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

      Drug teratogenicity has been demonstrated experimentally for more than 30 years. After the discovery of the thalidomide-induced embryopathies, the fetal dangers of maternal drug ingestion were overemphasized. Accumulation of additional information during the past 15 years has led to a more balanced viewpoint concerning drug teratogenicity. A complex set of circumstances must prevail for a specific teratogenic effect to result. Not only the drug or environmental pollutant in question but also its dose, timing, and frequency of administration as well as the genetic and individual susceptibility of the embryo are important factors. Herein we review the currently available information on drug and environmental effects on the fetus and neonate.
      Since biblical times, scattered reports have been published about the effects of maternal ingestion of drugs on the fetus.
      • Clarren SK
      • Smith DW
      The fetal alcohol syndrome.
      Only within the past few decades, however, have both the physician's interest in and his knowledge of this aspect of obstetrics substantially increased. Unfortunately, the understanding of fetal and placental physiology has not kept pace with the pharmaceutical industry's escalating production of drugs to which the mother, and hence her unborn child, may be exposed. At present, about 80% of all compounds on the drug market are not officially approved for use during pregnancy.
      • Yaffe SJ
      A clinical look at the problem of drugs in pregnancy and their effect on the fetus.
      In 1961, McBride
      • McBride WC
      Thalidomide and congenital abnormalities (letter to the editor).
      established a relationship between limb-reduction malformations (phocomelia) and maternal ingestion of thalidomide during the first trimester of pregnancy. Since that report, the public's consciousness of drug use during pregnancy has been raised to the extent that the safety not only of medications but also of innumerable products available within the home is being questioned.
      Although past reports of maternal drug ingestion are no longer applicable to the therapeutic nihilism of the 1980s, they illustrate the large number of medications that were prescribed for the multitude of minor complaints that arise during pregnancy. The National Institutes of Health Collaborative Perinatal Study, for example, found that more than 90% of pregnant women take at least one prescribed medication during pregnancy.
      • Heinonen OP
      • Slone D
      • Shapiro S
      In several reports published between 1967 and 1982, the mean number of drugs used by pregnant women was 3 to 5.4. More than 60% of women received more than one drug. About 16% received an antiemetic, and more than 25% of women used an antibiotic at some time during pregnancy
      • Heinonen OP
      • Slone D
      • Shapiro S
      • Brocklebank JC
      • Ray WA
      • Federspiel CF
      • Schaffner W
      Drug prescribing during pregnancy: a controlled study of Tennessee Medicaid recipients.
      • Forfar JO
      • Nelson MM
      Epidemiology of drugs taken by pregnant women: drugs that may affect the fetus adversely.
      • Kullander S
      • Källén B
      A prospective study of drugs and pregnancy. Parts 1–4.
      • Nora JJ
      • Nora AH
      • Sommerville RJ
      • Hill RM
      • McNamara DG
      Maternal exposure to potential teratogens.
      • Rayburn W
      • Wible-Kant J
      • Bledsoe P
      Changing trends in drug use during pregnancy.
      (Table 1).
      Table 1Drugs Commonly Used During Pregnancy
      Percentage use
      DrugForfar
      * Cited in “News of Hospital Interest.”
      • News of Hospital Interest
      Drugs in the ‘fetal echosphere.’.
      Nelson and Forfar
      • Nelson MM
      • Forfar JO
      Associations between drugs administered during pregnancy and congenital abnormalities of the fetus.
      Alcohol88
       Occasional use43
       Regular use31
       Heavy use14
      Iron8282
       First trimester26.4
      Tobacco57
      Analgesics4814.8
      Vitamins4039.8
      Antacids3411
      Antiemetics16.3
      Antibiotics15.6
      Cough medicine8.3
      * Cited in “News of Hospital Interest.”
      • News of Hospital Interest
      Drugs in the ‘fetal echosphere.’.
      In this article, our purpose is not to produce another compendium of drugs with known teratogenic effects, suspected teratogenicity, or presumed safety.
      • Adamsons Jr, K
      • Joelsson I
      The effects of pharmacologic agents upon the fetus and newborn.

      Shepard TH: Teratogenicity from drugs—an increasing problem. DM, June 1974, pp 1–32

      • Sutherland JM
      • Light IJ
      The effect of drugs upon the developing fetus.
      • Tuchmann-Duplessis H
      Influence of certain drugs on the prenatal development.
      We will instead describe the possible pathways of fetal teratogenicity and then review in some detail the evidence for and against the effects on the fetus of commonly used medications during pregnancy.
      Neither conception nor development can occur in a vacuum. Hence, the environment of not only the fetus in utero but also the sperm within the testes, the egg within the ovary, and the mother within her home or place of employment must be considered.

      DRUG EFFECT ON SPERMATOZOA

      Recently, the effects of the ingestion of drugs by males on the formation of sperm, the maturation and motility of sperm, and the development of the fetus and infant have been investigated. Within many animal species, litter size, birth weight, and neonatal survival decreased after the ingestion of lead, morphine, methadone, ethanol, caffeine, or thalidomide by the male before mating.
      • Soyka LF
      • Joffe JM
      Male mediated drug effects on offspring.
      Several clinical studies confirmed or implicated paternal exposure to drugs (caffeine, cigarettes, and anesthetic gases) when both reproductive loss and the incidence of low-birth-weight infants were increased.
      • Soyka LF
      • Joffe JM
      Male mediated drug effects on offspring.
      • Weathersbee PS
      • Olsen LK
      • Lodge JR
      Caffeine and pregnancy: a retrospective survey.
      • Yerushalmy J
      The relationship of parents' cigarette smoking to outcome of pregnancy—implications as to the problem of inferring causation from observed associations.
      In litters of Chinese hamsters, Weathersbee and associates
      • Weathersbee PS
      • Ax RL
      • Lodge JR
      Caffeine-mediated changes of sex ratio in Chinese hamsters, Cricetulus griseus.
      found a significant skewing of the sex ratio toward females (61.4%) (control animals, 49.2%) after caffeine (0.02 g/100 ml) was added to the drinking water of the males. The authors hypothesized that a selective inhibition of Y-chromosome-bearing spermatozoa by caffeine might be responsible for the sex differences found in their study. Thus, the astute clinician must now consider the drugged sperm as a potentially possible preconception source of teratogenicity.
      • Editorial
      The drugged sperm.
      Soyka and Joffe
      • Soyka LF
      • Joffe JM
      Male mediated drug effects on offspring.
      summarized the possible mechanisms involved in the effect of paternal ingestion of drugs on fetal outcome: (1) an indirect effect on the normal metabolic and endocrinologic function of the male, (2) damage to the spermatozoa themselves, and (3) the potential of the drug within the ejaculate to affect either the intrauterine environment or the newly fertilized ova.

