and spiral-artery remodeling [62].
• Oxidative stress: Excess reactive oxygen species and mitochondrial impairment compromise intervillous perfusion and heighten the risk of placental abruption, partly via altered SLC transporters [63]. Overproduction of reactive oxygen species (ROS) is initiated by the activation of cytochrome P450 (CYP2E1), NADPH oxidase (NOX), and nitric oxide synthase pathways [64]. Concurrently, down-regulation of the Nrf2-dependent antioxidant axis weakens the cell’s ability to buffer oxidative stress. Excess ROS impairs mitochondrial function, triggers cytochrome c release, and activates pro-apoptotic proteins such as Drp1, catalyzing the caspase cascade—most notably caspase-3 and caspase-9—and culminating in apoptosis. Oxidative stress also promotes the release of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and the opening of ROS-responsive cation channels such as TRPM2, thereby exacerbating cell death [65,66].
• Down-regulation of key transporters: Alcohol and opioids suppress pivotal ABC and SLC nutrient/gas carriers, whereas cannabinoids inhibit placental 11β-HSD-2, thereby amplifying fetal glucocorticoid exposure [67].
• Epigenetic remodeling: Drugs of abuse alter DNA methylation at loci such as IGF2/H19 and increase miR-210, reprogramming angiogenic and immunomodulatory pathways and promoting villous immaturity and inflammation [68,69].

In brief, drugs of abuse readily cross the placenta, disrupt critical windows of neuro- and cardio-development, and undermine placental vascular and metabolic integrity, jointly escalating obstetric risk and long-term child morbidity.

Multiple psychoactive drugs impair placental structure and function via converging mechanisms. First, vasoactive agents such as cocaine, nicotine, and methamphetamine blunt extravillous trophoblast invasion and spiral-artery remodeling by sustaining catecholaminergic vasoconstriction, up-regulating endothelin-1, and inhibiting nitric oxide synthase [41,46,47]. The resulting high-resistance uteroplacental circulation predisposes to pre-eclampsia, intra-uterine growth restriction (IUGR), and stillbirth [70,71]. Second, oxidative–endothelial injury, driven by reactive oxygen species (ROS) accumulation and mitochondrial dysfunction, compromises intervillous perfusion and increases the likelihood of placental abruption [72]. Third, several substances down-regulate key nutrient and gas transporters: alcohol and opioids suppress System A amino acid carriers and GLUT-1, while cannabinoids decrease placental 11β-HSD-2 activity, amplifying fetal glucocorticoid exposure [67]. Finally, these alterations curtail amino acid flux, glucose uptake, and oxygen delivery, further exacerbating IUGR and low birth weight. Finally, drug-induced epigenetic remodeling—illustrated by DNA-methylation shifts at IGF2/H19 loci and up-regulation of miR-210—disrupts angiogenic and immunomodulatory gene programs, fostering villous immaturity and a pro-inflammatory milieu [73].

In brief, abused substances readily cross the placenta, interfere with critical neuro- and cardiovascular developmental windows, and disrupt placental vascular and metabolic integrity. These converging mechanisms elevate obstetric risk and confer long-lasting health consequences on the child.

3.4. Fetal Susceptibility and Teratogenic Mechanisms

Prenatal exposure to abused substances such as ethanol, illicit or high-dose opioids (heroin, diverted fentanyl), non-prescribed benzodiazepines, cocaine, methamphetamine, and heavy cannabis exerts teratogenic or neurodevelopmental harm by converging on oxidative stress, vascular dysregulation, and neurotransmitter signaling derailment during organogenesis [74].

There are many teratogenic mechanisms in prenatal exposure (

Table 1. Summary of placental transfer mechanisms, pharmacotoxicity/teratogenic actions, and principal maternal and fetal clinical manifestations for each substance discussed. CB₁, cannabinoid receptor type 1; CNS, central nervous system; FASD, fetal alcohol spectrum disorders; GI, gastrointestinal; ROS, reactive oxygen species.

