Drug Risks in Pregnancy Revisited

Noel Guillozet, MD Salinas, C alifornia

In the important interface of assuring safe care for the pregnant convinced of the virtues of a particular mother and her developing child that falls to the family physician, drug. Often consigned the care of current knowledge of drug risks in pregnancy is essential. A recent especially difficult cases through their recognized expertise, they resent re­ survey showed that an average of 4.5 drugs are taken throughout striction of healing tools by commit­ the pregnancy. Eighty percent were self-prescribed, and a positive tees of medical scientists who are not correlation was shown between the incidence of congenital yet convinced of the value or safety of anomalies and drug intake. Numerous recent reports of previously a drug. They argue that provisional unrecognized fetal complications of commonly prescribed and self- approvals could allow the exploitation used drugs and heightened public awareness makes it imperative that of an apparently useful drug for diffi­ cult patient care problems without family physicians know the risk principles of major drug groups and allowing sales promotion efforts to be be able to recognize drug-induced symptoms and signs in the older made until approval was accorded on infant as well as in the newborn. the basis of longer patient care exper­ ience and research. This communication is intended to The discovery in late 1961 of the from older drugs. Have controls been call attention to drugs currently impli­ teratogenicity to the human fetus of effective or have we been unneces­ cated in fetal deformation or other thalidomide, a drug first marketed in sarily deprived of life-saving drugs as injury and to some of the newer 1956 in Germany and later available some critics believe? Unquestionably, recognized constellations of fetal ab­ non-commercially in the United we have seen the introduction of normalities associated with older States, was a landmark. A direct out­ fewer major drugs. The United King­ drugs.2 growth of public concern over the dom has often been the site for the thalidomide disaster,1 the Harris- introduction of new drugs,3 and clear­ The Diversity of Drug Intake during Kefauver Law of 1962, henceforth ly the experience gained there has Pregnancy accorded the Food and Drug Adminis­ been taken into account here as we A recent American survey of drug tration the responsibility of deciding have benefited from their trials. Most therapy in pregnancy disclosed an on the safety and efficacy of a drug. A new drugs introduced in the United average of 4.5 drugs taken throughout demand for sufficient observation of States have not been approved for pregnancy — 80 percent of which were performance and testing before a drug usage in pregnancy, and Food and self-prescribed. Not surprisingly, vita­ would be allowed widespread usage in Drug Administration procedures, ex­ mins, analgesics, and iron were the the United States was codified in law. clude pregnant women from control most frequent followed by antacids, Where are we in 1977 after a studies. Conceivably, apart from for­ antiemetics, barbiturates, and anti­ decade and a half of stringent controls eign reports and those noted inadver- biotics. In the first trimester, hor­ on new drug introduction? There have tant untoward effects on the fetus mones, antihistamines, and other drugs been no mishaps to equal the thalido­ provoked by drug intake in a woman were more prominent. A small group mide incident, but there have been who did not know that she was preg­ of women were found to have received numerous cautionary observations of nant, a drug hazardous only to the ten or more drugs. The same survey newly recognized fetal abnormalities human fetus could gain approval for supported other studies in docu­ usage in the United States. menting a definite correlation between From the Harvard University Project at the The test of time inherent in ob­ drug intake in pregnancy and the University Center for the Health Sciences, taining FDA approval for new drug Cameroon. Requests for reprints should be presence of congenital anomalies in addressed to Dr. Noel Guillozet, Family usage is difficult for many clinicians to the infant.4 Practice Residency Program, Natividad Med­ ical C e n te r, 1 3 3 0 N a tiv id a d R o a d , S a lin a s, endure, particularly experts in various The fetus will be reached by most Calif 93901. clinical fields who may be thoroughly of the drugs taken by its pregnant

