This is the first study to show a unique effect of prenatal cocaine exposure on obesity adjusted for alcohol exposure and other factors. The association of cocaine exposure and obesity was strongest in a subgroup of exposed children. Cocaine-exposed children were 4 times as likely to become obese at 9 years of age if they were not exposed to alcohol as well. Prenatal exposure to cocaine and alcohol did not increase the prevalence of obesity compared to exposure to neither drug or to alcohol alone. Others have found persistent growth decrements associated with alcohol exposure [20
] when cocaine and other drugs of abuse are adjusted. But this is the first report of a subgroup of children who were exposed to both cocaine and alcohol with findings that alcohol exposure may attenuate the effect of cocaine exposure on obesity and growth. This also suggests that failure to show a positive association between cocaine exposure and obesity may be in part be due to the practice of using both drugs together during pregnancy and to samples smaller than the MLS that may not permit analysis of interactions.
Longitudinal analysis revealed increased prevalence of obesity in the group with prenatal exposure to cocaine but not alcohol beginning at 7 years then continuing through 8 and 9 years, relative to the 3 other cocaine-by-alcohol exposure groups. Also found was increased BMI from 3 to 9 years in children with cocaine but not alcohol exposure versus the other 3 groups with the mean BMI at approximately the 77th
percentile (z-score 0.78) by 9 years. The 3 other groups showed similar mean BMI levels around the 69th
percentile (z-score 0.50) at 9 years. The mean weight increased from 1 to 9 years in all 4 groups. In the group exposed to cocaine but not alcohol, the mean weight at 9 years was at the 73rd
percentile (z-score 0.60) compared to the 63rd
percentiles (z-scores 0.30 to 0.40) in the other 3 groups. Unlike BMI, the increased weight associated with cocaine but not alcohol exposure was not statistically significant from 3 to 9 years except for 7 years. Height, on the other hand, was nearly identical for all 4 groups from 1 to 9 years, reaching the 50% percentile (z-score 0) at 5 years then staying between the 42nd
percentiles (z-scores −0.20 to 0) until 9 years. A decrease in stature gain associated with cocaine exposure had been reported [13
], but similar to other studies [33
] we did not find this effect. Taken together, the increase in obesity associated with exposure to cocaine but no alcohol appears to be related to increasing weight combined with small reductions in height percentiles albeit all close to average in all 4 groups.
Childhood obesity has previously been linked to higher birth weight, rapid early weight gain during early infancy [18
] independent of birth weight [50
], but not to SGA [10
]. In our study, early weight gain over the first year predicted obesity at 9 years, with 39 g/month higher weight gain in obese than non-obese children. Further, longitudinal analyses showed a continued association between early weight gain and obesity from 2 to 9. On the other hand, SGA children were less likely to be obese than children who were appropriate for gestational age, supporting the previously reported negative association with obesity in mostly term children [19
]. The possibility that the relationship between SGA and obesity is reversed due to its association with early weight gain was not supported and persisted with early weight gain excluded from the analysis. Our findings do not link SGA and early weight gain to each other in the development of obesity at 9 years. The positive relationship between SGA and obesity predicted by the fetal origins hypothesis may emerge in a longer follow-up than 9 years as found in older adolescents and adults [48
Although both early weight gain and SGA are associated with cocaine exposure, each makes a unique contribution to the prevalence of obesity independent of cocaine exposure. This pattern of effects is not consistent with catch-up growth due to in utero
growth restriction from cocaine exposure, but could be explained by the perspective of cocaine as an intrauterine stressor that disrupts the neuroendocrine environment, which impacts pre- and postnatal metabolic processes resulting in obesity [7
Early weight gain in infants with SGA may reflect catch-up growth, that is, rapid weight gain following growth restriction in utero,
resulting in postnatal ‘catching up’ to a normative, comparison sample or appropriate-for-age percentiles. This pattern has been reported in infants exposed to cocaine and tobacco but not with alcohol exposures [33
]. The reported ages when cocaine-exposed infants catch-up in weight range from 6 months to 2 years and in height from 1 to 7 years [13
]. Due in part to adjustment for SGA and early growth, our longitudinal analyses did not show the expected decrement in growth associated with cocaine exposure when alcohol exposure was not involved. However, the group exposed to both cocaine and alcohol had lower weight and height at birth and 4 months compared to the group not exposed to either drug, catching-up to the other groups by 8 months on both growth measures, which is within or close to the range reported for children with cocaine exposure. Most cocaine-exposed children are also exposed to alcohol. This is the first study to parse out the effects of cocaine and alcohol exposure. Our findings show early growth deficits with exposure to both drugs, but not with exposure to either cocaine or alcohol alone. On the other hand, all cocaine-by-alcohol groups show a pattern of increased weight by 4 months (range z-scores −0.28 to 0.20) while height remained less than the 50th
percentile (z-score 0) until 5 years, continuing between the 42nd
percentile (z-scores −0.20 to 0) until 9 years.