Substance	Placental Transfer Mechanism *	Pharmacotoxicity and Teratogenic Mechanism	Principal Clinical Manifestations
Benzodiazepines [22]	Passive diffusion (lipophilic)	Placental uptake rises late in gestation; potentiation of fetal GABAA leads to sedation and hypotonia; first-trimester exposure occasionally causes orofacial and cardiac malformations	Fetus: Hypotonia, respiratory difficulties, sleep disturbance; early exposure may cause craniofacial and cardiac defects Mother: Sedation, dizziness and fall risk; excretion in breast milk may sedate the neonate via lactation
Opioids [75]	Passive diffusion (lipophilic, low protein binding)	μ-receptor agonism produces central nervous system (CNS) depression in the fetus and neuroadaptation that leads to neonatal abstinence syndrome involving CNS, gastrointestinal and autonomic systems	Fetus: Neonatal abstinence syndrome (irritability, hypertonia, tachypnoea, gastrointestinal disturbances) Mother: Risk of preterm labor, fetal growth restriction, high rates of postnatal depression and anxiety, increased perinatal morbidity and mortality
Cocaine [41,76]	Rapid passive diffusion (~80% of antipyrine)	Uteroplacental vasoconstriction and acute fetal ischemia; blockade of monoamine reuptake and oxidative stress in the fetal CNS	Fetus: Placental abruption, growth restriction, preterm birth, low birth weight, neurobehavioral deficits (attention, impulsivity) Mother: Risk of preterm labor, premature rupture of membranes and cardiac arrhythmias
Alcohol [77]	Passive diffusion (fetal/maternal ≈ 1:1)	Oxidative stress mediated by acetaldehyde accumulation and ROS, triggering apoptosis during organogenesis	Fetus: Microcephaly, facial dysmorphisms, intrauterine growth restriction, neurobehavioral deficits (FASD) Mother: Increased risk of spontaneous abortion, placental abruption, preeclampsia
Cannabis (THC) [78]	Active efflux transport limits fetal levels.	Binding to placental and fetal CB1 receptors alters endocannabinoid signaling and placental vascularization (labyrinth), causing vascular defects and symmetrically reduced growth	Fetus: Low birth weight, preterm birth, increased neonatal intensive care admission, neurobehavioral alterations (memory, attention deficits, anxiety) Mother: Gestational hypertension, pre-eclampsia, abnormal weight gain, placental abruption
Methamphetamines [45]	Passive diffusion with high placental uptake	Excessive GABAa potentiation triggers fetal sedation, hypotonia; first-trimester exposure linked to orofacial and cardiac malformations in isolated cases	Fetus: Hypotonia, respiratory difficulties, sleep disturbance; early exposure may cause craniofacial and cardiac defects Mother: Sedation, dizziness, fall risk; excretion in breast milk may sedate neonate

* Column 2 now contains only the main physicochemical route across the placenta; dose-dependence, accumulation, or transporter details have been moved to Column 3.

).

Alcohol remains the paradigm, with its interference with retinoic acid and growth factor pathways producing facial dysmorphisms, microcephaly, and lifelong cognitive deficits from fetal alcohol spectrum disorders (FASD), largely mediated by oxidative stress resulting from alcohol metabolism via CYP2E1, which generates acetaldehyde and ROS [72]. These include superoxide anion (O₂⁻), hydrogen peroxide (H₂O₂), and hydroxyl radicals (OH), this redox imbalance promotes lipid peroxidation, DNA damage, and depletion of fetal antioxidant defenses such as glutathione, catalase, and superoxide dismutase. In turn, these events activate the intrinsic apoptotic pathway, characterized by mitochondrial membrane depolarization, cytochrome c release, Bax upregulation, Bcl-2 downregulation, and caspase-3 activation, contributing to widespread apoptosis in fetal brain, liver, and heart tissues [79]. Opioid μ-receptor agonism suppresses fetal breathing movements, perturbs trophoblast angiogenesis, and—when compounded by maternal hypoxia and malnutrition—predisposes to neural tube and cardiac septal defects, as well as postnatal neonatal abstinence syndrome [67]. Benzodiazepines readily traverse the placenta; tonic enhancement of GABA-A currents disrupts neuronal migration, and has been epidemiologically linked to oral clefts and “floppy-infant” hypotonia at birth. Cocaine induces severe uteroplacental vasoconstriction through the inhibition of catecholamine re-uptake, promoting placental abruption, limb-reduction defects, and periventricular cerebral infarcts [80]. Methamphetamine exposure markedly elevates reactive oxygen and reactive nitrogen species. Excessive dopamine auto-oxidation, mitochondrial respiratory-chain impairment, and NADPH oxidase activation generate O₂⁻, H₂O₂, OH, and peroxynitrite (ONOO⁻); the ensuing oxidative milieu overwhelms fetal antioxidant defenses and triggers the same intrinsic apoptotic cascade described above, contributing to neuronal apoptosis, growth restriction, and congenital heart malformations [81,82].

