A 27-year-old pregnant woman (week 12) took 20-40 mg of Rohypnol (flunitrazepam) in a suicide attem

Fråga: A 27-year-old pregnant woman (week 12) took 20-40 mg of Rohypnol (flunitrazepam) in a suicide attempt. She did not vomit and approximately 14 hours after the intake she was admitted to hospital. She was sleepy but awake and received treatment with Lanexat (flumazenil) 0.2 mg intravenously. The next day she was discharged from the hospital but came back in the evening the following day. This time she had taken 20 grams of paracetamol. She vomited after two hours and had a gastric lavage. 4.5 hours after intake the serum concentration of paracetamol was 1037 umol/l. Treatment with intravenous acetylcysteine was given. Can the overdoses of flunitrazepam and paracetamol have any harmful effects on the foetus? Is it safe to use flumazenil and acetylcysteine during early pregnancy?

Sammanfattning: We have not found any information in the literature indicating an increased risk of congenital abnormalities when using therapeutic doses of flumazenil and acetylcysteine during pregnancy. Concerning the risk after overdose of flunitrazepam or paracetamol during pregnancy, there is some documentation of spontaneous abortions but no evidence of congenital abnormalities due to exposure to these drugs.

Svar: Flunitrazepam is a commonly used benzodiazepine. It is readily absorbed from the gastrointestinal tract and extensively metabolised in the liver. The elimination half-life is reported to be about 19-22 hours. Flunitrazepam crosses the placental barrier (1).

According to Briggs´s handbook (2) there are no reports linking the use of the drug with congenital defects. On the other hand, an association between another benzodiazepine, diazepam, and an increased risk of cleft lip and/or palate has been suggested (3), but the evidence is not conclusive (4). In a recent study performed in the US on the use of benzodiazepine (flunitrazepam was not included as it is not licensed on the US market) during pregnancy among 104.000 women, it was found that 80 women were heavey users of benzodiazepine. Records of 64 surviving children from these mothers were investigated and six of these children had diagnoses consistent with different teratogenic abnormalities. However, the high rate of teratogenicity occurred in women with multiple alcohol and substance exposures and thus the teratogenic abnormalities may not be due to benzodiazepine exposure. Oral clefts were not found in any of the 1354 first trimester benzodiazepine exposures (5).

We have found only two reports concerning intoxication with benzodiazepines and outcome of pregnancy. Cerqueira et al (6) described four pregnant women in the second trimester who by mistake received about 10 gram of benzodiazepine (not specified) orally in one dose. They vomited up part of the dose after ingestion and had variable sensory depression. The patients delivered at term and all the babies were morphologically normal. A follow-up at six months of age showed normal psychomotor development. In a Hungarian study 13 cases of intoxication with benzodiazepines alone or in combination with other drugs were studied. Three pregnancies were terminated and in two cases miscarriage occurred. In the remaining eight, the children showed no congenital anomaly. Of these eight children two were exposed during the first trimester, three during the second and three during the last trimester (7).

Professor Källen (8), an embryologist, also has information from an unpublished Swedish study where the pregnancies of 70 women (exposed during the first trimester) after intoxication of benzodiazepines (though not flunitrazepam) and other psychotropic drugs were followed. No untoward effects to the exposed foetuses were found.

The manufacturer (9) has reports of four cases of flunitrazepam intoxication (20-40 mg) during the first trimester of pregnancy. One case resulted in abortion and it is unclear whether it was spontaneous or not. In the remaining three cases the pregnancies were normal and no malformations were reported.

Concerning FLUMAZENIL, a benzodiazepine receptor antagonist, controlled studies of use during pregnancy have not been carried out (10). The drug is classified as B:1 in FASS which means that clinical experience from treating pregnant woman is limited but data from animal experiments does not suggest an increased risk of foetal damage. The manufacturer has been contacted (9), but they have no additional data.

No information is available on the effects of ACETYLCYSTEINE on the human foetus according to Dollery´s textbook (11). This drug is also classified as B:1 in FASS.

PARACETAMOL is considered to be safe during pregnancy and Professor Källen (8) does not recommend termination of pregnancy even in cases of intoxication. In an English study the outcome of 48 pregnancies after paracetamol overdose were studied (12). There were 39 live-born infants with no malformations. Fourteen of these were exposed during the first trimester. There were two live-born infants with gross malformations (spina bifida occulta, cleft lip and palate). However, as the overdoses occurred at weeks 26 and 28, a long time after the structural development of these organs, it was judged that the malformations could not have been caused by paracetamol. There were two spontaneous abortions in the first trimester which occurred two weeks after the overdose that may have been related to paracetamol. The authors´ conclusion was that paracetamol overdose per se is not necessarily an indication for termination of pregnancy. In another report concerning paracetamol overdose and acetylcysteine treatment during pregnancy, 19 patients in the first trimester were studied. Six women had spontaneous abortions, eight had elective abortions and five delivered normal-term infants (13). The possibility that paracetamol intake in the pregnant woman may cause subsequent liver impairment when the child is born has previously been discussed (14).