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Effects of Drugs and Chemicals on the Fetus and Newborn (Second of Two Parts)

1984; Elsevier BV; Volume: 59; Issue: 11-12 Linguagem: Inglês

10.1016/s0025-6196(12)65586-4

1942-5546

Lyndon M. Hill, Fredric Kleinberg,

Pregnancy and Medication Impact

Physicians have become increasingly aware of the side effects of specific drugs. Obstetricians and family physicians should especially be cognizant of the implications of the administration of any drug, not only for the pregnant mother but also for the unborn child. In this second installment of our two-part article, we conclude our review of drugs, chemicals, and environmental pollutants that may affect the fetus or newborn. Physicians have become increasingly aware of the side effects of specific drugs. Obstetricians and family physicians should especially be cognizant of the implications of the administration of any drug, not only for the pregnant mother but also for the unborn child. In this second installment of our two-part article, we conclude our review of drugs, chemicals, and environmental pollutants that may affect the fetus or newborn. In the first part of this article, we reviewed the effects of drugs on spermatozoa, the germ cell, the embryo, the fetus, and subsequent reproductive function. In addition, the long-term neurobehavioral effects of drugs on the fetus were assessed. Because the primary function of the placenta is the transport of nutrients and wastes between maternal and fetal circulations, its role in determining fetal drug concentrations was reviewed. The difficulties inherent in establishing a direct relationship between a specific mediator and a particular fetal effect were addressed. Finally an attempt was made to quantitate the known effects of specific commonly used drugs (caffeine, ferrous sulfate, Bendectin, and over-the-counter medications). In this article, we complete our review of the known fetal effects of selected medications, environmental products, and drugs that may be administered or consumed during pregnancy. Warfarin (Coumadin) is completely absorbed from the small intestine, loosely bound to albumin in the blood, and degraded in the liver. It is a competitive inhibitor of vitamin K. Consequently with use of warfarin, formation of clotting factors II, VII, IX, and X by the liver decreases and anticoagulation results. The loss of these four procoagulants depends on their rates of degradation: factor VII disappears in 5 hours; factors IX and X, within 20 to 30 hours; and factor II, after about 100 hours.105Deykin D Warfarin therapy.N Engl J Med. 1970; 283: 691-694Crossref PubMed Scopus (59) Google Scholar The fact that warfarin derivatives cross the placenta has been known for several decades. Not until the mid-1970s, however, was a distinct fetal warfarin syndrome described—by Shaul and associates106Shaul WL Emery H Hall JG Chondrodysplasia punctata and maternal warfarin use during pregnancy.Am J Dis Child. 1975; 129: 360-362PubMed Google Scholar and by Others.107Holzgreve W Carey JC Hall BD Warfarin-induced fetal abnormalities (letter to the editor).Lancet. 1976; 2: 914-915Abstract PubMed Scopus (59) Google Scholar, 108Shaul WL Hall JG Multiple congenital anomalies associated with oral anticoagulants.Am J Obstet Gynecol. 1977; 127: 191-198Abstract Full Text PDF PubMed Scopus (109) Google Scholar, 109Stevenson RE Burton OM Ferlauto GJ Taylor HA Hazards of oral anticoagulants during pregnancy.JAMA. 1980; 243: 1549-1551Crossref PubMed Scopus (125) Google Scholar The most consistent features of warfarin embryopathy are nasal hypoplasia and stippling of bone. The latter characteristic, however, may not be present after the first year of life, because the stippled areas may be reabsorbed.108Shaul WL Hall JG Multiple congenital anomalies associated with oral anticoagulants.Am J Obstet Gynecol. 