High-THC cannabis, via CB₁-receptor over-activation during synaptogenesis, is associated with subtle cortical thinning, reduced birth weight, and, later, executive function deficits. Experimental data also show THC-induced lipid peroxidation and diminished superoxide dismutase and catalase activities in the fetal cortex, indicating a CB₁-mediated oxidative stress component [49]. Altogether, even in the absence of classic “thalidomide-like” dysmorphology, these substances impose substantial structural, functional, and behavioral burdens that warrant strict avoidance throughout pregnancy.

3.5. Inflammatory and Immunological Pathways

Chronic maternal alcohol use activates nuclear factor-κB signaling and elevates pro-inflammatory cytokines (IL-6, IL-1β, TNF-α). These mediators cross the fetal blood–brain barrier, sustaining neuroinflammation that may underlie long-term neurodevelopmental sequelae [83]. Alcohol-induced gut dysbiosis further increases intestinal permeability, allowing for the translocation of endotoxins and danger-associated molecular patterns; subsequent toll-like-receptor activation amplifies systemic inflammation, potentially disrupting fetal brain development [83]. Such pathways represent promising targets for future therapeutic or preventive interventions.

4. Obstetric, Fetal, and Neonatal Complications Associated with Prenatal Exposure to Drugs of Abuse

Maternal substance use remains a critical determinant of perinatal morbidity because most psychoactive drugs cross the placenta with little impediment, exposing the fetus to pharmacologically active concentrations throughout gestation and—via breast milk—well into the neonatal period. This chronic, bidirectional exposure underlies a cascade of obstetric, fetal, and neonatal complications driven by placental insufficiency, direct embryotoxicity, and difficulties in post-natal adaptation.

4.1. Obstetric Complications

From an obstetric standpoint, pregnancies complicated by illicit or misused prescription drugs show higher rates of hypertensive disorders, placental abruption, premature rupture of membranes, and spontaneous pre-term labor [84,85]. Cocaine-induced vasospasm and alcohol-related endothelial dysfunction are particularly implicated in abruptio placentae and intrapartum hemorrhage, whereas chronic opioid or methamphetamine use is frequently linked to precipitate pre-term birth [86]. Pharmacological treatment of opioid-use disorder markedly modifies risk: large pharmaco-epidemiological datasets indicate that buprenorphine maintenance is associated with fewer severe obstetric events than methadone, without increasing maternal complications [87,88].

4.2. Fetal Complications

Fetal sequelae reflect both the impaired placental transfer of oxygen/nutrients and drug-specific teratogenic mechanisms. Sustained intra-uterine growth restriction and small-for-gestational-age infants are common denominators across substance classes; early-pregnancy exposure to alcohol or benzodiazepines adds a burden of structural malformations, particularly in the cardio–neuro–craniofacial axis [16,89]. Comparative studies in opioid-exposed cohorts further show that buprenorphine (alone or combined with naloxone) yields higher birth weight centiles and larger head circumferences than methadone, suggesting the partial mitigation of growth restriction when modern medication-assisted therapies are implemented [90]. A recent systematic review corroborates the fetal safety profile of buprenorphine–naloxone, but emphasizes the need for continued surveillance, given heterogeneous dosing schedules and co-exposures reported in the literature (Figure 3).

4.3. Neonatal Complications

Neonatal outcomes encompass both acute and long-term domains. Immediately after birth, infants may present respiratory distress, infection susceptibility, and, in the context of opioid or benzodiazepine exposure, clinically significant withdrawal that prolongs hospitalization. Follow-up into childhood reveals persistent neuro-cognitive and behavioral vulnerabilities; nevertheless, population-based data indicate that, when maternal opioid-use disorder is stabilized with buprenorphine, long-term neurodevelopmental trajectories approach those of unexposed peers [91]. Conversely, heavy polysubstance exposure, especially when compounded by inadequate prenatal care, is linked to higher incidences of sudden infant death, attention-deficit phenotypes, and learning disorders [92,93].