THE JOURNAL OF FAMILY PRACTICE, VOL. 4, NO. 6, 1977 1043 mother. Whether the effect will be nil incremental and the variations in dos­ to pregnant women.10 Recent reports or disastrous, the teratogenic potential age and combination numerous. Apart in the efficacy of 17 alpha hydroxy- depends on the timing o f adminis­ from subjective complaints, some as progesterone caproate in the preven­ tration, the dose given, the duration of serious as thromboembolic phenom­ tion of premature labor11 has pro­ exposure, and the genetic disposition ena, the list of known fetal effects is voked valid controversy. The esti­ of both mother and fetus to respond lengthening. Masculinization of the mated 90,000 deaths associated with to the drug in question. fetus after the mother receives oral low birth weight delivery in the United In consideration of fetal develop­ progestin is known to occur.5 Long­ States in the early 1970s12 suggest the ment, the first two weeks after con­ term behavioral changes have been impetus for a continued search of all ception, the pre-implantation period, associated with perinatal hormone ad­ means to avert premature delivery. is when the fetus is most susceptible to ministration.6 Mothers have been The statistically low carcinogenic po­ severe damage and abortion. There­ shown by Janerich and others to be tential of diethylstilbestrol is equated after, from the second to eighth week, likely to become pregnant after dis­ to that of the 17 alpha hydroxy - when the basic organ systems are being continuing oral contraceptives.7 There progesterones and defended in light of created, the fetus is extremely sensi­ may be a continuing drug effect on the the risk and death rate of early de­ tive to deformation. Thalidomide is young fetus at its earliest stages. Occa­ livery.1 1 At this writing its safety in apparently harmless to the fetus unless sionally, the agents are taken during wide usage seems questionable. taken from the 28th to the 42nd early pregnancy by mothers unaware gestational days — a critical two of the inception of pregnancy, a usage weeks. A spectrum of minor and major associated with an increase in cardiac effects is possible. Some drugs are and other congenital anomalies on a dangerous through the entire preg­ low, but definite risk basis.8 New nancy and must be avoided, while York State data from 1963 to 1967, some may be nearly harmless to the after the thalidomide disaster9 respon­ Tranquilizers and Antianxiety Drugs baby’s development, but may jeop­ sible for a brief increase in limb Diazepam ardize its survival as a neonate. The reduction defects, disclosed a fall in Diazepam (Valium) has become the best way, in theory at least, is to avoid total malformations of about six per­ most commonly prescribed medication giving all drugs to pregnant women. A cent whereas the rate of limb reduc- n in the United States, and perhaps in compromise is often necessary to tion defects had increased by a third. the world.14 First used as a tran­ assure the health of a woman who may Oral contraceptive use increased sub­ quilizer and a muscle relaxant and have entered pregnancy with chronic stantially during these years. An in­ later as an anticonvulsant, it is now medical problems or who may develop teresting aspect of the association of frequently used for its calming effects acute problems during the pregnancy. limb reduction defects with oral con­ at delivery. Counseling mothers to avoid self­ traceptive and other sex steroids is the In the management of normal prescribing and an understanding by exclusive male sex incidence reported, active labor, in a mother who is not physicians and nurses of the risks of suggesting a sex-specific effect.7 receiving the drug chronically, brief certain drugs in early pregnancy are usage in lower doses seems compara­ good beginning points for the preven­ tively safe. Cree and co-workers report tion of unnecessary fetal deaths and that a total maternal dose of 30 mg or deformities. less in the 15 hours before delivery The first eight weeks of the preg­ had little effect on the infant’s state. nancy are the most dangerous. Drugs Larger doses, however, were often and immunizations should be avoided Therapeutic Risks in Treatment of associated with a low Apgar score, whenever possible during this period. Threatened Abortion and Premature apneic spells, poor feeding, hypotonia, Labor general depression, and hypothermia. The problem of pregnancies at a Further, the infants studied responded high risk of abortion, premature labor, abnormally to cold stress.1 5 and the delivery of premature infants The widespread chronic usage of of low viability are persistent thera­ diazepam poses different risks. With­ The Exogenous Sex Steroids: Oral peutic dilemmas. The use of diethyl- drawal symptoms have now been re­ Contraceptive and Therapeutic Agents stilbestrol in threatened abortions was ported in adults who discontinued The use of exogenous estrogenic popular from 1955 until the early diazepam after four to six months and progesteronal substances in medi­ 1970s, when it was shown that in the usage,16 and in newborns who mani­ cine is widespread and increasingly occurrence of a rare cancer — vaginal fested tremors, irritability, hyper­ controversial. Although pregnancy adenocarcinoma in young girls — the activity, hypertonicity, tachypnea, and testing, supportive hormone therapy, single common factor was the treat­ voracious feeding. The clinical presen­ and efforts to increase fertility and ment of the victim’s mother during tation is indistinguishable from that alter outcome in mothers with persis­ pregnancy with diethylstilbestrol. The seen in narcotic withdrawal states. The tent fetal loss and premature deliveries incidence of this tragic disease 15 or onset has been noted as early as 2Zi are important usages, the most wide­ more years after a brief exposure hours after delivery and as late as the spread use of exogenous sex steroids is suggests the caution with which new third day, with effects lasting from 4 in contraceptives. Growth in their use drugs or old drugs in new usages to 38 days. Phenobarbital has proven during the past two decades has been should be viewed when administered useful for calming.17

1 0 4 4 THE JOURNAL OF FAM ILY PRACTICE, VOL. 4, NO. 6, 1977 In chronic diazepam usage during childbearing age should be scrutinized newborns had measurable salicylate late pregnancy, the fetal fat stores and that it would be prudent to assure levels, some above usual adult anal- become saturated.15 ,ls Cord levels that the woman was avoiding concep­ gesic levels. While it has been shown have been shown on occasion to be tion before either agent is pre­ to produce congenital anomalies in higher than maternal ones, and high scribed.2 1 rats, human experience has not con­ dose cases may show a neonatal rise in Chlorpromazine given in maternal firmed this experience. Maternal usage levels suggesting drug release, or a doses in excess of 500 mg per day has in the ten days prior to delivery can, delayed fall. The active metabolite produced neonatal depression.22 however, provoke platelet dysfunction desmethyldiazepam (70 percent diaze­ Alpha adrenergic blocking effects and mild disturbance of the newborn’s pam activity) has been found to re­ could theoretically interfere with tem­ clotting mechanism. ’ Massive neo­ main at a plateau over seven post­ perature regulation of the newborn. natal hemorrhage necessitating trans­ partum days.15 Further, the half-life Apt and Gaffney, noting the large fusion following maternal intake of in near-term infants (54 hours at 28-34 number of teratogens affecting the calcium salicylate during 72 hours weeks) is much longer than in older eye, view the preferential accumula­ before delivery has been reported.30 children and adults, further delaying tion of chlorpromazine in the fetal eye The antihistamines, cyclizine, chlor- elimination. Exchange transfusion is with suspicion.23,24 Teratogenicity, cyclizine, and meclizine, frequently likely to be only partially successful in however, has not been demonstrated used as antinauseants in pregnancy, are the removal of these fat soluble sub- with chlorpromazine. Extrapyramidal highly teratogenic in rats. There has stances. l 8 reactions are occasionally seen with all been no documentation of terato­ Teratogenic effects have not been the phenothiazines and at all ages. genicity in humans but concern is reported with diazepam. Hydroxyzine (Vistaril, Atarax) appropriate that these drugs be seems safe in prenatal usage but re­ avoided whenever possible in the preg­ search information is sparse.20 nant mother. A higher incidence of congenital Chlordiazepoxide, Meprobamate, and malformations than usual was noted in the Phenothiazines a study of maternal antacid usage Transient effects observable in the during pregnancy. Although there was neonate have also been reported with no specificity of defect in the infants chlordiazepoxide. Placental passage Tricyclic Antidepressants of the study group, until further ex­ was demonstrated in four deliveries by The tricyclic antidepressants cannot plorations are performed a cautionary Cesarean section. Cord levels were be recommended until further infor­ note to avoid antacids whenever possi- 3 1 substantial and occasionally higher mation is available. Of the three com­ ble seems prudent. than maternal ones when the drug had monly used tricyclic antidepressants — been given intravenously in doses of nortriptyline (Aventyl), amitriptyline 100 mg 5 to 15 hours earlier. Affected (Elavil), and imipramine (Tofranil) — infants show hypotonia, listlessness, nortriptyline has been demonstrated reluctant feeding, and hypothermia to pass the placental barrier, provoking which may require a week to sub­ urine retention in the newborn. This side.20 effect has been noted in older Chlordiazepoxide and mepro­ children. Imipramine has been impli­ bamate accounted for almost 75 per­ cated but not proven to be a cause Anticoagulants cent of the non-barbiturate tran­ of exencephaly, thoracic dysrhaphia, The use of warfarin anticoagulants quilizers that were used for anxiety in cleft palate, and adrenal hypoplasia.26 in pregnancy for the treatment of pregnant mothers in a large study Desmethylimipramine (Pertofrane) thrombophlebitis has been a long group of over 19,000 births followed withdrawal symptoms in neonates, accepted practice. The chronic use of in the early to middle 1960s. When breathlessness, tachypnea, tachycardia, anticoagulants in pregnancy has also either drug was employed during the cyanosis, and profuse sweating have become more common as women with first 42 days of pregnancy, the inci­ been associated with weight loss and prosthetic valves survive corrected dence of congenital anomalies was slowi recovery. 27 mitral stenosis and other lesions to four times higher than paired cohorts carry pregnancies successfully to term. receiving no drug. The differing inci­ Early reports of fetal deaths and mal­ dence of anomalies in the study and formations associated with warfarin control groups became insignificant derivatives appeared in 1970. 3 2 when the drug was employed later in Recent reports call attention to pregnancy.21 The authors noted the Non-Prescribed Analgesics, Antacids, various facial stigmata, notably hazard of the frequent prescription of and Antihistamines hypoplastic noses with narrowed air either drug for anxiety when it was The intake of aspirin is ubiquitous passages.33,34,35 Radiologic studies not yet apparent that the mother was in the population at large and as many have shown stippling and hypoplasia pregnant (ie, in the earliest part of as 80 percent of all pregnant women of terminal phalanges, and stippling pregnancy when risks of teratogenicity take aspirin at sometime during preg­ and irregularity of proximal bones of are highest). Milkovich and Van Den nancy. A study of 272 consecutive the foot.34,35 The stippling of the Berg remark that use of chlordiaze­ deliveries in a university obstetrics epiphyses noted on roentgenograms poxide and meprobamate in women of service disclosed that ten percent of and the appearance of the infant may