1977; 127: 191-198Abstract Full Text PDF PubMed Scopus (109) Google Scholar, 110Hall JG Pauli RM Wilson KM Maternal and fetal sequelae of anticoagulation during pregnancy.Am J Med. 1980; 68: 122-140Abstract Full Text PDF PubMed Scopus (757) Google Scholar Exposure to warfarin during the sixth to ninth week of gestation seems necessary for warfarin embryopathy to occur. All patients with suspected abnormalities of the central nervous system secondary to maternal ingestion of warfarin, however, have been exposed during the second or third trimester of pregnancy. Optic atrophy, mental retardation, delayed development, seizures, and microcephaly have been found in some infants after the administration of warfarin to pregnant mothers.106Shaul WL Emery H Hall JG Chondrodysplasia punctata and maternal warfarin use during pregnancy.Am J Dis Child. 1975; 129: 360-362PubMed Google Scholar, 107Holzgreve W Carey JC Hall BD Warfarin-induced fetal abnormalities (letter to the editor).Lancet. 1976; 2: 914-915Abstract PubMed Scopus (59) Google Scholar, 109Stevenson RE Burton OM Ferlauto GJ Taylor HA Hazards of oral anticoagulants during pregnancy.JAMA. 1980; 243: 1549-1551Crossref PubMed Scopus (125) Google Scholar Hall and associates110Hall JG Pauli RM Wilson KM Maternal and fetal sequelae of anticoagulation during pregnancy.Am J Med. 1980; 68: 122-140Abstract Full Text PDF PubMed Scopus (757) Google Scholar summarized 418 reported pregnancies in which warfarin derivatives were used. They found that a sixth of these pregnancies ended in abortion or stillbirth, a sixth resulted in abnormal liveborn infants, and two thirds resulted in infants that appeared normal at birth. Long-term follow-up of the third group, however, has not yet been completed. The pathogenesis of warfarin embryopathy remains to be conclusively elucidated. Originally fetal microhemorrhages were considered the most likely cause. The clotting factors affected by warfarin, however, are not present at this early gestational age.111Bleyer WA Hakami N Shepard TH The development of hemostasis in the human fetus and newborn infant.J Pediatr. 1971; 79: 838-853Abstract Full Text PDF PubMed Scopus (141) Google Scholar Moreover, Barr and Burdi112Barr Jr, M Burdi AR Warfarin-associated embryopathy in a 17–week-old abortus.Teratology. 1976; 14: 129-134Crossref PubMed Scopus (31) Google Scholar found no hemosiderin deposits in areas of cartilage formation in a 17-week abortus after maternal ingestion of warfarin—a result that suggests that focal hemorrhage is not responsible for the abnormalities seen. On a molecular level, inhibitors of vitamin K may alter calcium binding for several proteins. Hence ossification is impaired and the characteristic bony abnormalities of the fetal warfarin syndrome result. Abnormalities of the central nervous system develop in about 3% of liveborn infants who have been exposed to warfarin derivatives in utero. In this situation, repeated microhemorrhages with resultant scarring could give rise to the plethora of abnormalities of the central nervous system that have been reported.108Shaul WL Hall JG Multiple congenital anomalies associated with oral anticoagulants.Am J Obstet Gynecol. 1977; 127: 191-198Abstract Full Text PDF PubMed Scopus (109) Google Scholar, 110Hall JG Pauli RM Wilson KM Maternal and fetal sequelae of anticoagulation during pregnancy.Am J Med. 1980; 68: 122-140Abstract Full Text PDF PubMed Scopus (757) Google Scholar Once the fetal complications associated with maternal administration of warfarin became apparent, many medical institutions substituted heparin as the anticoagulant of choice throughout pregnancy.113Bonnar J Venous thrombo-embolism and pregnancy.Recent Adv Obstet Gynaecol. 1979; 13: 173-192Google Scholar, 114Spearing G Fraser I Turner G Dixon G Long-term self-administered subcutaneous heparin in pregnancy.Br Med J. 1978; 1: 1457-1458Crossref PubMed Scopus (26) Google Scholar With a molecular weight of 1,000, heparin does not cross the placenta and thus should be an ideal anticoagulant for the gravid patient. Unfortunately difficulties in administration, questions about its efficacy in comparison with that of warfarin, and the incidence of maternal complications have prevented its wholehearted acceptance. If plasma levels of heparin are determined after subcutaneous administration, individual differences in absorption and breakdown of heparin become readily apparent. Thus some patients have elevated plasma levels of heparin and hence a greater tendency to hemorrhage, whereas other patients have levels so low that an antithrombotic effect is unlikely.115Brozović M Stirling Y Klenerman L Lowe L Subcutaneous heparin and postoperative thromboembolism (letter to the editor).Lancet. 