Abstract
Introduction:
Cannabis use among pregnant women has increased over time. Therefore, there is a great public health need to understand the consequences of in utero cannabis exposure. While several meta-analyses and reviews have summarized the evidence of in utero cannabis exposure on adverse obstetric outcomes (e.g., low birth weight and preterm birth) and long-term offspring development, there has not been a focus on in utero cannabis exposure and risk for structural birth defects.
Methods:
We conducted a systematic review using PRISMA guidelines to evaluate the association between in utero cannabis exposure and structural birth defects.
Results:
We identified 20 articles to include in our review and focused on interpreting findings from the 12 that adjusted for potential confounders. We report findings by seven organ systems. Within the 12 articles, four reported on cardiac malformations, three reported on central nervous system malformations, one reported on eye malformations, three reported on gastrointestinal malformations, one reported on genitourinary malformations, one reported on musculoskeletal malformations, and two reported on orofacial malformations.
Discussion:
Findings on associations between in utero cannabis exposure and birth defects reported in more than two articles were mixed (i.e., findings for cardiac, gastrointestinal, central nervous system malformations). Findings for associations between in utero cannabis exposure and birth defects reported in two articles (i.e., orofacial malformations) or in a single article (eye, genitourinary, and musculoskeletal) suggested that cannabis exposure was not associated with these types of malformations, but strong conclusions cannot be drawn from such sparce research. We review the limitations and gaps in the existing literature and call for more research to rigorously evaluate associations between in utero cannabis exposure and structural birth defects.
Systematic Review Registration:
identifier CRD42022308130.
1. Introduction
Research has documented an increase in rates of cannabis use among pregnant people over time. Among a nationally representative sample of pregnant individuals in the United States, the prevalence of self-reported prenatal cannabis use in the past month increased from 3.4% in 2002–2003, to 7.0% in 2016–2017 (1). Prenatal cannabis use may increase even more rapidly as more US states legalize cannabis for recreational use (2–7). Moreover, cannabis use in pregnancy could impact fetal development because cannabis is lipid soluble and is able to cross the placenta and blood-brain barrier (8), and some previous studies have suggested a potential link between in-utero cannabis exposure and adverse offspring outcomes [e.g., (9)]. Therefore, there is a great public health need to understand the consequences of in utero cannabis exposure on offspring development. Several meta-analyses and reviews have summarized the evidence of in utero cannabis exposure on adverse obstetric outcomes (e.g., low birth weight and preterm birth) and long-term offspring development (8, 10–15). However, reviews to date have not focused on research regarding in utero cannabis exposure and risk for structural birth defects. The causes and risk factors for many structural birth defects remains unknown, and understanding preventable causes and risk factors for structural birth defects is particularly important given the strong association between birth defects and morbidity/mortality (16). Given this need, we conducted a systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to evaluate whether in utero cannabis exposure is associated with structural birth defects compared to pregnancies with no cannabis exposure (Prospective Register of Systematic Reviews [PROSPERO] registration number: CRD42022308130; (17)].
2. Methods
Web of Science and PubMed databases were searched for English language articles published before February 1, 2022 utilizing the following key words: “(Pregnancy OR Prenatal OR In utero OR Perinatal) AND (Cannabis OR Marijuana) AND (Birth defects OR Congenital malformations OR Congenital anomalies OR Central nervous system defect OR Neural tube defects OR Holoprosencephaly OR Microcephaly OR Ear defect OR Eye defect OR Gastrointestinal defect OR Biliary atresia OR Esophageal atresia OR Tracheoesophageal fistula OR Intestinal atresia OR Intestinal stenosis OR Pyloric stenosis OR Hypospadias OR Renal agenesis OR Renal hypoplasia OR Renal dysplasia OR Cardiac defect OR Musculoskeletal defect OR Congenital diaphragmatic hernia OR Gastroschisis OR Limb deficiency OR Omphalocele OR Orofacial defect OR Respiratory defect OR Choanal atresia OR Cleft lip OR Cleft palate).” The inclusion criteria were English-language articles and epidemiological studies. Animal studies and review articles were excluded as the focus of our review was strictly on human outcomes.
The search revealed 299 potentially relevant articles of which 48 were duplicates. We created an EndNote library of 251 non-duplicate articles. Two authors then independently reviewed the titles and abstracts of the articles in the EndNote library to exclude articles that did not meet the inclusion criteria. After their independent reviews, the two authors discussed disagreements and together decided to include 37 articles for a full text review. During the full text review, 17 additional articles were excluded for the following reasons: study design was a case study (18), a comparable study was conducted by the same authors using the same dataset (19–23), and the study did not specifically evaluate associations between cannabis exposure in pregnancy and birth defects [e.g., cannabis was included in a general substance use exposure variable or the outcome studied was not a birth defect; (24–34)]. Therefore, the final review included 20 articles (9, 22, 35–53). See Figure 1 for a PRISMA flow diagram illustrating our identification process of articles for our final review.
Figure 1
3. Results
3.1. Study characteristics
Of the 20 included articles, 8 were from prospective studies using recruited samples (35–42), and 12 were from retrospective cohort or case-control studies using health care records (9, 43–53). Samples sizes varied from 50 to 3,067,069. Earliest birth years for cohorts varied from 1968 to 1980. Only 3 of the articles reported on studies using urine toxicology tests (46–48); the rest reported on studies that relied on self-report to measure prenatal cannabis use. Of the 17 articles that reported on studies using self-reports to measure cannabis use, 16 had measures of self-reported cannabis use, and 1 had a measure of self-reported cannabis-related diagnoses (43). The outcome definitions varied across studies with some investigating associations with specific malformations and other studies investigating associations with any malformation. While 8 studies did not adjust for any potential confounders (38, 40, 41, 44, 46, 47, 49, 53), the rest adjusted for confounding, though the specific factors adjusted for varied across studies. Table 1 provides information about the characteristics of each individual study.
