Oct 1999 Lancet paper, "Congenital anomalies after prenatal ecstasy exposure"
Press coverage of Lancet paper
Response to Lancet paper by Rick Doblin
January 1999 Dutch study, "Pregnancy outcome after ecstasy use"
The MAPS MDMA Research Page

In October 1999, the British medical journal The Lancet published the paper "Congenital anomalies after prenatal ecstasy exposure," reporting infants born to mothers who used MDMA (ecstasy) during pregnancy are at increased risk of congenital birth defects. This letter was covered widely by the press. Rick Doblin, president of MAPS, responded in a letter to the lead author of the letter. As of November 30, 1999, this letter has been ignored.

There is an earlier study that was conducted in the Netherlands which failed to see any dramatic problems in 49 pregnancies (leading to 40 live births). It was referenced in the Lancet article, in the sentence, "There are few data on the effects of ecstasy exposure in human pregnancy,[2-4]." A bit of a clue that this study provided conflicting evidence would have been valuable in the Lancet article.

Daniel Perrine, Ph.D. (Loyola College Chemistry Department) comments:
One thing about this study is that the anomalies only reach statistical significance when lumped together. As the authors admit:
"Although this small case series has insufficient statistical power to confirm a causal relation with any particular congenital anomaly, we consider that these initial data are important."
But it would be quite unusual for a single drug to cause such a diverse potpourri of birth defects. Thalidomide, e.g., causes phocomelia; alcohol causes fetal alcohol syndrome; dilantin causes fetal hydantoin syndrome (usually cleft lip or palate). I count about nine distinct birth anomalies in this list, affecting very different organs. This doesn't rule out the possibility that MDMA causes some of the problems, but it makes it seem less likely. But it would not be surprising if MDMA had an amphetamine-like effect on the embryo. Some animal studies should be done, and it is surprising that none have been published. [an animal toxicity study has been conducted, see below for details]
On the other hand, considering the prevalence of amphetamine as a substitute for genuine MDMA, it would also not be surprising if the cardiac anomalies here reported were due to amphetamine ingestion.

Prudence would suggest that women not take MDMA during pregnancy, though there is no clear evidence to suggest that doing so would be harmful to the fetus. We will update this page as more information becomes available.

[Rick Doblin in a letter to the lead author of the Lancet article]:

Dr McElhatton,

I imagine you are getting lots of inquiries regarding your Lancet paper. I direct a non-profit organization, the Multidisciplinary Association for Psychedelic Studies (MAPS, www.maps.org) that supports research into the psychotherapeutic use of MDMA, as well as research into the risks of MDMA. All our proposed human protocols exclude women who are pregnant or are not on birth control. Still, the issue of the risk of MDMA to the fetus is important both for non-medical users and for the possible extension of the psychotherapeutic use of MDMA to pregnant women.

Your research suggests risks that I have previously discounted, due to several cases I have seen in which prenatal use of MDMA did not lead to problems, to the absence of cases that I have heard of that raised this issue, and also due to an animal study I cite below. My first reaction is to try to find the weaknesses in the argument linking MDMA to birth defects, especially after seeing press accounts of your study that also link MDMA to Parkinson's, which even the most fervent proponents of MDMA neurotoxicity do not claim since Parkinson's is due to reduced dopamine levels which MDMA does not reduce (it impacts serotonin levels).

I'd appreciate any assistance you can offer in helping me understand your findings. I have a few questions for now and will probably have more as I continue to think about your paper. I hope you have time to respond.

1. You wrote that there are "no published teratological studies in animals." What do you make of this study:

St Omer VE; Ali SF; Holson RR; Duhart HM; Scalzo FM; Slikker W Jr (1991) Behavioral and neurochemical effects of prenatal methylenedioxymethamphetamine (MDMA) exposure in rats. Neurotoxicol Teratol (UNITED STATES) 13 (1) p13-20.

Which has been summarized by Dennis McKenna, Ph.D. as follows:

Prenatal exposure to MDMA
An important consideration for the human users of MDMA concerns possible adverse effects on the fetus. Relatively few studies have addressed this issue, however, a recent paper by St. Omar, et al. 1991 has done so. Groups of pregnant rats were administered varying doses of MDMA on alternate gestational days 16-18. Gestational duration, litter size, neonatal birth weights and physical appearance at birth were unaffected by MDMA treatment. Pregnancy weight gain was significantly reduced by MDMA. Progeny growth, maturational parameters, surface righting reflex, swimming performance, forelimb grip strength, milk induced behavior, passive avoidance behavior, figure 8 maze activity, and the density of 5-HT uptake sites, 5-HT, and 5-HIAA levels were unaffected by MDMA treatment. Olfactory discrimination was enhanced in both male and female progeny, and negative geotaxis was delayed in female pups. In the dams, MDMA caused significant reductions in 5-HT and 5-HIAA levels in discrete brain areas. It was concluded that prenatal exposure to MDMA causes only subtle behavioral changes in developing rats, while the dams are at risk for the characteristic spectra of serotonergic changes.

