Antiparasitic

General

1. MacLeod CL. Parasitic infections in pregnancy and the newborn. Oxford: Oxford University Press, 1988.

2. Cook GC. Use of antiprotozoan and antihelmintic drugs during pregnancy: side effects and contraindications. J Infect 1992; 25:1–9

3. Savioli L, Crompton DWT, Neira M, Use of anthelminthic drugs during pregnancy. Am J. Obstet Gynecol 2003 Jan; 188(1):5-6

Mebendazole

1. de Silva HJ. de Silva NR, Sirisena JL, Gunasekera DP, Ismail MM, Effect of mebendazole therapy during pregnancy on birth outcome. Lancet 1999 Apr 3;353(9159):1145-9 BACKGROUND: In areas endemic for hookworm, routine antenatal mebendazole therapy could greatly reduce the prevalence of anaemia in pregnancy. At present, however, this is not a widely accepted control strategy because of a lack of data on the safety of the drug. We assessed the effect of mebendazole therapy during pregnancy on birth outcome. METHODS: A cross-sectional study was done in Sri Lanka, where prescription of mebendazole to women in the second trimester of pregnancy is recommended. Two hospitals were chosen for the study, and women who gave birth there between May, 1996, and March, 1997, were recruited. We compared the rates of major congenital defects, stillbirth, perinatal death, and low birthweight (< or = 1500 g) among babies of mothers who had taken mebendazole during pregnancy with those whose mothers had not taken an anthelmintic (controls). FINDINGS: The rate of major congenital defects was not significantly higher in the mebendazole group than in the control group (97 [1.8%] of 5275 vs 26 [1.5%] of 1737; odds ratio 1.24 [95% CI 0.8-1.91], p=0.39). Among 407 women who had taken mebendazole in the first trimester (contrary to medical advice), 10 (2.5%) had major congenital defects (odds ratio vs controls 1.66 [0.81-3.56], p=0.23). The proportions of stillbirths and perinatal deaths were significantly lower in the mebendazole group (1.9 vs 3.3%, 0.55 [95% CI 0.4-0.77]), as was the proportion of low-birthweight babies (1.1 vs 2.3%, 0.47 [95% CI 0.32-0.71]). INTERPRETATION: Mebendazole therapy during pregnancy is not associated with a significant increase in major congenital defects, but our results indicate that it should be avoided during the first trimester. This therapy could offer beneficial effects to pregnant women in developing countries, where intestinal helminthiases are endemic.

2. Diav-Citrin O, Shechtman S, Arnon J, Lubart I, Ornoy A. Pregnancy outcome after gestational exposure to mebendazole: A prospective controlled cohort study. Am J Obstet Gynecol 2003 Jan;188(1):282-5 OBJECTIVE: Mebendazole is an anthelmintic that is commonly needed in women of reproductive age. Its use in pregnancy is a reason for concern for women and their health care providers. The purpose of this study was to examine the fetal safety of mebendazole.Study Design: The Israeli Teratogen Information Service prospectively collected and followed 192 pregnancies exposed to mebendazole in pregnancy, 71.5% of whom had first-trimester exposure. Pregnancy outcome was compared with that of a matched control group, who were counseled for nonteratogenic exposure. RESULTS: There was no increase in the rate of major malformations between the groups (5/150 pregnancies [3.3%; mebendazole] vs 3/175 pregnancies [1.7%; nonteratogenic control subjects]; P =.478). There was a higher rate of elective terminations of pregnancy in the exposed group compared with the control group (22/192 pregnancies [11.5%; mebendazole] vs 3/192 pregnancies [1.6% [nonteratogenic control subjects]; P =.000). CONCLUSION: This study suggests that mebendazole does not represent a major teratogenic risk in humans when it is used in the doses that are used commonly for pinworm (Enterobius vermicularis) infestation.

Metronidazole

1. Czeizel AE, Rockenbauer M. A population based case-control teratologic study of oral metronidazole treatment during pregnancy. Br J Obstet Gynaecol 1998 Mar;105(3):322-7 OBJECTIVE: To study human teratogenic risk of metronidazole. DESIGN: A case-control analysis of congenital abnormalities after oral metronidazole treatment during pregnancy grouped by months of gestation. The source of information concerning the use of drugs during pregnancy was the prospective data of the women's prenatal logbook and the retrospective data of a questionnaire filled in by mothers. SETTING: The large population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1991. PARTICIPANTS: The control group involved 30,663 pregnant women who had healthy babies; the response rate was 65%. The index group consisted of 17,300 pregnant women who had offspring with congenital abnormalities from the study pregnancy; data were available for 82% of these women. RESULTS: Of 30,663 pregnant women in the control group, 1041 (3.4%) were treated with metronidazole, 162 (0.53%) in the second to third month of gestation. Of 17,300 pregnant women in the index group, 665 (3.8%) were treated with metronidazole, 104 (0.66%) in the second to third months. McNemar analysis for case-matched control pairs indicated a somewhat higher maternal metronidazole treatment in the second-third months of gestation in nine cases with cleft lip with or without cleft palate, but it was not possible to exclude the recall bias. In addition, this finding was not confirmed by the comparison of cases with cleft lip with or without cleft palate and the total control group. CONCLUSION: Treatment with oral metronidazole during pregnancy presents no clinically important association with congenital abnormalities.