Table 1
| Citation | Design and sample | Sample size | Birth years | Cannabis exposure definition | Organ System | Birth defect | Confounding adjustment |
|---|---|---|---|---|---|---|---|
| 1. Astley et al. (41) | Prospective study of patients in their sixth month of pregnancy recruited from a health maintenance organization in Seattle, Washington, USA | 80 (40 exposed matched to 40 unexposed) | 1982–1984 | Self-reported use during the first trimester of pregnancy ascertained at an interview 6 weeks after delivery | Orofacial | Fetal alcohol like facial characteristics | None |
| 2. Bandoli et al. (43) | Retrospective, population-based cohort of births in California, USA | 3,067,069 | 2011–2017 | Self-reported cannabis-related diagnoses made during pregnancy or delivery | Cardiac, Central nervous system, Eye, Gastrointestinal, Orofacial | Any cardiac malformation, Any central nervous malformation, Neural tube defect Anencephaly, Spina Bifida, Eye malformation Gastrointestinal malformation | Demographics: race and ethnicity, payer source, maternal age and education Substance use: alcohol abuse, and nicotine and substance-related diagnoses Mental health: anxiety, depression, bipolar disorder Physical health: pre-pregnancy body mass index (BMI), preexisting hypertension, preexisting diabetes |
| 3. Bourque et al. (44) | Retrospective, population-based cohort study of births in Ontario, Canada | 1,001,080 | 2012–2018 | Self-reported use during pregnancy ascertained at the first prenatal visit or admission for birth | Gastrointestinal | Gastroschisis | None |
| 4. Coleman-Cowger et al. (35) | Prospective study of patients recruited from two obstetric clinics in Maryland, USA | 338 | 2017 | Self-reported use in the last month ascertained at prenatal visits | Unspecified | Birth defects | Demographics: marital status Pregnancy-specific: trimester of self-reported use |
| 5. Cornelius et al. (36) | Prospective study of patients 18 years or younger recruited from an outpatient prenatal clinic in Pittsburgh, USA | 310 | 1990–1993 | Self-reported first-trimester use | Unspecified | Major and minor physical anomalies | Demographics: race, infant sex, maternal age, household structure, mother's parent's education, full-time or part-time school status, Substance use: alcohol use, marijuana, cocaine/crack, and other illicit drug use Mental health: social support, depression Physical health: pre-pregnancy weight, gestational weight gain, maternal height, maternal nutrition Pregnancy-specific: gestational age at birth, gravidity, adequacy of prenatal care |
| 6. Day et al. (37) | Prospective study of patients recruited from an outpatient prenatal clinic in Pittsburgh, USA | 763 | 1982–1985 | Self-reported use at the fourth prenatal month visit, seventh prenatal month visit, and postpartum hospital stay about use in each trimester | Unspecified | Minor and major physical abnormalities | Demographics: maternal age, education, marital status, work status, income, race, Substance use: use of tobacco, alcohol, and other illicit drugs Mental health: social support, depression and anxiety Physical health: gestational weight gain, maternal height Pregnancy-specific: gravidity Other: life events |
| 7. Downing et al. (45) | Retrospective, population-based, case-control study of records from 10 Centers for Birth Defects Research and Prevention across the USA | 11,964 (135 cases, 11,829 controls) | 1997–2011 | Self-report of use during the first trimester of pregnancy ascertained between 6 and 24 months after delivery | Cardiac | Ebstein anomaly | Demographics: maternal age at delivery, paternal age at delivery, birth year, maternal race/ethnicity Substance use: none Mental health: none Physical health: maternal pre-pregnancy body mass index Pregnancy-specific: season of conception Other: family history of congenital heart defects |
| 8. Forrester et al. (46) | Retrospective, population-based, case-control study of births in Hawaii, USA | 316,508 | 1986–2002 | Urine toxicology during or shortly after delivery OR report of use on medical record | Gastrointestinal | Gastroschisis | None |
| 9. Forrester et al. (47) | Retrospective, population-based, case-control study of births in Hawaii, USA | 316,508 | 1986–2002 | Urine toxicology during or shortly after delivery OR report of use on medical record | Cardiac, Central nervous system, Eye, Gastrointestinal, Genitourinary, Musculoskeletal, Orofacial | 54 selected birth defects (see paper) | None |
| 10. Gibson et al. (42) | Prospective study of patients recruited from a hospital in London, England | 7,301 | 1975–1981 | Self-report use up to once a week and more than once a week at antenatal interview | Unspecified | Congenital anomalies | Demographics: maternal age Substance use: alcohol use, tobacco use Mental health: none Physical health: none Pregnancy-specific: parity Other: none |
| 11. Hingson et al. (38) | Prospective study of patients recruited from a hospital in Boston, USA | 1,690 | 1977–1979 | Self-report use during pregnancy ascertained post delivery | Orofacial | Features compatible with fetal alcohol syndrome | None |
| 12. Kharbanda et al. (48) | Retrospective, cohort study of births in Minnesota, USA | 3,435 | 2015–2017 | Urine toxicology screens at the first prenatal visit (generally between 6 and 14 weeks) | Unspecified | Major structural birth defect | Demographics: maternal race/ethnicity, age, Substance use: smoking during pregnancy Mental health: Physical health: pre-pregnancy body mass index Pregnancy-specific: none Other: none |
| 13. Lam et al. (49) | Retrospective, case-control of births in California, USA | 149 (55 cases, 94 control) | 1988–1990 | Self-reported when infant 3–6 months old | Gastrointestinal | Gastroschisis | None |