1974; 2: 99-100Abstract PubMed Scopus (12) Google Scholar In addition, plasma levels are considerably lower after subcutaneous administration of calcium heparin than after that of the sodium salt.116Thomas DP Sagar S Stamatakis JD Maffei FHA Erdi A Kakkar VV Plasma heparin levels after administration of calcium and sodium salts of heparin.Thromb Res. 1976; 9: 241-248Abstract Full Text PDF PubMed Scopus (31) Google Scholar Hull and associates117Hull R Delmore T Genton E Hirsh J Gent M Sackett D McLoughlin D Armstrong P Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis.N Engl J Med. 1979; 301: 855-858Crossref PubMed Scopus (520) Google Scholar compared the use of low doses of heparin (5,000 units every 12 hours) with that of sodium warfarin in the prevention of recurrent deep-vein thrombosis after an initial thrombus was treated with heparin given intravenously. In that study, warfarin in adjusted doses was more effective than heparin in preventing recurrent venous thromboembolism. Whether therapeutic doses of heparin given subcutaneously are as effective as warfarin remains to be evaluated.113Bonnar J Venous thrombo-embolism and pregnancy.Recent Adv Obstet Gynaecol. 1979; 13: 173-192Google Scholar, 114Spearing G Fraser I Turner G Dixon G Long-term self-administered subcutaneous heparin in pregnancy.Br Med J. 1978; 1: 1457-1458Crossref PubMed Scopus (26) Google Scholar, 118Wang RYC Lee PK Chow JSF Chen WWC Efficacy of low-dose, subcutaneously administered heparin in treatment of pregnant women with artificial heart valves.Med J Aust. 1983; 2: 126-128PubMed Google Scholar The maternal side effects of administration of heparin include bleeding, thrombocytopenia, and osteopenia. Hemorrhage as a complication of heparin therapy is much more common after intermittent intravenous administration than it is after subcutaneous or continuous intravenous use.119Salzman EW Deykin D Shapiro RM Rosenberg R Management of heparin therapy: controlled prospective trial.N Engl J Med. 1975; 292: 1046-1050Crossref PubMed Scopus (364) Google Scholar Bleeding has been shown to be a dose-related phenomenon that may be affected by use of alcohol and ingestion of aspirin.120Walker AM Jick H Predictors of bleeding during heparin therapy.JAMA. 1980; 244: 1209-1212Crossref PubMed Scopus (118) Google Scholar Cines and colleagues121Cines DB Kaywin P Bina M Tomaski A Schreiber AD Heparin-associated thrombocytopenia.N Engl J Med. 1980; 303: 788-795Crossref PubMed Scopus (207) Google Scholar reported that administration of heparin may be associated with complement-mediated platelet injury and eventual thrombocytopenia. Therefore a platelet count should be done before and about 1 week after the beginning of heparin therapy. Heparin-induced osteopenia was first reported in 1965.122Griffith GC Nichols Jr, G Asher JD Flanagan B Heparin osteoporosis.JAMA. 1965; 193: 91-94Crossref PubMed Scopus (253) Google Scholar The mechanism seems to be interference by heparin with the use of the normal matrix mucopolysac-charides by bone. This process results in defective ossification and eventual osteopenia.123Avioli LV Heparin-induced osteopenia: an appraisal.Adv Exp Med Biol. 1975; 52: 375-387Crossref PubMed Scopus (119) Google Scholar Wise and Hall124Wise PH Hall AJ Heparin-induced osteopenia in pregnancy.Br Med J. 1980; 281: 110-111Crossref PubMed Scopus (81) Google Scholar reported that multiple vertebral compression fractures occurred in a pregnant woman who received heparin for 9 months. The maternal complication rate associated with use of heparin throughout pregnancy could be accepted if fetal outcome were substantially improved. Hall and associates,110Hall JG Pauli RM Wilson KM Maternal and fetal sequelae of anticoagulation during pregnancy.Am J Med. 1980; 68: 122-140Abstract Full Text PDF PubMed Scopus (757) Google Scholar however, found no difference in overall neonatal outcome whether mothers were treated with heparin or warfarin during pregnancy. With heparin, the incidence of perinatal, neonatal, and maternal mortality was higher, whereas with warfarin, the incidence of early fetal loss and the incidence of persistent sequelae (such as warfarin embryopathy) in infants were higher. The likelihood of