]ournal of Infection (I992) zS, ~-9

Editorial Use o f antiprotozoan and anthelmintic drugs during pregnancy: side-effects and contra-indications

T h e pregnant woman and (even more importantly) her u n b o r n fetus are vulnerable to the potential side-effects of a wide range of chemoprophylactic and chemotherapeutic agents ;1 while there is good evidence for the safety (or otherwise) of many of these compounds, this is by no means always the case, and this is exemplified by a n u m b e r of antiprotozoan and anthelmintic a g e n t s ) '3 In general terms, caution should therefore be exercised (as with all medicinal preparations) in the prescribing of antiparasitic agents during pregnancy--especially during the first trimester; whenever possible chemotherapy should be delayed until delivery has taken place. Table I summarises some available data on side-effects of agents used to combat Plasmodium sp. Broadly speaking, antimalarial c o m p o u n d s can be divided into those which are of value in chemoprophylaxis, and those which are chemotherapeutic; however, chloroquine, pyrimethamine-sulphadoxine (' Fansidar '), and mefloquine are used in both clinical situations; 4 the two latter c o m p o u n d s are not without side-effects in the non-pregnant individual. T h e possibility of teratogenic effects (including visual impairment, ototoxicity and cochleovestibular dysfunction) from chloroquine has been raised; 1'2'5 if a significant risk exists, however, it m u s t be small because although two (I'2 %) of I69 infants born to w o m e n who had taken chloroquine (300 mg weekly) t h r o u g h o u t pregnancy had birth defects, so did four (0"9 %) of 454 whose mothers had not received antimalarial chemoprophylaxis. 6 T h e r e is clear evidence t h o u g h for fetal damage when chloroquine is used at high dosage in, for example, treatment of discoid lupus erythematosus. 7 Fourteen pregnancies in w o m e n receiving chloroquine at high dosage for rheumatic diseases have been recorded; 5 three occurred during periods of disease activity and these were not completed successfully; another resulted in still birth, four in spontaneous abortion, and the remaining six had a normal full-term delivery of a healthy infant. Overall, the enormous value of this c o m p o u n d when used as an antimalarial agent in developing countries clearly outweighs a very low possible risk. l'~'s Use of ' F a n s i d a r ' chemoprophylaxis during pregnancy remains controversial; 1'2 there is only very limited evidence that pyrim e t h a m i n e is potentially teratogenic (see below), but an element of doubt surrounds the sulphonamide moiety (which has caused problems when given at high dosage to rats)2 According to the manufacturer, this agent should be avoided during the first trimester and close to t e r m - - w h e n the sulphonamide c o m p o n e n t can cause hyperbilirubinaemia and kernicterus in the newborn. 1 Simultaneous administration of folate probably minimises risks to both m o t h e r and fetus. However, ' F a n s i d a r ' has in fact been safely used in the successful m a n a g e m e n t of Plasmodium falciparum infection during pregnancy. 10 Mefloquine is contra-indicated during pregnancy ;3 six fetal abnormalities were recorded in 66 h u m a n pregnanciesll--although there was not a consistent oi63-4453/92/o4oooi +09 $03.00/0 1

© I992 The British Society for the Study of Infection JIN 25

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Table I Antiprotozoan agents used in Plasmodium sp. infection 1'~

Compound Chloroquine Pyrimethaminesulphadoxine (' F a n s i d a r ') Mefloquine Proguanil Pyrimethamine Pyrimethaminedapsone (' M a l o p r i m ') Quinine

Halofantrine Qinghaosu Primaquine

P e r m e a b i l i t y at blood-placental barrier

Mutagenic effect

T e r a t o g e n i c effect

+ +

-

+ -

-

Hyperbilirubinaemia; kernicterus t

+ + * +

* +

+ * + *

+ + *

t Thrombocytopeniat~:

+

-

+

-

+ * +

+ * -

+ * *

* *

Hypoglycaemia; tachycardia; fetal d i s t r e s s * :~

Experimental Human

O t h e r fetal toxicity

* A v a i l a b l e data u n s a t i s f a c t o r y . t F o l i c acid s u p p l e m e n t s i n d i c a t e d . H a e m o l y s i s in g l u c o s e - 6 - p h o s p h a t e d e h y d r o g e n a s e ( G - 6 - P D ) deficient n e w b o r n .