| 14. Linn et al. (39) | Prospective study of patients recruited from a hospital in Boston, USA | 12,424 | 1977–1980 | Self-reported use during pregnancy ascertained during delivery admission | Unspecified | Major or minor malformations | Demographics: race, maternal age 35 or older, on welfare Substance use: alcohol use in pregnancy, smoking 3 or more cigarettes per day at delivery Mental health: none Physical health: previous miscarriages, previous stillbirths, previous induced abortions Pregnancy-specific: parity greater than 1 Other: none |
| 15. O’Connell et al. (40) | Prospective study of patients recruited from a hospital in Ottawa, Canada | 50 | Exact dates unknown (recruitment in 1978) | Self-reported use during pregnancy | Orofacial | Any minor physical anomalies, Anomalies of face and head | None |
| 16. Shaw et al. (50) | Retrospective, population-based, case-control study of births in California, USA | 1,077 (538 cases, 539 controls) | 1989–1991 | Self-reported use 3 months before pregnancy through pregnancy | Central Nervous System | Neural tube defect | Demographics: race/ethnicity, education, income, age Substance use: use of other substances in the periconception period Mental health: none Physical health: maternal vitamin use Pregnancy-specific: none Other: none |
| 17. Torfs et al. (51) | Retrospective, population-based case-control study of births in California, USA | 330 (110 cases, 220 controls) | 1988–1990 | Self-reported first-trimester use | Gastrointestinal | Gastroschisis | Demographics: maternal age Substance use: none Mental health: none Physical health: none Pregnancy-specific: none Other: none |
| 18. Van Gelder et al. (52) | Retrospective, case-control study of births in 10 states that were part of the National Birth Defects Studya | 20,415 (13,859 cases, 6,556 controls) | 1997–2005 | Self-reported use in the month before pregnancy or during the first 3 months of pregnancy | Cardiac, Gastrointestinal, Genitourinary, Musculoskeletal, Orofacial | Atrial septal defect not otherwise specified, Atrial septal defect secundum, Coarctation of Aorta, Dextrotransposition of the great arteries, Hypoplastic left heart syndrome, Peri membranous ventricular septal defect, Pulmonary valve stenosis, Tetralogy of Fallot, Anorectal atresia, Diaphragmatic hernia, Esophageal atresia with/without tracheoesophageal fistula, Gastroschisis, Hypospadias, Craniosynostosis, Transverse limb deficiency, Anotia/microtia, Cleft lip with or without cleft palate, Cleft palate | Demographics: maternal age at delivery, race or ethnicity, level of education Substance use: smoking in the periconceptional period, binge drinking in the periconceptional period Mental health: none Physical health: pre-pregnancy body mass index, any periconceptional folic acid use Pregnancy-specific: none Other: none |
| 19. Williams et al. (9) | Retrospective, case-control study of births in Atlanta, Georgia, USA | 3,151 (122 cases, 3,029 controls) | 1968–1980 | Maternal and paternal self-reported frequency of use 3 months prior to pregnancy through the first trimester | Cardiac | Ventral septal defect | Demographics: maternal age, maternal race, infant race, birth period, and hospital of birth Substance use: none Mental health: Physical health: maternal diabetes, multivitamin use Pregnancy-specific: none Other: none |
| 20. Witter et al. (53) | Retrospective study of patients in Baltimore, Maryland, USA | 8,350 | 1983–1985 | Self-reported use in pregnancy | Unspecified | Anomalies | None |
Description of 20 articles (listed in alphabetical order) included in the final review.
The 10 states included in the study conducted by Van Gelder et al. (52) were Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah.
3.2. Adjusted associations with specific birth defects
Table 2 includes information on adjusted associations between in utero cannabis exposure and specific birth defects. When examining associations, we only considered the 12 studies that adjusted for confounding, given the importance in doing so in assessing epidemiologic relationships (54). We included information about associations with specific malformations whenever available. However, given the rarity of specific malformations, most studies evaluated associations with organ specific malformations grouped together.
Table 2
| Organ system | Citation | Cannabis exposure definition | Birth defect | Association |
|---|---|---|---|---|
| Cardiac | Bandoli et al. (43) | Cannabis-related diagnosis made during pregnancy or delivery | Any cardiac malformation | RR: 1.0, 95% CI: 0.8–1.2 |
| Cannabis-related diagnosis without another substance use disorder diagnoses made during pregnancy or delivery | RR: 1.0, 95% CI: 0.8–1.3. | |||
| Downing et al. (45) | Self-reported first-trimester use | Ebstein anomaly | OR: 1.8, 95% CI: 0.9–3.8 | |
| Van Gelder et al. (52) | Self-reported use in the month before pregnancy or during the first trimester | Atrial septal defect not otherwise specified | OR: 1.1, 95% CI: 0.7–1.8 | |
| Atrial septal defect secundum | OR: 0.8, 95% CI: 0.6–1.1 | |||
| Coarctation of Aorta | OR: 1.2, 95% CI: 0.7–1.5 | |||
| Dextrotransposition of the great arteries | OR: 0.8, 95% CI: 0.5–1.5 | |||
| Hypoplastic left heart syndrome | OR: 0.8, 95% CI: 0.4–1.5 | |||
| Peri membranous ventricular septal defect | OR: 1.0, 95% CI: 0.8–1.4 | |||
| Pulmonary valve stenosis | OR: 1.0, 95% CI: 0.7–1.9 | |||
| Tetralogy of Fallot | OR: 1.1, 95% CI: 0.7–1.7 | |||
| Williams et al. (9) | Any self-reported use 3 months before pregnancy through the first trimester | Ventral septal defect | OR: 1.9, 95% CI: 1.3–2.8 | |
| Self-reported use <2 days/week 3 months before pregnancy through the first trimester | OR: 2.20, 95% CI: 1.2–3.9 | |||
| Self-reported use >3 days/week 3 months before pregnancy through the first trimester | OR: 3.7, 95% CI: 1.6–9.0 | |||
| Paternal-reported use <2 days/week 3 months before pregnancy through the first trimester | OR: 1.5, 95% CI: 0.6–3.9 | |||
| Paternal-reported use >3 days/week 3 months before pregnancy through the first trimester | OR: 3.2, 95% CI: 0.61–10.71 | |||
| Central nervous system | Bandoli et al. (43) | Cannabis-related diagnosis made during pregnancy or delivery | Any central nervous system malformation | RR: 1.2, 95% CI: 1.0–1.5. |
