Mathias B. Forrester and Ruth D. Merz

Hawaii Birth Defects Program, Honolulu, Hawaii, USA

Extracts from Study 

The literature on the association between prenatal illicit drug use and birth defects is inconsistent. The objective of this study was to determine the risk of a variety of birth defects with prenatal illicit drug use.

Data were derived from an active, population based adverse pregnancy outcome registry. Cases were all infants and foetuses with any of 54 selected birth defects delivered during 1986–2002.

The prenatal methamphetamine, cocaine, or marijuana use rates were calculated for each birth defect and compared to the prenatal use rates among all deliveries.

Among all deliveries, the prenatal use rate was 0.52% for methamphetamine,0.18% for cocaine, and 0.26% for marijuana.

Methamphetamine rates were significantly higher than expected for 14 (26%) of the birth defects.

Cocaine rates were significantly higher than expected for 13 (24%) of the birth defects.

Marijuana rates were significantly higher than expected for 21 (39%) of the birth defects. Increased risk for the three drugs occurred predominantly among birth defects associated with the central nervous system, cardiovascular system, oral clefts, and limbs. There was also increased risk of marijuana use among a variety of birth defects associated with the gastrointestinal system. Prenatal uses of methamphetamine, cocaine, and marijuana are all associated with increased risk of a variety of birth defects.

The affected birth defects are primarily associated with particular organ systems.

DISCUSSION

Using data from a Statewide, population-based registry that covered over 300,000 births and a 17-yr period, this investigation examined the association between over 50 selected birth defects and maternal use of methamphetamine, cocaine, or marijuana during pregnancy. Much of the literature on prenatal illicit drug use and birth defects involved case reports, involved a small number of cases, were not population-based, or focused on only one or a few particular birth defects.

There are various limitations to this investigation. The number of cases for many of the birth defects categories was relatively small, limiting the ability to identify statistically significant differences and resulting in large confidence intervals.

In spite of this, a number of statistically significant analyses were identified. Some statistically significant results might be expected to occur by chance. If 1 in every 20 analyses is expected to result in statistically significant differences solely by chance, then among the 162 analyses performed in this study, 8 would be expected to be statistically significant by chance. However, 48 statistically significant differences were identified. Thus, not all of the statistically significant results are likely to be due to chance.

This study included all pregnancies where methamphetamine, cocaine, or marijuana use was identified through either report in the medical record or positive toxicology test. This was done because neither self-report nor toxicology testing is likely to identify all instances of prenatal illicit drug use (Christmas et al., 1992).

In spite of using both methods for determining prenatal illicit drug use, all pregnancies involving methamphetamine, cocaine, or marijuana were not likely to have been identified. The degree of under ascertainment is unknown. A previous study examined the maternal drug use rate around the time of delivery in Hawaii during 1999 (Derauf et al., 2003). This study found 1.4% of the pregnancies involved methamphetamine use and 0.2% involved marijuana use. Among 1999 deliveries, the HBDP identified a prenatal methamphetamine use rate of 0.7% and a marijuana use rate of 0.4%. However, comparisons between the 2 studies should be made with caution because the previous study collected data from a single hospital during only a 2-mo period.

Another limitation is that the present study did not control for potential confounding factors such as maternal demographic characteristics, health behaviors, and prenatal care. Increased risk of birth defects has been associated with inadequate prenatal care (Carmichael et al., 2002), maternal smoking (Honein et al., 2001), and maternal alcohol use (Martinez-Frias et al., 2004).

These factors are also found with maternal illicit drug use (Cosden et al., 1997; Hutchins, 1997; Norton-Hawk, 1997). Thus the increased risk of selected birth defects with illicit drug use in this study might actually be due to one of these other underlying factors. Unfortunately, informationon some of the potential confounding factors such as socioeconomic status are not collected by the HBDP. Information collected on some other factors such as smoking and alcohol use is suspect because of negative attitudes toward their use during pregnancy. Moreover, the small number of cases among many of the birth defects groups would make controlling for these factors difficult.

Finally, this investigation included use of the illicit drugs at any time during the pregnancy. Most birth defects are believed to occur at 3–8 wk after conception (Makri et al., 2004; Sadler, 2000). In a portion of the cases, the drug use might have occurred at a time when it could not have caused the birth defect. Furthermore, this study does not include information on dose; however, teratogenicity of a substance may depend on its dose (Werler et al., 1990). In spite of the various potential concerns of the present study, data may suggest future areas of investigation where the limitations inherent in the present one are excluded.