      DRUG EFFECT ON THE GERM CELL

      The primordial germ cells appear by the third week after conception. They originate within the yolk sac and then migrate to the developing gonad. In the gonad, the germ cells divide to form oogonia, which in turn differentiate into the larger primary oocytes. By birth, the primary oocyte has completed the prophase of the first meiotic division. It remains in this resting stage until the female attains sexual maturity. A still undefined process dictates when ovulation of a specific oocyte will occur. While awaiting ovulation, the oocyte may be exposed to innumerable compounds and chemotherapeutic agents.
      To assess the possibility of maternal oocyte damage from cytotoxic agents, Van Thiel and associates
      • Van Thiel DH
      • Ross GT
      • Lipsett MB
      Pregnancies after chemotherapy of trophoblastic neoplasms.
      analyzed 88 pregnancies in 50 women who had been treated for gestational trophoblastic disease. In this admittedly limited study, no increase in fetal wastage or congenital abnormalities was found. Hence, the authors postulated that cells in the resting phase may be relatively immune to these agents.

      DRUG EFFECT ON THE EMBRYO

      Once fertilization has occurred, the blastocyst may be affected by alterations of its tubal environment. During this phase of development, drugs reach the embryo by means of the interstitial fluid and thus are present in much lower concentrations. Although no major congenital malformations have been attributed to administration of drugs during this period, the potential for destruction of the embryo exists. Intrauterine growth retardation has been observed in the offspring of pregnant rabbits that, during preimplantation, had been given an “environmental cocktail” of ethanol, nicotine, caffeine, sodium salicylate, and dichlorodiphenyltrichloroethane (DDT). Thus, exposure at this stage of pregnancy can produce embryonic damage that is reparable.
      • Fabro S
      • McLachlan JA
      • Dames NM
      Chemical exposure of embryos during the preimplantation stages of pregnancy: mortality rate and intrauterine development.
      Each organ system has a critical period after conception during which its development may be disrupted. By the end of the embryonic period (56th day of gestation), the location and general shape of the various organ systems have been established. Consequently, the teratogenic effects of various medications are greatly reduced.
      • Tuchmann-Duplessis H
      Influence of certain drugs on the prenatal development.
      Histogenesis, however, is far from complete.

      DRUG EFFECT ON THE FETUS

      The fetal period extends from the eighth week after conception until the end of intrauterine life. Although the central nervous system continues to proliferate throughout this stage of development, specific areas of the brain have their own critical periods for differentiation. This process necessitates the attainment of adult size by the nerve cell, maturation of the enzymatic processes of the cell, and development of the capacity to respond to both external and internal stimuli. Myelinization begins as early as the fifth month in utero, follows the order in which tracts were formed, and is not completed until adolescence. This process results in a severalfold increase in the rate of conduction. Thus, in effect, administration of drugs to the mother throughout pregnancy can potentially alter development of the nervous system and, hence, postnatal function.
      • Monie IW
      Development and physiology of the fetus.
      • Windle WF
      Labor and delivery should be considered a specific subdivision of the fetal period. Transport of drugs is affected by uterine contractility and the secondary alterations in blood flow that this produces. Medications that were equilibrated between the mother and the fetus and were metabolized by the former must suddenly, after delivery, be handled by the neonate. The enzymatic processes necessary for the metabolism of drugs by the liver are not fully developed in the neonate. In addition, the kidney of the newborn has limited excretory capabilities. Both the gestational age and the duration of extrauterine life contribute to maturation of renal function. At term, the creatinine clearance is 23 ml/min. By day 14, the creatinine clearance has increased to 50 ml/min; at 2 months, it is 69 ml/min; and by 1 year of age, an adult level of renal function has been obtained
      • Grupe WE
      The kidney.
      (Table 2).
      Table 2Effects of Drugs on the Developing Human
      Stage of reproductive developmentEffect
      Spermatozoa
      • Increased reproductive loss
      • Low birth weight
      OocyteNo effect noted to date
      Placenta
      • Alteration in uteroplacental blood flow
      • Interference with active transport
      Embryo
      • Primary period of potential teratogenesis
      • Congenital anomalies
      Fetus
      • Growth retardation
      • Alteration of external genitalia
      • Central nervous system effects
      • Altered skeletal growth
      Neonate
      • Respiratory depression
      • Neurobehavioral abnormalities
      • Hypothermia
      • Hypotonia
      • Narcotic withdrawal
      • Learning disabilities

      DRUG EFFECT ON SUBSEQUENT REPRODUCTIVE FUNCTION

      Some investigators have shown that administration of phenobarbital to gravid female rats results in reproductive dysfunction in both male and female offspring. Experimental evidence seems to indicate that phenobarbital acts at or above the level of the hypothalamus. The administration of phenytoin during the period of neuroendocrine differentiation similarly adversely affects the fertility of offspring.
      • Sonawane BR
      • Yaffe SJ
      Delayed effects of drug exposure during pregnancy: reproductive function.