| Cannabis-related diagnosis without another substance use disorder diagnosis made during pregnancy or delivery | RR: 1.2, 95% CI: 0.9–1.6 | |||
| Shaw et al. (50) | Self-reported use 3 months before pregnancy through pregnancy | Neural tube defect | OR: 0.7, 95% CI: 0.5–1.2 | |
| Van Gelder et al. (52) | Self-reported use in the month before pregnancy or during the first trimester | Anencephaly | OR: 2.2, 95% CI: 1.3–3.7 | |
| Spina Bifida | OR: 0.9, 95% CI: 0.6–1.4 | |||
| Eye | Bandoli et al. (43) | Cannabis-related diagnosis made during pregnancy or delivery | Eye malformation | RR: 1.1, 95% CI: 0.7–1.7 |
| Cannabis-related diagnosis without another substance use disorder diagnoses made during pregnancy or delivery | RR: 1.2, 95% CI: 0.7–2.2 | |||
| Gastrointestinal | Bandoli et al. (43) | Cannabis-related diagnosis made during pregnancy or delivery | Any gastrointestinal malformation | RR: 1.3, 95% CI: 1.1–1.5 |
| Cannabis-related diagnosis without another substance use disorder diagnoses made during pregnancy or delivery | RR: 1.3, 95% CI: 1.0–1.6 | |||
| Torfs et al. (51) | Self-report of first-trimester use | Gastroschisis | OR: 4.5, 95% CI 2.1–9.8 | |
| Van Gelder et al. (52) | Self-reported use in the month before pregnancy or during the first trimester | Anorectal atresia | OR: 0.8, 95% CI: 0.5–1.3 | |
| Diaphragmatic hernia | OR: 1.4, 95% CI: 0.9–2.2 | |||
| Esophageal atresia with/without tracheoesophageal fistula | OR: 1.4, 95% CI: 0.8–2.4 | |||
| Gastroschisis | OR: 1.2, 95% CI: 0.9–1.7 | |||
| Genitourinary | Van Gelder et al. (52) | Self-reported use in the month before pregnancy or during the first trimester | Hypospadias | OR: 0.8, 95% CI: 0.5–1.2 |
| OR: 0.8, 95% CI: 0.5–1.2 | ||||
| Musculoskeletal | Van Gelder et al. (52) | Self-reported use in the month before pregnancy or during the first trimester | Craniosynostosis | OR: 0.8, 95% CI: 0.5–1.3 |
| Transverse limb deficiency | OR: 1.0, 95% CI: 0.6–1.7 | |||
| Orofacial | Van Gelder et al. (52) | Self-reported use in the month before pregnancy or during the first trimester | Anotia/microtia | OR: 0.9, 95% CI: 0.5–1.7 |
| Cleft lip with or without cleft palate | OR: 1.0, 95% CI: 0.8–1.3 | |||
| Cleft palate | OR: 1.0, 95% CI: 0.7–1.5 | |||
| Bandoli et al. (43) | Cannabis-related diagnosis made during pregnancy or delivery | Oral cleft | RR: 1.1, 95% CI: 0.9–1.5. | |
| Cannabis-related diagnosis without another substance use disorder diagnoses made during pregnancy or delivery | RR: 1.1, 95% CI: 0.8–1.5. | |||
| Unspecified | Coleman-Cowger et al. (35) | Self-reported use during pregnancy | Any birth defects | OR: 1.2, 95% CI: 0.5–0.9. |
| Cornelius et al. (36) | Self-reported first-trimester use | Minor physical anomalies | OR: 3.2, 95% CI: 1.0–10.2 | |
| Day et al. (37) | Self-reported use by trimester | Minor and major physical abnormalities | No significant association (point estimate not reported) | |
| Gibson et al. 1983 (42) | Self-reported use by trimester | Congenital defects | No significant association (point estimate not reported) | |
| Kharbanda et al. (48) | Urine toxicology screens during first prenatal visit | Major structural birth defects | RR: 0.6 95% CI: 0.2–2.0 | |
| Linn et al. (39) | Self-reported use during pregnancy | Major or minor malformations | OR: 1.4, 95% CI: 1.0–1.9 |
Adjusted associations for specific birth defect, organized by organ system from 12 articles that adjust for confounding.
RR, relative risk; OR, odds ratio; CI, confidence interval.
3.2.1. Cardiac
Results were inconsistent across the four articles reporting findings from studies assessing associations between in utero cannabis exposure and cardiac malformations (9, 43, 45, 52). One article (9) indicated a dose-response relationship between self-reported cannabis use three months before pregnancy through the first trimester and ventral septal defect [any use OR: 1.9, 95% CI: 1.3, 2.8; use <2 days/week OR: 2.20, 95% CI: 1.2, 3.9; use >3 days/week OR: 3.7, 95% CI: 1.6, 9.0; (9)]. Another study found increased odds of Ebstein anomaly associated with maternal self-reported first-trimester cannabis use, though the confidence interval around the estimate was wide and included the null [OR: 1.8, 95% CI: 0.9, 3.8; (45)]. Additionally, two other articles (43, 52) reported no elevated risk of any cardiac malformation among infants born to individuals with a cannabis-related diagnosis made during pregnancy or delivery [RR: 1.0, 95% CI: 0.8, 1.2; (43)] and no associations between maternal self-reported cannabis use in the month before pregnancy or during the first trimester of pregnancy and eight specific cardiac malformations [Table 2; (52)].
3.2.2. Central nervous system
Three articles reported findings from studies assessing in utero cannabis exposure and central nervous system (CNS) malformations, and results were conflicting (43, 50, 52). Two studies focused on neural tube defects [NTD; (50, 52)]—Van Gelder et al. reported on two subtypes of NTD [anencephaly and spina bifida; (52)], while Shaw et al. focused on any NTD (50). Van Gelder et al. reported increased odds of anencephaly [odds ratio [OR]: 2.2, 95% CI: 1.3–3.7; (52)] but not spina bifida [OR: 0.9, 95% CI: 0.6–1.4; (52)] among infants born to individuals who self-reported cannabis use in the month before pregnancy or during the first trimester of pregnancy (52); and, Shaw et al. failed to find an association between self-reported cannabis use three months before pregnancy through pregnancy and any NTD [OR: 0.7, 95% CI: 0.5–1.2; (50)]. The third study (43) found an increased risk of any CNS malformations among infants born to individuals with a self-reported cannabis-related diagnosis [relative risk [RR]: 1.2, 95% CI: 1.0, 1.5; (43)].
3.2.3. Eye
One article reported on the association between in utero cannabis exposure and eye malformation (43). The study failed to find an association between a cannabis-related diagnosis made during pregnancy or delivery and eye malformation [RR: 1.1, 95% CI: 0.7, 1.7; (43)].