2. Diav-Citrin O, Shechtman S, Gotteiner T, Arnon J, Ornoy A. Pregnancy outcome after gestational exposure to metronidazole: a prospective controlled cohort study. Teratology 2001 May;63(5):186-92 BACKGROUND: Metronidazole is an important antibacterial agent commonly used in women of reproductive age. Its use in pregnancy is a reason for concern for women and their health care providers. The objective was to examine the fetal safety of metronidazole. METHODS: The Israeli Teratogen Information Service prospectively collected and followed up 228 women exposed to metronidazole in pregnancy, 86.2% of whom with first-trimester exposure. Pregnancy outcome was compared with that of a control group, who were counseled during the same period for nonteratogenic exposure. RESULTS: There was no difference in the rate of major malformations between the groups (3/190; 1.6% [metronidazole] vs. 8/575; 1.4% [control], P = 0.739). The rate of major malformations did not differ between the groups even after including elective terminations of pregnancy due to prenatally diagnosed malformations (5/192; 2.6% [metronidazole] vs. 12/579; 2.1% [control], P = 0.777). A reduced neonatal birth weight was found in the metronidazole group compared with controls without significant differences in the rate of prematurity or in gestational age at delivery. The mean birth weight was lower in the metronidazole group when comparing the subgroup of term infants. CONCLUSIONS: This study confirms that metronidazole does not represent a major teratogenic risk in humans when used in the recommended doses.

3. Int J Gynaecol Obstet 1998 Jun;61(3):311-2 ACOG committee opinion. Bacterial vaginosis screening for prevention of preterm delivery. Number 198, February 1998. Committee on Obstetric Practice. American College of Obstetricians and Gynecologists. Metronidazole may be used in the second trimester for bacterial vaginosis

Thiabendazole

1. Lankas GR, Nakatsuka T, Developmental toxicity of orally administered thiabendazole in ICR mice. Food Chem Toxicol 2001 Apr;39(4):367-74. Thiabendazole (TBZ) is a potent anthelmintic and fungicide used in the treatment of parasitic infections in humans and domestic animals and post-harvest protection of agricultural commodities. TBZ is not teratogenic or selectively foetotoxic in rats or rabbits, in contrast to several other benzimidazole derivatives. However, when administered orally to pregnant (Jcl:ICR) mice at lethal dosages, malformations were observed in treated fetuses. To assess whether the effects found in this previous study were attributable to maternal toxicity or TBZ the present study was conducted. TBZ doses of 25, 100 or 200 mg/kg/day were selected based on a preliminary range-finding study in which maternotoxicity was evident at doses of 200 mg/kg/day or above. The compound was administered during gestation days 6-15 as a solution in olive oil. Caesarean sections were completed on gestation day 18 and complete fetal examinations conducted. Decreases in maternal weight gain relative to controls were found at doses of 100 mg/kg/day or above, which paralleled decreases in foetal weights in these same dose groups. However, there were no treatment-related external, visceral or skeletal anomalies in any treatment group. Therefore, TBZ was not teratogenic or selectively foetotoxic in mice, with no-observed-effect levels (NOEL) of 25 and greater than 200 mg/kg/day for maternal and fetal weight effects and teratogenicity, respectively. These results indicate that foetal effects noted in previous studies in mice were probably secondary to severe maternal toxicity.

Ivermectin

1. Brown KR. Changes in the use profile of Mectizan: 1987-1997. Ann Trop Med Parasitol 1998 Apr;92 Suppl 1:S61-4. The usually conservative approach of Merck & Co. to drug development became even more so in the Mectizan (ivermectin, MSD) programme because of adverse experiences following 'extra-label' use in Collie dogs and the discovery of a low threshold for acute neurotoxicity in CF-1 mice. Although a very cautious approach and rapid development programme ensued, Merck remained conservative and excluded children under the age of 5 years, pregnant women, and mother who were nursing children under the age of 3 months from treatment. A subsequent, more relaxed set of standards was based on vast human clinical experience, inadvertent use in hundreds of pregnant women without ill-effect, and new laboratory information indicating that the presence of a protective blood-brain barrier protein component (P-glycoprotein) helped to stop Mectizan from crossing the placenta and from crossing the blood-brain barrier in most animal species, including humans. This has allowed more groups to be included in Mectizan treatments: pregnant women living in areas where the risk of loss of sight because of onchocerciasis is very high; and women who are nursing children as young as 1 week of age. Mass distribution of the drug continues to be largely under community control and the likelihood of serious adverse experiences related to finding a human population with unusually low levels of P-glycoprotein (or no P-glycoprotein) seems remote.

