In a prospective longitudinal UK cohort of 28 MDMA‑exposed and 68 unexposed infants followed to two years with multiple covariates controlled, prenatal MDMA exposure was associated with persistent fine and gross motor delays across the first two years and showed a dose‑dependent relation to motor deficits at 12 months. No other differences at birth were found except that MDMA‑exposed infants were more likely to be male.
Objective
This paper aims to review findings from a longitudinal study of prenatal methylenedioxymethamphetamine (MDMA, “ecstasy”) on infant development.
Methods
In a prospective, longitudinal cohort design, we followed 28 MDMA‐exposed and 68 non‐MDMA‐exposed infants from birth to 2 years of age. Women recruited voluntarily into a study of recreational drug use during pregnancy were interviewed to obtain type, frequency, and amount of recreational drug use. Their children were followed for a 2‐year period after birth. A large number of drug and environmental covariates were controlled. Infants were seen at 1, 4, 12, 18, and 24 months using standardized normative tests of mental and motor development.
Results
There were no differences between MDMA‐exposed and non‐MDMA‐exposed infants at birth except that MDMA‐exposed infants were more likely to be male. Motor delays were evident in MDMA infants at each age and amount of MDMA exposure predicted motor deficits at 12 months in a dose‐dependent fashion.
Conclusions
Prenatal MDMA exposure is related to fine and gross motor delays in the first 2 years of life. Follow‐up studies are needed to determine long‐term effects. Copyright © 2015 John Wiley & Sons, Ltd.
Recreational stimulant use, including 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"), is common among young adults worldwide, and a growing proportion of users are women of childbearing age. Earlier research has documented a range of psychological and physiological effects of MDMA in adults and animal evidence suggests prenatal MDMA exposure can impair memory and learning. In addition, maternal effects of MDMA use (for example hyperthermia, raised cortisol, appetite and sleep disruption) and a prior teratology signal in the UK raised concern that fetal MDMA exposure might affect neurodevelopment, particularly functions subserved by the serotonin system. Singer and colleagues set out to address a gap in human data by reporting findings from the first prospective longitudinal study of infants prenatally exposed to MDMA in the UK. The study tested the hypothesis that children exposed in utero to MDMA would show poorer developmental outcomes across the first 2 years of life than nonexposed children, after controlling for other drug exposures and relevant confounders.
The Drugs and Infancy Study was a prospective longitudinal cohort funded by the US National Institute on Drug Abuse and conducted in the UK between 2001 and 2005. Participants were volunteers recruited via midwives, clinic leaflets and advertisements for a study of recreational drug use in pregnancy; women with HIV, an intellectual disability (IQ < 70), severe psychiatric or medical illness, or infants with diagnosable illness at birth were excluded. Ninety-six mother–infant dyads were followed: 28 with maternal MDMA exposure and 68 without MDMA exposure. MDMA status and detailed patterns of use of MDMA, tobacco, cannabis, alcohol and cocaine were obtained by trained interviewers on three occasions during pregnancy or shortly after birth, using an adapted instrument that recorded lifetime use and trimester-specific use. Infants were assessed at 1, 4, 12, 18 and 24 months. Primary developmental measures included the Bayley Scales of Infant Development (Mental Development Index, MDI; Psychomotor Development Index, PDI; and Behavioural Rating Scales, BRS). Additional measures included the Neonatal Intensive Care Unit Network Neurobehavioral Scales (at 1 month), the Alberta Infant Motor Scales (AIMS at 4 and 12 months) and the Preschool Language Scales (at 12 months). Examiners were blinded to MDMA exposure. Maternal covariates measured to control confounding included psychological distress (Brief Symptom Inventory), addiction severity (Drug Abuse Screening Test), maternal IQ (two subscales of the Wechsler Abbreviated Scale of Intelligence), sociodemographic variables, postpartum drug use and the home caregiving environment (HOME inventory). Analyses compared MDMA versus non-MDMA groups and also used a three-group classification (heavier MDMA, lighter MDMA, non-MDMA). Heavier and lighter MDMA groups were defined by a median split of the total number of tablets averaged over pregnancy (heavier n = 13, lighter n = 15). Because many women reduced or ceased use across pregnancy, only one woman reported MDMA use in the third trimester. For longitudinal analyses of Bayley outcomes, mixed linear models with maximum likelihood estimation were employed. Potential covariates associated with both MDMA use and outcomes at p < 0.2 were evaluated and retained in models if significant at p < 0.10; gender effects were also examined.
