Advertisement
Mayo Clinic Proceedings Home

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

      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.

      ANTICOAGULANTS

      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.
      • Deykin D
      Warfarin therapy.
      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 associates
      • Shaul WL
      • Emery H
      • Hall JG
      Chondrodysplasia punctata and maternal warfarin use during pregnancy.
      and by Others.
      • Holzgreve W
      • Carey JC
      • Hall BD
      Warfarin-induced fetal abnormalities (letter to the editor).
      • Shaul WL
      • Hall JG
      Multiple congenital anomalies associated with oral anticoagulants.
      • Stevenson RE
      • Burton OM
      • Ferlauto GJ
      • Taylor HA
      Hazards of oral anticoagulants during pregnancy.
      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.
      • Shaul WL
      • Hall JG
      Multiple congenital anomalies associated with oral anticoagulants.
      • Hall JG
      • Pauli RM
      • Wilson KM
      Maternal and fetal sequelae of anticoagulation during pregnancy.
      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.
      • Shaul WL
      • Emery H
      • Hall JG
      Chondrodysplasia punctata and maternal warfarin use during pregnancy.
      • Holzgreve W
      • Carey JC
      • Hall BD
      Warfarin-induced fetal abnormalities (letter to the editor).
      • Stevenson RE
      • Burton OM
      • Ferlauto GJ
      • Taylor HA
      Hazards of oral anticoagulants during pregnancy.
      Hall and associates
      • Hall JG
      • Pauli RM
      • Wilson KM
      Maternal and fetal sequelae of anticoagulation during pregnancy.
      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.
      • Bleyer WA
      • Hakami N
      • Shepard TH
      The development of hemostasis in the human fetus and newborn infant.
      Moreover, Barr and Burdi
      • Barr Jr, M
      • Burdi AR
      Warfarin-associated embryopathy in a 17–week-old abortus.
      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.
      • Shaul WL
      • Hall JG
      Multiple congenital anomalies associated with oral anticoagulants.
      • Hall JG
      • Pauli RM
      • Wilson KM
      Maternal and fetal sequelae of anticoagulation during pregnancy.
      Once the fetal complications associated with maternal administration of warfarin became apparent, many medical institutions substituted heparin as the anticoagulant of choice throughout pregnancy.
      • Bonnar J
      Venous thrombo-embolism and pregnancy.
      • Spearing G
      • Fraser I
      • Turner G
      • Dixon G
      Long-term self-administered subcutaneous heparin in pregnancy.
      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.
      • Brozović M
      • Stirling Y
      • Klenerman L
      • Lowe L
      Subcutaneous heparin and postoperative thromboembolism (letter to the editor).
      In addition, plasma levels are considerably lower after subcutaneous administration of calcium heparin than after that of the sodium salt.
      • Thomas DP
      • Sagar S
      • Stamatakis JD
      • Maffei FHA
      • Erdi A
      • Kakkar VV
      Plasma heparin levels after administration of calcium and sodium salts of heparin.
      Hull and associates
      • Hull 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.
      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.
      • Bonnar J
      Venous thrombo-embolism and pregnancy.
      • Spearing G
      • Fraser I
      • Turner G
      • Dixon G
      Long-term self-administered subcutaneous heparin in pregnancy.
      • Wang RYC
      • Lee PK
      • Chow JSF
      • Chen WWC
      Efficacy of low-dose, subcutaneously administered heparin in treatment of pregnant women with artificial heart valves.
      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.
      • Salzman EW
      • Deykin D
      • Shapiro RM
      • Rosenberg R
      Management of heparin therapy: controlled prospective trial.
      Bleeding has been shown to be a dose-related phenomenon that may be affected by use of alcohol and ingestion of aspirin.
      • Walker AM
      • Jick H
      Predictors of bleeding during heparin therapy.
      Cines and colleagues
      • Cines DB
      • Kaywin P
      • Bina M
      • Tomaski A
      • Schreiber AD
      Heparin-associated thrombocytopenia.
      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.
      • Griffith GC
      • Nichols Jr, G
      • Asher JD
      • Flanagan B
      Heparin osteoporosis.
      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.
      • Avioli LV
      Heparin-induced osteopenia: an appraisal.
      Wise and Hall
      • Wise PH
      • Hall AJ
      Heparin-induced osteopenia in pregnancy.
      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,
      • Hall JG
      • Pauli RM
      • Wilson KM
      Maternal and fetal sequelae of anticoagulation during pregnancy.
      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.

      ANTICONVULSANTS

      Approximately 0.5% of pregnant women have epilepsy and must continue taking some type of anticonvulsant throughout pregnancy.
      • Reynolds EH
      Anticonvulsants, folic acid, and epilepsy.
      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.
      • Kochenour NK
      • Emery MG
      • Sawchuk RJ
      Phenytoin metabolism in pregnancy.
      Studies in animals have indicated that phenytoin is teratogenic in mice and rats but not in the rhesus monkey.57,
      • Harbison RD
      • Becker BA
      Relation of dosage and time of administration of diphenylhydantoin to its teratogenic effect in mice.
      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 Fuchs
      • Janz D
      • Fuchs U
      Are anti-epileptic drugs harmful when given during pregnancy?.
      were among the first to suggest a possible teratogenic role for the anticonvulsants. In 1970, Meadow
      • Meadow SR
      Congenital abnormalities and anticonvulsant drugs.
      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.
      • Watson JD
      • Spellacy WN
      Neonatal effects of maternal treatment with the anticonvulsant drug diphenylhydantoin.
      Speidel and Meadow
      • Speidel BD
      • Meadow SR
      Maternal epilepsy and abnormalities of the fetus and newborn.
      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 higher
      • Fedrick J
      Epilepsy and pregnancy: a report from the Oxford Record Linkage Study.
      (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-workers
      • Monson RR
      • Rosenberg L
      • Hartz SC
      • Shapiro S
      • Heinonen OP
      • Slone D
      Diphenylhydantoin and selected congenital malformations.
      and Annegers and associates,
      • Annegers JF
      • Elveback LR
      • Hauser WA
      • Kurland LT
      Do anticonvulsants have a teratogenic effect?.
      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 Smith
      • Hanson JW
      • Smith DW
      The fetal hydantoin syndrome.
      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.
      • Hanson JW
      • Myrianthopoulos NC
      • Harvey MAS
      • Smith DW
      Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome.
      After studying 139 children who had been exposed to hydantoin prenatally, Hanson and co-workers
      • Hanson JW
      • Myrianthopoulos NC
      • Harvey MAS
      • Smith DW
      Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome.
      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.
      • Nicholson HO
      Cytotoxic drugs in pregnancy: review of reported cases.
      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.
      • Schardein JL
      • Dresner AJ
      • Hentz DL
      • Patrere JA
      • Fitzgerald JE
      • Kurtz SM
      The modifying effect of folinic acid on diphenylhydantoin-induced teratogenicity in mice.
      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.
      • Hanson JW
      • Buehler BA
      Fetal hydantoin syndrome: current status.
      Other anticonvulsants have been incriminated as teratogens as well. German and associates
      • German J
      • Kowal A
      • Ehlers KH
      Trimethadione and human teratogenesis.
      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.
      • Goldman AS
      • Yaffe SJ
      Fetal trimethadione syndrome.
      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.
      • Browne TR
      Valproic acid. N.
      Approximately 700 to 1,000 pregnant women take valproic acid each year in the United States.
      • Robert E
      Valproic acid in pregnancy—association with spina bifida: a preliminary report.
      Nau and co-workers
      • Nau 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.
      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.
      • Whittle BA
      Pre-clinical teratological studies on sodium valproate (Epilim) and other anticonvulsants.
      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.
      • Robert E
      Valproic acid in pregnancy—association with spina bifida: a preliminary report.
      The craniofacial and limb abnormalities noted with use of phenytoin and primidone have not been seen to date with use of valproic acid.
      • Browne TR
      Valproic acid. N.
      • Kaneko 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.
      Phenobarbital has been available for more than 60 years. No congenital abnormalities have been associated with its use as a single agent during pregnancy. Auroux
      • Auroux 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.
      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.
      • Thomas CR
      Routine phenobarbital for prevention of neonatal hyperbilirubinemia.
      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.
      • Montouris GD
      • Fenichel GM
      • McLain Jr, LW
      The pregnant epileptic: a review and recommendations.
      Mountain and associates
      • Mountain KR
      • Hirsh J
      • Callus AS
      Neonatal coagulation defect due to anticonvulsant drug treatment in pregnancy.
      recorded coagulation defects during the first 24 hours of life in infants born to women who had received anticonvulsants. Bleyer and Skinner
      • Bleyer WA
      • Skinner AL
      Fatal neonatal hemorrhage after maternal anticonvulsant therapy.
      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.
      • Montouris GD
      • Fenichel GM
      • McLain Jr, LW
      The pregnant epileptic: a review and recommendations.