      NEUROBEHAVIORAL EFFECTS OF DRUGS ON THE FETUS

      The effect of drugs on the developing human need not be restricted to embryotoxicity, mutagenicity, or teratogenicity. By altering the time and the rate of cellular development, a medication may produce long-term effects that are not demonstrable to the observer. Because the brain continues to develop not only through the embryonic and fetal periods but also well into infancy, the intricate interrelationship between two adjacent neurons could potentially be affected. It is extremely difficult, however, to relate subtle infant neurologic abnormalities to maternal ingestion of drugs during pregnancy. With some impairments, either genetic or environmental (for example, drug use) factors could be of primary importance. Once delivery ensues, the neonate is subjected to a host of maternal, socioeconomic, and environmental factors that have the potential to modify any intrauterine effects that might have occurred. By using the laboratory animal, one can suitably control many environmental factors; however, extrapolations from the mammal or even the primate model to humans must be made with extreme caution.
      Rodier
      • Rodier PM
      Correlations between prenatally-induced alterations in CNS cell populations and postnatal function.
      showed that the time of ingestion of a drug is critical in assessing the resultant effect on the neonate. Drug-induced lesions of the central nervous system on embryonic day 15 in the mouse resulted in hyperactivity, delays in visual development, and changes in emotional behavior. When the same medication was given either on embryonic day 19 or on postnatal day 3, the effect was noted primarily on motor tasks such as righting.
      Spyker and associates
      • Spyker JM
      • Sparber SB
      • Goldberg AM
      Subtle consequences of methylmercury exposure: behavioral deviations in offspring from treated mothers.
      investigated the long-term developmental and behavioral effects of maternal ingestion of methyl mercury in mice. They found that although no overt signs of exposure to mercury were noted in utero, subtle deviations in behavior were apparent at various stages of postnatal life. When placed in water, for example, the mice that had been exposed to mercury in utero swam differently from the control mice. At 2½ months, gait disturbances were apparent, and at 2 years, results of various neuromuscular tests were still abnormal. As the animals exposed to mercury in utero reached old age, the incidence of muscular atrophy and general debilitation was also higher. Longitudinal studies of the Minamata Bay (Japan) victims who were exposed to methyl mercury may yet detect similar subtle behavioral abnormalities.
      • Takeuchi T
      Biological reactions and pathological changes in human beings and animals caused by organic mercury contamination.
      Although reports on amphetamine teratogenicity are conflicting, normal intrauterine and extrauterine growth has been found after fetal exposure to amphetamines.
      • Billing L
      • Eriksson M
      • Larsson G
      • Zetterstrom R
      Amphetamine addiction and pregnancy. III. One year follow-up of the children: psychosocial and pediatric aspects.
      A neurobehavioral effect of the drug has been demonstrated in laboratory animals.
      • Nora JJ
      • McNamara DG
      • Fraser FC
      Dexamphetamine sulphate and human malformations (letter to the editor).
      • Nora JJ
      • Vargo TA
      • Nora AH
      • Love KE
      • McNamara DG
      Dexamphetamine: a possible environmental trigger in cardiovascular malformations (letter to the editor).
      Hitzemann and associates
      • Hitzemann BA
      • Hitzemann RJ
      • Brase DA
      • Loh HH
      Influence of prenatal d-amphetamine administration on development and behavior of rats.
      administered 1 or 3 mg/kg of d-amphetamine sulfate (a pharmacologic dose) to rats subcutaneously twice daily from the fifth day of gestation until term. For the 3-month duration of the study, the amphetamine-exposed offspring showed a considerable reduction in the ability to habituate and a concomitant increase in activity for 10 to 20 minutes when placed in new surroundings. In addition, these animals had a decreased concentration of catecholamines within the brainstem. These differences between the study group and the control group might serve as a model for the minimal brain dysfunction syndrome seen in children, inasmuch as Snyder and Meyerhoff
      • Snyder SH
      • Meyerhoff JL
      How amphetamine acts in minimal brain dysfunction.
      found a correlation between this learning and behavioral disorder and a deficiency of norepinephrine in the brain.
      Methadone has been found to be teratogenic in some laboratory animals but not in others.
      • Geber WF
      • Schramm LC
      Comparative teratogenicity of morphine, heroin and methadone in the hamster (abstract).
      • Markham JK
      • Emmerson JL
      • Owen NV
      Teratogenicity studies of methadone HCI in rats and rabbits.
      To date, no reports of teratogenicity in the human have been published.
      • Blinick G
      • Jerez E
      • Wallach RC
      Methadone maintenance, pregnancy, and progeny.
      Besides the acute signs of narcotic withdrawal immediately after delivery, hyperactivity and sleep disturbances are believed to persist in the neonate for 2 years after delivery.
      • Ting R
      • Keller A
      • Berman P
      • Finnegan LP
      Follow-up studies of infants born to methadone-dependent mothers (abstract).
      Hutchings and co-workers
      • Hutchings DE
      • Towey JP
      • Gorinson HS
      • Hunt HF
      Methadone during pregnancy: assessment of behavioral effects in the rat offspring.
      administered methadone to pregnant rats from day 8 of gestation until term. During adulthood, the offspring showed no differences in learning ability from that of a control group of animals. The methadone-exposed rats, however, had a significantly higher rate of response to each of the given tasks. They also displayed difficulties in performing tasks that required paced responses to a stimulus. Hence, this study suggests that opiates, or their derivatives, may produce a long-term effect characterized by increased behavioral arousal. Szeto
      • Szeto HH
      Effects of narcotic drugs on fetal behavioral activity: acute methadone exposure.
      arrived at a similar conclusion when studying the effect of acute methadone exposure on fetal behavioral activity. His results indicated that methadone suppressed fetal quiet and rapid eye movement sleep and thereby produced a hyperactive state.
      Studies from several laboratories
      • McGinty JF
      • Ford DH
      Effects of prenatal methadone on rat brain catecholamines.
      have confirmed that levels of biogenic amine neurotransmitters are altered in the offspring of perinatally addicted rats. A delay in cellular maturation of the brain may produce deficits in synaptogenesis. These effects could be of importance in the behavioral alterations noted in the perinatal opiate syndrome.
      • Slotkin TA
      Effects of perinatal exposure to methadone on development of neurotransmission: biochemical bases for behavioral alterations.
      Similarly, diazepam, when administered to pregnant rats during the last week of gestation, induces behavioral and neurochemical alterations in the offspring which are evident long after the drug has disappeared from the brain.
      • Kellogg CK
      • Chisholm J
      • Simmons RD
      • Ison JR
      • Miller RK
      Neural and behavioral consequences of prenatal exposure to diazepam.
      Wilson and associates
      • Wilson GS
      • Desmond MM
      • Wait RB
      Follow-up of methadone-treated and untreated narcotic-dependent women and their infants: health, developmental, and social implications.
      studied 68 narcotic-dependent women (29 heroin-dependent and 39 methadone-treated women) who gave birth to 69 live-born infants; a drug-free control group was also studied. At a 1-year follow-up examination, mean developmental scores were within the normal range for both groups. Subtle signs of neurodevelopmental dysfunction (reduced attention span), however, were significantly more common in the children of the drug group than in those of the drug-free control subjects. These signs may be early indications of potential learning or behavioral deviance that may surface when the children enter school.
      On the basis of the aforementioned studies, if certain types of minimal brain dysfunction (such as restlessness, hyperactivity, and poor concentration) have a neurochemical basis, maternal ingestion of drugs must be carefully evaluated as a possible cause.
      • Weiss B
      • Spyker JM
      Behavioral implications of prenatal and early postnatal exposure to chemical pollutants.
      First-trimester exposure to progestins or estrogens has been reported to affect personality development.
      • Reinisch JM
      Prenatal exposure of human foetuses to synthetic progestin and oestrogen affects personality.
      Progesterone-exposed subjects were found to be more independent and individualistic, whereas members of the estrogen-treated group were more group-oriented and less self-sufficient than their collective sibling control subjects. Additional longitudinal studies on the long-term effects of in utero exposure to hormones are needed.
      Obstetric premedication may also have an effect on the neonate. Stechler
      • Stechler G
      Newborn attention as affected by medication during labor.
      showed that babies whose mothers received large doses of analgesia during labor were less attentive for the first 4 days after delivery than those babies whose mothers received smaller doses.
      Brackbill and co-workers
      • Brackbill Y
      • Kane J
      • Manniello RL
      • Abramson D
      Obstetric premedication and infant outcome.
      evaluated 25 babies whose mothers had received different doses of meperidine in labor. Rates of habituation to an auditory orienting reflex and to the Neonatal Behavioral Assessment Scale were studied. Infants of mothers who had not been premedicated with meperidine habituated twice as fast as infants whose mothers had been premedicated. In effect, the infants of the former group were able to assess the inutility of the auditory stimulus much more rapidly. Infants whose mothers had received no medication performed more capably on many of the items of the Neonatal Behavioral Assessment Scale. Consolability (a measure of inhibitory capacity) and cuddliness were both higher in babies of nonpremedicated mothers. This difference may be of importance for the appropriate development of maternal-infant bonding in the early postpartum period. Finally, the infants of premedicated mothers had fewer changes in state—for the most part, they remained asleep or drowsy. Additional effects of maternal administration of meperidine on the neonate include respiratory depression and feeding difficulties for as long as 48 hours after delivery.
      • Wiener PC
      • Hogg MIJ
      • Rosen M
      Effects of naloxone on pethidine-induced neonatal depression.