Nicotine has been linked with increased risk of obesity. Our null findings of prenatal tobacco exposure and obesity at 9 years were inconsistent with several other reports [14
]. To examine whether prenatal exposure to tobacco could impact earlier ages, we reanalyzed the longitudinal models including tobacco exposure as well as the interaction of tobacco and cocaine and alcohol. There was no association of tobacco exposure and increased obesity, BMI or weight from birth to 9 years. The only effects were decreased height at 4 and 8 months only. In other reports of increased obesity cited above, the studies did not include cocaine as well as nicotine and the participants were not as disadvantaged as MLS. This suggests that the impact of prenatal tobacco exposure on obesity may be less salient in high risk samples with illicit drug use and greater poverty as found by Lumeng and colleagues [33
]. Similarly, we analyzed for prenatal marijuana effects, but found no significant association with the 4 growth measures at any age.
Others have reported decreased BMI related to prenatal alcohol exposure [20
]. However, to our knowledge no one has examined the interaction of prenatal exposure to alcohol and cocaine. The rate of obesity when exposed to both cocaine and alcohol was similar to exposure to alcohol alone, suggesting that prenatal alcohol exposure may act to constrain weight gain in children despite other drug exposures. It is also possible that the neuroendocrine pathways that drive cocaine addiction also drive obesity. Eating is a behavior, which is primarily regulated by neuroendocrine pathways. We can speculate that families who are genetically predisposed to pure cocaine addiction (i.e. not cocaine and alcohol addiction) may also be predisposed to “comfort food consumption” for the same underlying neurobiological reasons. The observation that the group with cocaine but no alcohol exposure does not diverge until about age 7 years (and not earlier) may reflect greater autonomy in eating behavior that could be driven by affect due to underlying neurobiology.
In our study, inadequate physical activity and high caloric intake, but not excessive TV watching, were significant predictors of obesity. In children who were obese, 65% did not meet the minimum criterion of more than 30 minutes of regular exercise compared to 52% in those who were not obese. Even though the criterion for inadequate exercise in this study was less stringent than the national recommendations of 60 minutes per day [51
], the majority of children met the study criterion. Further, children who were obese consumed 166 calories more per day on average than those who were not obese, which is a modest but significant effect size. Surprisingly, excessive TV watching was not related to obesity in this study with 63% of children in both the obese and non-obese groups exceeding the criterion of 4 hours a day. A better discriminator of sedentary behavior was inadequate exercise.
This study has several limitations. The MLS was not designed to study obesity. Although the MLS has an extensive protocol with health-related concerns and growth examined on annual visits, the selection of predictor variables for this study was dependent on the existing dataset. Our measures of exercise and TV watching were straightforward questions that required the parent to recall and summarize across various contexts for amount and frequency of exercise and TV watching. We also did not have multiple respondents available to increase validity of these reports. Food diaries are difficult for both children and parents. We attempted to standardize the interview and data collection process as much as possible. Further, MLS recruited postpartum in order to enroll a community rather than a clinical sample of cocaine using mothers. It could be argued that self-report during pregnancy is more reliable than postnatal recall. However retrospective report appears to be as valid as prenatal report of cocaine use during pregnancy in terms of predicting outcomes such as birth size [24
]. As a subset of the MLS, the current study may not be representative of the original MLS term cohort. However, we found few differences in demographic and prenatal drug use variables and none in newborn growth measures between subjects included in this study and those excluded due to missing the 9-year visit. Further, there was minimal impact on growth measures from birth to 8 years when data from subjects who missed the 9-year visit were included at the previous ages. Our focus on obesity adjusting for other covariates including SGA and early weight gain may have contributed to the failure to observe prenatal insult linked to catch-up growth in cocaine-exposed infants as reported by others. Despite the large sample size of MLS, we were unable to test the interaction of heavy use of cocaine and alcohol due to small cell sizes. Dose-response analyses could have been more informative to clinical practice as well as public policy than any use of these drugs. Further, classification in the alcohol use category had a large range from 8% reporting 1 drink across pregnancy to 15% reporting 1 drink per day across pregnancy.
Finally, we have not measured genetic influences in MLS and epigenetic mechanisms could also explain associations between prenatal cocaine exposure and obesity. Our findings are consistent with a fetal origins model of cocaine as a prenatal stressor affecting placental gene expression, altering metabolic pathways, resulting in rapid postnatal early weight gain and childhood obesity [30
]. Others have reported epigenetic mechanisms (DNA methylation), showing that cocaine reduces placental norepinephrine transporter gene expression leading to increased circulating catecholamines and downregulation of a steroid metabolic enzyme [11β-HSD-2] that protects the fetus from exposure to high levels of maternal cortisol [30
]. Such exposure could affect the fetal neuroendocrine system and alter metabolic pathways leading to the development of later childhood obesity.
In summary, we have known for a long time that prenatal factors contribute to the origins of childhood obesity. We present the first evidence that prenatal cocaine exposure is one of those factors. But the findings must be understood in the context of alcohol exposure. Most cocaine users are polydrug users of alcohol, tobacco and marijuana as well. Although all these drugs have been associated with deficits in birth weight, height and head circumference, infants exposed to cocaine, tobacco or marijuana will catch-up to non-exposed peers, but alcohol-exposed infants do not catch-up. We find that cocaine exposure quadruples the prevalence of obesity but only for the subset of children who are not also alcohol-exposed. While providing a new direction for research on prenatal cocaine exposure, the challenge is to elucidate the mechanisms and pathways that lead from prenatal cocaine exposure to obesity in the context of alcohol exposure. One direction is to “drill down” and investigate neuroendocrine, metabolic and epigenetic factors, which may have prenatal origins and increased risk for obesity.