These biomedical risks are interwoven with ethical and healthcare system challenges. Qualitative syntheses of maternity care providers’ experiences describe moral distress arising from punitive policies, mandatory reporting requirements, and limited access to evidence-based addiction treatment—all of which can delay or fragment care and inadvertently amplify obstetric and neonatal harm [94,95]. Addressing the full spectrum of obstetric, fetal, and neonatal complications therefore demands a dual strategy: first, universal screening and rapid linkage to pharmacological and psychosocial interventions that demonstrably attenuate perinatal risk; and second, structural reforms that support non-stigmatizing, continuity-oriented models of care for pregnant people who use drugs [95] (Figure 4).

5. Psychosocial and Ethical Dimensions of Substance Use in Pregnancy

Maternal substance use during gestation lies at the intersection of mental health vulnerability, fetal development, and complex clinical ethics. In addition to direct pharmacological harm, social norms and legal frameworks shape women’s engagement with prenatal care and ultimately influence perinatal outcomes.

Stigma remains a primary obstacle to timely antenatal services and evidence-based addiction treatment [96]. Fear of child welfare referral, custody loss, or criminal prosecution often prompts late or inconsistent prenatal attendance. Clinicians report moral distress when mandated drug screening, and reporting requirements undermine their ability to provide empathetic, non-punitive care [97].

Mental health status strongly modulates drug use patterns across pregnancy. Longitudinal observations show that substance consumption and perceived stress typically decline in the second and third trimesters, then rebound during the early postpartum period as formal supports diminish [98]. Large cross-sectional surveys further reveal that unmet mental health needs substantially increase the likelihood of illicit drug use during pregnancy, highlighting the importance of integrating psychological services into routine prenatal care [99].

Population data indicate a sustained rise in psychoactive substance use among women of reproductive age, underscoring shortcomings in current educational and preventive strategies. These trends are amplified by co-occurring stressors such as poverty, violence, and food insecurity, which perpetuate intergenerational vulnerability [100].

Ethical tensions surface when clinicians attempt to balance maternal autonomy with fetal protection. Contemporary bioethical frameworks emphasize that privileging fetal interests while neglecting maternal well-being is counterproductive and deepens existing social inequities [101]. Patient-centered, harm-reduction approaches—such as maintenance therapy with buprenorphine rather than more restrictive or punitive interventions—consistently demonstrate superior maternal and neonatal outcomes, including lower rates of intra-uterine growth restriction and milder neonatal abstinence syndrome [102].

In summary, substance use in pregnancy is tightly linked to psychosocial adversity, unmet mental health needs, and policy-driven stigma. Effective mitigation requires integrated, non-punitive care pathways that combine addiction pharmacotherapy, mental health support, and social services while upholding pregnant individuals’ decisional authority and reducing provider moral distress.

6. Clinical Approach and Treatment

Early detection of substance use in pregnancy starts with validated questionnaires—4 P’s Plus, CRAFFT, T-ACE, AUDIT-C, and TWEAK—and is strengthened by objective matrices such as urine, hair, meconium, and blood measurements. Biomarkers, including phosphatidylethanol (PEth), ethyl-glucuronide (EtG), fatty acid ethyl esters (FAEE), and carbohydrate-deficient transferrin (CDT), uncover under-reporting and improve clinical assessment [103,104]. A multidisciplinary team should prioritize harm reduction and comprehensive patient support through care models that enhance access, coordination, and treatment quality. Opioid-agonist therapy with methadone or buprenorphine lowers maternal–fetal risks and shows excellent adherence, while naltrexone is emerging as a viable option [105,106]. Key barriers to high-quality care include social stigma, fear of losing infant custody, and the criminalization of pregnant patients. Facilitators—such as partner or family support—help offset inequities in access. Accordingly, evidence-based, patient-centered public policies are needed to foster stigma-free environments, ensure legal protection, and streamline obstetric substance use care [107].