      PLACENTAL TRANSPORT OF DRUGS

      By the fourth to fifth week after conception, the placental circulation has been established. This functions as a transporter of oxygen and nutrients to the rapidly growing embryo. Transport of drugs across the placenta occurs primarily by simple diffusion and hence depends on the molecular weight, lipid solubility, the percentage and tenacity of protein binding, and the concentration gradient of the particular drug under evaluation. As the placenta matures, the distance between the maternal and fetal circulations is reduced, the capillaries of the villi enlarge severalfold, and the amount of connective tissue diminishes.
      • Clewell WH
      • Stys SJ
      • Battaglia FC
      Fetal pathophysiology.
      Hence, diffusion is further facilitated. Although the placenta is virtually impermeable to compounds with a molecular weight of more than 1,000 (for example, heparin), most medications have a molecular weight of less than 500. Therefore, size is rarely a factor in the transfer of drugs between the maternal and fetal circulations.
      The concept of the placenta as a “barrier” between two independent organisms is, at best, simplistic. This belief is derived from the observations that substances of a molecular weight of more than 1,000 do not cross the placenta and that substances of low lipid solubility (for example, succinylcholine) diffuse across the placenta only if the concentration gradient is extremely high.
      • Moya F
      • Kvisselgaard N
      The placental transmission of succinylcholine.
      In rabbits, Kvisselgaard and Moya
      • Kvisselgaard N
      • Moya F
      Investigation of placental thresholds to succinylcholine.
      demonstrated that 1,000 times the maternal paralyzing dose was necessary to permit the passage of succinylcholine to the fetus. For some substances, the barrier concept functions in reverse: vitamin C may rapidly cross the placenta from the mother to the fetus but cannot return across the placenta to the mother.
      • Barnes AC
      Most drugs are fat-soluble. This characteristic greatly facilitates bidirectional transport across the placental barrier.
      The diffusion of specific drugs (for example, penicillin, barbiturates, and ethanol) may occur within minutes after administration to the mother. Equilibration of a drug between the mother and the fetus ranges from 2 minutes to 2 hours with various medications. Serum levels within the fetus are generally between 30 and 75% of the concentration in the mother's serum. Some agents—for example, diazepam—are found in substantially higher concentrations within the fetus.
      • Cree JE
      • Meyer J
      • Hailey DM
      Diazepam in labour: its metabolism and effect on the clinical condition and thermogenesis of the newborn.
      Some drugs may actually interfere with the active transport function of the placenta.
      • Juchau MR
      Drug biotransformation reactions in the placenta.
      Maternal hypotension, hemorrhage, and medical complications (pregnancy-induced hypertension, diabetus mellitus, and so forth) affect the maternal-fetal circulation and hence diffusion of drugs.
      • Moya F
      • Smith BE
      Uptake, distribution and placental transport of drugs and anesthetics.

