Medicines

Acetylsalicylic acid

There are few data available on the effects of acetylsalicylic acid (ASA) overdose in pregnancy. A report about a mother having taken 16 g ASA in week 38 describes a concentration of salicylic acid of 31.7mg/dl after having been admitted to hospital. Because of fetal distress with bradycardia down to 60/min, and late decelerations, cesarean delivery was performed. The ASA concentration in the mother directly before this was 14mg/dl. In the newborn, however, it amounted to 35.2 mg/dl. The umbilical artery pH was 7.49. pC02 27mmHg, and bicarbonate 18 mmol/l. The further development of the child until its discharge was uneventful (Anonymous 2001).

The National Teratology Information Service (NTIS) in Newcastle, UK, has follow-up data on 101 pregnancies. Of these, 26 involved aspirin only, and 75 involved aspirin compound preparations (or other drugs in addition). Only one child showed a birth defect (a foot deformity); 82 newborn babies were normal (McElhatton 2001). The concentration of ASA measured in some mothers ranged above that which had induced teratogenic effects in animal experiments. In the absence of severe maternal toxicity, there was no increase in the incidence of fetal hemorrhage, spontaneous abortion, or intrauterine death. These results are in contrast to some other studies that describe an increase of spontaneous abortions after therapeutic dosage of nonsteroidal antipholgistics (NSAIDs) like ASA and ibuprofen (Li 2003, Nielsen 2001). Palatnick (1998) postulated that, due to increased sen sitivity to ASA, the fetus is at greater risk than the mother.

Recommendation. Generally, a pregnant woman with high concentration of ASA should be treated in the same way as a woman who is not pregnant. In general, termination of pregnancy owing to fear that the fetus could be damaged is not justified.

Antidepressants

Tricyclic antidepressants like amitriptyline and dothiepin can cause severe maternal toxicity, including cardiac arrhythmia and seizures, thus endangering the fetus too. In a series of reports of the NTIS in Newcastle, UK, on 18 women who had taken between 150 and 1000 mg of amitriptyiine, in 16 cases a normal baby was born,

1 intrauterine death occurred, and 1 pregnancy was terminated (McElhatton 2001). Among the mothers of the 16 normal newborns, 6 had taken the overdose during the first trimester. 8 during the second (3 of whom had medium to severe toxic symptoms), and

2 in the third. The intrauterine death occurred shortly after mixed intoxication with severe symptoms at 24 weeks' gestation.

Again in an NTIS report, of 21 pregnant women who had taken overdoses of dothiepin, 10 had taken it during the first trimester, eight during the second, and three during the third. Two mothers developed severe toxic symptoms; one of them had convulsions. The outcomes were 18 normal newborns and 1 showing a systolic murmur (overdose at 23 weeks, additional maternal alcohol problem); 1 pregnancy aborted spontaneously and 1 was terminated. There are no further data regarding the aborted fetuses.

In another study, an overdose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine was ingested in 21 pregnancies; 16 of these were exposed in the first trimester. Among these, 13 infants were normal and 3 demonstrated anomalies - 1 cavernous hemangioma, 1 birthmark on the left cheek and an ear tag, and 1 severe CNS defect. However, a causal relationship cannot be established because all three pregnant women took multiple drug overdoses (McElhatton 2001). In the meantime, the NTIS in Newcastle has collected data on 160 pregnancies with overdoses of antidepressants that do not reveal any evidence of specific cffccts (McElhatton, personal communication 2003).

Recommendation. As serious maternal ASA poisoning (especially where the mother has had seizures or lost consciousness) is likely to be associated with pregnancy complications, the mother should be treated in the same way as a non-pregnant woman. Termination of pregnancy owing to fear that the fetus might be damaged is generally not justified.

A neonatal bromide intoxication with hypotonia after the mother had taken a high dose at the end of pregnancy indicates the substantial transfer of this drug to the fetus. The further development of the infant was described as normal (Pleasure 1975).

Carbamazepin

Following intoxication with carbamazepine in week 33. with suicidal intent, the mother was comatose and was treated with activated carbon and plasmapheresis. The baby did not show any damage after birth; the Apgar score and umbilical artery pH were normal (Saygan-Karamursel 2005).

Colchicine

In week 34 of pregnancy, a woman took 8 mg/kg colchicine. A healthy child was born 10 hours later by cesarean section; it showed only very little colchicine in its serum (<5 ng/ml). Although given intensive care, the mother died (Blache 1982).