Does this study, which showed no birth defects from MDMA, count as a teratological study in animals? I have cited this study to several women who contacted me concerning their use of MDMA while pregnant. Am I misleading them by doing so?

2. Do you have any data about how much exposure to Ecstasy the various women had? Are we talking about a single dose or repeated exposures over time, or is this data that was not available from the women?

3. Ecstasy users are very frequently poly-drug users. Yet in your sample more than 50% of the women reported only the use of Ecstasy. This seems surprising to me. Do you think this data is reliable?

4. How do you factor that a substantial percentage of Ecstasy tablets or capsules do not contain MDMA, but various other substances such as amphetamine and methamphetamine, ketamine, ephedrine, caffeine, dextromethorphan, DOB, 4-Methyl-thio-amphetamine, (According to the London Toxicology Group, about 25,000 tablets of 4-Methyl-thio-amphetamine were seized in London last November) etc. Have any of these compounds been linked to birth defects?

5. Of the 12 abnormal births, how many were from women who reported taking only Ecstasy and how many were from women who had taken Ecstasy in combination with other drugs?

6. People who attend raves often engage in vigorous exercise and get quite hot, often without sufficient hydration. Diets are often poor. Could elevated temperatures, poor diets etc have something to do with birth defects? Basically, I'm asking if the rave-going lifestyle itself could contribute to birth defects?

7. I know nothing about the UK National Teratology Information Service (NTIS). Are the inquiries you receive (302 for Ecstasy) considered to come from a representative sample of all women who have taken Ecstasy while pregnant, or perhaps from those most concerned about the link between their drug use and the health of their baby, perhaps being a subsample of mothers with more risk factors than average? Could you make the opposite argument that by mentioning their use of Ecstasy to their health practitioner that this is a sample of women who were most concerned about the health of their baby, therefore they may have fewer risk factors and/or take greater care?

8. Similarly, what can be said about the more than 50% of the women lost to follow-up. Are they likely to be a random sample of women or different in some important way from the women who remained in the study?

9. You mentioned that the evidence for birth defects from amphetamine and related compounds has produced conflicting results. MDMA is chemically similar to mescaline, the active ingredient in peyote cactus, which Native Americans have been using for thousands of years. The use of peyote by pregnant women is not uncommon, and no reports from a link between peyote and birth defects has been reported, though no systemmatic study has been conducted of which I am aware. Is this in any way reassuring regarding the risk of MDMA? I presume only slightly since every drug is unique.

Well, that's certainly enough questions for one e-mail message! Thank you in advance for any time you can spare to respond to these questions.

Rick Doblin
November 1999

Ned Tijdschr Geneeskd 1999 Jan 2;143(1):27-31

[Pregnancy outcome after ecstasy use; 43 cases followed by the Teratology Information Service of the National Institute for Public Health and Environment].

[Article in Dutch]

van Tonningen-van Driel MM, Garbis-Berkvens JM, Reuvers-Lodewijks WE

Rijksinstituut voor Volksgezondheid en Milieu, Teratologie Informatie Service/Nationaal Vergiftigingen Informatie Centrum, Bilthoven.

OBJECTIVE: To determine if use of ecstacy during pregnancy has any harmful effects on pregnancy and the (unborn) child.
DESIGN: Prospective, descriptive.
METHODS: After the Teratology Information Service of the National Institute of Public Health and the Environment. Bilthoven, the Netherlands, was approached by a physician or midwife for information, the pregnancies that involved the use of ecstacy were followed by a follow-up questionnaire one month after the estimated date of birth.
RESULTS: A total of 49 pregnancies were followed. For 43 women, exposed early in pregnancy, data on course of pregnancy and health of baby are known. There were 3 elective terminations of pregnancy and 2 spontaneous abortions. There were 40 live-born babies (including one set of triplets); one of them had a congenital cardiac malformation. Beside ecstacy the mothers frequently also used other substances potentially harmful to pregnancy and child. The pregnancies were often unplanned; previous pregnancies had frequently been terminated.
CONCLUSION: The sample size was too small to draw conclusions. As yet spontaneous abortions and congenital malformations did not appear to occur more frequently in pregnancies with use of ecstacy. The lifestyle of the ecstacy users seemed to be potentially harmful for pregnancy and child.