Mothers averaged 29 years of age, were predominantly white (85%), largely partnered (82%), had some university education, were of middle socioeconomic status and had average intelligence. MDMA-using and non-MDMA-using women did not differ on most background variables, although MDMA users had fewer children. Polydrug use was common in both groups, primarily tobacco, cannabis and alcohol, and overall drug use decreased over the trimesters with cannabis most likely to persist. At birth there were no group differences in birthweight, prematurity, length or gestational age. However, MDMA-exposed infants were more likely to be male (71% vs 46%), with an odds ratio (OR) = 3.2, 95% confidence interval 1.2–8.2, p < 0.02 (an OR greater than 1 indicates higher odds of being male in the MDMA group). One MDMA-exposed child had Townes–Brocks syndrome; inclusion or exclusion of this case did not alter results. Neonatal neurobehavioral assessment showed no statistically significant group differences, though there were non-significant trends for MDMA-exposed infants to be more lethargic and less hypertonic. Motor outcomes diverged by 4 months. On the BRS, MDMA-exposed infants showed slower, more delayed movements at 4 months, and on the AIMS heavier-exposed infants scored lower: mean percentile 35.1 ± 24 for the heavier MDMA group versus 65.7 ± 23 for the lighter group and 45.9 ± 28 for nonexposed infants (p < 0.03). At 12 months motor deficits were more pronounced: the heavier MDMA group had a mean PDI of 76 ± 12 compared with 92.0 ± 16 and 99.8 ± 12 in the nonexposed and lighter groups respectively (F = 10.7, p < 0.002; the Bayley standard score average is 100). Examiner-rated motor quality on the BRS also differed, with heavier-exposed infants rated more poorly (F = 12.4, p < 0.001). Mental development differences were apparent only at 12 months: amount of prenatal MDMA exposure predicted lower MDI scores (β = 0.28, p < 0.012), though the decrement in the heavier group remained within the average range. When MDI and PDI were analysed longitudinally across 4, 12, 18 and 24 months using mixed models, no overall significant effect was found for MDI, but a significant main effect of MDMA exposure on motor outcomes persisted. By 24 months the heavier MDMA-exposed group had a lower modeled PDI (90.8, SE = 3.8) compared with lighter and nonexposed children combined (98.7, SE = 1.4). Language outcomes and several behavioural subscales (attention, arousal, orientation, emotional regulation) did not differ between groups at 4, 12, 18 or 24 months.
The investigators conclude that prenatal MDMA exposure was associated with an altered sex ratio and with persistent motor delays across the first 2 years of life, and that higher amounts of prenatal exposure were linked to lower mental and motor scores at 12 months. Motor deficits were detectable from 4 months and persisted through 24 months on standardised measures; mental outcome differences were limited to the 12-month assessment. Because most women ceased MDMA use after the first trimester, the findings are attributable primarily to first trimester exposure in this cohort. Potential mechanisms discussed by the authors include indirect effects mediated via increased maternal stress hormones (notably cortisol) associated with MDMA use and the drug’s known ability to cross the placenta, and direct effects on the developing serotonergic system, which plays a role in motor system development. The altered sex ratio is noted as consistent with other epidemiological observations linking fetal toxic exposures to shifts in sex ratios, though mechanisms remain unclear. Singer and colleagues identify strengths of the work as its prospective longitudinal design, blinded outcome assessment and control for polysubstance exposure and environmental confounders such as the home caregiving environment. They acknowledge key limitations: small sample size, reliance on self-reported drug use without biological biomarkers, and self-selection into the voluntary study that could introduce selection bias. The sample’s relative homogeneity and middle socioeconomic status reduced the presence of other common risk factors but may limit generalisability. The authors state that the motor delays observed could signal risk for later learning or school-age problems and therefore warrant long-term follow-up. They also recommend clinicians and public health practitioners caution pregnant women about potential developmental risks from MDMA, and call for research on newer recreational compounds (novel psychoactive substances) and on interactions between multiple drug exposures and maternal stress.