2. Chippaux JP, Gardon-Wendel N, Gardon J, Ernould JC. Absence of any adverse effect of inadvertent ivermectin treatment during pregnancy. Trans R Soc Trop Med Hyg 1993 May-Jun;87(3):318

3. Doumbo O, Soula G, Kodio B, Perrenoud M. [Ivermectin and pregnancy in mass treatment in Mali] [Article in French]. Bull Soc Pathol Exot 1992;85(3):247-51. During july 1989, we have done a retrospective study, in Koba's valley in a savanna onchocerciasis area of Mali, after a mass treatment in rural community with ivermectin. 435 women aged from 15 to 45 years, among 461 with can be submitted to ivermectin risk during their pregnancy period, was seen and overhauled. In 1987, the frequency of women who received ivermectin during their pregnancy period (treated by error), was 17.7%, and 17.3% in 1988. We have seen any difference, between exposed and not exposed women to this error ivermectin treatment, comparing their in utero-mortality, new born mortality an the level of malformations. In spite of careful clinical monitoring in the field, the risk to give ivermectin to pregnancy women in rural community, is very high during mass treatment. Because traditionally (taboos), pregnancy is a forbidden subject. Sociological and anthropological studies, pregnancy field laboratory test and health education, are needed in african rural community before mass treatment with ivermectin.

4. Pacque M, Munoz B, Poetschke G, Foose J, Greene BM, Taylor HR. Pregnancy outcome after inadvertent ivermectin treatment during community-based distribution. Lancet 1990 Dec 15;336(8729):1486-9. Ivermectin is the drug of choice for community-based treatment of onchocerciasis. Since pregnancy testing during mass distribution campaigns is not feasible, the safety of ivermectin in pregnancy must be established. During a 3-year study, ivermectin was distributed to the population of a rubber plantation (14,000 people) in Liberia. Only 31% of women were aware of their pregnancy status during the first month; it was calculated that about half of women in the first trimester of pregnancy are likely to be treated inadvertently. 203 children born to women inadvertently treated during pregnancy were identified. In this limited sample, there was no significant difference in birth defects between treated and untreated mothers in the same population or compared with a reference population. Children of treated and untreated mothers showed no difference in developmental status or disease patterns. Further surveillance is necessary; however, since no major effects of ivermectin on pregnancy outcome were detected, there seems no need to change existing strategies of ivermectin distribution.

Albendazole

1. Torlesse H, Hodges M. Albendazole therapy and reduced decline in haemoglobin concentration during pregnancy (Sierra Leone). Trans R Soc Trop Med Hyg 2001 Mar-Apr;95(2):195-201. WHO recommends that anthelmintic treatment be included in strategies to improve maternal nutrition in areas where hookworms are endemic and anaemia is prevalent. At present, few countries have adopted this recommendation, partly owing to the lack of data to support the adverse effects of hookworms on maternal health. A longitudinal study was conducted on 125 women in Sierra Leone (in 1995/96) to measure the impact of single-dose albendazole (400 mg) and daily iron-folate supplements (36 mg iron and 5 mg folate) on haemoglobin and serum ferritin concentration during pregnancy. Women who received both albendazole and iron-folate supplements experienced no significant change (P > 0.05) in the prevalence of anaemia and iron-deficiency anaemia between the first and third trimesters. These prevalence levels significantly increased (P < 0.05) in women who received either albendazole or iron-folate supplements or neither. After controlling for baseline haemoglobin concentration and season, the mean decline in haemoglobin concentration between the first and third trimester in women who received albendazole was 6.6 g/L less than in women who received the control (P = 0.0034). The corresponding value for iron-folate supplements was 13.7 g/L haemoglobin (P < 0.001). The effects of albendazole and iron-folate supplements were additive. These findings lend support to WHO's recommendation for anthelmintic treatment during pregnancy.