THE JOURNAL OF FAMILY PRACTICE, VOL. 4, NO. 6, 1977 1045 mimic a heritable form of chondro­ Antidiabetic Drugs D igitalis, Antihypertensives, Anti­ dysplasia punctata, in which epi­ The use of oral hypoglycemic arrhythmia Drugs, and Diuretics physeal and extraepiphyseal calcifi­ agents in pregnancy was widely cations, a flattened and hypoplastic frowned upon even prior to recent nose, limb asymmetry, rhizomelia, and discussions of accelerated vascular dis­ The effects on the fetus of the eye defects are common.33 The fre­ ease processes possibly associated with various cardiovascular drugs are num­ quency of multiple medication intake their usage. Chlorpropamide and erous and their interrelationships too in these often-difficult pregnancies tolbutamide have both been associated complex to pursue in detail in this may yield abnormalities attributable with multiple congenital anomalies communication. The principal drug to drugs other than the warfarin when used in early gestation.36,37 group, the digitalis glycosides, are groups. Chlorpropamide taken in late preg­ known to cross the placenta and are It would be prudent to avoid, if nancy has been associated with pro­ thought to produce no untoward fetal possible, the use of oral anticoagulants found and prolonged neonatal hypo- effects; but this is presumptive. in the first trimester, with substitution glycemia. Both drugs should be Magnesium sulfate is the most com­ of heparin which does not cross the avoided. monly used agent in treating toxemia placental barrier if anticoagulation is Insulin is the preferred antidiabetic of pregnancy and advanced pre­ considered mandatory. The costliness drug for pregnant diabetic women. It eclampsia. With careful usage, it re­ of heparin and the occasional occur­ is more controllable, has no known mains reasonably safe if maternal mag­ rence of alopecia during long usage are teratogenic effect in man, and its nesium concentrations do not exceed worrisome, but pose no fetal risk. In placental transfer is probably insigni­ 6 to 8 mg/100 ml in the presence of pregnancy management at term, oral ficant. In one animal experiment, adequate renal excretion.22 A series of anticoagulants are customarily stopped chickens treated with insulin before 7,000 infants, in which the newborn two weeks or so before delivery with hatching have shown caudal regression, serum concentrations of magnesium substitution of parenteral heparin if or rumplessness. A small number of were equal to that of their mothers, anticoagulation is to be continued infants of diabetic mothers are born showed no ill effect.39 Excessive levels without interruption. Hemorrhagic dis­ with a syndrome of mild caudal regres­ of magnesium may cause neonatal ease of the neonate secondary to sion. Such pregnancies, however, yield hypermagnesemia with hypotonia and warfarin anticoagulants can thus be far more anomalies than occur in respiratory insuffiency requiring tem­ avoided. nondiabetic gestation. porary ventilatory support. In light of the frequency of its usage in large doses and without serum monitoring, Table 1. Drugs Carrying the Risk of Deformation (Teratogenicity) magnesium sulfate has provoked re­ markably few problems for either

Drug Administered to Mother Possible Effects on Fetus mother or newborn. Hydralazine is perhaps second only to magnesium sulfate in frequency of