      VAGARIES OF TERATOGENICITY

      After one reviews the possible pathways of teratogenicity, it seems almost inevitable that every fetus will be affected by either environmental factors or a maternally ingested drug. Wilson,
      • Wilson JG
      Environmental factors: teratogenic drugs.
      however, estimated that only 2 or 3% of developmental defects have a known drug or environmental origin. It should be remembered that the teratogenic effect of a particular drug may be specific to the species. The rabbit, for example, is highly susceptible to thalidomide as a teratogen, whereas the rat is relatively resistant to this drug. Hence, drug teratogenicity in animals cannot be uncritically extrapolated to humans. Individual sensitivity to a specific medication may likewise occur within a species. In addition, gestational age, drug dose, duration of administration, maternal-fetal blood pH gradient, differences in protein binding, variations in absorption and transplacental transfer, placental metabolism, and environmental factors must be considered. Just as a particular drug may cause several different congenital anomalies, a specific abnormality may be caused by many different drugs or environmental factors.
      • Yaffe SJ
      A clinical look at the problem of drugs in pregnancy and their effect on the fetus.
      • Barnes AC
      Occasionally, the incidence of congenital malformations is reduced after exposure to specific drug combinations. Vitamins of the B group, for example, have been shown to protect against the effects of hyper-vitaminosis A. Other drug combinations have been implicated in the genesis of induced embryotoxicity in both humans and experimental animals. Chemical interactions during pregnancy may be of two distinct types: (1) pharmacokinetic (that is, one drug interacts with another drug during absorption, distribution, or elimination) and (2) pharmacodynamic (that is, one drug modifies the action of another at a specific receptor).
      • Fraser FC
      Interactions and multiple causes.
      Gibson and Becker
      • Gibson JE
      • Becker BA
      Effect of phenobarbital and SKF 525-A on the teratogenicity of cyclophosphamide in mice.
      treated mice with phenobarbital and the alkylating agent cyclophosphamide. Embryotoxicity decreased because of the enhancement of drug metabolizing enzymes by phenobarbital. Pretreatment with SKF 525A (a compound that specifically inhibits the metabolic function of the liver), however, increased the toxic response to cyclophosphamide.
      Harbison and Becker
      • Harbison RD
      • Becker BA
      Effect of phenobarbital on SKF 525A pretreatment on diphenylhydantoin teratogenicity in mice.
      performed a similar experiment with use of phenytoin instead of cyclophosphamide. The results were comparable to those in the aforementioned study—a decrease in embryotoxicity with use of phenobarbital and an increase with use of SKF 525A. Thus, although maternal exposure to a single drug with embryotoxic potential may not be of overwhelming concern, the possible interaction with other medications taken concomitantly must be considered.
      • Skalko RG
      • Kwasigroch TE
      The interaction of chemicals during pregnancy: an update.
      The interplay of all these factors makes it very difficult to establish a direct relationship between a specific congenital malformation and the patient's drug history. Only the rarity of the congenital anomaly (phocomelia) associated with thalidomide led to rapid detection of the drug as a teratogen.
      • McBride WC
      Thalidomide and congenital abnormalities (letter to the editor).
      If the malformation produced by this medication had naturally occurred at a higher frequency, the time required to detect its teratogenic potential would have been prolonged.
      • Yaffe SJ
      A clinical look at the problem of drugs in pregnancy and their effect on the fetus.
      • Hill RM
      • Stern L
      Drugs in pregnancy: effects on the fetus and newborn.
      At present, the rat remains the reference animal for teratogenic investigation, because it has genetic stability, a high fertility rate, and only rare spontaneous malformations. The rabbit and the mouse are much more susceptible to teratogens, and the rate of spontaneous malformations is higher. The susceptibility of monkeys to various drugs is highly variable. Wilson and Fradkin
      • Wilson JG
      • Fradkin R
      Comparison of teratogenic sensitivity of rats and rhesus monkeys (abstract).
      showed that the teratogenic dose of specific drugs in rats must be increased 3 to 20 times to produce a similar effect in monkey fetuses. This finding once again illustrates the species specificity of teratogens and raises the possibility that the rat is too sensitive to the teratogenic effects of drugs to be used as a single reference animal. Hence, a number of species need to be tested with each drug under investigation. The cell culture approach, although widely criticized, might also be used to study drug effects on the fetus.
      • News of Hospital Interest
      Drugs in the ‘fetal echosphere.’.
      • Tuchmann-Duplessis H
      Influence of certain drugs on the prenatal development.
      Despite the widespread use of contraceptives, most pregnancies remain unplanned. The average time for the first antenatal visit is about the third month; however, the higher the socioeconomic level of the gravida, the earlier she seeks prenatal care. With a home pregnancy test now readily available, some women are even being examined just after the last menstrual period. Although the obstetrician must carefully consider what medications can be given to a pregnant patient, in most instances, organogenesis of the developing fetus is complete before the first visit.
      The drugs, other ingested products, and environmental agents that are reviewed herein were selected because of their pervasiveness in American life. Although a direct teratogenic effect on humans has not been substantiated for every product, results of animal studies have at least implied an association.