Across drugs, common pathogenic threads emerge. Cannabis interferes with the endocannabinoid milieu, impairs trophoblast invasion, and down-regulates CB1 in fetal neural tissue, findings that parallel epidemiologic links to growth restriction, pre-term birth, and, later, externalizing or psychotic-like behaviors [95]. Cocaine’s potent vasoconstriction limits placental perfusion and, together with oxidative neurotoxicity, drives intra-uterine growth restriction, abruption, and aberrant neuronal maturation; dual-modality testing (self-report + toxicology) shows a several-fold gap between disclosure and biochemical positivity [76,108].

The public health impact is substantial: global fetal alcohol spectrum prevalence is 15–50 per 1 000 births [77,109]; cannabis use is rising where legalization normalizes consumption [92]; and cocaine, although less prevalent, remains clinically significant yet widely under-detected [41,108]. All three exposures predict long-term cognitive, behavioral, and physical morbidity, often magnified by poverty, violence, and unmet mental health needs.

Biomarkers of Exposure

Objective confirmation of prenatal substance exposure relies on matrix-specific biomarkers. Direct markers—such as fatty acid ethyl esters (FAEE), ethyl-glucuronide (EtG), phosphatidylethanol (PEth), and carbohydrate-deficient transferrin (CDT)—measured in maternal or neonatal samples, complement history-based assessments (Figure 5) [110,111]. Direct markers offer greater diagnostic certainty, and should be prioritized whenever feasible.

Table 2. Direct biomarkers of prenatal substance exposure—optimal matrix, approximate detection window *, and principal interpretive caveats.

Substance Class	Principal Direct Biomarker(s)	Optimal Specimen(s)	Detection Window *	Key Advantages	Key Limitations
Ethanol [112,113]	• Phosphatidylethanol (PEth) • Ethyl-glucuronide (EtG) • Fatty acid ethyl esters (FAEE) • Carbohydrate-deficient transferrin (CDT)	• Whole blood (PEth) • Urine (EtG) • Meconium/hair (FAEE) • Serum (CDT)	• PEth: ≤4 wk • EtG: ≤80 h urine, ≤3 mo hair • FAEE: ≥3 mo meconium/hair	PEth highly specific; FAEE + EtG extend window	• Incidental alcohol (EtG) • Microbial degradation (EtG) • Hair treatments (FAEE)
Nicotine [114]	• Cotinine	• Maternal urine /serum • Meconium • Hair	• ≤48 h (blood) • ≤1 wk (urine) • ≤3 mo (hair)	Quantifies active vs. passive smoke	Rapid clearance; overlap with nicotine-replacement therapy
Cannabis [115]	• Δ9-THC-COOH • 11-OH-THC	• Maternal blood /urine • Meconium • Cord tissue • Hair	• ≤36 h (blood) • ≤30 d (urine) • ≤3 mo (hair)	Distinguishes recent vs. historic use	Lipid partitioning leads to variable windows; hair external contamination
Cocaine [116]	• Benzoylecgonine • Cocaethylene (with ethanol)	• Maternal urine • Meconium • Hair	• ≤3 d (urine) • ≤3 mo (hair)	Parent + metabolite confirm timing	False positives from anesthetic use (rare)
Opioids [117]	• 6-Monoacetylmorphine (6-MAM, heroin) • Norbuprenorphine/nor-methadone	• Maternal urine • Meconium • Cord tissue	• 6-MAM ≤8 h • Metabolites ≤3 d (urine) • ≤3 mo (meconium/hair)	6-MAM is heroin-specific; metabolite ratios indicate compliance with MOUD	Short 6-MAM window; poppy-seed ingestion confounder (morphine)
Benzodiazepines [118]	• Nordiazepam • Desmethyldiazepam	• Maternal urine • Hair	• ≤7 d (urine) • ≤90 d (hair)	Identifies chronic vs. intermittent use	Numerous analogs require panel testing
Ketamine/ Synthetic cathinones [119]	Norketamine • Parent cathinone	• Maternal urine • Hair	• ≤3 d (urine) • ≤3 mo (hair)	Distinctive metabolites	Limited obstetric validation
Methamphetamine/Amphetamine [120]	• d-Amphetamine • p-Hydroxy-methamphetamine	• Maternal urine • Meconium • Hair	• ≤3–5 d (urine) • ≤3 mo (hair)	Quantifies frequency/intensity	OTC sympathomimetics may cross-react