Progestogens, estrogens, and androgens Prolonged use in pregnancy can cause usage for toxemia of pregnancy. Un­ masculinization of the fetus. toward effects on the fetus have not Adenocarcinoma of the vagina in women been reported. Reserpine is remark­ o f 16 to 20 years o f age has been seen ably innocuous and, apart from tran­ when threatened ab ortion has been treated with diethylstilbestrol. Phocomelia sient nasal stuffiness, rarely causes and limb reduction defects, recently difficulty in the newborn. linked w ith oral contraceptive usage. Diazoxide, when used in the mother, has been found in the cord Barbiturates When administered in the first trimester, blood at a level of a little less than half Aspirin there is a low but increased risk of fetal Dextroamphetamine malformation. the maternal level. Excretion con­ tinued in the urine for a week in four Diphenyl hydantoin Increasingly linked with a broad variety children who, subjected to prolonged Trimethadione of anomalies when employed in early follow -up, developed alopecia. pregnancy. Another hair abnormality, hyper­ Meprobamate When used in the first six weeks of trichosis lanuginosa, has been re­ pregnancy, the incidence of congenital ported. Unexpectedly advanced bone anomalies rises significantly. age has been observed.40 Hexamethonium, a ganglionic Trimethoprim-sulfisoxazole Unproven effects, but the folic acid antagonist contained suggests danger to blocker has found some use in toxemia the fetus. of pregnancy and has been found in cord blood. It may cause in the new­ Antihistamines Some are teratogenic to animals, but born a paralytic ileus which resolves risks are unproven in humans. with conservative treatment.41 Aminopterin Folic acid antagonists with known risks Alpha methyldopa (Aldomet) has Methotrexate for congenital anomalies. not been adequately studied in preg­ nancy to permit judgments on its

•Modified with permission from Catz CS, Abuelo D: Drugs and pregnancy. Drug Ther Bull 4(4):90, 1974. safety.

1 0 4 6 THE JOURNAL OF FAM ILY PRACTICE, VOL. 4, NO. 6, 1977 Propranolol (Inderal), a beta- to chronic hypokalemia.47 Ethacrynic iodine are as low as 0.2 mg per day adrenergic blocking agent is finding acid and furosemide are potent natriu­ and intensive therapy in adults may be more usage in pregnancy in treatment retics capable of placental passage and as much as 300 mg of potassium of maternal arrhythmias, hyper­ can cause symptomatic hyponatremia iodide every two hours.4 9 tension, and hypertrophic subaortic m the newborn. Both should be Many over-the-counter cough mix­ stenosis. It has been shown to cross avoided in the week prior to delivery, tures and preparations contain iodine the placenta in intravenous usage. 4 2 if possible. Both may be ototoxic to and may not be considered and men­ With continuous usage during preg­ the mother. Their ototoxicity is a tioned to the physician. Their use nancy, it is implicated in fetal depres­ potential risk to the fetus but has not should be elicited and halted in preg­ sion, postnatal hypoglycemia, brady­ been documented. nancy, eliminated in mothers who cardia, and intrauterine growth re­ breast-feed their infants, and used tardation.43,44’45 Growth retarda­ cautiously at all times unless individual tion, however, is not uncommon in efficacy is documented. pregnancies marked by severe maternal In the hyperthyroid mother the hypertension and other illnesses, and course of therapy can affect the fetus. the disease process rather than the Radioactive thyroid I 131 has also medication could be implicated. Hypo­ caused fetal cataracts.23,55 Propyl­ glycemia is apparently caused by the thiouracil or methimazole taken by drug’s interference with the fall in the mother can provoke neonatal blood sugar associated with the normal goiter. epinephrine-m edicated response. Another halide, bromide, has been Bradycardia, frequently seen with pro­ Iodides and the Antithyroid Drugs implicated in profound neonatal hypo­ pranolol administration, results from The adverse reactions to the fetus tonia and depression compatible with cardiac beta receptor blockage. The of maternal iodide therapy of asthma many other causes.56,57 Used in pregnancy in which propranolol is con­ and other pulmonary diseases are be- mothers being treated for emotional tinuously employed is appropriately coming increasingly realized. Iodine disorders, and more frequently as a considered to be “high risk” for the drugs taken after the first three self-prescribed over-the-counter cal- infant and close monitoring is advised months of pregnancy can produce mant, the bromide ion passes trans- for early recognition of the metabolic, congenital goiter in the infant, occa­ placentally with ease. Slow renal clear­ respiratory, and cardiac complications sionally severe enough to provoke ance has resulted in elevated levels which may ensue.43 Since the drug is death from upper airway obstruc­ recorded at 69 days of age, thus metabolized by the functionally im­ tion.50,51,52 In the goitrous patient, depression and hypotension may be mature liver, the expected adult three- thyrotoxicosis is a risk. In the normal protracted. As with the iodides, bro­ hour half-life of the drug45 may be patient subject to excessive iodide mide usage may be casual and not prolonged, explaining the bradycardia intake, goiter, hypothyroidism, and mentioned to the physician. and hypoglycemia which may persist hypersensitivity reactions may result, beyond the first day of life. Considera­ and in both the fetus and nursing tion might be given to dose reduction infant the maternal risk of iodide or to brief discontinuation prior to therapy is shared. Suppression of delivery since this might avoid most organic iodine binding in utero with untoward neonatal effects. depression of thyroid hormone syn­ thesis is suspect.50 Iodides in chronic intake can induce goiter and hypo­ thyroidism in normal children, the mechanism believed to be the impaired release of T4 and blocked uptake of iodine by the thyroid.54 Anticonvulsants in Pregnancy A postpartum risk of maternal The use of anticonvulsants during iodide intake to be considered is its pregnancy presents a worrisome prob­ excretion in breast milk which may lem, but rarely a therapeutic dilemma, constitute a long-term risk to nursing since the decision is infrequently one Diuretics infants under treatment self- or physi­ of suspending treatment in a patient The thiazide diuretics administered cian-prescribed for asthma.50 The whose convulsive disorder can be con­ to mothers in late pregnancy have Committee on Drugs of the American trolled. been shown to provoke neonatal Academy of Pediatrics notes the wide Anticonvulsants are increasingly im­ thrombocytopenia in their newborns, advocacy of the use of iodides in plicated as a cause of abortion and albeit infrequently.46 An interesting chronic asthma, the limited effective­ fetal defect with a broad range of observation in thiazide usage unproven ness of the products in objective abnormalities in morphology and ef­ in human pregnancy is the ultimate studies and the high doses recom­ fects on performance and develop­ development of hypertension in mended. Suggested daily doses for ment.58,59 Complicating clear judg­ mature rats born of pregnancies potassium iodide may represent 10 to ments on their individual toxicities treated with chronic low doses of 30 times the total body iodide con­ are, first, the low incidence of preg­ chlorothiazide, which is believed due tent! Nutritional requirements of nancy complicated by a seizure dis-