3.2.4. Gastrointestinal
Three articles reported findings from studies assessing associations between in utero cannabis exposure and gastrointestinal malformations (43, 51, 52). The findings from these three studies were mixed. Two articles suggested in utero cannabis exposure was associated with increased risk of gastrointestinal malformations. Specifically, one article (43) reported an association between cannabis-related diagnoses made during pregnancy or delivery and any gastrointestinal malformation [RR: 1.3, 95% CI: 1.1, 1.5; (43)]; and, one article (51) reported an association between self-reported cannabis use in the first trimester and gastroschisis [OR: 4.5, 95% CI 2.1–9.8; (51)]. However, another article (52) did not find any significant associations between self-reported cannabis use in the month before pregnancy or during the first trimester and several specific gastrointestinal birth defects [Table 2; (51)], including gastroschisis [OR: 1.2, 95% CI: 0.9, 1.7 (52)].
3.2.5. Genitourinary
One article reported on associations between in utero cannabis exposure and genitourinary malformations (52). This study failed to find an association between self-reported cannabis use in the month before pregnancy or during the first trimester and hypospadias [OR: 0.8, 95% CI: 0.5–1.2; (52)].
3.2.6. Musculoskeletal
One article reported on association between in utero cannabis exposure and musculoskeletal malformations (52). The study failed to find associations between self-reported cannabis use in the month before pregnancy or during the first trimester and (a) craniosynostosis (OR: 0.8, 95% CI: 0.5–1.3) or (b) transverse limb deficiency [OR: 1.0, 95% CI: 0.6–1.7; (52)].
3.2.7. Orofacial
Associations between in utero cannabis exposure and specific orofacial malformations were reported on in two articles (43, 52). Both articles reported associations close to the null for each malformation [Table 2; (43, 52)]. Specifically, Van Gelder et al. reported associations close to the null for anotia/microtia (OR: 0.9, 95% CI: 0.5–1.7), cleft lip with or without cleft palate (OR: 1.0, 95% CI: 0.8–1.3), and cleft palate [OR: 1.0, 95% CI: 0.7–1.5; (52)]; and Bandoli et al. reported an association close to the null for oral cleft [RR: 1.1, 95% CI: 0.9, 1.5; (43)].
4. Discussion
This systematic review found mixed and inconclusive associations between in utero cannabis exposure and risk for structural birth defects. Results were mixed among (a) the four articles reporting on adjusted associations with cardiac malformations (9, 43, 45, 52), (b) the three articles reporting on adjusted associations with central nervous system malformations (43, 50, 52), and (c) the three articles reporting on adjusted associations with gastrointestinal malformations (43, 51, 52). Some studies suggested in utero cannabis exposure was not associated with these types of birth defects; and, other articles suggesting that in utero cannabis exposure was associated with increased risk of these types of birth defects. Only two articles reported on adjusted associations with orofacial malformations (43, 52); and, only single articles reported on adjusted associations with eye malformation (43), genitourinary malformations (52), and musculoskeletal malformations (52). Though the articles reporting on associations with orofacial, eye, genitourinary, and musculoskeletal malformations all suggested that in utero cannabis exposure was not associated with these types of malformations (43, 52), strong conclusions cannot be drawn from these few studies that all had limitations.
There were several limitations of the included studies that may have contributed to the mixed findings on in utero cannabis exposure and birth defects. These limitations are similar to those of studies on in utero cannabis exposure and other outcomes, such as long-term neurodevelopmental and psychiatric problems (15). First, many of the studies had samples that were relatively small (e.g., 6 of the 20 studies had samples under 500) and reported findings with wide confidence intervals. Therefore, these studies had poor precision and likely were underpowered to detect associations that truly exist. Second, several studies (i.e., 16 of 20) utilized birth cohorts with births occurring more than 20 years ago, which could be problematic given increasing cannabis potency in recent years (55–57) and the proliferation of newer modes of administration (e.g., vaping, edibles) with potentially different risk profiles (58). Third, most studies utilized self-report data, which may underestimate cannabis exposure (59, 60). Therefore, these studies may have mistakenly classified exposed offspring as unexposed, reducing the likelihood of detecting a true association. Fourth, many studies did not address timing of exposure, which is particularly problematic when studying birth defects given that exposures early in pregnancy may be particularly risky for the development of major structural birth defects (61). Fifth, most studies did not assess associations with dose of cannabis exposure. This is a major limitation given that some research has supported a dose-response relationship between in utero cannabis exposure and birth defects (9), and research has shown dose-dependent associations between in utero cannabis exposure and other outcomes (8). Sixth, most studies did not adequately account for potential confounders, such as co-exposure to other substances. Despite the high co-occurrence of cannabis use and use of other substances, particularly tobacco and alcohol, in pregnancy 12 of the 20 studies did not take this into consideration. Therefore, observed associations between in utero cannabis exposure and birth defects could be attributable to exposure to a substance other than cannabis or could be explained by an interactive effect of cannabis use plus use of another substance (62, 63). We note that one study did find similar associations with and without limiting the sample to pregnancies with substance use disorder diagnoses other than cannabis-related diagnoses (43). Nonetheless, more research is needed to parse apart the effects of in utero cannabis exposure from exposure to other substances.
It is important to recognize that the mixed and inconclusive results on associations between in utero cannabis exposure and structural birth defects should not be interpreted as evidence suggesting cannabis use in pregnancy is safe. Rather these results indicate that the relationship between in utero cannabis exposure and structural birth defects is unknown and point to a critical need for future research. This need is particularly pressing given the documented increasing rates in prenatal cannabis use (1).