Ecstasy Use in Pregnant Women Associated With Increased Incidence of Congenital Birth Defects

WESTPORT, Oct 25 (Reuters Health) - Infants born to mothers who used methylenedioxymethamphetamine (ecstasy) during pregnancy are at increased risk of congenital birth defects.

Dr. Patricia R. McElhatton and colleagues of the National Teratology Information Service in Newcastle upon Tyne, UK, reviewed outcomes of 136 pregnancies that occurred between 1989 and 1998. Among the 136 women, 74 reported taking ecstasy only and 62 took a combination of ecstasy and some other recreational drug, including amphetamines, cocaine, marijuana, LSD or alcohol.

A majority of the women, 127, reported exposure to ecstasy during the first trimester, and almost all women discontinued use of the drug after this time.

Of 78 liveborn infants, 12 (or 15.4%) had congenital defects, a significantly higher rate than the "...expected incidence of 2% to 3%."

In an interview with Reuters Health, Dr. McElhatton said that it is unclear whether the birth defects result from a synergistic effect of combining compounds or whether the effect is caused by ecstasy alone.

She added that although the data do not support a causal link between ecstasy and birth defects, the results led her and her co-authors to believe that either ecstasy or amphetamines played a causal role.

The UK investigator pointed out that the compounds are structurally related, and that "...of the 12 babies [in this study] with birth defects, six of the mothers were on ecstasy alone and the remainder were either on [ecstasy plus] amphetamines or [ecstasy plus] alcohol."

Lancet 1999;354:1441.
_________________________

Here is the Lancet article from:
www.thelancet.com/newlancet/reg/issues/vol354no9188/menu_NOD999.html

Volume 354, Number 9188 23 October 1999

Congenital anomalies after prenatal ecstasy exposure

P R McElhatton, D N Bateman, C Evans, K R Pughe, S H L Thomas

Prospective follow-up of 136 babies exposed to ecstasy in utero indicated that the drug may be associated with a significantly increased risk of congenital defects (15.4% [95% CI 8.2-25.4]). Cardiovascular anomalies (26 per 1000 livebirths [3.0-90.0]) and musculoskeletal anomalies (38 per 1000 [8.0-109.0]) were predominant.

The illicit use of ecstasy (methylenedioxymethamphetamine) has increased during the past decade and there is growing concern about its potential toxicity.1 There are few data on the effects of ecstasy exposure in human pregnancy,2-4 and no published teratological studies in animals. Whereas amphetamines and related compounds have been associated with an increased risk of structural malformations of the heart and great vessels in various species, studies on the teratogenicity of amphetamines in human pregnancy have produced conflicting results on both the overall risk of malformations and the risk of any specific birth defect.5

_________________________
Drug exposure Anomalies

Ecstasy

4 weeks Left 4th toe underlying the 3rd toe

6-12 weeks Right-sided plagiocephaly

4-5 weeks Unilateral talipes

First trimester Unilateral talipes

6 and 9 weeks Bilateral talipes

First trimester Pyloric stenosis

First trimester Absent upper limbs, left scapula, clavicles, and hypoplasticity of the first rib pair; pregnancy terminated at 22 weeks.

Ecstasy, amphetamine and gamma hydroxybutyric acid

0-7 weeks Ventricular septal defect (possibly atrio and ventricular), bilateral hydronephrosis, and bilateral clinodactyly

Ecstasy and alcohol

6 weeks Venticular septal defect

Ecstasy and amphetamine

0-12 weeks One of twins born at 25 weeks, intrauterine growth retardation hydrocephalus, ambiguous sex

Ecstasy and alcohol

17 weeks Ptosis of the left eye

First trimester Pigmentation of the right thigh

Ecstasy and amphetamine

First trimester Clicking hips

Malformations reported after exposure of fetus to ecstasy and other drugs of abuse

_________________________

The UK National Teratology Information Service (NTIS) collected prospective follow-up data on the outcome of 136 pregnancies (one pair of twins), in which exposure to ecstasy occurred between January, 1989, and June, 1998. Within this period there were 302 enquiries involving ecstasy. 31 (10%) of these pregnancies are not yet completed and 135 (45%) were lost to follow-up because the enquiring health professional (in most cases the patient's general practitioner) could no longer identify the patient, or the patient did not return to the surgery.