THE JOURNAL OF FAMILY PRACTICE, VOL. 4, NO. 6, 1977 1 0 4 7 order (0.1-0.4 percent); and secondly, logical investigations, mothers exposed Barbiturates the relatively small numbers of epilep­ to hydantoin regularly during the first Third trimester maternal ingestion tic women followed during their preg- three months are apparently at a two- of barbiturates may give symptoms in nancies in control groups. In addi­ to threefold risk in the overall fre­ the newborn that are similar to those tion, there is a frequent association of quency of single major malforma- .. 6 0 from opiate withdrawal. Character­ two or more agents to obtain seizure tions. istically, symptoms occur later, often control which may cloud appraisal of a Hill remarks on the mounting in­ after hospital discharge, and are un­ single drug’s teratogenicity. In a recent formation concerning the effect of accompanied by undernutrition. An diphenylhydantoin in the human study including 50,591 pregnant infant may appear normal, followed being, including chromosome break­ women, the 306 women with history by depression and hyperexcitability of of convulsive disorders tended to have age, depression of cellular and humoral onset as early as 63 hours and as late other characteristics associated with immunity, induced folic acid defi­ as one week. Crying, tremors, sleep­ increased risk of malformations: they ciency, enzyme induction, altered lessness, sweating, and hyperacusis were older, gave birth more frequently cortisol metabolism, and carcino- respond well to paregoric or pheno- to stillborn children, and more often genesis, among others. From a barbital, but may continue for two to had hydramnios. Monson and co­ practical viewpoint, it is clear that the six months. Maternal doses as low as workers remarked that malformations majority of infants born of preg­ 60 mg/day throughout the pregnancy were more often noted in black chil­ nancies in which diphenylhydantoin have evoked withdrawal symptoms in dren and that epilepsy was more com­ was employed are free of major de­ the neonate.66 Phenobarbital has not mon among white mothers, providing fects. In the face of its utility, cautious been proven a teratogen, but its fre­ a possible negative factor in a clear usage with monitoring of blood levels quent association as an anticonvulsant association of epilepsy and deformi­ to minimal acceptable levels consistent in a patient group with a higher than ties.60 Two of the more widely used with seizure control is recom­ normal incidence of birth and func­ agents with recent further evidence of mended.60 tional defects is cautionary. teratogenicity are discussed.

Diphenylh ydan to in Trimethadione Diphenylhydantoin has for nearly This oxazolidene derivative widely forty years been a mainstay in the used in the treatment of petit mal treatment of grand mal epilepsy with epilepsy has recently been implicated Hemorrhagic Disorders Associated recognized hematologic, gastric, cu­ in abortion and fetal defect.64,65 Sur­ with Anticonvulsant Therapy in Preg­ taneous, and central nervous system viving children may show facial nancy toxicities. Its congeners are less widely dysmorphia including V-shaped eye­ A coagulation defect similar to vita­ used and, hence, their complications brows, low-set ears with anteriorly min K.! deficiency has been recognized less frequently observed. It is by far folded helix, epicanthal and palatal in neonates born of mothers receiving the most widely used of long-term abnormalities. Performance may also barbiturates and the hydantoins as anticonvulsants. It is a known tera­ be affected by poor speech, psycho­ anticonvulsants through pregnancy. togen in animals,61 a folic acid antago­ motor and statural retardation. Num­ Either or both drugs apparently de­ nist,62 and has produced a high mal­ erous visceral anomalies have been crease the levels of vitamin Kj depen­ formation rate (61/1000) in 98 chil­ reported in liver, kidney, and heart; dent clotting factors. They may pro­ dren exposed during the first trimester and, at the sensory level, both hearing voke a low prothrombin time, low of pregnancy when daily diphenyl- and visual problems have been asso­ levels of factors II, VII, IX, and X and hydantoin was taken by the mother. 5 8 ciated handicaps.64 Limited data of other abnormalities. Typically, bleed­ Infants born of mothers receiving experience in pregnancy makes it im­ ing occurs earlier than with the classic diphenylhydantoin have been observed possible to estimate the true frequency hemorrhagic disease of the newborn, is to have hypoplasia of distal phalanges and risk of fetal defect in trimetha­ more severe, and tends to occur in and nails of hands and feet and ab­ dione. The physician managing the sites unusual for the classic disease normalities of palmar creases.63 Facial pregnant mother should determine that such as the pleural and abdominal dysmorphology, including mouth and the diagnosis of classic petit mal is cavities. Suggested management in­ gum abnormalities, may be striking. secure. The disorder is often over­ cludes measurement of prothrombin Mental retardation and delays in physi­ diagnosed and treated without benefit time at birth, and, if ten percent or if cal development have also been re­ of the distinctive three per second there is evidence of bleeding, adminis­ ported. On the basis of epidemio­ spike and wave tracing. tration of fresh frozen plasma or fac-