a normal outcome of pregnancy was about 67% when either anticoagulant was used. Therefore the authors concluded that heparin was not a clearly superior alternative to warfarin and that anticoagulant therapy during pregnancy must be individualized. This study, however, was a retrospective review of reported pregnancies, in 418 of which warfarin had been used and in 135 of which heparin had been used as the anticoagulant of choice. By design, the patient population could be neither randomized nor controlled. The reason for using one anticoagulant rather than the other could not be elucidated. Thus the patient population that received heparin could conceivably have had a higher inherent risk than the warfarin recipients. As a result, the conclusions of these investigators must be further substantiated. At present, heparin remains the anticoagulant of choice during pregnancy. Approximately 0.5% of pregnant women have epilepsy and must continue taking some type of anticonvulsant throughout pregnancy.125Reynolds EH Anticonvulsants, folic acid, and epilepsy.Lancet. 1973; 1: 1376-1378Abstract PubMed Scopus (81) Google Scholar Phenytoin is prescribed in about two thirds of cases, sometimes in combination with other medications. Because it readily crosses the placenta, the maternal and fetal serum concentrations are approximately equivalent. During pregnancy, the absorption, metabolism, and excretion of phenytoin are altered, and the maternal serum level gradually decreases. Consequently serum levels of this drug should be determined monthly throughout pregnancy, and the dosage should be adjusted accordingly.126Kochenour NK Emery MG Sawchuk RJ Phenytoin metabolism in pregnancy.Obstet Gynecol. 1980; 56: 577-582PubMed Google Scholar Studies in animals have indicated that phenytoin is teratogenic in mice and rats but not in the rhesus monkey.57,127Harbison RD Becker BA Relation of dosage and time of administration of diphenylhydantoin to its teratogenic effect in mice.Teratology. 1969; 2: 305-311Crossref PubMed Scopus (129) Google Scholar Cleft lip and cleft palate occur most frequently; if the dose of this anticonvulsant is increased in mice, skeletal and visceral abnormalities will be seen as well. Janz and Fuchs128Janz D Fuchs U Are anti-epileptic drugs harmful when given during pregnancy?.German Med Monthly. 1964; 9: 20-22Google Scholar were among the first to suggest a possible teratogenic role for the anticonvulsants. In 1970, Meadow129Meadow SR Congenital abnormalities and anticonvulsant drugs.Proc R Soc Med. 1970; 63: 48-49PubMed Google Scholar reported on 32 cases of cleft lip or palate in infants born to women who had taken anticonvulsants during pregnancy. Other studies, however, have found no increase in the incidence of facial clefts after the use of anticonvulsant medications during pregnancy.130Watson JD Spellacy WN Neonatal effects of maternal treatment with the anticonvulsant drug diphenylhydantoin.Obstet Gynecol. 1971; 37: 881-885PubMed Google Scholar Speidel and Meadow131Speidel BD Meadow SR Maternal epilepsy and abnormalities of the fetus and newborn.Lancet. 1972; 2: 839-843Abstract PubMed Scopus (341) Google Scholar retrospectively reviewed 427 pregnancies in 186 women with epilepsy. They found a twofold increase in major malformations (such as facial clefts, congenital heart disease, and abnormalities of the central nervous system). When phenobarbital is used in combination with phenytoin, the incidence of anomalies is higher132Fedrick J Epilepsy and pregnancy: a report from the Oxford Record Linkage Study.Br Med J. 1973; 2: 442-448Crossref PubMed Scopus (197) Google Scholar (in contradistinction to the finding in mice of decreased embryotoxicity after pretreatment with phenobarbital before maternal administration of phenytoin60). Further evidence on the teratogenicity of the anticonvulsants was provided by Monson and co-workers133Monson RR Rosenberg L Hartz SC Shapiro S Heinonen OP Slone D Diphenylhydantoin and selected congenital malformations.N Engl J Med. 1973; 289: 1049-1052Crossref PubMed Scopus (192) Google Scholar and Annegers and associates,134Annegers JF Elveback LR Hauser WA Kurland LT Do anticonvulsants have a teratogenic effect?.Arch Neurol. 