pattern of birth defect; and epididymal hypoplasia has been recorded in rats and mice. 1 This agent has a long half-life (up to 2I days); the manufacturer therefore recommends delaying pregnancy for 3 months after discontinuation of mefloquine chemoprophylaxis. In chemoprophylaxis, proguanil (which has been very widely used in pregnancy over several decades) seems completely safe; no case of teratogenesis associated with this agent has been recordedfl however, folate status should be monitored. Pyrimethamine also seems safe (though not generally recommended2) despite evidence for teratogenicity when given at high dosage to rats,i° however, severe congenital defects in a stillborn child whose mother had received this agent (together with dapsone and chloroquine) during early pregnancy, have been recorded. ~,1~ Like 'Fansidar ', pyrimethamine-dapsone (' Maloprim ') is not recommended during pregnancy (although the manufacturer does not specifically restrict its use in chemoprophylaxis). 1° Folic/folinic acid supplementation is advised when a pyrimethaminecontaining preparation is used in pregnancy. T h e pregnant woman is relatively immunosuppressed and she certainly needs protection against the ravages of malaria; this fact must always be balanced against drug side-effects. In the chemotherapy of P. falciparum malaria, quinine is the most widely used agent in non-endemic areas. 4 Quinine has been reported to be teratogenic to guinea-pigs--damage to the fetal inner ear, and central nervous system anomalies have been recorded ;1 however, using monkey embryos, no problems were encountered. Quinine has been used to treat P. falciparum malaria in millions of pregnant women, and very few problems have arisen. No evidence

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of teratogenicity was detected in Io4 children whose mothers had received quinine during the first 4 months of pregnancy. 2 However, hearing loss has been documented in infants and pre-school children who were exposed to this agent pre-natally ;~3 congenital abnormalities were recorded in 2I infants when large doses were used as an abortifacient. 1 T h e importance (or otherwise) of the oxytocic action of quinine when used in pregnancy remains difficult to evaluate; although most physicians with wide experience of the management of P. falciparum infection have encountered cases of abortion and premature delivery, a study carried out in Thailand has indicated that this action is of limited importance in late pregnancy. 14'1~ Hypoglycaemia is a recognised accompaniment of severe P. falciparum infection, and this complication seems to be exacerbated by the addition of quinine. 16 This observation might not, however, be as important as has been suggested, glucose homeostasis in children having been recently shown to be unaffected during quinine treatment of this infection. 17 Halofantrine and qinghaosu have both been used in the chemotherapy of P. falciparum infection, mostly in east Africa and China, respectively; there are no reliable data on the use of either compound in pregnancy, although limited evidence of embryotoxicity, but not teratogenicity, has been recorded experimentally with the former compound. Primaquine, which is used solely for eradication of the exo-erythrocytic (hypnozoite) stage in the life cycle of P. vivax and P. ovale infections, should in general be avoided during pregnancy; this recommendation results not from evidence of potential teratogenicity (which has not been clearly documented either experimentally or in human studies), but from rapid haemolysis of infected erythrocytes (containing fetal haemoglobin) which are deficient in glucose-6-phosphate dehydrogenase. ~ Various broad-spectrum antibiotics (including tetracyclines) have anti-Plasmodium sp. activity; however, they should not be used alone in a P. falciparum infection. T h e tetracyclines are strictly contra-indicated during pregnancyfl ,~ Table I I summarises some available data on agents used in the chemotherapy of intestinal protozoan infections. In the chemotherapy of these, including Entamoeba histolytica and Giardia lamblia (and also Trichomonas vaginalis), the 5-nitroimidazole compounds--usually metronidazole and t i n i d a z o l e J a r e now most widely used. T h e long-term safety of these compounds is unclear. ~ T h e r e is clear evidence of mutagenicity in bacteria 2 and carcinogenicity in rodents, ~8'~9 and their safety in h u m a n pregnancy remains controversial. 2 Whereas one group of workers considers that metronidazole 'should be avoided during pregnancy ,,s0 another investigator has concluded that 'for all practical purposes.., we can regard metronidazole as a safe drug for shortterm t r e a t m e n t ' ; 21 others have restricted its use in the first trimester only. 2 Probably the most convincing evidence for the safety of metronidazole came from a study of 597 pregnant women who received a 7 - I o day course (6oo mg daily) for a T. vaginalis infection; 22 the author of this retrospective study confidently concluded: ' T h e incidence of low birth-weight infants, stillbirths and congenital abnormalities was not affected by metronidazole treatment ' - - w h e n administered at any stage during the pregnancy. This does not of course answer the question fully, for in an E. histolytica infection, daily dosage of metronidazole may be as high as 2"4 g. No reliable data are available 1-2