To date, case reports concerning intoxication with diazepam have not shown a specific toxic risk for the fetus (Cerqueira 1988). One report describes a pregnant woman in week 33 who had taken about lOOmg of a benzodiazepine, probably diazepam. Her serum contained 175|ig/I benzodiazepine, her urine 303|ig/l. Kinetocar-diotocography about 8 hours after ingestion showed, as expected, decreased modulation of the fetal heart rate. Furthermore, immediately after the patient had been admitted to the hospital, decelerations were observed that did not correspond to uterine contractions but to increased fetal movement. The basic heart rate was not noticeable. After about 6 hours, fetal heart rate modulation had normalized - i.e. accelerations followed fetal movements. This phenomenon, being independent from the pregnant woman's position, was interpreted as transitory hypoxemia resulting from intoxication (Heinrich 1996).

Digitalis

One report deals with intoxication with digitalis (8.9 mg digitoxin) in month 7. After spontaneous delivery in week 30. the child died on its third day of life. Hemorrhagic infarctions in both kidneys and degenerative changes in the CNS were found, which were interpreted as hypoxic due to continuous intrauterine bradycardia (Sherman 1960).

In a case series of 60 pregnancies exposed to ibuprofen overdose, 1 child had a malformation of the soft palate (which could not be attributed to the drug as exposure was in week 27), and there were 4 spontaneous abortions and 16 terminations of pregnancy (McRlhatton 2001). The same author has collected information on 100 pregnant women exposed to overdoses of ibuprofen. Of the 73 children who were born alive, 3 had cardiac anomalies. Although this is more than expected, it is not enough to conclude a causal relationship (McElhatton, personal communication 2003). The higher rate of spontaneous abortion after the therapeutic use of NSAlDs discussed by other authors (Li 2003) was not confirmed by McElhatton.

Recommendation. Pregnant women with ibuprofen overdose must be treated in the same way as non-pregnant women. There is no indication for termination of pregnancy owing to fear of malformations.

Iron compounds

There are several publications on iron overdose during pregnancy (Tran 2000, 1998, McElhatton 1998, 1993, Lacoste 1992, Dugdalc 1964). In a case series, 85 pregnancies were evaluated; 6 were exposed in the first trimester, 37 in the second, and 41 in the third. There were 73 live-born infants without congenital malformations. Five of these infants were delivered prematurely, one had genital herpes. and one had severe jaundice following exposure at week 36/37. Five infants, all exposed in the second and third Lrimesters, had malformations. Two fetal deaths, in weeks 22 and 29, were observed, one of them immediately after intoxication and another following abdominal trauma. Five pregnancies were terminated.

Serum iron levels were available in 51 patients; 21 were in the moderately toxic range (60-89 p mol/l) and 8 were in the severely toxic range (>90 p mol/l) (McElhatton 1998).

Chelation therapy with intravenous desferoxamine is indicated if the serum iron level is >55 n mol/l or if an overdose was clearly taken and the pregnant woman develops seizures, is unconscious, or presents with circulatory shock. In these cases, there is not time to wait for serum iron levels.

In the NTIS series, 41 women received deferoxamine and another 20 underwent other elimination procedures (ipecacuanha 10, gastric lavage 6, activated charcoal 3, bicarbonate 1). All the mothers survived. No maternal or fetal toxicity was observed following treatment of the mother with desferoxamine. Similar results have been reported in other studies (Khoury 1995, Turk 1993).

Recommendation. There is no substantial risk for the fetus if a mother with iron intoxication is treated in the same way as a non-pregnant woman. However, as experience with first-trimester overdose is limited, specific statements regarding teratogenicity are not possible. Termination of pregnancy owing to fear that the fetus might be damaged is not indicated.

Haloperidol

After an overdose of 300 mg Haloperidol in week 34, a decrease of fetal movement was observed for some days. The child was born in week 39 and developed normally until at least month 18 (Hansen 1997).

In adults, paracetamol is metabolized to an active metabolite which, in high concentration, is hepatotoxic. There is only a limited capacity of detoxifying by conjugation with glutathione. The fetal capacity to conjugate increases with age. The metabolism of paracetamol by the fetal liver is estimated to be 10 times slower than in the adult; therefore it produces the toxic metabolite much more slowly, which affords some protection to the fetus.

The NT1S in Newcastle, UK, has prospective follow-up data on 450 pregnancies in which paracetamol overdoses occurred (McElhatton 2001), including 40 who look combination compounds which also contained dextropropoxyphene. There were 140 first-trimester exposures. Eleven infants had various malformations, but a causal relationship could not be established, particularly as exposure was beyond the first trimester.

The spontaneous abortion rate was not increased (8-10°/o). Furthermore, neither the aborted fetuses, which underwent postmortem examinations, nor the live infants showed signs of liver or kidney damage. This included one infant born to a mother considered for liver transplant following two large paracetamol overdoses at 32-33 weeks (Rosevear 1989).