1 0 4 8 THE JOURNAL OF FAM ILY PRACTICE, VOL. 4, NO. 6, 1977 tor concentrates and vitamin Kt intra­ Cephaloridine passes the placental born. Congenital malformations result­ venously is indicated.67 barrier with ease after intramuscular ing from narcotics have not been administration. Two grams given to documented. Withdrawal symptoms the mother raised cord blood levels to may follow methadone usage as a no less than 1.0/rg/ml in a controlled heroin replacement in pregnant senes. 7 7 mothers. These infants may show low Erythromycin crosses the placenta birth weights at term and may be but levels are low in relation to ma­ stressed by maternal withdrawal ternal doses, levels of 800 mg or more symptoms.48 A higher incidence of being required before cord levels are “sudden infant death” among the in­ Common Antiinfective Agents detectable.78 fants of narcotic-addicted women has Penicillin, ampicillin, and carbeni- Tetracyclines accumulate in the been reported. 8 1 cillin are considered safe in pregnancy fetal skeleton, may temporarily arrest The use of non-narcotic obstetric and can reach therapeutic levels in the bone growth, often discolor teeth in analgesics, such as mepivacaine and fetus.68,69 Antistaphylococcal drugs the infant when given after the fifth lidocaine, in paracervical anesthesia such as oxacillin and methicillin are month of pregnancy, and have been and continuous caudal anesthesia have partially bound to maternal serum incriminated as a cause of congenital been associated with fetal depression proteins but cross the placenta and can cataract; thus, they should not be and death, or agitation and convul­ reach therapeutic fetal levels7 0 ’ 7 1 given to the pregnant mother48’73 As sions. Exchange transfusion has been without apparent harm. Dicloxacillin a group, the tetracyclines are heavily required to detoxify the infant. has little placental transfer at term, used for adults and children in non- Truncal ataxia, dysarthria, and other and cord levels are detectable but diagnosed febrile illnesses as well as apparently permanent sequelae five low.72 Gentamicin reaches the fetus at upper respiratory tract infections, a years after delivery have been de­ term, but at reduced blood levels. Its practice sharply criticized by pediatric scribed in a survivor and attributed to known ototoxic effect on the mother drug authorities.7 3 Their special risk neonatal intoxication by mepiva­ has not yet been reported in the in provoking renal and hepatic failure caine.82 The increasing acceptance of infant. The effect on the fetus of in the pregnant mother when the an unrestricted and usually nonaddic- kanamycin is at this time uncertain, intravenous route is employed is well tive analgesic, pentazocine (Talwin), as but its ototoxicity to the mother is known and recently, fatal hepato- a substitute for meperidine during well known and a retrospective Japa­ toxicity has been reported in children labor has proven capable of fetal ad­ nese study of treated mothers noted as well.79,80 Rarely a first choice for diction.83,84 Affected infants exhibit deafness in several children. Dihydro­ any but rickettsial diseases, the tetra­ jitteriness, hypertonia, opisthotonus, streptomycin is known to provoke cycline family has little place in the and inability to feed. Phenobarbital, deafness' in the fetus. Chloro- treatment of pregnant women or chlorpromazine, and paregoric have amphenicol can be given to the mother young children and poses unusual risks been used in treatment, as in the and although some transmission to the fetus.52 narcotic withdrawal state in neo- occurs, it apparently does not harm nates.* 8 3 , 8 5 the fetus. Two medications commonly used for urinary tract infections may be troublesome. The nitrofurantoins may cause hemolysis of fetal red cells in G-6-PD dehydrogenase deficiency and the sulfonamides given near term may compete with bilirubin for albu­ min binding and increase the risk of hyperbilirubinemia. 7 3 Trimethoprim-sulfisoxazole com­ binations pose the additional risk, un- proven, of a folic acid antagonist..48 Tobramycin, an aminoglycoside, Prescribed and Nonprescribed Nar­ passes the placenta at 8 to 20 weeks cotics and Nonaspirin Analgesics: Social Customs o f Varying Risk: and appears in fetal blood and am­ Mixed Risks Tobacco, Alcohol, Stimulants, and nionic fluid 74 Of the cephalosporins, It has been long known that the Hallucinogens cephalothin is detectable in amniotic newborn infant of a mother, who has fluid 15 minutes after intravenous either taken narcotics on her own In the infants of mothers who administration of one gram to the initiative or has received them for smoke there is a greater number of still mother, and the level rises for at least obstetric pain, may be bom depressed births and premature births, and in­ the first hour. Cord blood levels may or suffer withdrawal symptoms. The creased perinatal mortality, which was continue to be bactericidal for at least presence of either unexplained depres­ first shown convincingly in the British six hours after a one gram maternal sion in the newborn, or agitation and Perinatal Study.86 The effects of dose has been given.7 5,76 Its potential sweating in the first few days of life, smoking by the mother on the fetus for renal toxicity has not been demon­ should prompt inquiry and, where have been under extensive study in the strated in the fetus. possible, serum sampling of the new­ United States for several years. An

THE JOURNAL OF FAMILY PRACTICE, VOL. 4, NO. 6, 1977 1 0 4 9 Table 2. Practical Considerations in Prescribing Commonly Used Drugs in Pregnancy*

Contraindicated Administered Under Supervision Probably Not Contraindicated

Throughout Pregnancy

Tetracycline analogues Other antibiotics Iron and vitamins (recommended doses)

Amin opteri n / methotrexate Anticonvulsants

Oral hypoglycemics Bronchodilators Occasional Use Only

Diethylstilbestrol Selected antiemetics and diuretics Aspirin (except at term)

Iodides ? Endocrine drugs A lco holic beverages

Psychopharmalogic drugs Simple non-absorbable laxatives

Near Term Heparin

Sulfonamides Selected antihistamines

Novobiocin Warfarin anticoagulants

Warfarin anticoagulants

Salicylates

’ Modified with permission from Catz CS, Abuelo D: Drugs and pregnancy. Drug Ther Bull 4(4):90, 1974.