Editorial Table II Agents used against intestinal protozoan infections I

Compound Metronidazole Tinidazole Diloxanide furoate Trimethoprimsulphamethoxazole (' co-trimoxazole ') Spiramycin Furazolidone

Permeability at Teratogenic effect blood-placental Mutagenic barrier effect Experimental H u m a n

Other fetal toxicity

+

+

-

±

Fetal alcohol syndrome ~0

+

*

*

*

Kernicterus

*

÷

Haemolysis in G-6-PD deficiency

* Available data unsatisfactory.

for tinidazole. Diloxanide furoate--which is used to eradicate E. histolytica cysts from the colonic lumen4--is best avoided during pregnancy because there are no reliable data on safetyfl Trimethoprim-sulphamethoxazole (' co-trimoxazole ') is used in Isospora belli infection in immunosuppressed individuals (including A I D S ) ; 4 however, safety (especially that of the trimethoprim moiety) in early pregnancy has not been established, and the manufacturer is rightly cautious. In the later stages of pregnancy, it should certainly be avoided because the sulphamethoxazole component can cause kernicterus in the newborn infantfl Cryptosporidium sp. infection is a major 'opportunistic' event in A I D S ; there is no satisfactory chemotherapeutic agent. Spiramycin is frequently prescribed for this infection (and also acute Toxoplasma gondii during pregnancy),--no adverse effects on mother or fetus have been recorded in France (where it is widely prescribed) which strongly suggests safety in pregnancy ;~ it certainly crosses the blood-placental barrier (BPB). 4'23 Furazolidone has been used in a wide range of intestinal (and less often systemic) protozoan infections; here also, safety in pregnancy has not been established. Table III summarises some available data on agents used in the chemotherapy of systemic protozoan infections. A wide range of agents has been used in their management; this review deals only with those which are widely used at present. Pentamidine is of value in leishmaniasis and African trypanosomiasis. It has also been used in trypanosome chemosuppression campaigns in Africa, and in the treatment of Pneumocystis carinii pneumonia; although it is presumed that pregnant women were among those treated, no details have been published. 1 One report specifically states that 'pregnancy is not a contra-indication ,.24 Evidence for the safety of meglumine antimonate is also incomplete; one report has documented agranulocytosis in a 23-monthold child, which possibly resulted from a side-effect of this agent. 2 Amphotericin B is also prescribed in leishmaniasis. A case is on record of a

Editorial T a b l e I I I Agents used for systemic protozoan infections 1

Compound

Permeability at Teratogenic effect blood-placental Mutagenic barrier effect Experimental Human

Other fetal toxicity

Pentamidine Meglumine antimonate Amphotericin B Suramin Melarsoprol

+ +

* ±

* -

* *

--

+ +

* + +

* + +

+

Eflornithine Benznidazole Nifurtimox Sulfadiazine

* + + +

* + + -

* * -

* * * -

Haemolysis in 6-G-PD deficiency ? Kernicterus

* Available data unsatisfactory. normal child being born to a w o m a n suffering from blastomycosis (a mycotic infection) who was treated with this c o m p o u n d intravenously during pregnancy ;2a in a review of 2o other p r e g n a n t women, who were also treated with this agent, no good evidence ofteratogenesis or any other persisting effect on the infant was produced, despite the fact that amphotericin diffuses freely into the fetal circulationfl S u r a m i n and melarsoprol (Mel B) are used in the m a n a g e m e n t of African trypanosomiasis. T h e former agent (which is also used in onchocerciasis as a macrofilaricide---see below) is closely related chemically to t r y p a n blue, which is a k n o w n teratogen (in hamsters, guinea-pigs and chicks) and also causes abortion in monkeys ;1 in mice it produces ocular and skeletal abnormalities, and in rats it is embryolethal. S u r a m i n is teratogenic in the mouse, b u t not the r a t ) However, there are no reports of teratogenicity in w o m e n - - w h i c h can probably be accounted for by differences in placental development between rodents and man. 3 Nevertheless, the m a n u f a c t u r e r considers pregnancy a contra-indication to its use in onchocerciasis. Arsenic, which is a c o m p o n e n t of melarsoprol, produces chromosomal aberrations, and is teratogenic in mice and r a t s - - w i t h the p r o d u c t i o n of exencephaly, agnathia, a n o p h t h a l m o s , skeletal defects and cleft palate; 1 low birth-weight, abortion and multiple malformations have also been recorded. Despite this, several reports exist of p r e g n a n t w o m e n who suffered f r o m arsenical poisoning, and who later gave birth to normal infants. 1 Data are not presently available on eflornithine, which has been the subject of encouraging chemotherapeutic trials in Trypanosoma brucei gambiense infection in west Africa. 4 T h e two agents which have a beneficial effect (although neither is entirely satisfactory) in s o u t h e r n A m e r i c a n trypanosomiasis (congenital infection with T. cruzi is a major problem 26) are: benznidazole and nifurtimox. T h e former is mutagenic to some bacteria, and carcinogenic in animals ;1 however, deleterious effects on the h u m a n fetus have not been recorded. T h i s agent is only indicated in acute maternal disease and the m o t h e r should be told of the possibility of fetal damage. N i f u r t i m o x also possesses mutagenic and embryotoxic properties; ~