The available data on acetylcysteine used as an antidote do not indicate that it is associated with fetal toxicity.

Recommendation. Treatment is similar to that for overdoses in non pregnant women. According to the level of serum concentration of paracetamol, therapy with the antidote has to be started at once due to the needs of the mother and fetus. Postponing this therapy has in some cases led to the death of fetus and mother. On the other hand, there is no evidence of fetal toxicity, if toxic symptoms of the mother do not appear and the concentration in the serum is not toxic. Therefore, in general, paracetamol overdose is no indication for termination of pregnancy owing to the fear of malformations.

Podophyllotoxin

Podophyllotoxin, externally applied in high doses, led to psychiatric symptoms in a few pregnant women. Furthermore, there was one maternal death, one fetal death (Stoudemire 1981, Slater 1978, Montaldi 1974, Chamberlain 1972, Ward 1954), and one malformation of extremities, heart and ear after exposure between weeks 5 and 9 of pregnancy (Karol 1980).

2.22.5 Animal toxins

More than 90 cases of snake bites in pregnant women have been reported in the literature, although only in a few have clinical data been described in detail (Sebe 2005B, Langley 2004, Nasu 2004, Dao 1997, Pantanowitz 1996). In addition, there are a very few case reports on spider bites (see below; Pantanowitz 1996). Not much is known about the effects on the fetus of the various neurotoxins, cytotoxins, and hematotoxins. There is a report concerning four women in Sri Lanka, of whom two were bitten by cobras and two by vipers (James 1985). Three of the women had no symptoms, but noticed a significant decrease in fetal activity. The fetal heart rate also diminished. Following administration of antitoxins, the fetal movements and heart rate were normal within 24 hours. These three mothers delivered healthy full-term infants. The fourth woman also noticed a decrease in fetal activity in the first 24 hours, but was only treated with the antitoxin after a severe toxic state with hemolysis and renal failure had developed. Shortly afterwards, the baby was stillborn. The observation by all four women of diminished fetal activity indicates that small doses of snake toxin apparently reach the fetus even when no toxic symptoms are observed in the mother. In another case series of four pregnant women in Burkina Faso, there were two cases of fetal death. One of the two mothers also died, as a result of a severe coagulopathy and anemia (Dao 1997). Another fetus died in a mother whose leg was extremely swollen and who suffered from oculomotorius paresis and rhabdomyolysis after being bitten by a viper in week 10, although she was treated intensively (Nasu 2004).

Only in one case a birth defect was reported, after the mother had been bitten by a viper in her third month of pregnancy. The baby, who was hydrocephalic and had many other anomalies, died shortly after birh (Pantanowitz 1996). A teratogenic potential in humans cannot be deduced from this case report. In about half of the published case descriptions, spontaneous abortion or fetal death occurred. The percentage is actually higher among those treated with antitoxins; however, this may be due to the underlying severe illness. Premature birth and placental abruption - with or without coagulopathy - may also result from snake bites.

Two case reports on spider bites (black widow) during pregnancy described healthy newborns. The mothers were treated sympto-matically and received antitoxin (survey in Pantanowitz 1996).

Antitoxins against bites of poisonous animals have not been suspected of having any toxic effect on prenatal development. However, maternal anaphylaxis can indirectly endanger the fetus.

A case report on a baby with multiple birth defects whose mother was stung by a bee in Lhe third month (Schneegans 1961) has only anecdotal character and does not, of course, verify any causality.

Recommendation. Treatment with antitoxins following snake or poisonous spider bites should not be withheld because of pregnancy. It may also be indicated when the mother has no toxic symptoms herself, but fetal activity or heart rate is irregular.

2.22.6 Mushrooms

Following poisoning with Amanita phalloides (death cap), spontaneous abortion occurred in the first trimester (Kaufmann 1978). The cyclic octapeptide toxin, alpha-amanitin, blocks the synthesis of protein and can damage the fetal liver through the placenta. A woman treated with plasmapheresis for Amanita phalloides poisoning in the eighth month delivered a healthy baby (Belliadro 1983). Alpha-amanitin was found in her blood, but not in the amniotic fluid. In further reports on more than 20 poisonings with Amanita phalloides in pregnancy, there was no indication of fetotoxic effects if the mother was treated adequately (Schleufe 2003, Timar 1997). Compared to a control group, a relatively low birth weight was observed (Timar 1997). However, the number of cases is not high enough to interpret this as intrauterine growth retardation caused by poisoning.

Recommendation. Ingestion of poisonous mushrooms, especially Amanita phalloides (death cap), must be treated as in non-pregnant women, which means that all the therapeutic measures indicated should be applied.

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