      CAFFEINE

      The data on caffeine as a teratogen are derived from studies that link high doses of the compound with limb-reduction abnormalities and other birth defects in the offspring of rats. The level of caffeine administration by gavage that produced the limb deformities and low-birth-weight pups in rats was 80 to 125 mg/kg (equivalent to 12 to 24 cups of coffee per day).

      Collins TFX, Welsh JJ, Black TN, Collins EV: A comprehensive study of the teratogenic potential of caffeine in rats when given by oral intubation. J Environ Toxicol Pathol (in press)

      There seems to be little doubt that caffeine is a teratogen in rats.
      • Nishimura H
      • Nakai K
      Congenital malformations in offspring of mice treated with caffeine.
      The embryotoxicity of caffeine in the rat, however, is complicated by a variety of factors, such as species and strain specificity, route of administration, and dosage. Yielding and co-workers
      • Yielding LW
      • Riley TL
      • Yielding KL
      Preliminary study of caffeine and chloroquine enhancement of x-ray induced birth defects.
      have shown that caffeine may function as a coteratogen—that is, may potentiate the embryotoxic effect of other teratogenic agents. Skalko and Kwasigroch
      • Skalko RG
      • Kwasigroch TE
      The interaction of chemicals during pregnancy: an update.
      treated mice with both phenytoin and caffeine. Pretreatment with caffeine enhanced the embryotoxicity of phenytoin, and phenytoin potentiated the maternal toxicity of caffeine. Those investigators postulated that the serum level of each agent was increased by the action of the other.
      Borlée and associates
      • Borlée I
      Cited by Jacobson MF: Diet and cancer (letter to the editor).
      • Lechat MF
      • Borlée I
      • Bouckaert A
      • Misson C
      Caffeine study (letter to the editor).
      found that the consumption of coffee was statistically higher (P<0.05) in a group of 202 mothers of newborn children with birth defects than in a control group of 175 mothers of normal children. Weathersbee and associates
      • Weathersbee PS
      • Olsen LK
      • Lodge JR
      Caffeine and pregnancy: a retrospective survey.
      found an increase in fetal wastage with a daily caffeine intake of 600 mg or greater. Because these were retrospective studies, several methodologic and other confounding variables could not be controlled.
      Kirkinen and associates
      • Kirkinen P
      • Jouppila P
      • Koivula A
      • Vuori J
      • Puukka M
      The effect of caffeine on placental and fetal blood flow in human pregnancy.
      studied the acute effect of maternal ingestion of two cups of coffee in 20 pregnancies during the third trimester. Intervillous blood flow, which was measured by use of xenon-133, decreased an average of 25%. Inasmuch as this effect was transient and sufficiently mild, no alteration was noted in umbilical venous blood flow. Thus, although an effect of maternal use of caffeine can be demonstrated, whether this effect is a potential perinatologic risk remains to be elucidated.
      Linn and co-workers
      • Linn S
      • Schoenbaum SC
      • Monson RR
      • Rosner B
      • Stubblefield PC
      • Ryan KJ
      No association between coffee consumption and adverse outcomes of pregnancy.
      interviewed 12,205 women to assess the relationship between consumption of coffee and adverse outcome of pregnancy. The malformation rate was not increased among the newborns of the coffee drinkers. Furthermore, the incidence of low birth weight and shortened gestation in neonates was not affected by maternal consumption of coffee. In a case-control study of 2,030 malformed infants, Rosenberg and associates
      • Rosenberg L
      • Mitchell AA
      • Shapiro S
      • Slone D
      Selected birth defects in relation to caffeine-containing beverages.
      found that coffee was not a major teratogen with regard to the defects studied (cleft lip, cleft palate, or both; cardiac defects; pyloric stenosis; neural tube defects; and inguinal hernia).
      Caffeine has also been found in breast milk. Consequently, moderate consumption of products that contain caffeine (coffee, cola drinks, and so on) may explain the wakefulness and irritability noted in the sensitive nursing infant.
      • Gardner D
      • Rayburn W
      Drugs in breast milk.

      FERROUS SULFATE

      An increased incidence of congenital malformations was found in fetuses of women who ingested iron-containing drugs during the first 8 weeks of pregnancy.
      • Nelson MM
      • Forfar JO
      Associations between drugs administered during pregnancy and congenital abnormalities of the fetus.
      Nelson and Forfar
      • Nelson MM
      • Forfar JO
      Associations between drugs administered during pregnancy and congenital abnormalities of the fetus.
      particularly implicated ferrous sulfate. McBride
      • McBride WG
      The teratogenic action of drugs.
      and others, however, found no relationship between ingestion of iron and congenital anomalies.
      The incidence of gastrointestinal upset during the first 2 or 3 months of pregnancy is quite high. Iron may exacerbate the patient's symptoms. To maintain her hemoglobin concentration during pregnancy, the gravid patient should begin iron therapy by 20 weeks of gestation. Hence, prenatal vitamins need not be taken until after organogenesis.