Editorial

Table IV Anthelmintic agents I Permeability at blood-placental barrier

Compound

Teratogenic Mutagenic effect

Experimental

effect Human

Intestinal and biliary helminthiases Mebendazole Albendazole Thiabendazole Niclosamide Bithionol

* * + * +

* * *

+ + + -

_+ * *

Schistosomicides Praziquantel Oxamniquine Metriphonate

+ + +

+

--

* +

Filaricides Diethylcarbamazine Ivermectin

* *

* *

+

* -

* Available t

Other fetal toxicity

i

t

data unsatisfactory.

Raises serum theophylline Avoid general anaesthesia

concentration. for 24 h after administration.

although low fetal weight has been demonstrated in the rat and mouse (a tendency to develop benign tumours is also recorded), no documented fetal malformations have been detected ;3.57 there are, however, no available data to eliminate h u m a n teratogenicity. In the management of T. gondii infection, as an alternative to spiramycin (see above), sulphadiazine is frequently combined with pyrimethamine; fetal abnormalities have not been recorded, but a riskbenefit analysis should always be made before this agent is prescribed during pregnancy. 3 In the last trimester, kernicterus has been suggested as a complication, but this remains unsubstantiated, z Table IV summarises some available data on anthelmintic agents. Numerous unsolved problems exist. T h e benzimidazole compounds--mebendazole, albendazole, and thiabendazole--are widely used in the chemotherapy of intestinal nematode helminthiases. ~s.29 Mebendazole is teratogenic in the rat, 2 but only one human malformation was recorded in a retrospective study of r I2 pregnancies; z° however, reports of its use during the first trimester are limited. 1 Absorption from the small-intestine is slow, and it is therefore conceivable that albendazole (absorbed at a greater rate) will prove to possess more side-effects. T h e r e is no documented evidence of albendazole having been given to pregnant women; therefore no data on the possibility of teratogenicity (or indeed of human placental transfer) are available. 3 Pregnancy is best avoided for one cycle after completion of a > 3 day treatment course. Thiabendazole is teratogenic in mice; however, studies in rabbits, rats, sheep and cattle have failed to demonstrate any fetal abnormality which could be attributed to this compound. 3 It seems clear, therefore, that all benzimidazole compounds should ideally be avoided during pregnancy. Praziquantel (see below) is now the chemotherapeutic agent of choice for cestode infections, but