      DIAZEPAM

      Safra and Oakley
      • Safra MJ
      • Oakley Jr, GP
      Association between cleft lip with or without cleft palate and prenatal exposure to diazepam.
      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.
      • Gillberg C
      “Floppy infant syndrome” and maternal diazepam (letter to the editor).
      Withdrawal symptoms may occur in the neonate if the mother ingests 10 to 15 mg of diazepam daily during the last trimester.
      • Mazzi E
      Possible neonatal diazepam withdrawal: a case report.

      METRONIDAZOLE

      Ganter and associates,
      • Ganter P
      • Julou L
      • Cosar C
      Etude de I'action du métronidazole (n° 8 823 R. P.) sur le systéme génital du rat.
      who administered 100 mg/kg of metronidazole during the entire pregnancy of rats, observed no change in either litter size or congenital malformations. Morgan
      • Morgan I
      Metronidazole treatment in pregnancy.
      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,
      • Berget A
      • Weber T
      Metronidazole and pregnancy.
      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.

      HEXACHLOROPHENE

      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.
      • Check W
      New study shows hexachlorophene is teratogenic in humans.
      Hailing
      • Hailing H
      Suspected link between exposure to hexachlorophene and malformed infants.
      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.
      • Källén B
      Hexachlorophene teratogenicity in humans disputed (letter to the editor).
      In a study by Baltzar and associates,
      • Baltzar B
      • Ericson A
      • Kállen B
      Pregnancy outcome among women working in Swedish hospitals (letter to the editor).
      infants born to women employed in hospital work in Sweden from 1973 to 1975 were compared with those born to women in the general population in Sweden during the same period. Although those investigators found a cluster of congenital malformations similar to those found by Hailing, perinatal mortality and rates of occurrence of congenital malformations did not differ between the two groups. Once again, the reports on teratogenicity are controversial. Because hexachlorophene is rapidly absorbed from the skin and transplacental passage has been documented, restriction of the use of this product seems wise during pregnancy, at least during the first trimester.

      POVIDONE-IODINE

      Povidone-iodine (Betadine) is occasionally used to treat vaginal infections. The vagina, like any mucosal surface, is a highly absorptive organ. Vorherr and associates
      • Vorherr H
      • Vorherr UF
      • Mehta P
      • Ulrich JA
      • Messer RH
      Vaginal absorption of povidone-iodine.
      found 5-fold and 15-fold increases in total iodine and inorganic iodine levels, respectively, after povidone-iodine had been applied to the vaginas of 12 nonpregnant volunteers for 2 minutes. The serum levels obtained were equivalent to those of neonates who were washed with a povidone-iodine solution.
      • Chabrolle JP
      • Rossier A
      Goitre and hypothyroidism in the newborn after cutaneous absorption of iodine.
      In the latter instance, goiter and hypothyroidism resulted. Because the substantial increase in blood flow to the pelvic tissues which occurs with pregnancy can only enhance the absorptive process, vaginal preparations with povidone-iodine should not be used during pregnancy.

      MATERNAL FLUID ADMINISTRATION

      Maternal fluid administration illustrates the dynamic relationships that may occur between the mother and her unborn child. Hyponatremia in the newborn has been associated with the intravenous administration of salt-free fluids to the mother during labor.
      • Battaglia F
      • Prystowsky H
      • Smisson C
      • Hellegers A
      • Bruns P
      Fetal blood studies. XIII. The effect of the administration of fluids intravenously to mothers upon the concentrations of water and electrolytes in plasma of human fetuses.
      Because sodium readily crosses the placenta, maternal and fetal levels are similar. The infusion of 5% dextrose to the mother rapidly produces a net transfer of sodium to the mother and water to the fetus. The clinical signs and symptoms of hyponatremia in the neonate include hypotonia, poor feeding, and pallor.
      • Dahlenburg GW
      • Burnell RH
      • Braybrook R
      The relation between cord serum sodium levels in newborn infants and maternal intravenous therapy during labour.
      By infusing hypertonic solutions into pregnant monkeys, Bruns and colleagues
      • Bruns PD
      • Hellegers AE
      • Seeds Jr, AE
      • Behrman RE
      • Battaglia FC
      Effects of osmotic gradients across the primate placenta upon fetal and placental water contents.
      produced fetal dehydration.
      Rapid administration of dextrose to the mother results in a concomitant increase in fetal blood sugar. Fetal hyperinsulinism may result in neonatal hypoglycemia in the hours after delivery. When oxygen supplies are limited, an increase in fetal metabolism of glucose results in production of carbon dioxide and lactate. The end result is fetal acidemia.
      • Kenepp NB
      • Shelley WC
      • Kumar S
      • Gutsche BB
      • Gabbe S
      • Delivoria-Papadopoulos M
      Effects on newborn of hydration with glucose in patients undergoing caesarean section with regional anaesthesia (letter to the editor).

      ENVIRONMENTAL POLLUTANTS

      The American public has only recently become aware of environmental pollution by an ever-increasing number of chemicals. The chemical abstract service of the American Chemical Society had 1 million entries in 1977. About 100,000 of these chemicals have been estimated to be in common use. More than 1,000 new compounds are added yearly. The biologic effects (possible teratogenicity, carcinogenicity, and so on) of most of these compounds are unknown.
      • Longo LD
      Environmental pollution and pregnancy: risks and uncertainties for the fetus and infant.

      Halogenated Hydrocarbons.

      All of the halogenated hydrocarbons are known to be hepatotoxic and renotoxic. Polychlorinated biphenyls (PCBs) used in the manufacture of plastics are probably the most widely known compounds within this group. Pregnant Japanese women who used cooking oil that had been contaminated with PCBs gave birth to infants who were small for gestational age, had cola-colored skin, and had eye defects.
      • Kuratsune M
      • Yoshimura T
      • Matsuzaka J
      • Yamaguchi A
      Epidemiologic study on Yusho, a poisoning caused by ingestion of rice oil contaminated with a commercial brand of polychlorinated biphenyls.
      A 1975 study undertaken by the Environmental Protection Agency found that 31 % of 1,038 samples of breast milk contained measurable amounts of PCBs.
      • Machol L
      Environmental hazards: what they'll mean to your patients in the 1980s.
      In addition, studies in animals have demonstrated neurobehavioral effects of exposure to PCBs in utero. Rhesus monkeys were found to be hyperactive and slower in learning reversal tasks than control monkeys. These effects persisted despite total clearance of PCBs from body fat.
      • Bowman RE
      • Heironimus MP
      • Allen JR
      Correlation of PCB body burden with behavioral toxicology in monkeys.
      • Allen JR
      • Barsotti DA
      • Lambrecht LK
      • Van Miller JP
      Reproductive effects of halogenated aromatic hydrocarbons on non-human primates.
      PCB-exposed rats likewise showed hyperactivity and slower response times than control rats.
      • Geller I
      • Hartmann RJ
      • Garcia C
      Effects of polybrominated biphenyl on a discrimination task in rats.
      For 1 year (May 1973 to May 1974), residents of Michigan ingested dairy products that had become contaminated with polybrominated biphenyls (PBBs) when a fire retardant was inadvertently substituted for a feed supplement.
      • Carter LJ
      Michigan's PBB incident: chemical mix-up leads to disaster.
      Seagull
      • Seagull EAW
      Developmental abilities of children exposed to polybrominated biphenyls (PBB).
      evaluated the neuropsychologic development of 19 PBB-exposed Michigan children between the ages of 2 years 5 months and 3 years 11 months. Children with higher concentrations of PBBs scored significantly lower on four of five tests of the McCarthy Scales of Children's Abilities and thereby demonstrated a dose-related adverse effect of ingestion of these PBBs.
      Dioxin derivatives, present in wood preservatives and herbicides, are known teratogens in animals. Pregnant rhesus monkeys that were exposed to amounts of tetrachlorodibenzo-p-dioxin sufficient to produce a fetal concentration in parts per trillion had an appreciable increase in rates of abortions and birth defects.
      • Van Miller JP
      • Marlar RJ
      • Allen JR
      Tissue distribution and excretion of tritiated tetrachlorodibenzo-p-dioxin in non-human primates and rats.