There are several important avenues for future research. First, samples should be sufficiently large to have adequate statistical power to identify associations if they truly exist. Second, studies with large sample sizes should evaluate associations with specific malformations within organ-specific malformation groups. Third, studies would benefit from including samples comprised of recent birth cohorts given changes in cannabis potency and modes of administration that have occurred in recent years. Fourth, utilizing biological measures (e.g., urine toxicology tests) in addition to self-reported cannabis use would reduce measurement error related to in utero cannabis exposure. Fifth, assessing the influence of timing of exposure and particularly focusing on first-trimester exposure is important. Sixth, it is also important for future studies to quantify the amount of prenatal cannabis exposure by considering the dose, frequency, potency, mode of administration and duration of use during pregnancy. Seventh, studies should utilize methods that rigorously evaluate the potential influence of confounding factors. Using conceptual models based on previous literature, researchers can identify potential factors that may confound associations between in utero cannabis exposure and birth defects. Researchers could also consider using advanced epidemiological methods that have been utilized to study other in utero exposures to help adjust for confounding factors, such as propensity scores, cannabis use before but not during pregnancy as a comparator, and comparisons of differentially exposed siblings [see Sujan et al. for a review of methods that have been used to study antidepressant medications during pregnancy (64)].
Importantly, no single study can implement all of these recommendations, particularly given common obstacles faced by researchers, such as funding limitations restricting the scope of studies, challenges enrolling participants, difficulty obtaining biological samples, and loss to follow-up. However, future research should try to incorporate as many of these recommendations as possible to reduce biases and maximize the overall quality of the studies. Rigorous, high-quality information on the potential consequences of in utero cannabis exposure is vital for individuals to make informed choices about cannabis use in pregnancy, as well as for families and providers caring for infants exposed to cannabis in utero.
Statements
Data availability statement
The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.
Author contributions
All authors conceptualized the study. AS and AP conducted the literature review and extracted information from the reviewed studies. All authors interpreted the findings. AS drafted the manuscript, and all authors provided critical revisions of the manuscript. KY and LA supervised AS. AS and KY supervised AP. All authors contributed to the article and approved the submitted version.
Funding
This study was supported by grants R01DA047405 funded by National Institute on Drug Abuse (NIDA) and R01DA48033 funded by NIDA and Office of the Director, NIH (OD). The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1.
VolkowNDHanBComptonWMMcCance-KatzEF. Self-reported medical and nonmedical Cannabis use among pregnant women in the United States. JAMA. (2019) 322(2):167–9. 10.1001/jama.2019.7982
2.
GeigerA. Support for marijuana legalization continues to rise. (2016). Available at: http://www.pewresearch.org/fact-tank/2016/10/12/support-for-marijuana-legalization-continues-to-rise/
3.
State Medical Marijuana Laws. (2017). Available at: http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx
4.
GnofamMAllshouseAAStickrathEHMetzTD. Impact of marijuana legalization on prevalence of maternal marijuana use and perinatal outcomes. Am J Perinatol. (2020) 37(1):59–65. 10.1055/s-0039-1696719
5.
SkeltonKRHechtAABenjamin-NeelonSE. Recreational Cannabis legalization in the US and maternal use during the preconception, prenatal, and postpartum periods. Int J Environ Res Public Health. (2020) 17(3):909. 10.3390/ijerph17030909
6.
SkeltonKRHechtAABenjamin-NeelonSE. Association of recreational Cannabis legalization with maternal Cannabis use in the preconception, prenatal, and postpartum periods. JAMA Netw Open. (2021) 4(2):e210138. 10.1001/jamanetworkopen.2021.0138
7.
Young-WolffKCAdamsSRPadonASilverLDAlexeeffSEVan Den EedenSKet alAssociation of cannabis retailer proximity and density with cannabis use among pregnant women in northern California after legalization of cannabis for recreational use. JAMA Netw Open. (2021) 4(3):e210694. 10.1001/jamanetworkopen.2021.0694
8.
SharapovaSRPhillipsESiroccoKKaminskiJWLeebRTRolleI. Effects of prenatal marijuana exposure on neuropsychological outcomes in children aged 1–11 years: a systematic review. Paediatr Perinat Epidemiol. (2018) 32(6):512–32. 10.1111/ppe.12505
9.
WilliamsLJCorreaARasmussenS. Maternal lifestyle factors and risk for ventricular septal defects. Birth Defects Res A Clin Mol Teratol. (2004) 70(2):59–64. 10.1002/bdra.10145
10.
NashedMGHardyDBLavioletteSR. Prenatal cannabinoid exposure: emerging evidence of physiological and neuropsychiatric abnormalities. Front Psychiatry. (2021) 11:10. 10.3389/fpsyt.2020.624275
11.
RonceroCValriberas-HerreroIMezzatesta-GavaMVillegasJLAguilarLGrau-LopezL. Cannabis use during pregnancy and its relationship with fetal developmental outcomes and psychiatric disorders. A systematic review. Reprod Health. (2020) 17(1):9. 10.1186/s12978-020-0880-9
12.
ConnerSNBedellVLipseyKMaconesGACahillAGTuuliMG. Maternal marijuana use and adverse neonatal outcomes: a systematic review and meta-analysis. Obstet Gynecol. (2016) 128(4):713–23. 10.1097/AOG.0000000000001649
13.
GunnJKLRosalesCBCenterKENunezAGibsonSJChristCet alPrenatal exposure to cannabis and maternal and child health outcomes: a systematic review and meta-analysis. BMJ Open. (2016) 6(4):e009986. 10.1136/bmjopen-2015-009986
14.
SinghSFilionKAbenhaimHEisenbergM. Prevalence and outcomes of prenatal recreational cannabis use in high-income countries: a scoping review. BJOG. (2020) 127(1):8–16. 10.1111/1471-0528.15946
15.
SujanACYoung-WolffKCAvalosLA. In-utero cannabis exposure and long-term psychiatric and neurodevelopmental outcomes: the limitations of existing literature and recommendations for future research. Birth Defects Res. (2022) 114(13):689–713. 10.1002/bdr2.2060
16.
ChungCSMyrianthopoulosNC. Congenital anomalies: mortality and morbidity, burden and classification. Am J Med Genet. (1987) 27(3):505–23. 10.1002/ajmg.1320270304
17.
SujanACPalAAvalosLAYoung-WolffKC. Systematic review and meta-analyses of cannabis exposure during pregnancy and risk for birth defects in infants. PROSPERO CRD42022308130. (2022). Available at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022308130
18.
QaziQHMarianoEMilmanDHBellerECrombleholmeW. Abnormalities in offspring associated with prenatal marihuana exposure. Dev Pharmacol Ther. (1985) 8(2):141–8. 10.1159/000457031
19.