The authors conclude that prenatal MDMA exposure is associated with early fine and gross motor delays that may carry risk for later developmental problems, and they advocate for long-term follow-up to determine persistence and functional impact. Given the prevalence of MDMA use among women of childbearing age and misconceptions about its safety, they recommend warning pregnant women about potential adverse developmental effects, noting that negative outcomes may occur even when use stops prior to pregnancy. The authors also emphasise the need to study effects of newer recreational drugs and the combined influence of polysubstance use and maternal stress.
Recreational use of stimulant drugs is now widespread worldwide, especially in the Americas, Europe, Japan, Australia, and New Zealand and particularly among young adults aged 18-34 years. Because of greater social acceptability and changing gender and social mores, many users are women of child-bearing age. Numerous studies have documented the physical and mental health effects of stimulant drug use in adults (see the aforementioned reviews). However, there are relatively few studies of the effects of recreational stimulant drugs on offspring who have been prenatally exposed, as these studies are costly, require long-term tracking and follow-up, and are methodologically complex. In this paper, we present a review of findings from such a study. This was a longitudinal cohort study of infants prenatally exposed to 3,4methylenedioxymethamphetamine, MDMA or "ecstasy" in the UK. 3,4-Methylenedioxymethamphetamine is a widely used, illicit recreational drug, especially among young adults. MDMA is a powerful, indirect monoaminergic agonist that both inhibits the reuptake and promotes the release of serotonin (5-HT) and dopamine, affecting physiological and psychological functions. Previous studiesuncovered a wide range of psychological effects in adult ecstasy users, suggesting that fetal exposure may affect serotonergic functioning across the central nervous system and negatively affect those functions subserved by serotonin. A range of maternal effects from MDMA use during pregnancy may also affect the fetus, including physiological overstimulation, hyperthermia, increased cortisol levels, and post-use depression, sleep impairment, and decreased appetite. In addition, animal studies have found prenatal MDMA exposure to be related to long-term memory and learning impairments. Further, a UK Teratology Services Information study found a four to seven times higher risk of congenital malformations in 136 MDMAexposed pregnancies. A strong conceptual framework for prenatal drug exposure studies can be found in neurobehavioral teratology, the study of the causes of abnormalities in behavioral and physiologic development from toxic or environmental factors. The developing fetus is highly vulnerable to agents that have negligible or nontoxic effects in adults, and toxic exposure can cause a range of effects. To date, there have been no human studies of the developmental outcomes of infants exposed prenatally to MDMA. We report on the findings from the first study to investigate patterns of use of MDMA-using women during pregnancy and to assess child developmental outcomes until the age of 2 years. We hypothesized that MDMA infants would perform more poorly than nonexposed infants on developmental outcomes after controlling for other drugs and relevant confounders.
The Drugs and Infancy Study was funded by the US National Institute on Drug Abuse as a collaborative effort of the University of East London and Case Western Reserve University in Cleveland, Ohio. This prospective study, funded from 2001 to 2005, monitored self-reported recreational drug users of MDMA, tobacco, cannabis, alcohol, and cocaine during pregnancy in the UK with a focus on assessing patterns of use and developmental effects of MDMA on offspring. Participants were volunteers who responded to nurse midwives or to advertisements requesting participation in a study of recreational drug use in pregnancy, listing ecstasy, tobacco, cannabis, alcohol, and cocaine as examples. Women with positive HIV status, significant intellectual disability (IQ < 70), or severe known psychiatric or medical illness were excluded as were infants with diagnosable illness at birth. Ninety-six (28 MDMA and 68 non-MDMA) women were recruited by the University of East London staff through midwives, leaflets in prenatal clinics, or advertisements in pregnancy magazines to participate in a study of recreational drug use during pregnancy (details of recruitment, exclusion, and participation can be found in. MDMA status was determined by maternal interview on three occasions during pregnancy or after birth and information on frequency, amount, and duration of use before and after pregnancy obtained for MDMA and other drugs. To obtain drug use patterns, trained researchers interviewed women/mothers at home or in a private room at the university or, in a few cases, by phone. The interview was an adaptation of the interview for a US cocaine exposure studythat added questions related to substances commonly used in the UK and comprised three parts: (i) lifetime use; (ii) use in the month prior to pregnancy and the first two trimesters; and (iii) use in the third trimester (see. Infants were evaluated at 1, 4, 12, 18, and 24 months of age with the Bayley Scales of Infant Development, including the Mental (Mental Development Index (MDI)), Motor (Psychomotor Development Index (PDI)), and Behavioral Rating Scales (BRS)by examiners blinded to infant drug status. At 1 month, infants were administered the Neonatal Intensive Care Unit Network Neurobehavioral Scales. At 4 and 12 months, the Alberta Infant Motor Scales) and, at 12 months, the Preschool Language Scaleswere given. To control for confounding factors known to be related to child outcomes that are frequently associated with drug use, all mothers were assessed for psychological distress symptoms using the Brief Symptom Inventory, and for addiction severity with the Drug Abuse Screening Test. Intellectual ability was measured through two subscales of the Wechsler Abbreviated Scale of Intelligence. Maternal age, years of education, marital and employment status, income, socioeconomic status, and parity were also obtained. At each visit, maternal postpartum drug use was assessed, and the quality of the caregiving environment was evaluated with the Home Observation for Measurement of the Environment Inventory. All child examiners were masked to MDMA status. To assess the effects of MDMA, both two-group (MDMA versus non-MDMA) and three-group status (heavier versus lighter MDMA versus non-MDMA) comparisons were evaluated at each age controlling 291 prenatal mdma exposure for significant covariates. For a longitudinal assessment of effects of MDMA over time on Bayley outcomes, a mixed linear model approach with maximum likelihood estimation procedures was used. Covariates related to both outcomes and MDMA use at p < 0.2 were evaluated and retained if significant at p < 0.10 in the regression model. Gender effects were also examined.
Women in this sample were, on average, 29 years of age, primarily white (85%), married or partnered (82%), had some university education, and were of largely middle socioeconomic status and of average intelligence. There were no differences between MDMA-using and non-MDMA-using women on any parameter except that women in the MDMA group had fewer children. The majority of women in both groups were polydrug users up to and during pregnancy, primarily using tobacco, cannabis, and alcohol. Methylenedioxymethamphetamine users were divided into heavier (n = 13) and lighter (n = 15) groups based on a median split of the total number of tablets taken averaged over the pregnancy. Heavier users averaged 1.3 (1.4) tablets in total over the three trimesters and 1 month prior to pregnancy compared with 0.07 (0.04) for lighter users. The amount of drugs used during pregnancy decreased over the trimesters for all women with use of cannabis most likely to persist if at all (see. Only one woman reported using MDMA in the third trimester.
3,4-Methylenedioxymethamphetamine-exposed infants did not differ from non-MDMA-exposed infants on any birth parameter including birthweight, prematurity, length, or gestational age, except that the MDMA group was more likely to be male, 71% vs. 46%; O.R. (Odds Ratio) = 3.2, 95% confidence interval: 1.2-8.2, p < 0.02. One child in the MDMA group was diagnosed with Townes-Brocks syndrome, a rare genetic malformation. Inclusion or exclusion of this child from comparisons did not affect results of any statistical analysis. Comparison of Neonatal Intensive Care Unit Network Neurobehavioral Scales outcomes in the neonatal period yielded no significant differences between exposed and nonexposed groups although there were nonsignificant trends for exposed infants to be more lethargic (91% vs. 73%, X 2 = 3.3, p < 0.069) and less hypertonic (9% vs. 27%, X 2 = 3.3, p < 0.069). At 4, 12, 18, and 24 months, there were no differences on the Preschool Language Scale or the Attention, Arousal, Orientation, and Emotional Regulation subscales of the BRS. However, at 4 months, MDMA-exposed infants had slower and more delayed movements as assessed by the BRS, and more heavily exposed infants performed less well on the Alberta Infant Motor Scales (AIMS). Mean percentile scores were 35.1 ± 24 for the heavier MDMA group versus 65.7 ± 23 and 45.9 ± 28 for the lighter MDMA and nonexposed groups, p < 0.03, on the AIMS. At 12 months, motor deficits in the MDMA group were even more pronounced, with PDI mean scores of 92.0 ± 16 and 99.8 ± 12 in the none and lighter groups, respectively, versus 76 ± 12 for the more heavily exposed MDMA group (F = 10.7, p < 0.002), compared with an average standard score of 100. These delays were also reflected in the examiner-rated BRS motor quality scale. Heavier MDMA-exposed infants were rated more poorly in motor quality than lighter or nonexposed infants on the Motor Quality Scale at percentile, respectively, F = 12.4, p < 0.001. At 12 months, the amount of prenatal MDMA exposure predicted lower MDI scores, β = 0.28, p < 0.012, with a slight decrement in scores in the heavier group that was within average range. This was the only time point at which mental outcomes were affected, possibly because many items on the test at 12 months have a significant motor component. When MDI and PDI scores were analyzed through mixed model longitudinal analyses using measures from all time points (4, 12, 18, and 24 months), no significant effects were found for MDI. However, there was a significant main effect of MDMA exposure on motor outcomes, with the heavier MDMA-exposed group showing motor delays compared with lighter and nonexposed children, PDI = 90.8 (SE = 3.8) for heavier versus 98.7 (SE = 1.4) for lighter and nonexposed at 24 months.