      BENDECTIN

      Bendectin was first marketed as an antinauseant in 1956. Richardson-Merrell, Inc., estimated that 25% of pregnant women in the United States were taking this medication at that time.
      • Kolata GB
      How safe is Bendectin?.
      Its original ingredients were dicyclomine (an antispasmodic), doxylamine (an antihistamine), and pyridoxine (antinauseant properties). In 1976, dicyclomine was removed from this mixture. In 1979, Rothman and associates
      • Rothman KJ
      • Fyler DC
      • Goldblatt A
      • Kreidberg MB
      Exogenous hormones and other drug exposures of children with congenital heart disease.
      reported a weak association between Bendectin and congenital heart defects. Because their study was subject to recall bias, the authors believed that the results were, at best, “exploratory” and thus needed confirmation. In a study free of recall bias, Smithells and Sheppard,
      • Smithells RW
      • Sheppard S
      Teratogenicity testing in humans: a method demonstrating safety of Bendectin.
      who compared results with those in 11,000 control subjects, found no evidence for an increase in birth defects in 2,000 women who had taken the medication during pregnancy.
      To date, most studies that have evaluated Bendectin have found no increase in incidence of birth defects associated with its use during the first trimester.
      • Cordero JF
      • Oakley GP
      • Greenberg F
      • James LM
      Is Bendectin a teratogen?.
      • Milkovich L
      • van den Berg BJ
      An evaluation of the teratogenicity of certain antinauseant drugs.
      • Mitchell AA
      • Rosenberg L
      • Shapiro S
      • Slone D
      Birth defects related to Bendectin use in pregnancy. I. Oral clefts and cardiac defects.
      • Shapiro S
      • Heinonen OP
      • Siskind V
      • Kaufman DW
      • Monson RR
      • Slone D
      Antenatal exposure to doxylamine succinate and dicyclomine hydrochloride (Bendectin) in relation to congenital malformations, perinatal mortality rate, birth weight, and intelligence quotient score.
      • Morelock S
      • Hingson R
      • Kayne H
      • Dooling E
      • Zuckerman B
      • Day N
      • Alpert JJ
      • Flowerdew G
      Bendectin and fetal development: a study at Boston City Hospital.
      Because of its widespread use for many years, Bendectin has been more thoroughly studied than any other antinauseant during pregnancy. Inasmuch as about 30 million women have taken the drug worldwide, the likelihood of its altering the rate of congenital malformation to an appreciable extent without detection to date seems extremely unlikely. Nevertheless, because of the number of lawsuits brought against the manufacturer, Bendectin has been withdrawn from the market.

      OVER-THE-COUNTER DRUGS

      A common misconception is that all over-the-counter drugs are reviewed by the Food and Drug Administration and hence are effective and safe to use during pregnancy. In fact, not until 1938 did manufacturers have to show that over-the-counter drugs were actually safe for use. The Kefauver-Harris Bill of 1962 introduced the requirement that all new drugs be proved effective as well as safe. Although only 200 active ingredients are used in the over-the-counter market, an estimated 100,000 to 500,000 products are available.
      • Moxley III, JH
      • Yingling GL
      • Edwards CC
      The Food and Drug Administration's over-the-counter drug review: why review OTC drugs?.
      Schenkel and Vorherr
      • Schenkel B
      • Vorherr H
      Non-prescription drugs during pregnancy: potential teratogenic and toxic effects upon embryo and fetus.
      reviewed the components of over-the-counter drugs in detail, and their conclusions on the possible fetal effects of these medications are summarized inTable 3.
      Table 3Fetal Effects of Active Ingredients of Over-the-Counter Medications
      * Data from Schenkel and Vorherr.
      • Schenkel B
      • Vorherr H
      Non-prescription drugs during pregnancy: potential teratogenic and toxic effects upon embryo and fetus.
      DrugPossible fetal effects
      Para-aminophenolsAnemia
       AcetaminophenMethemoglobinemia
       Phenacetin
      • Liver toxicity
      • Hypotension
      • Respiratory depression
      AntihistaminesHypotension
       Dimenhydrinate (Dramamine)Liver toxicity
       DiphenhydramineRespiratory depression
       Chlorpheniramine
      SympathomimeticsPalpitations
       EphedrineCentral nervous system irritability
       PseudoephedrineAlkalosis
       Phenylpropanolamine
      Belladonna derivativesTachycardia
       AtropineRespiratory depression
       Scopolamine
      LaxativesIncreased intestinal peristalsis resulting in release of meconium in utero
       AloeKidney damage
      Antacids
       Sodium bicarbonate
      • Metabolic alkalosis
      • Circulatory overload
      • Edema, congestive heart failure
       Magnesium trisilicateDamage to fetal kidneys
      PhenolsLiver toxicity
       ThymolBone marrow depression
       HexylresorcinolConvulsions
      Dextromethorphan
      • Respiratory depression
      • Withdrawal symptoms
      CamphorConvulsions
      XanthinesTachycardia
       CaffeineLiver damage
       TheophyllineClotting deficiencies
       Theobromine
      * Data from Schenkel and Vorherr.
      • Schenkel B
      • Vorherr H
      Non-prescription drugs during pregnancy: potential teratogenic and toxic effects upon embryo and fetus.

       Antacids.

      Studies in animals have shown no teratogenic effects from constant ingestion of antacids throughout pregnancy. The high sodium concentration in certain antacids should be avoided if maternal retention of fluid is a problem. Adverse effects from use of antacids include impaired absorption of certain medications and constipation if their use is chronic. The possible fetal effects of sodium bicarbonate and magnesium trisilicate are outlined inTable 3.

       Antispasmodics.

      Atropine sulfate produces skeletal anomalies in mice but not in dogs.
      • Schardein JL
      No reports of teratogenicity in humans have been published.

       Antihistamines.

      Meclizine has been shown to be teratogenic in animals. Cleft palate is one of the most frequently associated abnormalities seen. King and associates
      • King CTG
      • Horigan E
      • Wilk AL
      Fetal outcome from prolonged versus acute drug administration in the pregnant rat.
      demonstrated competitive binding between benzhydrylpiperazine derivatives and calcium for cartilage if the former was used during pregnancy. Alteration of calcium binding was consequently proposed as the mechanism for the teratogenicity of antihistamines. King and co-workers
      • King CTG
      • Weaver SA
      • Narrod SA
      Antihistamines and teratogenicity in the rat.
      also correlated the teratogenic effects of these compounds with the presence of the ethylamine group in a ring rather than in a straight chain. The conclusions of several retrospective human studies on the teratogenicity of antihistamines have been conflicting.
      • McColl JD
      Dimenhydrinate in pregnancy (letter to the editor).
      • Saxén I
      Cleft palate and maternal diphenhydramine intake (letter to the editor).
      If the potential for teratogenicity is present, it seems to be low.