      Pesticides.

      Once these toxic substances (DDT, chlordane, and others) enter the food chain, they are almost impossible to eliminate. The effect of fetal exposure to low concentrations of pesticides is unknown. Duffy and associates
      • Duffy FH
      • Burchfiel JL
      • Bartels PH
      • Gaon M
      • Sim VM
      Long-term effects of an organophosphate upon the human electroencephalogram.
      demonstrated long-term effects of organophosphates on the electroencephalogram in humans. Smokers who breast-feed run the risk of exposing their infants to the pesticides used to spray the tobacco plants.
      • Machol L
      Environmental hazards: what they'll mean to your patients in the 1980s.

      Heavy Metals.

      As previously mentioned, heavy metals may affect spermatozoa.16 They are also embryotoxic. The adverse effects of exposure to lead during pregnancy include an increase in spontaneous abortions, stillbirths, and prematurity. Oliver
      • Oliver T
      Lead poisoning from industrial and medical points of view.
      found lead in the brains and livers of stillborn infants of women lead workers. Studies in animals have implicated maternal exposure to lead as a possible cause of learning disabilities in offspring. Women living near heavily traveled roads have an increase in blood lead levels.
      • Machol L
      Environmental hazards: what they'll mean to your patients in the 1980s.
      Needleman and co-workers
      • Needleman HL
      • Rabinowitz M
      • Leviton A
      • Linn S
      • Schoenbaum S
      The relationship between prenatal exposure to lead and congenital anomalies.
      found prenatal exposure to lead to be associated, in a dose-related fashion, with an increased risk of occurrence of minor anomalies (P⩽ 0.05). No single characteristic anatomic defect was noted. This finding suggests that lead may act as a coteratogen with other risk factors to increase the probability of occurrence of congenital malformations.
      Mercury is concentrated within the fetal compartment. Discharge of this heavy metal into Minamata Bay, Japan, contaminated the food chain and gave rise to an increased incidence of children born with cerebral palsy.
      • Koos BJ
      • Longo LD
      Mercury toxicity in the pregnant woman, fetus, and newborn infant: a review.
      Garfunkel
      • Garfunkel JM
      Environmental hazards and the pediatrician (editorial).
      emphasized the importance of considering parental occupation when evaluating an atypical illness in a child. Mangurten and Kaye
      • Mangurten HH
      • Kaye CI
      Neonatal bromism secondary to maternal exposure in a photographic laboratory.
      described an infant transferred to their neonatal intensive care unit with cyanosis at 90 hours of age. The infant's severe hypotonia and neurologic depression gradually diminished with time. Her urinary bromide concentration was 33 mg/dl (normal range, less than 0.25 mg/dl). On detailed questioning, the mother was found to work in a photographic laboratory where she prepared or used chemicals for development of film—compounds that are known to contain sodium and potassium bromides. On the 18th day after delivery of the infant, serum bromide concentrations in the infant and mother were 15 and 19 mg/dl, respectively.

      Formaldehyde.

      Common sources of formaldehyde vapors within the home include wood paneling and foam insulation. Eye nose, and throat irritation, headache, shortness of breath, and chest pains are among the most commonly reported symptoms of exposure to formaldehyde. A Russian study showed that women who worked with formaldehyde had an increased rate of spontaneous abortion. In women who carried their babies to term, the incidence of delivering small-for-gestational-age infants was 27%.
      • Shumilina AV
      Menstrual'naia i detorodnaia funktsii rabotnits, imeiushchikh po usloviiam proizvodstva kontakt s formal 'degidom.