1 0 5 0 THE JOURNAL OF FAMILY PRACTICE, VOL. 4, NO. 6, 1977 early observation that the infants of Comment directed only when there are definite mothers who smoked regularly during Pregnancy offers a certain amount medical indications, the young fetus pregnancy tend to be smaller — by as of discomfort, a disposition toward can be guarded against many known much as 300 gm — and shorter, is now some new medical problems, such as and many yet-unassessed risks. We can well-established. More sinister were re­ urinary infection, fatigue, and the use judgment again at delivery, avoid­ ports of a persistent lag in growth, musculoskeletal discomforts associated ing the unnecessary risks of drugs that with children remaining smaller than with changing posture. The mother may prejudice the infant’s survival at controls at four and eight years, and may be able to accept much of this if life’s most dangerous moment and in exhibiting lower reading achievement she understands that treatment may the days ahead. scores than those seen in children of have unfavorable effects on her baby. on o o nonsmoking mothers. ■’ A well- With more serious problems such as controlled matched-pair study per­ chronic or life-threatening infection, formed in the United States has con­ seizure disorders, or psychiatric aber­ firmed growth retardation of an aver­ ration, undesirable risks may be un­ age of 250 gm and reduced length in avoidable to maintain the mother’s surviving infants of smoking mothers. well-being or even her survival. Long-term prognosis, however, was Carefully drawn prospective studies favorable; at four and seven years of drug usage in pregnancy, particu­ there were no significant differences in larly those in long-term prepaid group intellectual functions nor in physical health plans with medication proto­ measurements.89 The mode by which cols, afford new opportunities to tobacco affects the fetus is unclear study drug risks in pregnancy. Amnio­ but, clearly, pregnant women should centesis, now frequently done when avoid smoking since the statistical out­ genetic risks of malformation or dis­ come for infants is less favorable from ease are exaggerated, affords another smoking than from nonsmoking occasion for the study of fetal drug women. handling which should receive further Chronic maternal alcoholism has exploration. A high index of clinical been associated with a range of mal­ suspicion will remain as helpful as it formations and intrauterine growth has in the past, when it was discerned retardation termed “the fetal alcohol that a rising incidence of aplastic syndrome.”69 Microcephaly, short anemia was associated with chlor­ palpebral fissures, severe refractive amphenicol intake and that phoco- error, and altered palmar crease con­ melia was linked with thalidomide. Fitch has pointed out that the failure References figurations may be striking findings. 1. Curran WJ: Thalidomide tragedy: Cardiac anomalies are occasionally to look for teratogens may result from The end of a historic medicolegal trial. N Engl J Med 284:481, 1971 noted and the facies may show charac­ the unwarranted presumption that 2. Franklin W, Lowell FC: Unapproved teristic abnormalities.90,91 With­ teratogens always act bilaterally, not­ drugs in the practice of medicine. N Engl J Med 292:1076, 1975 drawal symptoms may present in the ing that animal experiments with 3. Wardell WM: Introduction of new newborn. The occurrence of micro­ acetazolamide and thalidomide have therapeutic drugs in the United States and Great Britain: An international comparison. cephaly, delayed postnatal growth, shown strong preferential unilater­ Clin Pharmacol Ther 14:773, 1973 and the early mental and motor re­ ality.94 Non-drug-linked syndromes, 4. Bleyer WA, Au WY, Lange WA, Sr, et al: Studies on the detection of adverse tardation in 10 out of 11 children too, can be confused with pheno- drug reactions in the newborn. I. Fetal 9 2 typically similar teratogen-provoked exposure to maternal medication. JAMA studied by Jones and co-workers 213:2046, 1970 indicate the seriousness of the prob­ abnormalities as in the Holt-Oram and 5. W ilkins L: Masculinization of female 9 5 fetus due to use of orally given progestins. lem. thalidomide syndromes. JAMA 172:1028, 1960 Amphetamines, now in declining The first two weeks after conception 6. Bern HA, Gorski RA, Kawashima, S: Long term effects of perinatal hormone licit supply, may be teratogenic and pose the most vulnerable fetal period adm inistration. Science 181 :189, 1973 should be avoided by pregnant for severe damage and spontaneous 7. Janerich DT, Piper JM, Glebatis DM: Oral contraceptives and congenital women. Marihuana is widely used and abortion. From the crucial 14th to limb reduction defects. N Engl J Med 56th day of organ development, there 291:697, 1974 no substantial studies confirm un­ 8. Levy EP, Cohen A, Fraser FC: toward fetal effects in humans. Animal may be no awareness of pregnancy; Hormone treatment during pregnancy and congenital heart defects. Lancet 1:611, studies indicating a teratogenic poten­ yet live viral vaccines taken prior to a 1 9 7 3 tial are, however, sufficient to recom­ foreign vacation, or a myriad of other 9. Mellin GW, Katzenstein M: The saga of thalidomide-neuropathy to embroy- mend avoidance of exposure to mari­ medications, generally harmless to the opathy, with case reports of congenital woman, but of definite risk to a fetus, anomalies. N Engl J Med 267:1184, 1962 huana by women who are or may 10. Herbst AL, Scully RE, Robboy ST: become pregnant.93 Lysergic acid if consumed, may be taken at this The significance of adenosis and clear cell adenocarcinoma of the genital tract in diethylamide (LSD), in declining pop­ time. Thalidomide taken during the young females. J Reprod Med 15:5, 1975 ularity among drug abusers, causes in 28th to 42nd gestational day, appar­ 11. Johnson JWC, Austin K L, Jones GS, et al: Efficacity of 17 alpha hydroxy- vitro chromosomal breakage. While ently harmless either before or after, progesterone caproate in the prevention of feared as a teratogen, it has not been a left hundreds pf crippled survivors. premature labor. N Engl J Med 293:675, 1 9 7 5 documented cause of congenital With care and conservative use of 12. Chase, HC: Perinatal mortality: anomalies in human beings. m edications, prescribed or self- Overview and current trends. Clin Perinatol

