Abstract
We present the case of a 20-year-old student with an undiagnosed pregnancy who had taken ecstasy and LSD (lysergic acid diethylamide). Twenty-four hours later she delivered a stillborn term infant, and subsequently developed eclampsia with seizures, hypertension and proteinuria. Illicit drug use is relatively common in women of child-bearing age in Australia, and is a risk factor for adverse obstetric outcomes. Ecstasy (MDMA [3,4-methylenedioxymethamphetamine]) is a sympathomimetic amine, similar to amphetamine in its cardiovascular effects. LSD is a hallucinogen with complex pharmacology and has potential for significant compromise of placental blood flow. We propose that the combined vasoconstrictive effects of MDMA and LSD caused placental ischaemia, contributing to the fetal death and precipitating a cascade of endothelial dysfunction which resulted in an eclamptic syndrome.
CASE HISTORY
A 20-year-old Caucasian university student presented to hospital following the stillbirth at home of a near-term male infant. She had not been aware of her pregnancy and had taken ‘ecstasy’ (MDMA [3,4-methylenedioxymethamphetamine]) and ‘acid’ (LSD [lysergic acid diethylamide]) in the 24 hours prior to delivery. She gave a history of having taken these ‘party’ drugs every month over the preceding year, with concurrent alcohol intake of 2–3 standard drinks. She was a non-smoker with no medical or surgical history of note and a normal body mass index. On presentation she was tearful but coherent, heart rate 80 bpm, blood pressure 100/70 mmHg and the placenta was delivered without complication. Five hours later she had three generalized tonic–clonic seizures over a period of 20 minutes, each lasting only 2–3 minutes. At that time observations were heart rate 78 bpm, blood pressure 140/100 mmHg and reflexes were normal. She remained afebrile throughout. Urgent bloods showed mildly elevated creatinine (83 µmol/L) and urate (0.56 mmol/L), other electrolytes, liver function tests and full blood count were within normal limits. Dipstick urine showed 4+ protein and subsequent urine protein:creatinine ratio was 880 g/mol. Urine drug screen confirmed MDMA and MDMA metabolites with no other illicit substances present. Due to the recurrent seizures she was intubated and sedated, commenced on magnesium sulphate infusion for presumed eclampsia and transferred to the intensive care unit (ICU). In ICU blood pressure reached 210 mmHg systolic and was treated with ongoing magnesium sulphate infusion and metoprolol. Computed tomography brain showed a small subdural haematoma, thought to be secondary to the seizure. Thrombophilia screen was normal.
The patient was extubated the following day and had moderate ongoing proteinuria and hypertension up to 140/105 mmHg requiring antihypertensive treatment. On the ward she expressed grief and disbelief at having not recognized her pregnancy, particularly as she had been on the oral contraceptive pill throughout. She was discharged from hospital with ongoing metoprolol on day eight postpartum, which was ceased in the outpatient clinic two weeks later.
Neonatal postmortem examination revealed a normal term male infant weighing 2760 g, with minimal maceration. LSD and MDMA were detected in blood and urine. Placental histology showed several small infarcts and a single focus of villitis.
DISCUSSION
Illicit substance use is increasingly common globally, including among women of reproductive age, and is associated with both high-risk sexual behaviour 1 and poorer obstetric outcomes. 2
The most recent Australian survey 3 found 8.7% of women aged 20–29 and 6.0% of females aged 14–19 reported recent use of ecstasy, for amphetamines the rates are 4.8% and 2.2%, respectively (15.9%, 12.7% for cannabis). Reported rates of drug use are generally lower in pregnancy, which reflects both improved maternal health behaviour, and under-reporting due to fear of stigmatization, having children taken into care or legal consequences. 4 Drug use may be detected on urine drug screening or by meconium analysis in the neonate. 5 Recent data from our institution show 0.3% of mothers reporting use of amphetamines during pregnancy. 6
Literature regarding the effect of illicit substances in pregnancy is sparse and limited by low rates of self-report and the presence of multiple significant confounders, including high rates of smoking and polydrug abuse, lack of prenatal care, poor nutrition, low socio-economic status and limited social supports. 7
There are two previous case reports of amphetamine use associated with an eclamptic syndrome. 8,9 In each case the mother presented late to antenatal care, and the exposure was identified on a positive urine drug screen rather than maternal report. The pathophysiology of preeclampsia/eclampsia involves a complex interaction of environmental, genetic, immunological and vascular factors resulting in reduced placental blood flow. In response the placenta produces an array of factors that cause maternal systemic endothelial dysfunction and the characteristic features of preeclampsia. 10 It is possible that the vasoconstrictive effects of amphetamine may cause significant placental hypoperfusion, precipitating preeclampsia. Our patient had taken MDMA and LSD which both have vasoconstrictive effects.
Ecstasy
MDMA causes release of endogenous catecholamines, particularly noradrenaline and dopamine, and is structurally similar to serotonin. Features of MDMA toxicity are similar to those of amphetamine with hypertension, tachycardia and central nervous system stimulation, but the more common causes of morbidity and even mortality in MDMA is serotonin syndrome or the syndrome of inappropriate ADH. 11 There are however reports of myocardial ischaemia and stroke among young MDMA users without traditional cardiovascular risk factors.
Amphetamine use is associated with increased rates of adverse obstetric outcomes, 12 including premature rupture of membranes, premature delivery, intrauterine growth restriction, placental abruption and convulsions. This likely relates to the marked vasoconstrictive effects of amphetamine; however, formal studies are few. In rats, MDMA does cross the placenta 13 and has also been shown to affect the developing brain, with reduced anxiety and heightened response to novelty, 14 as well as learning and memory impairments. 15 One human epidemiological study has shown an association between prenatal exposure to MDMA and increased rates of congenital abnormalities, 16 although the rate of confounding conditions was high.
LSD
The literature on LSD use in pregnancy is sparse. In animal studies LSD readily crosses the placenta 17 and effects include decreased placental blood flow. In pregnant ewes, this is mediated by uterine artery constriction, 18 as well as umbilical artery constriction in the fetus. LSD and its metabolites have also been shown to have oxytoxic effects. 19 One epidemiological study of mainly preconception exposure to LSD found a trend to increased rates of miscarriage in the ‘non-medical use’ group, although this was a heterogeneous population. 20
SUMMARY
In our patient, we propose that the combined vasoconstrictive effects of MDMA and LSD caused placental ischaemia, contributing to the fetal death and precipitating the cascade of endothelial dysfunction which caused eclampsia.