* Detection windows assume the recommended cutoff concentrations; hair and meconium reflect cumulative exposure from the previous trimester.

summarizes these direct biomarkers, their optimal matrices, and interpretive caveats. Typical analytic cut-offs are as follows: PEth ≥ 0.02 µmol L⁻¹; urine EtG ≥ 100 ng mL⁻¹; hair FAEE sum ≥ 0.5 ng mg⁻¹; and urine cotinine ≥ 500 ng mL⁻¹. However, thresholds vary by laboratory.

Indirect indices—including γ-glutamyl-transferase, aspartate aminotransferase, and mean corpuscular volume—aid first-line screening, but lack specificity, particularly in the presence of hepatopathy or hematological disorders [110]. PEth remains the most reliable long-term marker of significant alcohol intake, persisting up to four weeks post-consumption and showing minimal influence from sex or chronic liver disease [110]. Interpretation must, however, consider potential false positives from incidental ethanol exposure (e.g., alcohol-based hand sanitizers) and false negatives due to bacterial hydrolysis during urinary tract infection.

Emerging biomarkers—micro-RNAs (miR-122, miR-210), DNA adducts, and exosomal cargo—offer promise for earlier or longer detection windows, but still require validation in obstetric populations.

7. Public Health Policy and Prevention

Effective prevention begins with continuous prenatal engagement. In Mexico, the “first 1 000 days” framework integrates nutrition counseling with post-natal follow-up to blunt toxic exposure sequelae, yet structural discrimination still limits timely care, particularly for Indigenous women [121,122]. International evidence shows that universal, first-trimester psychosocial interventions can ease maternal distress—an upstream trigger of substance use—while targeted nutrition classes for short-stature gravidas curb growth-restriction risk exacerbated by alcohol and stimulant exposure [123,124]. Multiservice “wrap-around” clinics that co-locate obstetrics, psychiatry, and addiction treatment improve adherence and neonatal outcomes; home-visiting platforms such as Nurse-Family Partnership extend these benefits to rural settings [125,126]. Canadian opioid guidelines likewise endorse initiating agonist therapy with psychosocial support before 20 weeks of gestation to lower neonatal abstinence rates [127].

Health literacy initiatives remain pivotal. Community programs (e.g., “Vive saludable, vive feliz”) strengthen maternal self-care, while a quasi-experimental trial grounded in self-efficacy theory showed that six educational sessions reduced non-prescribed benzodiazepine use and urinary-tract infections—conditions often worsened by stimulant consumption [128]. Community resilience, driven by local leadership, has delayed adolescent pregnancy and substance initiation in rural regions [129]. At the same time, the Motherisk scandal in Canada underscores the need for strict scientific and ethical oversight to preserve public trust in perinatal toxicology services [130].

Policy design critically shapes outcomes. U.S. jurisdictions emphasizing voluntary treatment and support—rather than punishment—report lower neonatal abstinence syndrome incidence and better postpartum follow-up [131,132]. Conversely, mandatory-reporting laws for alcohol or methamphetamine use deter prenatal attendance and widen care gaps, perpetuating stigma and inequity [133,134]. Wrap-around and home-visiting models counter these effects by offering non-judgmental, rights-based care that integrates addiction therapy with obstetric monitoring [125,126]. California’s early-detection program demonstrates that comprehensive screening can curb prenatal cocaine and methamphetamine exposure, yet the concurrent rise in cannabis use after legalization highlights that regulation without intensive prevention is insufficient to safeguard maternal–infant health [41].

Future research must move beyond single-substance models in high-income settings to unravel how polysubstance use, social adversity, and unrecognized consumption patterns jointly shape maternal–fetal risk, evaluate emerging treatments—including tailored opioid agonist regimens, endocannabinoid modulators, and app-based longitudinal care—in culturally diverse populations, and track exposed offspring into adulthood through multigenerational, omics-enabled cohorts that also measure family resilience, thereby generating the mechanistic and translational insights needed to build truly preventive perinatal health policies.