      ALCOHOL

      Ancient historic sources refer to prohibition of alcohol to young women for fear that the child they either carried or were about to conceive would be affected. Surprisingly the variety of malformations produced by ethanol abuse was not fully recognized until the late 1960s. The first report of the effects on the fetuses of mothers who used alcohol during pregnancy was published in the French literature.
      • Lemoine P
      • Harousseau H
      • Borteyru J-P
      • Menuet J-C
      Les enfants de parents alcooliques: anomalies observées, à propos de 127 cas (abstract).
      Ulleland
      • Ulleland CN
      The offspring of alcoholic mothers.
      reported the effect of alcohol in reducing birth weight and in retarding intrauterine growth. Jones and associates,
      • Jones KL
      • Smith DW
      • Ulleland CN
      • Streissguth AP
      Pattern of malformation in offspring of chronic alcoholic mothers.
      however, first recognized the pattern of malformations in the fetuses of chronic alcohol abusers which revealed a relatively consistent and aberrant morphogenesis. Not only were infants of chronic alcohol abusers small for gestational age but they also had a specific pattern of craniofacial, limb, and other somatic anomalies along with delay in prenatal and postnatal growth and development.
      Subsequent reviews of this subject expanded the concept of the fetal alcohol syndrome and extensively described the morphologic sequelae.
      • Hanson JW
      • Jones KL
      • Smith DW
      Fetal alcohol syndrome: experience with 41 patients.
      • Jones KL
      • Smith DW
      Recognition of the fetal alcohol syndrome in early infancy.
      • Mau G
      Moderate alcohol consumption during pregnancy and child development.
      • Tuotant C
      • Lippmann S
      Fetal alcohol syndrome.
      Jones and colleagues'
      • Jones KL
      • Smith DW
      • Streissguth AP
      • Myrianthopoulos NC
      Outcome in offspring of chronic alcoholic women.
      estimates of the frequency of the syndrome, derived from the Collaborative Perinatal Project, suggested that the rate of severe chronic alcoholism is 0.42 to 1.25 per 1,000 pregnancies. Review of experience with these pregnancies revealed a perinatal mortality of 17% and an incidence of mental deficiency of 44% among surviving infants. Women who drink regularly may also have an increased incidence of spontaneous abortion.
      • Kline J
      • Stein Z
      • Shrout P
      • Susser M
      • Warburton D
      Drinking during pregnancy and spontaneous abortion.
      • Harlap S
      • Shiono PH
      Alcohol, smoking, and incidence of spontaneous abortions in the first and second trimester.
      The original descriptions of the syndrome suggested that only infants born to severely alcoholic mothers are at risk. Among a group of infants born to mothers who admitted using moderate quantities of alcohol daily, neither abnormalities of growth nor any stigmas of the fetal alcohol syndrome were recorded.
      • Quellette EM
      • Rossett HL
      • Rosman NP
      • Weiner L
      Adverse effects on offspring of maternal alcohol abuse during pregnancy.
      In most studies of consumption of alcohol, the consumption was assumed to have taken place during morphogenesis in the first trimester. The syndrome, therefore, seems to be a consequence of excess intake of alcohol. In one study, however, women who were alcoholic but abstained during pregnancy and even before conception had infants with generally lower than normal birth weights.
      • Little RE
      • Streissguth AP
      • Barr HM
      • Herman CS
      Decreased birth weight in infants of alcoholic women who abstained during pregnancy.
      The cause of the fetal alcohol syndrome is not entirely clear. Nor is it exactly clear how much alcohol is necessary to produce the syndrome. Presumably the alcohol has some particularly toxic effect on fetal growth and development. Whether the deficit in intelligence is simply a result of microcephaly is not clear. Alcohol administered postnatally even for a brief period in young rats produced diminished brain size in the exposed animal.
      • Diaz J
      • Samson HH
      Impaired brain growth in neonatal rats exposed to ethanol.
      Studies of chick embryos have shown both a high mortality rate and abnormalities of morphogenesis, specifically cardiac anomalies.
      • Chernoff GF
      A mouse model of the fetal alcohol syndrome (abstract).
      The alcohol itself has generally been assumed to be the offending agent, and its metabolites are thought to be less likely to cause morphologic abnormalities. This concept derives from the fact that alcohol dehydrogenase is known to be in extremely low levels in fetal liver tissues,
      • Pikkarainen PH
      • Räihä NCR
      Development of alcohol dehydrogenase activity in the human liver.
      and one would not expect high concentrations of acetaldehyde. Thus reduction in the clearance of ethanol would enhance the toxic influence of alcohol.
      Brien and colleagues
      • Brien JF
      • Loomis CW
      • Tranmer J
      • McGrath M
      Disposition of ethanol in human maternal venous blood and amniotic fluid.
      evaluated the levels of ethanol in amniotic fluid at 16 and 18 weeks of gestation after the pregnant mothers had ingested 0.3 g/kg of ethanol. At 3.5 hours, ethanol was absent in maternal serum but still present in the amniotic fluid. The authors proposed that the amniotic fluid acted as a reservoir for ethanol so that the fetus was exposed for a longer period than would be predicted on the basis of maternal serum concentrations.
      Diagnosis of the fetal alcohol syndrome is based on three major factors: (1) prenatal and postnatal growth retardation; (2) facial dysmorphogenesis, including microcephaly and short palpebral fissures, epicanthal folds, maxillary hypoplasia, cleft palate, and micrognathia; and (3) abnormalities of the central nervous system, usually including mental retardation (Table 4). Although 5 of 126 children with the fetal alcohol syndrome in one study had IQs in the normal range, only 2 of the 5 had scores of more than 96.
      • Shaywitz SE
      • Cohen DJ
      • Shaywitz BA
      Behavior and learning difficulties in children of normal intelligence born to alcoholic mothers.
      Besides the morphogenic abnormalities, specific organ systems have been affected. Joint abnormalities, including subluxations, and abnormal palmar creases have occurred. Among 56 infants with the fetal alcohol syndrome in another study, 16 had congenital heart disease. The incidence seemed to be highest among those with the most flagrant form of the disease. Atrial septal defect, the most common defect noted, was followed in frequency by ventricular septal defect.
      • Löser H
      • Majewski F
      Type and frequency of cardiac defects in embryofetal alcohol syndrome: report of 16 cases.
      Liver abnormalities have been reported.
      • Habbick BF
      • Zaleski WA
      • Casey R
      • Murphy F
      Liver abnormalities in three patients with fetal alcohol syndrome.
      Neuroblastoma and adrenal carcinoma have been noted in children with the fetal alcohol syndrome.
      • Hornstein L
      • Crowe C
      • Gruppo R
      Adrenal carcinoma in a child with history of fetal alcohol syndrome (letter to the editor).
      • Kinney H
      • Faix R
      • Brazy J
      The fetal alcohol syndrome and neuroblastoma.
      Table 4Pattern of Fetal Alcohol Syndrome
      AbnormalityFrequency
      + + + = common; ++ = moderately frequent; + = occasional.
      Growth
       Microcephaly+++
       Developmental delay+++
       Intrauterine growth retardation+++
      Craniofacial
       Short palpebral fissures+++
       Midfacial hypoplasia+++
       Maxillary hypoplasia+++
      Limb
       Palmar crease abnormalities++
       Joint abnormalities (mild to severe)++
      Miscellaneous
       Cardiac
        Atrial septal defect++
        Ventricular septal defect+
        Tetralogy of Fallot+
       Liver disease (hepatic fibrosis)+
      * + + + = common; ++ = moderately frequent; + = occasional.
      X-ray abnormalities, especially of the cervical spine and the radioulnar joint, have been of help in the diagnosis of the fetal alcohol syndrome. Cervical vertebral body fusion, radial synostosis and hypoplasia of the radial head, clinodactyly, and thoracic cage abnormalities have also been reported.
      Even without the stigmas of the fetal alcohol syndrome, children born to alcoholic mothers have reportedly had behavior and learning difficulties.
      • Shaywitz SE
      • Cohen DJ
      • Shaywitz BA
      Behavior and learning difficulties in children of normal intelligence born to alcoholic mothers.
      In that report, children referred for study to a learning disorder unit were hyperactive and had short attention spans. Although a few of the children later identified as having been born to alcoholic mothers had normal IQs, a substantial number had learning difficulties. Because many of the women who use alcohol also use other drugs and tobacco, these subtle findings about school performance are difficult to relate to the independent insult of ethanol.
      Electroencephalograms have been obtained from neonates of mothers who drank heavily. The investigators found that the neonatal electroencephalogram was affected even in the absence of the aforementioned characteristic dysmorphology and thus may be a sensitive indicator of fetal alcohol toxicity. By controlling for smoking, Chernick and co-workers
      • Chernick V
      • Childiaeva R
      • loffe S
      Effects of maternal alcohol intake and smoking on neonatal electroencephalogram and anthropometric measurements.
      were able to demonstrate a toxic effect unrelated to maternal smoking habits.
      Most of the reviews of the subject emphasize that the syndrome occurs with extreme alcohol abuse.
      • Rosett HL
      • Weiner L
      • Lee A
      • Zuckerman B
      • Dooling E
      • Oppenheimer E
      Patterns of alcohol consumption and fetal development.
      No level of alcohol use can be considered entirely safe, however, and even formerly alcoholic women deserve special attention during pregnancy.
      • Little RE
      Moderate alcohol use during pregnancy and decreased infant birth weight.
      • Rosett HL
      • Weiner L
      • Edelin KC
      Strategies for prevention of fetal alcohol effects.