FriedPA. Postnatal consequences of maternal marijuana use in humans. Ann N Y Acad Sci. (1989) 562:123–32. 10.1111/j.1749-6632.1989.tb21011.x
20.
ConnerCS. Marijuana and alcohol use in pregnancy. Drug Intell Clin Pharm. (1984) 18(3):233–4.
21.
ZhangAMarshallRKelsbergG. Clinical inquiry: what effects–if any–does marijuana use during pregnancy have on the fetus or child?J Fam Pract. (2017) 66(7):462–6.
22.
DayNSambamoorthiUTaylorPRichardsonGRoblesNJhonYet alPrenatal marijuana use and neonatal outcome. Neurotoxicol Teratol. (1991) 13(3):329–34. 10.1016/0892-0362(91)90079-C
23.
van GelderMMReefhuisJCatonARWerlerMMDruschelCMRoeleveldN. Maternal periconceptional illicit drug use and the risk of congenital malformations. Epidemiology. (2009) 20(1):60–6. 10.1097/EDE.0b013e31818e5930
24.
KennareRHeardAChanA. Substance use during pregnancy: risk factors and obstetric and perinatal outcomes in South Australia. Aust N Z J Obstet Gynaecol. (2005) 45(3):220–5. 10.1111/j.1479-828X.2005.00379.x
25.
VenturaCVVenturaLOMillerMTCronembergerMFDiasCSDiasMJMet alTeratogen exposure and congenital ocular abnormalities in Brazilian patients with mobius sequence. Arq Bras Oftalmol. (2014) 77(5):300–4. 10.5935/0004-2749.20140076
26.
WilsonPDLoffredoCACorrea-VillaseñorAFerenczC. Attributable fraction for cardiac malformations. Am J Epidemiol. (1998) 148(5):414–23. 10.1093/oxfordjournals.aje.a009666
27.
WeinsheimerRLYancharNL. Impact of maternal substance abuse and smoking on children with gastroschisis. J Pediatr Surg. (2008) 43(5):879–83. 10.1016/j.jpedsurg.2007.12.032
28.
AugerNRheaumeMALowNLeeGEAyoubALuuTM. Impact of prenatal exposure to opioids, cocaine, and Cannabis on eye disorders in children. J Addict Med. (2020) 14(6):459–66. 10.1097/ADM.0000000000000621
29.
DayNLRichardsonGAGevaDRoblesN. Alcohol, marijuana, and tobacco: effects of prenatal exposure on offspring growth and morphology at age six. Alcohol Clin Exp Res. (1994) 18(4):786–94. 10.1111/j.1530-0277.1994.tb00041.x
30.
ReeceASHulseGK. Cannabis teratology explains current patterns of coloradan congenital defects: the contribution of increased cannabinoid exposure to rising teratological trends. Clin Pediatr (Phila). (2019) 58(10):1085–123. 10.1177/0009922819861281
31.
ReeceASHulseGK. Contemporary epidemiology of rising atrial septal defect trends across USA 1991–2016: a combined ecological geospatiotemporal and causal inferential study. BMC Pediatr. (2020) 20(1):539. 10.1186/s12887-020-02431-z
32.
ReeceASHulseGK. Canadian Cannabis consumption and patterns of congenital anomalies: an ecological geospatial analysis. J Addict Med. (2020) 14(5):E195–210. 10.1097/ADM.0000000000000638
33.
ReeceASHulseGK. Geotemporospatial and causal inference epidemiological analysis of US survey and overview of cannabis, cannabidiol and cannabinoid genotoxicity in relation to congenital anomalies 2001–2015. BMC Pediatr. (2022) 22(1):47. 10.1186/s12887-021-02996-3
34.
PetersonBSRosenTDingmanSTothZRSawardekarSHaoXet alAssociations of maternal prenatal drug abuse with measures of newborn brain structure, tissue organization, and metabolite concentrations. JAMA Pediatr. (2020) 174(9):831–42. 10.1001/jamapediatrics.2020.1622
35.
Coleman-CowgerVHOgaEAPetersENMarkK. Prevalence and associated birth outcomes of co-use of Cannabis and tobacco cigarettes during pregnancy. Neurotoxicol Teratol. (2018) 68:84–90. 10.1016/j.ntt.2018.06.001
36.
CorneliusMDTaylorPMGevaDDayNL. Prenatal tobacco and marijuana use among adolescents: effects on offspring gestational age, growth, and morphology. Pediatrics. (1995) 95(5):738–43. 10.1542/peds.95.5.738
37.
DayNCorneliusMGoldschmidtLRichardsonGRoblesNTaylorP. The effects of prenatal tobacco and marijuana use on offspring growth from birth through 3 years of age. Neurotoxicol Teratol. (1992) 14(6):407–14. 10.1016/0892-0362(92)90051-B
38.
HingsonRAlpertJJDayNDoolingEKayneHMorelockSet alEffects of maternal drinking and marijuana use on fetal growth and development. Pediatrics. (1982) 70(4):539–46. 10.1542/peds.70.4.539
39.
LinnSSchoenbaumSCMonsonRRRosnerRStubblefieldPCRyanKJ. The association of marijuana use with outcome of pregnancy. Am J Public Health. (1983) 73(10):1161–4. 10.2105/AJPH.73.10.1161
40.
O’ConnellCMFriedPA. An investigation of prenatal cannabis exposure and minor physical anomalies in a low risk population. Neurobehav Toxicol Teratol. (1984) 6(5):345–50.
41.
AstleySJClarrenSKLittleRESampsonPDDalingJR. Analysis of facial shape in children gestationally exposed to marijuana, alcohol, and/or cocaine. Pediatrics. (1992) 89(1):67–77. 10.1542/peds.89.1.67
42.
GibsonGTBaghurstPAColleyDP. Maternal alcohol, tobacco and cannabis consumption and the outcome of pregnancy. Aust N Z J Obstet Gynaecol. (1983) 23(1):15–9. 10.1111/j.1479-828X.1983.tb00151.x
43.