This series of studies was undertaken to investigate whether use of recreational MDMA during pregnancy was damaging to the children of ecstasy-using mothers. The main findings were that prenatal exposure to MDMA led to an alteration in sex ratio, significantly lower cognitive development scores (MDI) at 12 months of age, and persistent and significantly poorer motor quality and milestone achievement over the first 2 years of life, controlling for polysubstance exposure and other confounding variables. At 12 months of age, higher amounts of prenatal exposure had negative effects on both cognitive and motor outcomes and motor quality, controlling for multiple confounding factors. Motor deficits were identifiable at 4 months and persisted through 24 months of age on standardized, normative outcome measures, while mental outcomes were only different at 12 months. Because so few women continued to use MDMA after the first trimester, findings could be attributed only to first trimester exposure. There may be persistent mediated effects of MDMA via the release of stress hormones in the pregnancy period. Stress hormones, in particular cortisol, may have neurotoxic effects on hypothalamic-pituitary-adrenal axis development in infancy, and levels of these hormones appear to be increased when MDMA use has been high. In the case of pregnant women, higher levels could persist for some time after the last use of the drug. In MDMAusing dance clubbers, cortisol levels are increased by around 800%, thought to be influenced by thermal stress, physical exertion, and psychosocial stimulation. Likewise, MDMA is known to pass through the placental barrier to the fetus. Serotonin, the neurotransmitter primarily affected by MDMA use, has significant effects on the development of the fetal brain, and the serotonin system is involved in various components of motor control. Alterations in the serotonin system during fetal development are associated with changes in somatosensory systems and motor output. Findings of alterations in sex ratio are of interest as several epidemiologic studies implicate the influence of fetal toxins on sex ratios, for example, with dioxinand polybrominated biphenyl exposure, although mechanisms are unknown. The present study has both strengths and limitations. Strengths include a prospective longitudinal design, control for polysubstance exposure, and other confounding variables, which are known to impact child outcomes, such as the home environment. Limitations include the small sample size, the absence of biomarkers of substance exposure, and the self-selection of a voluntary group, which could introduce selection bias. However, the homogeneous sample, of middle socioeconomic status, did not have many of the risk factors found in other studies of drug exposure.
There is extensive empirical evidence on the adverse effects of recreational stimulants, because when taken regularly, they impair the psychobiological integrity of adolescents and adults. Many young female drug users may be at risk of becoming pregnant, and hence, it is particularly important to investigate the effects of drug usage within this subgroup. The adverse effects of cocaine on the developing fetus are well established.. Because the early fine and gross motor delays found in children of MDMA users in this study may indicate risk for later learning problems, long-term follow-up is needed to assess whether deficits persist and affect school-age functioning. Given the widespread but erroneous view that MDMA is a safe drug and because of its pervasive recreational use among women of childbearing age, pregnant women should be cautioned about potential adverse developmental effects-as revealed in this study. Note that women also need to be made aware that negative outcomes may be found even when women stop using MDMA prior to pregnancy. There is also the urgent need to study other more recent recreational drugs (so called Novel Psychoactive Substances or "legal highs") such as mephedrone, when taken during human pregnancy and to have a better understanding of the interactions between multiple drug use and exposure to other known risks, including maternal stress.
No conflicts of interest have been declared. The study was funded by the National Institutes on Drug Abuse (National Institute of Health, USA), grant DA14910-01.
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