This investigation found significantly higher than expected rates for prenatal use of methamphetamine, cocaine, and marijuana among a number of specific birth defects. Although not identical, there were general similarities between the three illicit drugs and the birth defects with which they were associated. Increased rates for methamphetamine, cocaine, and marijuana occurred predominantly among birth defects affecting the central nervous system, cardiovascular system, oral clefts, and limbs. There were also increased rates of marijuana use with a variety of birth defects associated with the gastrointestinal  system. With the exception of marijuana and encephalocele, none of illicit drugs were associated with neural-tube defects (anencephaly, spina bifida, encephalocele). The rates of use for the three illicit drugs were not significantly elevated with eye defects other than anophthalmia/microphthalmia, genitourinary defects, and musculoskeletal defects aside from limb defects.

In the majority of instances, the associations between particular illicit drugs and birth defects were found whether or not those cases involving use of multiple types of drugs were included.

Of the 14 significant associations between methamphetamine and specific birth defects, 10 (71.4%) remained once multiple drug cases were excluded. Corresponding rates were 61.5% (8 of 13) for cocaine and 81.0% (17 of 21) for marijuana.

The similarities in the patterns of birth defects with which methamphetamine, cocaine, and marijuana are associated might suggest that the three drugs exert similar effects on embryonic and foetal development. This might not be expected, considering that the three illicit drugs differ in their mechanisms of action and clinical effects (Leiken & Paloucek, 1998).

Some of the associations between methamphetamine, cocaine, and marijuana observed in the present investigation were previously reported. Other studies observed similar associations, or lack thereof, of methamphetamine or amphetamine with neural-tube defects (Shaw et al., 1996) and cardiovascular and musculoskeletal defects (McElhatton et al., 2000); cocaine with neural-tube defects (Shaw et al., 1996), cardiovascular defects (Lipshultz et al., 1991), ventricular septal defect and atrial septal defect (Ferencz et al., 1997c; Martin & Edmonds, 1991), tricuspid atresia (Ferencz et al., 1997d), craniosynostosis (Gardner et al., 1998), and situs inversus (Kuehl & Loffredo, 2002); and marijuana with neural-tube defects (Shaw et al., 1996), single ventricle (Steinberger et al., 2002), ventricular septal defect (Williams et al., 2004), tricuspid atresia (Ferencz et al., 1997d), and gastroschisis (Torfs et al., 1994).

In contrast, this study differed from other research with respect to their findings regarding methamphetamine or amphetamine and gastroschisis (Torfs et al., 1994); cocaine and microcephaly (Martin & Edmonds, 1991), conotruncal defects (Adams et al., 1989), endocardial cushion defect (Ferencz et al., 1997b), situs inversus (Ferencz et al., 1997a), oral clefts (Beatyet al., 2001), and genitourinary defects (Abe et al., 2003; Battin et al., 1995; Martin & Edmonds, 1991); and marijuana and conotruncal defects (Adams et al., 1989), Ebstein anomaly (Ferencz et al., 1997e; Correa-Villasenor et al., 1994), and oral clefts (Beaty et al., 2001).

The inconsistent findings between this and the other studies could be due to differences in study methodology, case classification, or number of cases. The mechanisms by which methamphetamine, cocaine, and marijuana might contribute to the rates for birth defects is currently unknown. Any potential explanation would have to take into account the observation that each of the illicit drugs was associated with a variety of specific birth defects affecting different organ systems. This might suggest that these three drugs would need to influence a basic, common factor involved in embryonic development.

Folic acid is involved in nucleic acid synthesis and cellular division (Scholl & Johnson, 2000) and thus would play an important role in the early growth and cellular proliferation of the embryo. Folic acid has been found to prevent a variety of birth defects (Forrester & Merz, 2005). Thus, anything that interferes with the activity of folic acid might be expected to increase the risk for these birth defects. Many of these birth defects were associated with methamphetamine, cocaine, and/or marijuana in the present study.

However, two of the birth defects most closely affected by folic acid—anencephaly and spina bifida—were not associated with any of the three illicit drugs. Vascular disruption has been suggested as a potential cause for a variety of different birth defects such as intestinal atresia/stenosis, limb reduction defects, and gastroschisis.

Since cocaine is a vasoconstrictor, it has been hypothesized that cocaine use could increase the risk of these vascular disruption defects (Hume et al., 1997; Martin et al., 1992; Hoyme et al., 1983; de Vries, 1980). Although this investigation found an association between cocaine and limb reduction deformities, no association was found with intestinal atresia/stenosis or gastroschisis.

In conclusion, this study found that prenatal use of methamphetamine, cocaine, or marijuana were associated with increased risk of a variety of birth defects. The affected birth defects were primarily associated with particular organ systems. Because of various limitations of the study, further research is recommended.

Source:  Journal of Toxicology and Environmental Health, Part A, 70: 7–18, 2007