       Aspirin and Acetaminophen.

      Salicylates have been shown to be teratogenic in animals. Differences in fetal susceptibility to salicylates, as with other teratogenic agents, depend on environmental as well as genetic factors.
      • Eriksson M
      Salicylate-induced foetal damage late in pregnancy: an experimental study in mice.
      Indeed, the teratogenicity of salicylates in animals has been shown to be enhanced by the emotional stress of maternal immobilization. Prior treatment of the pregnant rat with a central nervous system depressant (for example, pentobarbital) prevents the augmentative effects of immobilization.
      • Goldman AS
      • Yakovac WC
      Prevention of salicylate teratogenicity in immobilized rats by certain central nervous system depressants.
      Because salicylates freely cross the placenta, their potential for altering platelet aggregation could present a risk to the fetus and neonates. Indeed, Corby and Schulman
      • Corby DG
      • Schulman I
      The effects of antenatal drug administration on aggregation of platelets of newborn infants.
      showed that the platelets of newborn infants are much more susceptible to the effects of membrane-active drugs (aspirin) than are those of adults. Aspirin is an ingredient of more than 200 products currently available.
      • Leist ER
      • Banwell JG
      Products containing aspirin.
      Therefore, physicians should review every combined preparation taken by their patients (particularly those obtained without prescriptions) for the presence of salicylates.
      Haslam and associates
      • Haslam RR
      • Ekert H
      • Gillam GL
      Hemorrhage in a neonate possibly due to maternal ingestion of salicylate.
      reported a case of severe gastrointestinal hemorrhage in an infant born to a mother who had ingested salicylate before delivery. Bleyer and Breckenridge
      • Bleyer WA
      • Breckenridge RT
      Studies on the detection of adverse drug reactions in the newborn. II. The effects of prenatal aspirin on newborn hemostasis.
      compiled single cases of neonatal petechiae, purpura, and cephalohematoma after maternal ingestion of salicylate. Stuart and co-workers
      • Stuart MJ
      • Gross SJ
      • Elrad H
      • Graeber JE
      Effects of acetyl-salicylic-acid ingestion on maternal and neonatal hemostasis.
      validated a positive or negative history of maternal ingestion of aspirin by the in vitro evaluation of platelet malondialdehyde formation. When pregnant mothers had ingested aspirin within 5 days before delivery, 6 of 10 mothers and 9 of 10 infants had bleeding tendencies. Serious hemorrhage was not observed. A study by Rumack and associates
      • Rumack CM
      • Guggenheim MA
      • Rumack BH
      • Peterson RG
      • Johnson ML
      • Braithwaite WR
      Neonatal intracranial hemorrhage and maternal use of aspirin.
      suggested that in the premature infant, in whom the risk of severe hemorrhage is already increased, the use of aspirin might exacerbate this bleeding tendency. In contrast, Turner and Collins,
      • Turner G
      • Collins E
      Fetal effects of regular salicylate ingestion in pregnancy.
      in a study of 144 mothers who had consumed aspirin products throughout pregnancy, found no evidence of neonatal hemorrhage despite increased concentrations of salicylates in cord blood. In the same study, the authors found an association between chronic use of aspirin and increased perinatal mortality, low birth weight, prolonged gestation, and antepartum and postpartum hemorrhage.
      • Turner G
      • Collins E
      Fetal effects of regular salicylate ingestion in pregnancy.
      • Collins E
      • Turner G
      Maternal effects of regular salicylate ingestion in pregnancy.
      In a much larger study, Slone and associates
      • Slone D
      • Siskind V
      • Heinonen OP
      • Monson RR
      • Kaufman DW
      • Shapiro S
      Aspirin and congenital malformations.
      and Shapiro and co-workers
      • Shapiro S
      • Siskind V
      • Monson RR
      • Heinonen OP
      • Kaufman DW
      • Slone D
      Perinatal mortality and birth-weight in relation to aspirin taken during pregnancy.
      used information from 50,282 gravidas and their offspring in the prospective Collaborative Perinatal Project to evaluate the teratogenic effects of ingestion of aspirin. After controlling for several variables, they concluded that a conventional dose of aspirin did not seem to be related to congenital malformations or low birth weight. Recently, Perkin and colleagues
      • Perkin RM
      • Levin DL
      • Clark R
      Serum salicylate levels and right-to-left ductus shunts in newborn infants with persistent pulmonary hypertension.
      reported that maternal ingestion of aspirin may be one cause of persistent pulmonary hypertension in the newborn infant. They hypothesized that transplacental passage of aspirin, an inhibitor of prostaglandin synthetase, may decrease the fetal prostaglandins necessary to keep vascular smooth muscle relaxed and the ductus arteriosus patent. Constriction of the ductus arteriosus would then possibly result in fetal pulmonary arteriole hypertension.
      In conclusion, although certain fetal and neonatal abnormalities have been linked with maternal ingestion of salicylates, the data in most instances remain conflicting. Large doses of aspirin should be avoided near the end of pregnancy if at all possible.
      Char and associates
      • Char VC
      • Chandra R
      • Fletcher AB
      • Avery GB
      Polyhydramnios and neonatal renal failure—a possible association with maternal acetaminophen ingestion (letter to the editor).
      reported a case of fetal renal damage after maternal ingestion of large quantities of acetaminophen. Although acetaminophen is not without potential fetal effects, at least the abnormalities in various hematologic values and platelet function associated with ingestion of aspirin do not occur.
      • Mielke Jr, CH
      • Ramos JC
      • Britten AFH
      Aspirin as an antiplatelet agent: template bleeding time as a monitor of therapy.
      • Waltman R
      • Tricomi V
      • Tavakoli FM
      Effect of aspirin on bleeding time during elective abortion.
      Certainly if the mother has a febrile illness, acetaminophen should be recommended to continue to maintain her temperature at or below 38.3°C.

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