BandoliGJelliffe-PawlowskiLSchumacherBBaerRJFelderJNFuchsJDet alCannabis-related diagnosis in pregnancy and adverse maternal and infant outcomes. Drug Alcohol Depend. (2021) 225:108757. 10.1016/j.drugalcdep.2021.108757
44.
BourqueDKMengLDouganSMomoliFRiddellCWalkerMet alGastroschisis in Ontario, Canada: 2012–2018. Birth Defects Res. (2021) 113(14):1044–51. 10.1002/bdr2.1896
45.
DowningKFRiehle-ColarussoTGilboaSMLinAEOsterMETinkerSCet alPotential risk factors for ebstein anomaly, national birth defects prevention study, 1997–2011. Cardiol Young. (2019) 29(6):819–27. 10.1017/S1047951119000970
46.
ForresterMBMerzRD. Comparison of trends in gastroschisis and prenatal illicit drug use rates. J Toxicol Environ Health A. (2006) 69(13):1253–9. 10.1080/15287390500361750
47.
ForresterMBMerzRD. Risk of selected birth defects with prenatal illicit drug use, Hawaii, 1986–2002. J Toxicol Environ Health A. (2007) 70(1):7–18. 10.1080/15287390600748799
48.
KharbandaEOVazquez-BenitezGKunin-BatsonANordinJDOlsenARomittiPA. Birth and early developmental screening outcomes associated with cannabis exposure during pregnancy. J Perinatol. (2020) 40(3):473–80. 10.1038/s41372-019-0576-6
49.
LamPKTorfsCP. Interaction between maternal smoking and malnutrition in infant risk of gastroschisis. Birth Defects Res A Clin Mol Teratol. (2006) 76(3):182–6. 10.1002/bdra.20238
50.
ShawGMVelieEMMorlandKB. Parental recreational drug use and risk for neural tube defects. Am J Epidemiol. (1996) 144(12):1155–60. 10.1093/oxfordjournals.aje.a008894
51.
TorfsCPVelieEMOechsliFWBatesonTFCurryCJ. A population-based study of gastroschisis: demographic, pregnancy, and lifestyle risk factors. Teratology. (1994) 50(1):44–53. 10.1002/tera.1420500107
52.
van GelderMDondersARTDevineORoeleveldNReefhuisJ. Natl birth defects prevention S. Using Bayesian models to assess the effects of under-reporting of Cannabis use on the association with birth defects, national birth defects prevention study, 1997–2005. Paediatr Perinat Epidemiol. (2014) 28(5):424–33. 10.1111/ppe.12140
53.
WitterFRNiebylJR. Marijuana use in pregnancy and pregnancy outcome. Am J Perinatol. (1990) 7(1):36–8. 10.1055/s-2007-999442
54.
D’OnofrioBMClassQARickertMESujanACLarssonHKuja-HalkolaRet alTranslational epidemiologic approaches to understanding the consequences of early-life exposures. Behav Genet. (2016) 46(3):315–28. 10.1007/s10519-015-9769-8
55.
Centers for Disease Control and Prevention & Office of Noncommunicable Diseases Injury and Environmental Health. What you need to know about marijuana and pregnancy. Atlanta, GA (2017).
56.
ElSohlyMAMehmedicZFosterSGonCChandraSChurchJC. Changes in Cannabis potency over the last 2 decades (1995–2014): analysis of current data in the United States. Biol Psychiatry. (2016) 79(7):613–9. 10.1016/j.biopsych.2016.01.004
57.
American College of Obstetricians and Gynecologist. Marijuana use during pregnancy and lactation: committee opinion No. 722. Obstet Gynecol. (2017) 130:e205–9. 10.1097/AOG.0000000000002354
58.
Young-WolffKCAdamsSRWiSWeisnerCConwayA. Routes of cannabis administration among females in the year before and during pregnancy: results from a pilot project. Addict Behav. (2020) 100:106125. 10.1016/j.addbeh.2019.106125
59.
Young-WolffKCTuckerL-YAlexeeffSArmstrongMAConwayAWeisnerCet alTrends in self-reported and biochemically tested marijuana use among pregnant females in California from 2009 to 2016. JAMA. (2017) 318(24):2490–1. 10.1001/jama.2017.17225
60.
Young-WolffKCSarovarVTuckerLYGolerNConwayAWeisnerCet alValidity of self-reported Cannabis use among pregnant females in northern California. J Addict Med. (2020) 14(4):287–92. 10.1097/ADM.0000000000000581
61.
BleylSBSchoenwolfGC. What is the timeline of important events during pregnancy that may be disrupted by a teratogenic exposure? Teratology primer. 3rd ed. Reston, VA: The Society for Birth Defects Research and Prevention (2018).
62.
GolerNConwayAYoung-WolffKC. Data are needed on the potential adverse effects of marijuana use in pregnancy. Ann Intern Med. (2018) 169(7):492–3. 10.7326/M18-1141
63.
KoJYFarrSLTongVTCreangaAACallaghanWM. Prevalence and patterns of marijuana use among pregnant and nonpregnant women of reproductive age. Am J Obstet Gynecol. (2015) 213(2):201.e1–e10. 10.1016/j.ajog.2015.03.021
64.
SujanACObergASQuinnPDD’OnofrioBM. Annual research review: maternal antidepressant use during pregnancy and offspring neurodevelopmental problems—a critical review and recommendations for future research. J Child Psychol Psychiatry. (2019) 60(4):356–76. 10.1111/jcpp.13004
Summary
Keywords
pregnancy, prenatal exposure, in utero exposure, cannabis, marijuana
Citation
Sujan AC, Pal A, Avalos LA and Young-Wolff KC (2023) A systematic review of in utero cannabis exposure and risk for structural birth defects. Front. Pediatr. 11:1149401. doi: 10.3389/fped.2023.1149401
Received
21 January 2023
Accepted
09 May 2023
Published
25 May 2023
Volume
11 - 2023
Edited by
Gabrielle Lynn McLemore, Morgan State University, United States
Reviewed by
Camille Fung, The University of Utah, United States Jessie Maxwell, University of New Mexico, United States
Updates
Copyright
© 2023 Sujan, Pal, Avalos and Young-Wolff.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ayesha C. Sujan asujan@stanford.edu
These authors contributed equally to this work and share senior authorship.
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.