1051 THE JOURNAL OF FAMILY PRACTICE, VOL. 4, NO. 6, 1977 1 :3 , 1 9 7 4 40. Milner RDG, Chouksey SK: Effects 68. Biro V, Ivan E, Elek E, Arr M: Data 13. Blackwell B: Psychotropic drugs in of fetal exposure to diazoxide in man. Arch on the tissue concentration of antibiotics in use today. JAM A 225:1637, 1973 Dis Child 47:537, 1972 man: Tissue concentrations of semi­ 14. Altman LK: New York Times, p 1, 41. Morris N: Hexamethonium com­ synthetic penicillins in the fetus. Internat May 19,1974 pounds in the treatment of preeclampsia Ztschr Klin Pharmakol, Ther U Toxikol 15. CreeJE, Meyer J, Hailey DM: Diaze­ and essential hypertension during preg­ 3 : 3 2 1 , 1 9 7 0 pam in labour: Its metabolism and effect on nancy. Lancet 1:322,1953 69. Wasz-Hockert O, Nummi S, Vuopala the clinical condition and thermogenesis of 42. Barnes AB: Chronic propranolol ad­ S, et al: Transplacental passage of azido- the newborn. Br Med J 4:251-255, 1973 ministration during pregnancy. J Reprod cillin, ampicillin and penicillin G during 16. Haskell D: Withdrawal of diazepam. Med 5:79, 1970 early and late pregnancy. Scand J Infect Dis JAMA 233:135, 1975 43. Gladstone GR, Hordof A, Gersony 2:125, 1970 17. Rementeria JL, Bhatt K: With­ WM: Propranolol adm inistration during preg­ 70. Prigot A, Froix CJ, Rubin E: Ab­ drawal symptoms in neonates from intra­ nancy : Effects on the fetus. J Pediatr 86: 962, sorption, diffusion and excretion of a new uterine exposure to diazepam. J Pediatr 1 9 7 5 penicillin, oxacillin. In Sylvester JC (ed): 90:123-126, 1977 44. Reed RL, Cheny CB, Fearon RE, et Antimicrobial Agents and Chemotherapy 18. O'Connell B, McCarthy G, Robinson al: Propranolol therapy throughout preg­ 3 : 4 0 2 , 1 9 6 3 AE: Diazepam in the newborn. Br Med J nancy: A case report. Anesth Analg 53:214, 71. MacAulay MA, Molloy WB, Charles 4:610, 1973 1 9 7 4 D: Placental transfer of methicillin. Am J 19. Morselli PL, Principi N, Tognani G, 45. Faulkner SL, Hopkins JT, Boerth Obstet Gynecol 115:58, 1973 et al: Diazepam elimination in premature RC, et al: Tim e required for complete 72. MacAulay MA, Berg SR, Charles D: and full-term infants, and children. J Perinat recovery from chronic propranolol therapy. Placental transfer of dicloxacillin at term. Med 1:133, 1973 N Engl J Med 289:607, 1973 Am J Obstet Gynecol 102:1 162, 1968 20. Stirrat GM, Edington PT: Trans­ 46. Rodriguez SV, Leikin SL, Hiller 73. Palmisano PA, Polhill RB: Fetal placental passage of chlordiazepoxide. Br MC: Neonatal thrombocytopenia associated pharmacology. In Yaffe SJ (ed): Sympo­ Med J 2:729, 1974 with antepartum administration of thiazide sium on Pediatric Pharmacology. Pediatr 21. Milkovich L, Van Den Berg BJ: drugs. N Engl J Med 270:881, 1964 Clin North Am 19:3, 1972 Effect of prenatal meprobamate and chlor­ 47. Grollman A, Grollman EF: The tera­ 74. Bernard B, Garcia S, Ballard C, etal: diazepoxide hydrochloride on human togenic induction of hypertension. J Clin Maternal-placental-fetal transport of tobra­ embryonic and fetal development. N Engl J Invest 41 :710, 1962 mycin. Clin Res 21:308, 1973 Med 291:1268, 1974 48. Catz CS, Abuelo, D: Drugs and 75. M orrow S, Palmisano P, Cassady G: 22. Pomerance JJ, Yaffe SJ: Maternal pregnancy. Drug Ther Bull 4(4):79, 1974 The placental transfer of cephalothin. J medication and its effect on the fetus. Curr 49. Committee on Drugs, American Pediatr 73:262, 1968 Probl Pediatr 4(1):43, 1973 Academy of Pediatrics: Adverse reactions to 76. Paterson L, Henderson A, Lunan 23. Apt L, Gaffney WL: Ocular terato­ iodide therapy of asthma and other pul­ CB, et al: Transfer of cephalothin sodium to gens: A commentary. J Pediatr 87:844, monary diseases: Pediatrics 57:272, 1976 the fetus. J Obst Gynaec Brit Common­ 1 9 7 5 50. Martin MM, Rento RD: Iodide wealth 77:565, 1970 24. 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J Pediatr 80:496, 53. Wolff K: Iodide goiter and the Academy of Pediatrics: Requiem for tetra­ 1 9 7 2 pharmacologic effects of excess iodide. Am cyclines. Pediatrics 55:142, 1975 26. Kuenssberg EV, Knox JDE: Imi- J Med 47:101, 1969 80. Lloyd-Still JD, Grand RJ, Vawter pramine in pregnancy. Br Med J 2:292, 54. Caplin I, Parker GF, Hall JH, et al: GF: Tetracycline hepatoxicity in the dif­ 1 9 7 2 Goiter and myxedema from iodine. J Al­ ferential diagnosis of postoperative jaundice. 27. Webster PAC: Withdrawal symp­ lergy Clin Immunol 32:402, 1961 J Pediatr 84:366, 1974 toms in neonates associated w ith maternal 55. Fisher WD, Voorhees, Gardner LI: 81. Kandall SR: Delayed onset of neo­ antidepressant therapy. Lancet 2:318, 1973 Congenital hypothyroidism in infant fol­ natal drug withdrawal symptoms. Pediatr 28. Palmisano PA, Cassady G: Salicylate lowing maternal I 131 therapy. J Pediatr Ann 4:391, 1975 exposure in the perinate. JAMA 209:556, 62:132,1963 82. Guillozet, N: The risks of para­ 1 9 6 9 56. Rossiter EJR, Rendle-Short TJ: cervical anesthesia: Intoxication and neuro­ 29. Bleyer WA, Breckenridge RT: Congenital effects of bromism. Lancet logical injury of the newborn. Pediatrics Studies on the detection of adverse drug 2:705, 1972 55:533,1975 reactions in the newborn II: The effects of 57. Mangurten HH, Ban R: Neonatal 83. Kopelman AE: Fetal addiction to prenatal aspirin on newborn hemostasis. hypotonia secondary to transplacental bro­ pentazocine. Pediatrics 54:888, 1975 JAMA 213:2049, 1970 mism. J Pediatr 85:426, 1974 84. Goetz RL, Bain RV: Neonatal with­ 30. Haslam RR, Ekert H, Gillam GL: 58. Hill RM: Teratogenesis and anti­ drawal associated with maternal use of Hemorrhage in a neonate possibly due to epileptic drugs. N Engl J Med 289:1089, pentazocine. J Pediatr 84:887, 1974 maternal ingestion of salicylate. J Pediatr 1 9 7 3 85. Klein RB, Blatman S, Little GA: 84:556,1974 59. 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1052 T H E J O U R N A L OF F A M IL Y P R A C T IC E , V O L . 4, NO. 6, 1977