1974; 31: 364-373Crossref PubMed Scopus (98) Google Scholar who independently reported that in patients with epilepsy who did not receive medication during pregnancy, the rate of occurrence of congenital malformations was identical to that in a treated control group. Hanson and Smith135Hanson JW Smith DW The fetal hydantoin syndrome.J Pediatr. 1975; 87: 285-290Abstract Full Text PDF PubMed Scopus (485) Google Scholar noticed that many congenital anomalies were present in infants who had been exposed to phenytoin in utero. Hence the concept of a specific syndrome arose. Stigmas of the fetal hydantoin syndrome are (1) abnormalities in growth and performance—intrauterine growth retardation, mental retardation, and developmental delay; (2) craniofacial abnormalities—depressed nasal bridge, ptosis, inner epicanthal folds, and ocular hypertelorism; (3) limb abnormalities—digital and nail hypoplasia; and (4) other abnormalities—cardiac defects and hernias.136Hanson JW Myrianthopoulos NC Harvey MAS Smith DW Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome.J Pediatr. 1976; 89: 662-668Abstract Full Text PDF PubMed Scopus (380) Google Scholar After studying 139 children who had been exposed to hydantoin prenatally, Hanson and co-workers136Hanson JW Myrianthopoulos NC Harvey MAS Smith DW Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome.J Pediatr. 1976; 89: 662-668Abstract Full Text PDF PubMed Scopus (380) Google Scholar concluded that about 11% could be classified as having the fetal hydantoin syndrome and that another 31 % had some features consistent with in utero exposure to hydantoin. Half of the infants with the fetal hydantoin syndrome had reduced intellectual ability. The specific effect of the phenytoin that gives rise to the aforementioned abnormalities is unknown. Initially the decrease in folate levels associated with use of phenytoin was considered the most likely mechanism, particularly in view of the known teratogenicity of the antifolate cancer chemotherapeutic agents.137Nicholson HO Cytotoxic drugs in pregnancy: review of reported cases.J Obstet Gynaecol Br Commonw. 1968; 75: 307-312Crossref PubMed Scopus (221) Google Scholar Because administration of folinic acid does hot appreciably reduce the incidence of cleft palate in mice that have been exposed prenatally to phenytoin, the presumed importance of reduced maternal serum levels of folate needs further evaluation.138Schardein JL Dresner AJ Hentz DL Patrere JA Fitzgerald JE Kurtz SM The modifying effect of folinic acid on diphenylhydantoin-induced teratogenicity in mice.Toxicol Appl Pharmacol. 1973; 24: 150-158Crossref PubMed Scopus (29) Google Scholar Other possible mechanisms for the action of the anticonvulsants, as reviewed by Schardein,84 are interference with production of collagen, influence on plasma steroids, and irreversible binding to nucleic acid.139Hanson JW Buehler BA Fetal hydantoin syndrome: current status.J Pediatr. 1982; 101: 816-818Abstract Full Text PDF PubMed Scopus (39) Google Scholar Other anticonvulsants have been incriminated as teratogens as well. German and associates140German J Kowal A Ehlers KH Trimethadione and human teratogenesis.Teratology. 1970; 3: 349-361Crossref PubMed Scopus (100) Google Scholar reported the fetal effects of trimethadione. V-shaped eyebrows, low-set ears with anteriorly folded helices, and lack of phalangeal hypoplasia clearly distinguish the trimethadione syndrome from the hydantoin syndrome.141Goldman AS Yaffe SJ Fetal trimethadione syndrome.Teratology. 1978; 17: 103-105Crossref PubMed Scopus (16) Google Scholar Additional major abnormalities are similar to those that occur after prenatal exposure to phenytoin: intrauterine growth retardation, developmental delay, mental retardation, and cardiac anomalies. Valproic acid is an anticonvulsant drug with a broad spectrum of activity which was approved in 1978.142Browne TR Valproic acid. N.Engl J Med. 1980; 302: 661-666Crossref PubMed Scopus (141) Google Scholar Approximately 700 to 1,000 pregnant women take valproic acid each year in the United States.143Robert E Valproic acid in pregnancy—association with spina bifida: a preliminary report.Clin Pediatr. 