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niclosamide remains in use; experience of its use during the first trimester is limited to a few cases who were treated, without problems, at 8-Io weeks pregnancy, 3 but clearly treatment is best postponed until after delivery. Bithionol remains the most effective chemotherapeutic agent against Fasciola hepatica infection; it is known to cross the BPB, but there are no satisfactory teratogenicity data in man. 1 Older agents which have been widely used against intestinal nematode infections include: pyrantel, piperazine and levamisole. T h e former is reported to be safe in pregnancy, despite evidence that it crosses the BPB; one viewpoint is that it is the ' d r u g of choice' for treating Ascaris lumbricoides infection during pregnancy. 1 Piperazine also seems safe, ~ although only three reports of its use during the first trimester are available; 1 the manufacturer, however, recommends caution over its use during pregnancy. 2 Levamisole is probably contra-indicated; in the rat a reduction in implantation and viability has been demonstrated, although there was not an increase in the incidence of birth defects; 1 at high dosage the mother lost weight (in one study nine of I5 died), and associated features were: infertility, abortion, low birth-weight and testicular dislocation in the fetus. T h r e e newer schistosomicides (also of values in other trematode and cestode infections)--praziquantel, oxamniquine and metriphonate--certainly cross the BPB. Mutagenicity studies with praziquantel have failed to reveal a problem. Praziquantel does not exert a significant influence on reproductive performance, nor is it teratogenic in the mouse, rat or rabbit, 31 but there are no satisfactory recorded studies during human pregnancy. 1'~ Oxamniquine (active against Schistosoma mansoni only) is not recommended for use in pregnant women, but (as with praziquantel) many such individuals have undoubtedly received this compound, and related abnormalities have not to date been recorded. 1.32At least one case report exists of multiple congenital abnormalities (not necessarily cause-effect related) after metriphonate administration for a S. haematobium infection; 3~ the manufacturer's literature emphasises mutagenicity (in Salmonella typhimurium), but mutagenic, embryotoxic, and teratogenic effects have not been recorded in the mouse, rat, or hamster. 1,2 Diethylcarbamazine has been very widely used for all of the h u m a n filariases; it has been administered to the pregnant rat and rabbit at a dosage of 30 times that used in man 34 with no evidence of teratogenic or abortifacient activity, although there is limited evidence for the latter in some animal experiments. 2 Recently, ivermectin has been widely used in the communitybased management of onchocerciasis in west Africa. During a 3-year evaluation of this compound in Liberia, the compound was distributed to about 140o0 people on a rubber plantation; a5 203 children were born to women who had been 'inadvertently' treated during pregnancy and there were no significant differences in the incidence of birth defects when compared with untreated mothers on the same plantation. In the mouse, however, ivermectin has been associated with cleft palate and the occasional unexplained maternal death despite its safety in the rat and rabbit; 2 as a result it is not recommended for use in pregnancy. Suramin (Table III)--also used in onchocerciasis--is a toxic compound, 36 and should not, in the opinion of the manufacturer, be used in pregnancy (see above); however, apart from teratogenicity in mice, no untoward toxic effects have been recordedfl

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Editorial

In the past, vast n u m b e r s of w o m e n have u n d o u b t e d l y been treated with most (if not all) of the agents m e n t i o n e d in this review; m a n y have been, often unknowingly, pregnant. I f brief reports of the outcome of these pregnancies had been d o c u m e n t e d , the present position regarding the safety (or otherwise) of these c o m p o u n d s in this clinical situation would be far clearer than at present. A good case can therefore be m a d e for d o c u m e n t a t i o n o f cases (even single ones) when an anti-parasitic agent has been a d m i n i s t e r e d - - e v e n inadvertently or m i s t a k e n l y w d u r i n g pregnancy. It seems clear that at present answers to m a n y questions involving the use of antiprotozoan and anthelmintic c o m p o u n d s in pregnancy are not, and in m a n y cases will probably never be, available. Occasionally, physicians are compelled to treat a severe parasitic infection during pregnancy, P. falciparum malaria, and acute T. gondii infections in a previously uninfected w o m a n being important examples; however, in the vast majority of cases (including most gastro-intestinal infections), c h e m o t h e r a p y should be delayed until delivery has taken place. O f p a r a m o u n t importance the possible risk(s) to the patient and her u n b o r n infant m u s t always be carefully weighed-up against the likely deleterious consequences of the infection per se. W h e n c h e m o t h e r a p y is clearly indicated (as in P. falciparum and acute T. gondii infections), careful selection of the safest available c o m p o u n d is vital. G. C. Cook

Hospital for Tropical Diseases, S t Pancras Way, London N W I oPE, U.K. References

I. MacLeod CL (Ed). Parasitic infections in pregnancy and the newborn. Oxford: Oxford University Press, I988: 308. 2. Reynolds JEF (Ed). Martindale: the extra pharmacopoeia, 29th ed. London: The Pharmaceutical Press, I989: I896. 3. Dollery C. Therapeutic drugs. London: Churchill Livingstone, I99I: 2 vols. 4. Cook GC. Parasitic disease in clinical practice. Berlin: Springer-Verlag, I99O: 272. 5. Parke A. Antimalarial drugs and pregnancy. Am J Med I988; 85 (Suppl 4A): 30-33. 6. Wolfe MS, Cordero JF. Safety of chloroquine in chemosuppression of malaria during pregnancy. Br Med J I985 ; 29o : I466-I467. 7. Hart CW, Naunton RF. The ototoxicity of chloroquine phosphate. Arch Otolaryng I964; 8o : 4o7-412. 8. Centers for Disease Control. Prevention of malaria in travellers. I982; 3I(IS): 1-28. 9. Main EK, Main DM, Krogstad DJ. Treatment of chloroquine-resistant malaria during pregnancy. J Am Med Assoc I983 ; z49 : 3207-3209. IO. Editorial. Pyrimethamine combinations in pregnancy. Lancet I983 ; ii: IOO5-IOO7. II. Mefloquine--a new antimalarial. Drugs Therapeut Bull I99I; 29:5I-52. I2. Harpey J-P, Darbois Y, Lef6bvre G. Teratogenicity of pyrimethamine. Lancet I983 ; ii: 399. I3. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation, 2nd ed. Baltimore : Williams and Wilkins, I986: 537. I4. Looareesuwan S, Phillips RE, White NJ et al. Quinine and severe falciparum malaria in late pregnancy. Lancet I985; ii: 4-8. I5. Looareesuwan S, White NJ, Silamut K, Phillips RE, Warrell DA. Quinine and severe falciparum malaria in late pregnancy. Acta Leidensia I987; 55: I I5-I2O. I6. Phillips RE. Hypoglycaemia is an important complication of falciparum malaria. Q .7 Med I989; 7I: 477-483.