Amphotericin B

1. Thakur CP, Singh RK, Hassan SM, Kumar R, Narain S, Kumar A. Amphotericin B deoxycholate treatment of visceral leishmaniasis with newer modes of administration and precautions: a study of 938 cases. Trans R Soc Trop Med Hyg 1999 May-Jun;93(3):319-23. Out of 938 parasitologically confirmed patients with visceral leishmaniasis treated with amphotericin B (1 mg/kg bodyweight daily infused in 2 h for 20 days), 935 were cured clinically, 933 parasitologically and 931 ultimately (no relapse within 6 months). Two parasitologically 'not cured' and 4 relapsed patients were cured with 25 infusions, and 1 with double relapse with 30 infusions. The treatment was started only when serum haemoglobin reached 5 g/dL, serum electrolyte imbalance was corrected and sodium stibogluconate-induced myocardial damage stabilized after 10 days' rest. Bronchopneumonia, cardiac failure and acute renal failure caused the death of 1 patient each. Nightblindness, angular stomatitis, neuritis, and petechial haemorrhages improved with appropriate treatment; 2 patients were given blood transfusion for post-treatment anaemia. Nausea and anorexia, and changes in serum creatinine and potassium, became normal in 2 weeks. Immediate withdrawal of the drug and restart after 10 days cured 2 patients who developed acute renal failure. Infusion-related toxicities--shivering, rigor and fever--were minimized but not eliminated by prior administration of hydrocortisone. Tuberculosis and visceral leishmaniasis were treated concurrently. Four pregnant patients were successfully treated without harmful effects on mother and child. It was concluded that the dosage of amphotericin B used was an effective and well-tolerated regimen and achieved 99% cure. Toxicity could be minimized with some precautions. All unresponsive and relapsed patients responded to more amphotericin and no resistance to the drug was seen.

Praziquantel

1. Montero R, Ostrosky P. Genotoxic activity of praziquantel. Mutat Res 1997 Dec;387(3):123-39. Praziquantel is a synthetic drug with a remarkable activity against parasites, particularly treamatodes and cestodes. Initial genotoxicity tests used a spectrum of endpoints including tests in bacteria, yeasts, mammalian cells and Drosophila and each one gave negative results. Effects on reproductive cells of mice were negative as well. However, host mediated studies in mice and humans were contradictory and a comutagenic effect with several mutagens and carcinogens was found. Later studies, including monitoring in humans and pigs have shown that Praziquantel induces a greater frequency of hyperploid lymphocytes as well as structural chromosomal aberrations, but not in all the individuals treated. In vitro studies have demonstrated that Praziquantel can induce micronuclei in syrian hamster embryonic (SHE) cells and in lymphocytes of some individuals. The same was found about structural chromosomal aberrations. Fetal death and fetal resorption were found when Praziquantel was administered in high doses to pregnant rats between the 6th and 10th day of gestation. Due to its efficiency as a parasiticide, Praziquantel is in use in Latin-American, Asiatic, African and East-European countries where infections by trematodes and cestodes are frequent. However, the extensive use of Praziquantel in multiple reinfections, in non-infected and non-diagnosed individuals for prevention, in higher doses or repeated doses for cysticercosis treatment and in individuals exposed to environmental mutagens, in conjunction with new findings about its metabolism and genotoxic properties, make it necessary to further evaluate the potential of this drug not only to be mutagenic per se, but to contribute in the development of neoplasm.

2. Frohberg H. Results of toxicological studies on praziquantel. Arzneimittelforschung 1984;34(9B):1137-44. Praziquantel (2-cyclohexylcarbonyl-1,2,3,6,7, 11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one, EMBAY 8440, Biltricide) is an anthelminthic drug with activity against all species of schistosomes pathogenic to man and a wide range of cestodes, including the cysticerci of Taenia solium in human tissues and organs, also the CNS. Praziquantel does not reveal any undesired pharmacodynamic effects. After oral administration praziquantel is quantitatively and rapidly absorbed, metabolized and excreted as a variety of metabolites predominantly via the kidneys. The acute toxicity in rats, mice, rabbits and dogs is very low. Rats tolerated by oral administration doses of up to 1000 mg/kg repeated daily for four weeks, and dogs up to 180 mg/kg for 13 weeks without any organ damage. Praziquantel did not disturb reproduction in rats (up to F2-generation), nor did it reveal teratogenic effects in mice, rats and rabbits. In extensive mutagenicity trials performed by different laboratories worldwide, in a variety of test systems, no induction of point mutations, gene conversion, DNA-repair, sister chromatid exchanges (SCEs), or X-linked recessive lethals was detected. Besides, Salmonella tests with urines of praziquantel treated mice, rats, healthy and Schistosoma-infected persons gave no indication of a mutagenic effect. In different in vivo mammalian assays praziquantel not mutagenic either. Low toxicity of praziquantel was not mutagenic either. Low toxicity of praziquantel was demonstrated also in the combined chronic toxicity and carcinogenicity tests which were performed in rats and Syrian hamsters. In none of these species praziquantel exerted a carcinogenic action, and both doses were tolerated.