1983; 22: 336Crossref PubMed Scopus (7) Google Scholar Nau and co-workers144Nau H Rating D Koch S Hauser I Helge H Valproic acid and its metabolites: placental transfer, neonatal pharmacokinetics, transfer via mother's milk and clinical status in neonates of epileptic mothers.J Pharmacol Exp Ther. 1981; 219: 768-777PubMed Google Scholar studied its pharmacokinetics in 11 mothers with epilepsy and then in 12 newborns. A higher concentration of valproic acid was consistently found in cord blood than in maternal serum (factor, 1.6 ± 0.6). The mean neonatal half-life of valproic acid (47 ± 15 hours) was approximately four times the mean value found in adults. Breast milk was found to contain 3% of the maternal serum concentration. Concomitant therapy with phenytoin or primidone (or both) did not alter the half-life of valproic acid in the neonate. Hence valproic acid apparently is metabolized by a hepatic enzyme system that is not inducible by either of the previously mentioned anticonvulsant medications. Unlike phenobarbital and primidone, perinatal exposure to valproic acid does not enhance the degradation of bilirubin in the neonate. By administration of increasing doses of valproic acid, a dose-related teratogenic effect (kidney abnormalities, cleft palate, and encephalocele) has been produced in rodents, but only at levels considerably higher than those used for therapy.145Whittle BA Pre-clinical teratological studies on sodium valproate (Epilim) and other anticonvulsants.in: Legg NJ Clinical and Pharmacological Aspects of Sodium Valproate (Epilim) in the Treatment of Epilepsy. MSC Consultants, Tunbridge Wells, England1976: 105-111Google Scholar The use of valproic acid during the first trimester of pregnancy has been associated with an incidence of spina bifida of 1.29 per 1,000.143Robert E Valproic acid in pregnancy—association with spina bifida: a preliminary report.Clin Pediatr. 1983; 22: 336Crossref PubMed Scopus (7) Google Scholar The craniofacial and limb abnormalities noted with use of phenytoin and primidone have not been seen to date with use of valproic acid.142Browne TR Valproic acid. N.Engl J Med. 1980; 302: 661-666Crossref PubMed Scopus (141) Google Scholar, 146Kaneko S Otani K Fukushima Y Sato T Nomura Y Ogawa Y Transplacental passage and half-life of sodium valproate in infants born to epileptic mothers.Br J Clin Pharmacol. 1983; 15: 503-506Crossref PubMed Scopus (23) Google Scholar Phenobarbital has been available for more than 60 years. No congenital abnormalities have been associated with its use as a single agent during pregnancy. Auroux147Auroux M Influence de certaines substances médicamenteuses sur le développement tardif du système nerveux central du rat: alteration dés capacités d'apprentissage de la progéniture par administration de phénobarbital à la mère.C R Soc Biol (Paris). 1973; 167: 797-801PubMed Google Scholar however, found alterations of learning capacity in the offspring of rats that were given phenobarbital during pregnancy. In addition, barbiturates are known to induce activity of hepatic and microsomal enzymes and, thereby, to reduce the incidence of neonatal hyperbilirubinemia.148Thomas CR Routine phenobarbital for prevention of neonatal hyperbilirubinemia.Obstet Gynecol. 1976; 47: 304-308PubMed Google Scholar Induction of enzyme activity, however, is nonspecific, and the long-term consequences of this effect on neonatal and adult development and metabolism have not been evaluated. Prolonged maternal use of barbiturates may lead to fetal addiction and withdrawal symptoms after delivery.149Montouris GD Fenichel GM McLain Jr, LW The pregnant epileptic: a review and recommendations.Arch Neurol. 1979; 36: 601-603Crossref PubMed Scopus (38) Google Scholar Mountain and associates150Mountain KR Hirsh J Callus AS Neonatal coagulation defect due to anticonvulsant drug treatment in pregnancy.Lancet. 1970; 1: 265-268Abstract PubMed Scopus (174) Google Scholar recorded coagulation defects during the first 24 hours of life in infants born to women who had received anticonvulsants. Bleyer and Skinner151Bleyer WA Skinner AL Fatal neonatal hemorrhage after maternal anticonvulsant therapy.JAMA. 1976; 235: 626-627Crossref Scopus (71) Google Scholar reported a 36% mortality in infants who bled. The most common sites for hemorrhage are intracranial and into the thoracic and abdominal cavities. Consequently in all instances, delivery should be carefully and atraumatically accomplished, and routine neonatal clotting studies should be done afterward. Vitamin K reverses the clotting abnormalities.149Montouris GD Fenichel GM McLain Jr, LW The pregnant epileptic: a review and recommendations.Arch Neurol. 