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17. Kawo N G , Msengi AE, Swai ABM, Orskov H, Alberti K G M M , McLarty D G . T h e metabolic effects of quinine in children with severe and complicated Plasmodium falciparum malaria in D a r e s Salaam. Trans R Soc Trop Med Hyg 1991; 85:711-713 • 18. Rustia M, Shubik, P. Induction of lung tumors and malignant lymphomas in mice by metronidazole, ff Natl Canc Inst 1972; 48: 721-729. 19. Coulter JR. Mutagenicity of metronidazole. Lancet 1979; i: 6o9. 2o. D u n n PM, Stewart-Brown S, Peel R. Metronidazole and the fetal alcohol syndrome. Lancet 1979; ii: 144. 2I. Hartley-Asp B. Mutagenicity of metronidazole. Lancet 1979; i: 275. 22. Morgan I. Metronidazole treatment in pregnancy. Int J Gynaecol Obstet 1978; 15: 5Ol-5O2. 23. Forestier F, Daffos F, Rainaut M, Desnottes JF, Gaschard JC. Suivi th6rapeutique foetomaternel de la spiramycine en cours de grossesse. Arch Fr Pediatr 1987 ; 4 4 : 539-544. 24. World Health Organization. Expert committee on trypanosomiasis. Tech Rep Ser 1962; 2 4 7 : 28-33. 25. Ismail MA, Lerner SA. Disseminated blastomycosis in a pregnant woman: review of amphotericin B usage during pregnancy. Am Rev Respir Dis 1982: 126:35o-353 . 26. Bittencourt AL. Congenital Chagas disease. Am J Dis Child 1976; I3o: 97-1o3. 27. Lorke D. Embryotoxocity studies of nifurtimox in rats and mice and study of fertility and general reproductive performance. Arzneimittelforschung (Drug Res) 1972; 22 : 16o3-I 607. 28. Cook G.C. Anthelminthic agents : some recent developments and their clinical application. Postgrad Afed J 1991 ; 67: 16-22. 29. Cook GC. Reviews in medicine: tropical medicine. Postgrad Med J 1991; 67: 798-822. 30. Shepard T H . Catalog of teratogenic agents, 4th ed. Baltimore: Johns Hopkins Hospital, 1983 : 529 . 31. Frohberg H. Results of toxicological studies on praziquantel. Arzneimittelforschung (Drug Res) 1984; 34: 1137-1144. 32. Foster R. A review of clinical experience with oxamniquine. Tram R Soe Trop B/Ied Hyg 1987; 81: 55-59. 33. Monson M H , Alexander K. Metrifonate in pregnancy. Tram R Soc Trop Med Hyg 1984; 78 : 565. 34. Fraser PJ. Diethylcarbamazine: lack of teratogenic and abortifacient action in rats and rabbits. Indian J Med Res 1972; 6 0 : 1529-1532. 35. Pacqu6 M, Mufioz B, Poetschke G, Foose J, Greene BM, Taylor HR. Pregnancy outcome after inadvertent ivermectin treatment during community-based distribution. Lancet 199o; 336 : 1486-1489. 36. Anderson J, Fuglsang H, Marshall T F de C. Effects of suramin on ocular onchocerciasis. Tropenmed Parasit 1976; 27: 279-296.

Use of antiprotozoan and anthelmintic drugs during pregnancy: side-effects and contra-indications.

]ournal of Infection (I992) zS, ~-9 Editorial Use o f antiprotozoan and anthelmintic drugs during pregnancy: side-effects and contra-indications T h...
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