      TOBACCO

      Tobacco was first recognized as harmful to the developing fetus by Simpson.
      • Simpson WJ
      A preliminary report on cigarette smoking and the incidence of prematurity.
      In that initial report, the incidence of infants with a birth weight of less than 2,500 g was substantially higher among mothers who smoked cigarettes. The effect of maternal smoking on the developing fetus has since been well recognized.
      The use of tobacco in society is pervasive. In the late 1960s, the British Perinatal Mortality Survey revealed that the incidence of smoking during pregnancy was between 21 and 36% and correlated closely with the socioeconomic class of the mother. Smoking was more common among women in lower socioeconomic classes. One study estimated that half of the women of childbearing age in Britain smoke.
      • Baric L
      • Mac Arthur C
      • Sherwood M
      A study of health education aspects of smoking in pregnancy.
      In that same study, efforts to persuade women to alter smoking habits during pregnancy were not entirely successful.
      Evidence exists that abruptio placentae and placenta previa are more common among women who smoke during pregnancy than among nonsmokers. Naeye
      • Naeye RL
      Abruptio placentae and placenta previa: frequency, perinatal mortality, and cigarette smoking.
      suggested that the placental lesion in smoking mothers is decidual necrosis and that the peripheral ischemic changes noted in placentas of affected infants are induced by smoking. Christianson
      • Christianson RE
      Gross differences observed in the placentas of smokers and nonsmokers.
      noted that smokers have thin, round placentas suggestive of the changes found among infants born at high altitude, whose mothers also have a substantially increased frequency of abruptio placentae and placenta previa.
      Asmussen,
      • Asmussen I
      Ultrastructure of the villi and fetal capillaries in placentas from smoking and nonsmoking mothers.
      who studied placental villi from 10 heavy smokers and 16 nonsmokers, found a decrease in fetal capillaries, thickening of the basement membrane, and an increase in the collagen content of the villous stroma. These findings suggest that placental blood flow is decreased in smokers.
      The effect of nicotine on a pregnant woman is related to its vasospastic characteristics and the placental ischemia that may result. Other products of combustion are known to increase during smoking. In one study, the level of serum thiocyanate varied directly with the amount of smoking and was correlated in the infant and the mother.
      • Meberg A
      • Sande H
      • Foss OP
      • Stenwig JT
      Smoking during pregnancy—effects on the fetus and on thiocyanate levels in mother and baby.
      In the same study, an inverse relationship between birth weight and thiocyanate level implied that thiocyanate also has a direct dose-related effect on fetal growth.
      Early speculation about the effect of smoking on the developing fetus questioned whether the insult is from tobacco or is related to differences between women who smoke and those who do not.
      • Yerushalmy J
      Mother's cigarette smoking and survival of infant.
      Further epidemiologic investigation suggested that the effect on the developing fetus is dose-related and independent of caloric intake.
      • Haworth JC
      • Ellestad-Sayed JJ
      • King J
      • Dilling LA
      Relation of maternal cigarette smoking, obesity, and energy consumption to infant size.
      Sexton and Hebel
      • Sexton M
      • Hebel JR
      A clinical trial of change in maternal smoking and its effect on birth weight.
      demonstrated that a reduction in smoking during pregnancy increases the birth weight of the infant. This dose-mediating relationship suggests that the smoker is not characteristically different from the nonsmoker. Other factors such as higher social class and maternal weight gain proved to have little effect in maintaining the birth weight of infants born to mothers who smoke.
      Recent investigations of the effect of cigarette smoking on the activity level of the fetus further emphasized the detrimental effects of tobacco.
      • Phelan JP
      Diminished fetal reactivity with smoking.
      A nonreactive non-stress test result was found considerably more often among women who smoked than among those who did not. The author hypothesized that this outcome was due to either the effects of carbon monoxide or a nicotine-induced reduction in uterine blood flow. The same study showed that, in comparison with infants of nonsmokers, perinatal mortality rates were higher among infants born to smokers and fetal birth weights were about 200 g lower, results similar to those reported from other studies.
      • Meyer MB
      • Tonascia JA
      Maternal smoking, pregnancy complications, and perinatal mortality.
      • Naeye RL
      Influence of maternal cigarette smoking during pregnancy on fetal and childhood growth.
      The same diminution in birth weight and increase in mortality among infants born to mothers who smoke were noted in a large population of twins.
      • Fabia J
      • Drolette M
      Twin pairs, smoking in pregnancy and perinatal mortality.
      The risk of perinatal death for twin pairs born to mothers who smoke is higher, and the implication is that the relative risk for twins born to mothers who smoke is higher than that for twins born to mothers who do not smoke.
      Nicotine crosses the placenta and has been found in cord blood. Manning and Feyerabend
      • Manning FA
      • Feyerabend C
      Cigarette smoking and fetal breathing movements.
      reported that cigarette smoking causes a reduction in the frequency of fetal breathing movements. The use of a nonnicotine (herbal) cigarette did not have a similar effect on fetal breathing movements despite an equivalent level of carboxyhemoglobin in both groups. Chewing gum containing nicotine was also found to inhibit fetal breathing activity. Hence nicotine seemed to be the factor responsible for reducing fetal breathing movements.
      Nicotine produces a sympathomimetic response in the human.
      • Boyle MN
      • Wegria R
      • Cathcart RT
      • Nickerson JL
      • Levy RL
      Effects of intravenous injection of nicotine on the circulation: in normal persons and in patients with cardiovascular disease.
      Uterine vasoconstriction is a recognized consequence of sympathetic stimulation.
      • Gough ED
      • Dyer DC
      Responses of isolated human uterine arteries to vasoactive drugs.
      • Suzuki K
      • Minei LJ
      • Johnson EE
      Effect of nicotine upon uterine blood flow in the pregnant rhesus monkey.
      Therefore, the use of nicotine could result in an intermittent reduction of uterine blood flow, thereby giving rise to fetal hypoxia and a decreased frequency of fetal breathing movements.
      • Manning FA
      • Walker D
      • Feyerabend C
      The effect of nicotine on fetal breathing movements in conscious pregnant ewes.
      A review by Butler and associates
      • Butler NR
      • Goldstein H
      • Ross EM
      Cigarette smoking in pregnancy: its influence on birth weight and perinatal mortality.
      suggested that in mothers who smoke throughout pregnancy, the possibility of producing either a stillborn infant or one who dies shortly after birth is increased 28%.
      Sudden infant death syndrome occurs twice as frequently in infants of mothers who smoke than of those who do not. The known effects of nicotine on fetal breathing may extend into the neonatal period. Krous and co-workers
      • Krous HF
      • Campbell GA
      • Fowler MW
      • Catron AC
      • Farber JP
      Maternal nicotine administration and fetal brain stem damage: a rat model with implications for sudden infant death syndrome.
      exposed pregnant Sprague-Dawley rats to nicotine. When the medullas of the fetuses were sectioned, the exposed rats had substantially more dead cells than did the control animals. Although the degree of fetal brainstem injury was limited, the authors were concerned that a similar lesion might be produced in the human fetus and might thereby increase the risk of sudden infant death syndrome.
      Divers and associates
      • Divers Jr, WA
      • Wilkes MM
      • Babaknia A
      • Yen SSC
      Maternal smoking and elevation of catecholamines and metabolites in the amniotic fluid.
      attempted to assess the effect of maternal smoking on fetal adrenergic activity by measuring several catecholamines and their derivatives in the amniotic fluid of 8 smokers and 36 nonsmokers during the third trimester of pregnancy. They found elevated levels of norepinephrine, epinephrine, and 3,4-dihy-droxyphenylglycol (a metabolite of norepinephrine); these findings suggested that fetal adrenergic activity was increased because of fetal hypoxia or a direct effect on the adrenergic system (or both). Their findings corresponded to those of Manning and Feyerabend.
      • Manning FA
      • Feyerabend C
      Cigarette smoking and fetal breathing movements.
      The increased incidence of infants with low birth weight among mothers who smoke might thus be explained by changes in regional blood flow produced by the hyperactivity of the adrenergic system.
      Sokol and co-workers
      • Sokol RJ
      • Miller SI
      • Reed G
      Alcohol abuse during pregnancy: an epidemiologic study.
      studied the relative risk of heavy drinking to offspring of 12,000 pregnant patients at a single hospital. They found that nicotine and alcohol compounded the risk of an adverse outcome: with cigarette smoking alone the risk was 1.8, and for alcohol abuse the risk was 2.4. When alcohol and cigarette use was combined, the relative risk increased to 3.9.
      Passive smoking—that is, exposure of the nonsmoker to air contaminated with tobacco smoke—may also result in appreciable levels of nicotine and thiocyanate (a metabolic by-product of smoking) and hence have an effect on fetal growth and development.
      • Asmussen I
      Ultrastructure of the villi and fetal capillaries in placentas from smoking and nonsmoking mothers.
      • Manning FA
      • Feyerabend C
      Cigarette smoking and fetal breathing movements.
      • Bottoms SF
      • Kuhnert BR
      • Kuhnert PM
      • Reese AL
      Maternal passive smoking and fetal serum thiocyanate levels.
      The incidence and the frequency of preeclampsia during pregnancy seem to be lower among smokers than among nonsmokers, but if preeclampsia does develop, infant mortality is especially high.
      Although no reports have been published of clearly defined patterns of malformation in infants born to mothers who smoke, occasional reports of increased frequency of certain anomalies have appeared. Cleft lip and cleft palate were found etiologically related to smoking during pregnancy.
      • Ericson A
      • Källén B
      • Westerholm P
      Cigarette smoking as an etiologic factor in cleft lip and palate.
      Naeye
      • Naeye RL
      Relationship of cigarette smoking to congenital anomalies and perinatal death: a prospective study.
      reported that the mortality among infants born with congenital anomalies was higher if the mothers smoked more than 10 cigarettes a day. This study revealed a dose-related effect and a surprising association between maternal smoking and anencephaly.