In each case the enquirer was asked to provide information on drug exposure, both prescribed and non-prescribed, at the time of the enquiry, together with the mother's expected date of delivery. Follow-up was done by contacting the enquirer, after the expected date of delivery. Where necessary, information was then sought from other clinical specialists.

74 pregnant women reported taking ecstasy only and 62 took ecstasy with other drugs of abuse (ecstasy and amphetamine 37 women; ecstasy and cocaine 20; ecstasy and cannabis 16; ecstasy and alcohol 13; ecstasy and LSD nine; ecstasy and other drugs of abuse 13). Acute toxicity from ecstasy was reported in only two of the mothers. The maternal age at the time of exposure was obtained for 82 (60%) women: 26 women were aged 16-20 years; 31 21-25 years, 20 26-31 years, and five 31-36 years.

127 women (71 exposed to ecstasy alone and 56 exposed to ecstasy and other drugs of abuse) were exposed in the first trimester, two in the first and second trimesters, two in the second trimester, and one in the third trimester. Four women were exposed to several drugs of abuse throughout pregnancy.

11 pregnancies resulted in miscarriage, 48 women had elective terminations (one after prenatal diagnosis of malformations). No necropsy data were available on any of the other aborted fetuses. The rate of miscarriage was 8%, within the expected range; but the rate of elective terminations was 35%; higher than the UK average.

There were 78 liveborn infants; 66 were normal. 12 had congenital anomalies (15.4% [95% CI 8.2-25.4]), which is significantly higher than the expected incidence of 2-3% (table).

Eight infants were born prematurely between 25 and 36 weeks of gestation (including one pair of twins born at 25 weeks of gestation). There were two cases of fetal distress among those born prematurely that were thought not to be related to ecstasy. One neonatal death occurred in an infant without apparent abnormalities at birth who was born to a mother who had taken ecstasy, heroin, and methadone throughout pregnancy. No necropsy data are available.

No adverse effects were observed in the sex ratio. Birthweights were within the expected range for term infants (>37 weeks), with only three infants weighing less than 2.5 kg.

There were three female infants with talipes (rate of 38 per 1000 [95% CI 8-109] vs expected rate of 1 per 1000). Idiopathic talipes equinovarus has a male predominance of three to one in the UK.

The spontaneous incidence of congenital heart disease (CHD) is 5-10 per 1000 livebirths. Of infants with CHD, 24-34% have ventricular septal defects, 7% atrial septal defects, and 3% atrial and ventricular septal defects. In this case series there were two infants with CHD (one with ventricular septal defects, one with ventricular septal defects or possible atrial and ventricular septal defects) among the 78 livebirths (26 per 1000 [95% CI 3.0-90.0]). We are aware of one other case of CHD after exposure to ecstasy.3,4 Although this small case series has insufficient statistical power to confirm a causal relation with any particular congenital anomaly, we consider that these initial data are important.

We thank the patients, the Drug Information pharmacists, healthcare personnel who provided the data on exposure and pregnancy outcome, and G Masters for statistical advice.

References:

1 Henry JA. Ecstasy and the dance of death. BMJ 1992; 305: 5-6.

2 McElhatton PR, Bateman DN, Evans C, Pughe KR, Worsley AJ. Does prenatal exposure to ecstasy cause congenital malformations?: a prospective follow-up of 92 pregnancies. Br J Clin Pharmacol 1998; 45: 184.

3 Rost van Tonningen M, Garbis H, Reuvers M. Ecstasy exposure during pregnancy. Teratology 1998; 58: 33.

4 van Tonningen-van Driel M M, Garbis Berkvens JM, Reuvers Lodewijks WB. Zwangerschapsuitkomst na ecstacygebruik: 43 gevallen gevolgd door de Teratologie Informatie Service van het RIVM. Ned Tijdschr Geneeskd 1999; 143: 27-31.

5 Schardein JL. Chemically induced birth defects, 2nd edn. New York, Marcel Dekker, 1993.

National Teratology Information Service, Regional Drug and Therapeutics Centre, Wolfson Unit, Newcastle upon Tyne NE2 4HH, UK (P R McElhatton PhD, C Evans BSc, K R Pughe BSc, S H L Thomas MD); and Scottish Poisons Information Bureau, Royal Edinburgh NHS Trust, Edinburgh, EH3 9YW, UK (D N Bateman MD)

Correspondence to: Dr P R McElhatton (e-mail: Patricia.McElhatton@ncl.ac.uk)

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