What is the risk of teratogenicity associated with diclofenac/misoprostol treatment?/nBackground: a

Fråga: What is the risk of teratogenicity associated with diclofenac/misoprostol treatment?

Background: a woman was prescibed Arthrotec (50 mg diclofenac and 200 microgram of misoprostol), 3 tablets per day for one week, while pregnant in week 10. At that time, the patient did not know she was pregnant. She is now in week 15-16.

Sammanfattning: Diclofenac is not associated with an increased risk for congenital malformations. The use of misoprostol during the first trimester of pregnancy has been associated with the Möbius´ syndrome (congenital facial paralysis with or without limb defects) and other, often serious, congenital anomalies. Unfortunately, no published studies reporting the frequency of such a teratogenic effect after misoprostol use could be found, making an adequate risk assessment in this case very difficult. The risk is probably rather small, considering the large-scale illegal use of this drug in South-America. Ultrasound investigation of the fetus may be of value in the evaluation process.

Svar: Misoprostol is a synthetic prostaglandin E1 analogue, used to prevent and treat gastrointestinal lesions induced by nonsteroidal anti-inflammatory drugs. It is not recommended for use during pregnancy, because it may cause uterine bleeding and contractions, resulting in an abortion (1, 2). In Brazil, where elective abortions are prohibited, 57 to 75 per cent of women attempting abortion use misoprostol, which can be obtained over the counter. However, the drug (when used on its own) often fails to induce abortion in the first trimester and up to 80 per cent of these pregnancies are continued to term (3).

The first report of fetal damage from the unsuccessful use of misoprostol to induce abortion described frontal and/or temporal defects of the cranium and overlying scalp, exposing dura mater, in 5 infants (4). All mothers had taken misoprostol orally and/or vaginally during the first trimester (exact time not reported). The doses used were not clearly stated in this paper, but probably ranged from 400 to 1200 microgram. According to (1), another paper from 1993 reported 7 cases of limb defects involving the hands and feet following first trimester use of misoprostol. The dose ranged from 600 to 1800 microgram. Four of the 7 infants also demonstrated bilateral palsy of various cranial nerves leading to a diagnosis of Möbius´ sequence. Misoprostol exposure was thought to have occurred between 30 and 60 days following conception. The anomalies were attributed to misoprostol-induced vascular disruption.

The teratogenicity of misoprostol was questioned (5) by the teratogenic information system in Brazil. The centre reported 29 cases of women exposed to misoprostol during the first trimester. Doses ranged from one tablet (200 microgram) to 56 tablets. Three pregnancies ended in second-trimester spontaneous abortion, 3 mothers were still pregnant during follow-up and contact was lost with 6 others (which means absence of data for a total of 9 (31 per cent) of the cases). Of the remaining 17 livebirths, no major malformations were found. However, only 8 infants were examined by the authors, 4 by pediatricians not associated with the authors and in 5 cases, verbal information was received from the mother.

A recent study (6) aimed at finding more systematically the phenotypic effects of misoprostol and to define the period of greatest sensitivity to the drug. Forty-two infants exposed to misoprostol and born with congenital abnormalities were studied. The time of exposure ranged from the first month to the third month of gestation. The dose ranged from 200 to 16000 microgram. The most common dose was 800 microgram. The most common phenotype was equinovarus with cranial nerve paralysis (most commonly nerves V, VI and VII). Ten children had equinovarus as part of a more extensive arthrogryposis (persistent flexure/contracture of joints) and amyoplasia. Shortness or absence of one or more fingers or toes and tapered digits were also seen. Congenital hydrocephalus was seen in 8 children. Vascular anomalies and vascular disruption caused by misoprostol was considered the potential basis for the Möbius´ syndrome and its related phenotypical expression.

One study (3) compared the frequency of misoprostol use by mothers of 96 infants diagnosed with Möbius´ syndrome, matched with 96 infants with neural-tube defects. Among the mothers of the infants with Möbius´ syndrome, 49 per cent had used misoprostol during the first trimester, compared to 3 of the mothers of infants with neural tube defects (odds ratio 29.7). The mean (SD) dose was 842 (543) microgram. In 35 cases, misoprostol exposure was assigned to have occurred in the first 2 months of pregnancy, in 8 cases to the third month.

Reference (6) briefly mentioned in its discussion a cohort study of 86 misoprostol-exposed pregnancies lacking adequate power to assess the frequency of a teratogenic effect. To our knowledge, there are no other published studies yet addressing this important question. Considering the fact that this drug is used illegally on a large scale in South-America, the risk is probably rather small. This issue was also discussed with Professor Källen, consultant embryologist, who considered the increase in risk for congenital malformations due to misoprostol likely to be small (7). The uncertainty about its teratogenic potential and the fact that in the nearby future, misoprostol might be prescribed more frequently in combination with mifegyne, was reason for a recent publication in the Swedish Medical Journal (8).

The question of diclofenac use during pregnancy has been answered previously (9). The drug is not associated with an increased risk for congenital malformations (10). 1 Briggs GB, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 5th ed. Baltimore: Williams & Wilkins; 1998. p. 740-744 2 Drugline no 10277 (year 1994) 3 Pastuszak AL, Schuler L, Speck-Martins CE et al. Use of misoprostol during pregnancy and Möbius´ syndrome in infants. N Engl J Med 1998; 338: 1881-1885 4 Fonseca W, Alencar AJC, Mota FSB, Coelho HLL. Misoprostol and congenital malformations. Lancet 1991; 338: 56 5 Schuler L, Ashton PW, Sanseverino MT. Teratogenicity of misoprostol. Lancet 1992; 339: 437 6 Gonzalez CH, Marques-Dias J, Kim CA et al. Congenital abnormalities in Brazilian children associated with misoprostol misuse in first trimester of pregnancy. Lancet 1998; 351: 1624-1627

7 Personal communication with Professor Bengt Källen, Department of Embryology, University of Lund, Sweden
8 Bygdeman M. Misoprostol kan ge fosterskador. Läkartidningen 1998; 95: 3268-3269
9 Drugline no 07863 (year 1991)

10 Briggs GB, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 5th ed. Baltimore: Williams & Wilkins; 1998. p. 321-323