      CONCLUSIONS

      The complexities involved in evaluating the possible teratogenic effects of medications given during and even before conception have been reviewed. The lack of an immediately obvious adverse effect can no longer be accepted as the only criterion that must be met before a pregnant woman is permitted to use a particular medication. Any maternal-fetal exposure—drug, environmental, chemical, or otherwise—should be considered potentially harmful if it occurs at a certain time in gestation and in sufficient dose. To protect the fetus more fully from unwanted exposure, we must drastically alter the way our society views illness, discomfort, and “not feeling well.” Occasionally, a person may be ill. Immediate drug therapy is not necessarily warranted, however. If the use of medications in general is decreased, the inadvertent exposure of the fetus will be reduced.
      Throughout pregnancy, the therapeutic value of a drug must be weighed against the known and possibly unknown effects it might have on the fetus before and after birth. Although therapeutic nihilism may be the goal of the physician during pregnancy, it cannot always be attained. A knowledge of the relative importance of various external factors on fetal growth and development enables the physician to select a course of therapy for the mother while manifesting appropriate concern for her unborn child.

      REFERENCES

        • Deykin D
        Warfarin therapy.
        N Engl J Med. 1970; 283: 691-694
        • Shaul WL
        • Emery H
        • Hall JG
        Chondrodysplasia punctata and maternal warfarin use during pregnancy.
        Am J Dis Child. 1975; 129: 360-362
        • Holzgreve W
        • Carey JC
        • Hall BD
        Warfarin-induced fetal abnormalities (letter to the editor).
        Lancet. 1976; 2: 914-915
        • Shaul WL
        • Hall JG
        Multiple congenital anomalies associated with oral anticoagulants.
        Am J Obstet Gynecol. 1977; 127: 191-198
        • Stevenson RE
        • Burton OM
        • Ferlauto GJ
        • Taylor HA
        Hazards of oral anticoagulants during pregnancy.
        JAMA. 1980; 243: 1549-1551
        • Hall JG
        • Pauli RM
        • Wilson KM
        Maternal and fetal sequelae of anticoagulation during pregnancy.
        Am J Med. 1980; 68: 122-140
        • Bleyer WA
        • Hakami N
        • Shepard TH
        The development of hemostasis in the human fetus and newborn infant.
        J Pediatr. 1971; 79: 838-853
        • Barr Jr, M
        • Burdi AR
        Warfarin-associated embryopathy in a 17–week-old abortus.
        Teratology. 1976; 14: 129-134
        • Bonnar J
        Venous thrombo-embolism and pregnancy.
        Recent Adv Obstet Gynaecol. 1979; 13: 173-192
        • Spearing G
        • Fraser I
        • Turner G
        • Dixon G
        Long-term self-administered subcutaneous heparin in pregnancy.
        Br Med J. 1978; 1: 1457-1458
        • Brozović M
        • Stirling Y
        • Klenerman L
        • Lowe L
        Subcutaneous heparin and postoperative thromboembolism (letter to the editor).
        Lancet. 1974; 2: 99-100
        • Thomas 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: 241-248
        • Hull 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: 855-858
        • Wang 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: 126-128
        • Salzman EW
        • Deykin D
        • Shapiro RM
        • Rosenberg R
        Management of heparin therapy: controlled prospective trial.
        N Engl J Med. 1975; 292: 1046-1050
        • Walker AM
        • Jick H
        Predictors of bleeding during heparin therapy.
        JAMA. 1980; 244: 1209-1212
        • Cines DB
        • Kaywin P
        • Bina M
        • Tomaski A
        • Schreiber AD
        Heparin-associated thrombocytopenia.
        N Engl J Med. 1980; 303: 788-795
        • Griffith GC
        • Nichols Jr, G
        • Asher JD
        • Flanagan B
        Heparin osteoporosis.
        JAMA. 1965; 193: 91-94
        • Avioli LV
        Heparin-induced osteopenia: an appraisal.
        Adv Exp Med Biol. 1975; 52: 375-387
        • Wise PH
        • Hall AJ
        Heparin-induced osteopenia in pregnancy.
        Br Med J. 1980; 281: 110-111
        • Reynolds EH
        Anticonvulsants, folic acid, and epilepsy.
        Lancet. 1973; 1: 1376-1378
        • Kochenour NK
        • Emery MG
        • Sawchuk RJ
        Phenytoin metabolism in pregnancy.
        Obstet Gynecol. 1980; 56: 577-582
        • Harbison RD
        • Becker BA
        Relation of dosage and time of administration of diphenylhydantoin to its teratogenic effect in mice.
        Teratology. 1969; 2: 305-311
        • Janz D
        • Fuchs U
        Are anti-epileptic drugs harmful when given during pregnancy?.
        German Med Monthly. 1964; 9: 20-22
        • Meadow SR
        Congenital abnormalities and anticonvulsant drugs.
        Proc R Soc Med. 1970; 63: 48-49
        • Watson JD
        • Spellacy WN
        Neonatal effects of maternal treatment with the anticonvulsant drug diphenylhydantoin.
        Obstet Gynecol. 1971; 37: 881-885
        • Speidel BD
        • Meadow SR
        Maternal epilepsy and abnormalities of the fetus and newborn.
        Lancet. 1972; 2: 839-843
        • Fedrick J
        Epilepsy and pregnancy: a report from the Oxford Record Linkage Study.
        Br Med J. 1973; 2: 442-448
        • Monson RR
        • Rosenberg L
        • Hartz SC
        • Shapiro S
        • Heinonen OP
        • Slone D
        Diphenylhydantoin and selected congenital malformations.
        N Engl J Med. 1973; 289: 1049-1052
        • Annegers JF
        • Elveback LR
        • Hauser WA
        • Kurland LT
        Do anticonvulsants have a teratogenic effect?.
        Arch Neurol. 1974; 31: 364-373
        • Hanson JW
        • Smith DW
        The fetal hydantoin syndrome.
        J Pediatr. 1975; 87: 285-290
        • Hanson 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: 662-668
        • Nicholson HO
        Cytotoxic drugs in pregnancy: review of reported cases.
        J Obstet Gynaecol Br Commonw. 1968; 75: 307-312
        • Schardein 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: 150-158
        • Hanson JW
        • Buehler BA
        Fetal hydantoin syndrome: current status.
        J Pediatr. 1982; 101: 816-818
        • German J
        • Kowal A
        • Ehlers KH
        Trimethadione and human teratogenesis.
        Teratology. 1970; 3: 349-361
        • Goldman AS
        • Yaffe SJ
        Fetal trimethadione syndrome.
        Teratology. 1978; 17: 103-105
        • Browne TR
        Valproic acid. N.
        Engl J Med. 1980; 302: 661-666
        • Robert E
        Valproic acid in pregnancy—association with spina bifida: a preliminary report.
        Clin Pediatr. 1983; 22: 336
        • Nau 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: 768-777
        • Whittle 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: 105-111
        • Kaneko 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: 503-506
        • Auroux 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: 797-801
        • Thomas CR
        Routine phenobarbital for prevention of neonatal hyperbilirubinemia.
        Obstet Gynecol. 1976; 47: 304-308
        • Montouris GD
        • Fenichel GM
        • McLain Jr, LW
        The pregnant epileptic: a review and recommendations.