1979; 36: 601-603Crossref PubMed Scopus (38) Google Scholar Safra and Oakley152Safra MJ Oakley Jr, GP Association between cleft lip with or without cleft palate and prenatal exposure to diazepam.Lancet. 1975; 2: 478-480Abstract PubMed Scopus (213) Google Scholar identified a fourfold relative risk for first-trimester exposure to diazepam among the mothers of infants with cleft lip with or without cleft palate. The authors stated, however, that their findings did not necessarily mean that the relationship was causal. Further studies on the teratogenic potential of diazepam are needed. Cree and co-workers54 evaluated the use of diazepam during labor. They found that with a total maternal dosage of more than 30 mg during the 15 hours before delivery, Apgar scores were reduced, hypotonia, hypothermia, poor feeding, and apneic spells were increased, and metabolic response to stress was impaired in the infants. In addition, cord levels of diazepam and its active metabolism were higher than maternal levels and metabolism. Appreciable levels of diazepam are detectable within the neonate for up to 8 days after delivery.153Gillberg C “Floppy infant syndrome” and maternal diazepam (letter to the editor).Lancet. 1977; 2: 244Abstract PubMed Scopus (68) Google Scholar Withdrawal symptoms may occur in the neonate if the mother ingests 10 to 15 mg of diazepam daily during the last trimester.154Mazzi E Possible neonatal diazepam withdrawal: a case report.Am J Obstet Gynecol. 1977; 129: 586-587PubMed Google Scholar Ganter and associates,155Ganter P Julou L Cosar C Etude de I'action du métronidazole (n° 8 823 R. P.) sur le systéme génital du rat.Gynecol Obstet. 1960; 59: 609-620PubMed Google Scholar who administered 100 mg/kg of metronidazole during the entire pregnancy of rats, observed no change in either litter size or congenital malformations. Morgan156Morgan I Metronidazole treatment in pregnancy.Int J Gynaecol Obstet. 1978; 15: 501-502PubMed Google Scholar reported on the use of metronidazole in 597 pregnant patients. Sixty-two were treated in the first trimester, 284 in the second trimester, and 251 in the third trimester. The incidences of low-birth-weight infants, stillbirths, and congenital abnormalities were the same in the treated and control groups. Berget and Weber,157Berget A Weber T Metronidazole and pregnancy.Ugeskr Laeger. 1972; 134: 2085-2089PubMed Google Scholar in an earlier review of 1,469 pregnant women who received metronidazole, came to the same conclusion. Despite these findings, delaying the treatment of trichomoniasis until the second or third trimester seems prudent in patients with symptoms. Asymptomatic trichomoniasis may be treated after delivery. After studies demonstrated the neurotoxicity of hexachlorophene (pHisoHex) to the newborn, its use in neonatal units was largely discontinued. Measurable blood levels of hexachlorophene are present in persons who wash frequently with soaps that contain hexachlorophene. Samples of cord blood have been found to contain hexachlorophene after a single bath by the mother.158Check W New study shows hexachlorophene is teratogenic in humans.JAMA. 1978; 240: 513-514Crossref PubMed Scopus (17) Google Scholar Hailing159Hailing H Suspected link between exposure to hexachlorophene and malformed infants.Ann NY Acad Sci. 1979; 320: 426-435PubMed Google Scholar reported a significant increase in congenital anomalies in infants born to nurses who had been exposed to hexachlorophene (15% compared with 3% in the general Swedish population). This study, however, has been criticized on methodologic grounds. Indeed most of the “exposed” cases were selected because of a malformation rather than because of exposure to hexachlorophene.160Källén B Hexachlorophene teratogenicity in humans disputed (letter to the editor).JAMA. 1978; 240: 1585-1586Crossref PubMed Scopus (8) Google Scholar In a study by Baltzar and associates,161Baltzar B Ericson A Kállen B Pregnancy outcome among women working in Swedish hospitals (letter to the editor).N Engl J Med. 1979; 300: 6