        Arch Neurol. 1979; 36: 601-603
        • Mountain KR
        • Hirsh J
        • Callus AS
        Neonatal coagulation defect due to anticonvulsant drug treatment in pregnancy.
        Lancet. 1970; 1: 265-268
        • Bleyer WA
        • Skinner AL
        Fatal neonatal hemorrhage after maternal anticonvulsant therapy.
        JAMA. 1976; 235: 626-627
        • Safra MJ
        • Oakley Jr, GP
        Association between cleft lip with or without cleft palate and prenatal exposure to diazepam.
        Lancet. 1975; 2: 478-480
        • Gillberg C
        “Floppy infant syndrome” and maternal diazepam (letter to the editor).
        Lancet. 1977; 2: 244
        • Mazzi E
        Possible neonatal diazepam withdrawal: a case report.
        Am J Obstet Gynecol. 1977; 129: 586-587
        • Ganter 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: 609-620
        • Morgan I
        Metronidazole treatment in pregnancy.
        Int J Gynaecol Obstet. 1978; 15: 501-502
        • Berget A
        • Weber T
        Metronidazole and pregnancy.
        Ugeskr Laeger. 1972; 134: 2085-2089
        • Check W
        New study shows hexachlorophene is teratogenic in humans.
        JAMA. 1978; 240: 513-514
        • Hailing H
        Suspected link between exposure to hexachlorophene and malformed infants.
        Ann NY Acad Sci. 1979; 320: 426-435
        • Källén B
        Hexachlorophene teratogenicity in humans disputed (letter to the editor).
        JAMA. 1978; 240: 1585-1586
        • Baltzar B
        • Ericson A
        • Kállen B
        Pregnancy outcome among women working in Swedish hospitals (letter to the editor).
        N Engl J Med. 1979; 300: 627-628
        • Vorherr H
        • Vorherr UF
        • Mehta P
        • Ulrich JA
        • Messer RH
        Vaginal absorption of povidone-iodine.
        JAMA. 1980; 244: 2628-2629
        • Chabrolle JP
        • Rossier A
        Goitre and hypothyroidism in the newborn after cutaneous absorption of iodine.
        Arch Dis Child. 1978; 53: 495-498
        • Battaglia F
        • Prystowsky H
        • Smisson C
        • Hellegers A
        • Bruns P
        Fetal blood studies. XIII. The effect of the administration of fluids intravenously to mothers upon the concentrations of water and electrolytes in plasma of human fetuses.
        Pediatrics. 1960; 25: 2-10
        • Dahlenburg GW
        • Burnell RH
        • Braybrook R
        The relation between cord serum sodium levels in newborn infants and maternal intravenous therapy during labour.
        Br J Obstet Gynaecol. 1980; 87: 519-522
        • Bruns PD
        • Hellegers AE
        • Seeds Jr, AE
        • Behrman RE
        • Battaglia FC
        Effects of osmotic gradients across the primate placenta upon fetal and placental water contents.
        Pediatrics. 1964; 34: 407-411
        • Kenepp NB
        • Shelley WC
        • Kumar S
        • Gutsche BB
        • Gabbe S
        • Delivoria-Papadopoulos M
        Effects on newborn of hydration with glucose in patients undergoing caesarean section with regional anaesthesia (letter to the editor).
        Lancet. 1980; 1: 645
        • Longo LD
        Environmental pollution and pregnancy: risks and uncertainties for the fetus and infant.
        Am J Obstet Gynecol. 1980; 137: 162-173
        • Kuratsune M
        • Yoshimura T
        • Matsuzaka J
        • Yamaguchi A
        Epidemiologic study on Yusho, a poisoning caused by ingestion of rice oil contaminated with a commercial brand of polychlorinated biphenyls.
        Environ Health Perspect. 1972; 1: 119-128
        • Machol L
        Environmental hazards: what they'll mean to your patients in the 1980s.
        Contemp Ob/Gyn. 1980; 15: 22
        • Bowman RE
        • Heironimus MP
        • Allen JR
        Correlation of PCB body burden with behavioral toxicology in monkeys.
        Pharmacol Biochem Behav. 1978; 9: 49-56
        • Allen JR
        • Barsotti DA
        • Lambrecht LK
        • Van Miller JP
        Reproductive effects of halogenated aromatic hydrocarbons on non-human primates.
        Ann NY Acad Sci. 1979; 320: 419-425
        • Geller I
        • Hartmann RJ
        • Garcia C
        Effects of polybrominated biphenyl on a discrimination task in rats.
        Neurobehav Toxicol Teratol. 1979; 1: 263-267
        • Carter LJ
        Michigan's PBB incident: chemical mix-up leads to disaster.
        Science. 1976; 192: 240-243
        • Seagull EAW
        Developmental abilities of children exposed to polybrominated biphenyls (PBB).
        Am J Public Health. 1983; 73: 281-285
        • Van Miller JP
        • Marlar RJ
        • Allen JR
        Tissue distribution and excretion of tritiated tetrachlorodibenzo-p-dioxin in non-human primates and rats.
        Food Cosmet Toxicol. 1976; 14: 31-34
        • Duffy FH
        • Burchfiel JL
        • Bartels PH
        • Gaon M
        • Sim VM
        Long-term effects of an organophosphate upon the human electroencephalogram.
        Toxicol Appl Pharmacol. 1979; 47: 161-176
        • Oliver T
        Lead poisoning from industrial and medical points of view.
        Clin J Lond. 1914; 43: 417-424
        • Needleman HL
        • Rabinowitz M
        • Leviton A
        • Linn S
        • Schoenbaum S
        The relationship between prenatal exposure to lead and congenital anomalies.
        JAMA. 1984; 251: 2956-2959
        • Koos BJ
        • Longo LD
        Mercury toxicity in the pregnant woman, fetus, and newborn infant: a review.
        Am J Obstet Gynecol. 1976; 126: 390-409
        • Garfunkel JM
        Environmental hazards and the pediatrician (editorial).
        J Pediatr. 1981; 99: 400-401
        • Mangurten HH
        • Kaye CI
        Neonatal bromism secondary to maternal exposure in a photographic laboratory.
        J Pediatr. 1982; 100: 596-598
        • Shumilina AV
        Menstrual'naia i detorodnaia funktsii rabotnits, imeiushchikh po usloviiam proizvodstva kontakt s formal 'degidom.
        Gig Tr Prof Zabol. 1975; 12: 18-21
        • Lemoine P
        • Harousseau H
        • Borteyru J-P
        • Menuet J-C
        Les enfants de parents alcooliques: anomalies observées, à propos de 127 cas (abstract).
        Arch Fr Pediatr. 1968; 25: 830-831
        • Ulleland CN
        The offspring of alcoholic mothers.
        Ann NY Acad Sci. 1972; 197: 167-169
        • Jones KL
        • Smith DW
        • Ulleland CN
        • Streissguth AP
        Pattern of malformation in offspring of chronic alcoholic mothers.
        Lancet. 1973; 1: 1267-1271
        • Hanson JW
        • Jones KL
        • Smith DW
        Fetal alcohol syndrome: experience with 41 patients.
        JAMA. 1976; 235: 1458-1460
        • Jones KL
        • Smith DW
        Recognition of the fetal alcohol syndrome in early infancy.
        Lancet. 1973; 2: 999-1001
        • Mau G
        Moderate alcohol consumption during pregnancy and child development.
        Eur J Pediatr. 1980; 133: 233-237
        • Tuotant C
        • Lippmann S
        Fetal alcohol syndrome.
        Am Fam Physician. July 1980; 22: 113-117
        • Jones KL
        • Smith DW
        • Streissguth AP
        • Myrianthopoulos NC
        Outcome in offspring of chronic alcoholic women.
        Lancet. 1974; 1: 1076-1078
        • Kline J
        • Stein Z
        • Shrout P
        • Susser M
        • Warburton D
        Drinking during pregnancy and spontaneous abortion.
        Lancet. 1980; 2: 176-180
        • Harlap S
        • Shiono PH
        Alcohol, smoking, and incidence of spontaneous abortions in the first and second trimester.
        Lancet. 1980; 2: 173-176
        • Quellette EM
        • Rossett HL
        • Rosman NP
        • Weiner L
        Adverse effects on offspring of maternal alcohol abuse during pregnancy.
        N Engl J Med. 1977; 297: 528-530
        • Little RE
        • Streissguth AP
        • Barr HM
        • Herman CS
        Decreased birth weight in infants of alcoholic women who abstained during pregnancy.
        J Pediatr. 1980; 96: 974-977
        • Diaz J
        • Samson HH
        Impaired brain growth in neonatal rats exposed to ethanol.
        Science. 1980; 208: 751-753
        • Chernoff GF
        A mouse model of the fetal alcohol syndrome (abstract).
        Teratology. 1975; 11: 14A
        • Pikkarainen PH
        • Räihä NCR
        Development of alcohol dehydrogenase activity in the human liver.
        Pediatric Res. 1967; 1: 165-168
        • Brien JF
        • Loomis CW
        • Tranmer J
        • McGrath M
        Disposition of ethanol in human maternal venous blood and amniotic fluid.
        Am J Obstet Gynecol. 1983; 146: 181-186
        • Shaywitz SE
        • Cohen DJ
        • Shaywitz BA
        Behavior and learning difficulties in children of normal intelligence born to alcoholic mothers.
        J Pediatr. 1980; 96: 978-982
        • Löser H
        • Majewski F
        Type and frequency of cardiac defects in embryofetal alcohol syndrome: report of 16 cases.
        Br Heart J. 1977; 39: 1374-1379
        • Habbick BF
        • Zaleski WA
        • Casey R
        • Murphy F
        Liver abnormalities in three patients with fetal alcohol syndrome.
        Lancet. 1979; 1: 580-581
        • Hornstein L
        • Crowe C
        • Gruppo R
        Adrenal carcinoma in a child with history of fetal alcohol syndrome (letter to the editor).
        Lancet. 1977; 2: 1292-1293
        • Kinney H
        • Faix R
        • Brazy J
        The fetal alcohol syndrome and neuroblastoma.
        Pediatrics. 1980; 66: 130-132
        • Chernick V
        • Childiaeva R
        • loffe S
        Effects of maternal alcohol intake and smoking on neonatal electroencephalogram and anthropometric measurements.
        Am J Obstet Gynecol. 1983; 146: 41-47
        • Rosett HL
        • Weiner L
        • Lee A
        • Zuckerman B
        • Dooling E
        • Oppenheimer E
        Patterns of alcohol consumption and fetal development.
        Obstet Gynecol. 1983; 61: 539-546
        • Little RE
        Moderate alcohol use during pregnancy and decreased infant birth weight.
        Am J Public Health. 1977; 67: 1154-1156
        • Rosett HL
        • Weiner L
        • Edelin KC
        Strategies for prevention of fetal alcohol effects.
        Obstet Gynecol. 1981; 57: 1-7
        • Simpson WJ
        A preliminary report on cigarette smoking and the incidence of prematurity.
        Am J Obstet Gynecol. 1957; 73: 808-815
        • Baric L
        • Mac Arthur C
        • Sherwood M
        A study of health education aspects of smoking in pregnancy.
        Int J Health Educ. 1976; 19: 1-16
        • Naeye RL
        Abruptio placentae and placenta previa: frequency, perinatal mortality, and cigarette smoking.
        Obstet Gynecol. 1980; 55: 701-704
        • Christianson RE
        Gross differences observed in the placentas of smokers and nonsmokers.
        Am J Epidemiol. 1979; 110: 178-187
        • Asmussen I
        Ultrastructure of the villi and fetal capillaries in placentas from smoking and nonsmoking mothers.
        Br J Obstet Gynaecol. 1980; 87: 239-245
        • Meberg A
        • Sande H
        • Foss OP
        • Stenwig JT
        Smoking during pregnancy—effects on the fetus and on thiocyanate levels in mother and baby.
        Acta Paediatr Scand. 1979; 68: 547-552
        • Yerushalmy J
        Mother's cigarette smoking and survival of infant.
        Am J Obstet Gynecol. 1964; 88: 505-518
        • Haworth JC
        • Ellestad-Sayed JJ
        • King J
        • Dilling LA
        Relation of maternal cigarette smoking, obesity, and energy consumption to infant size.
        Am J Obstet Gynecol. 1980; 138: 1185-1189
        • Sexton M
        • Hebel JR
        A clinical trial of change in maternal smoking and its effect on birth weight.
        JAMA. 1984; 251: 911-915
        • Phelan JP
        Diminished fetal reactivity with smoking.
        Am J Obstet Gynecol. 1980; 136: 230-233
        • Meyer MB
        • Tonascia JA
        Maternal smoking, pregnancy complications, and perinatal mortality.
        Am J Obstet Gynecol. 1977; 128: 494-502
        • Naeye RL
        Influence of maternal cigarette smoking during pregnancy on fetal and childhood growth.
        Obstet Gynecol. 1981; 57: 18-21
        • Fabia J
        • Drolette M
        Twin pairs, smoking in pregnancy and perinatal mortality.
        Am J Epidemiol. 1980; 112: 404-408
        • Manning FA
        • Feyerabend C
        Cigarette smoking and fetal breathing movements.
        Br J Obstet Gynaecol. 1976; 83: 262-270
        • Boyle MN
        • Wegria R
        • Cathcart RT
        • Nickerson JL
        • Levy RL
        Effects of intravenous injection of nicotine on the circulation: in normal persons and in patients with cardiovascular disease.
        Am Heart J. 1947; 34: 65-79
        • Gough ED
        • Dyer DC
        Responses of isolated human uterine arteries to vasoactive drugs.
        Am J Obstet Gynecol. 1971; 110: 625-629
        • Suzuki K
        • Minei LJ
        • Johnson EE
        Effect of nicotine upon uterine blood flow in the pregnant rhesus monkey.
        Am J Obstet Gynecol. 1980; 136: 1009-1113
        • Manning FA
        • Walker D
        • Feyerabend C
        The effect of nicotine on fetal breathing movements in conscious pregnant ewes.
        Obstet Gynecol. 1978; 52: 563-568
        • Butler NR
        • Goldstein H
        • Ross EM
        Cigarette smoking in pregnancy: its influence on birth weight and perinatal mortality.
        Br Med J. 1972; 2: 127-130
        • Krous HF
        • Campbell GA
        • Fowler MW
        • Catron AC
        • Farber JP
        Maternal nicotine administration and fetal brain stem damage: a rat model with implications for sudden infant death syndrome.
        Am J Obstet Gynecol. 1981; 140: 743-746
        • Divers Jr, WA
        • Wilkes MM
        • Babaknia A
        • Yen SSC
        Maternal smoking and elevation of catecholamines and metabolites in the amniotic fluid.
        Am J Obstet Gynecol. 1981; 141: 625-628
        • Sokol RJ
        • Miller SI
        • Reed G
        Alcohol abuse during pregnancy: an epidemiologic study.
        Alcoholism (NY). 1980; 4: 135-145
        • Bottoms SF
        • Kuhnert BR
        • Kuhnert PM
        • Reese AL
        Maternal passive smoking and fetal serum thiocyanate levels.
        Am J Obstet Gynecol. 1982; 144: 787-791
        • Ericson A
        • Källén B
        • Westerholm P
        Cigarette smoking as an etiologic factor in cleft lip and palate.
        Am J Obstet Gynecol. 1979; 135: 348-351
        • Naeye RL
        Relationship of cigarette smoking to congenital anomalies and perinatal death: a prospective study.
        Am J Pathol. 1978; 90: 289-293