Maternal Drugs and the Developing Fetus



Maternal Drugs and the Developing Fetus


Gideon Koren

David A. Beckman

Lynda B. Fawcett

Robert L. Brent



While most medications are not labeled for use in pregnancy, millions of pregnant women have conditions that need to be treated, including diabetes, urinary tract infections, and nausea and vomiting. The limited knowledge regarding the impact of medications on the fetus leads to serious challenges for practitioners, situates the mother at risk of suboptimal therapy for her condition, and places her unborn baby at a potential risk of toxicity (1,2).

Since the thalidomide disaster, medicine is practiced by many as if any medication is teratogenic to the fetus, leading physicians and pregnant women to refrain from the use of medications, even for the management of life-threatening conditions. In reality, very few drugs have been proven teratogenic in humans.

In this chapter, we will try to put the existing knowledge into clinical perspective, allowing readers to better understand the fetal risk of drugs, the risks of misinformation about safe drugs, and the optimal counseling of the pregnant patient.


▪ MECHANISMS OF ADVERSE DRUG EFFECTS ON THE FETUS

In some cases, intrauterine exposure to a drug can affect fetal functions and structures undergoing rapid development at the time of exposure. The term teratogenesis includes a group of adverse events such as miscarriage, stillbirth, intrauterine growth restriction, major malformations, chromosomal abnormalities, prematurity, and long-term developmental delays. For each of these adverse events, mechanisms need to be characterized and understood in order to put it in clinical perspective.


Miscarriage

Every conception has a risk of ending in miscarriage (spontaneous abortion) or serious congenital anomaly (Tables 14.1 and 14.2).

The definition of spontaneous abortion is loss of the fetus when viability was not possible outside the uterus. This stage is presently considered to be 20 weeks or less of gestation and a fetal weight of less than 500 g, although these criteria are not universally accepted. When fetal death occurs after 20 weeks of gestation, it is defined as stillbirth.

The frequency of spontaneous abortion varies with the stage of gestation (Table 14.2); more than 80% of abortions occur in the first trimester, and there is a steady decline in the risk of abortion as pregnancy progresses. Therefore, it is essential that epidemiologic studies into the cause of abortion compare control and “exposed” populations at the same mean stage of pregnancy and range of abortion risk (Table 14.3).

The earlier the abortion, the higher the incidence of fetal chromosomal abnormalities (3,4). Approximately 53% of spontaneous abortions in the first trimester result from fetal chromosomal abnormalities, 36% result from chromosomal abnormalities in the second trimester, and only 5% of stillbirths in the third trimester are as a result of chromosomal abnormalities. In over 95% of abortuses with chromosomal abnormalities, they result from autosomal trisomy, double trisomy, monosomy, triploidy, or tetraploidy (5,6). Most chromosomal abnormalities are not the cause of repetitive abortion, although in about 4% of couples with two or more spontaneous abortions, a normal-appearing parent could be a carrier for a balanced translocation or may be a mosaic with abnormal cells in the germ cell line. Environmental exposures during pregnancy cannot account for any of these abortions, because most aneuploidies result from meiotic nondisjunction during gametogenesis before conception.

There have been multiple studies indicating that malformed or blighted embryos are a cause of abortion. These embryonic losses may occur later in the first trimester and have been shown to have normal karyotypes (5). The etiology of these abortions is manifold and includes the following:


Genetic Abnormalities

Dominant mutations, polygenic genetic abnormalities, and recessive disease may rarely account for repetitive abortion, but in most instances, they will occur sporadically. A review of gene knockouts and mutations in mice suggests that embryonic death results from the disruption of basic maternal cellular functions, vascular circulation, and hematopoiesis, or interference with fetal nutritional supply, rather than an affect on embryonic organ systems (5).


Congenital Malformations

The etiology of congenital malformations can be divided into three categories: unknown, genetic, and environmental (Table 14.4). The etiology of 65% to 75% of human malformations is unknown. A significant proportion of congenital malformations of unknown etiology are likely to have an important genetic component. Malformations with an increased recurrence risk, such as cleft lip and palate, anencephaly, spina bifida, certain congenital heart diseases, pyloric stenosis, hypospadias, inguinal hernia, talipes equinovarus, and congenital dislocation of the hip, fit in the category of multifactorial disease and also the category of polygenic inherited disease (7). The multifactorial/threshold hypothesis postulates the modulation of a continuum of genetic characteristics by intrinsic and extrinsic (environmental) factors (7). Although the modulating factors are not known, they probably include placental blood flow, placental transport, site of implantation, maternal disease states, maternal malnutrition, infections, drugs, chemicals, and spontaneous errors of development.

Spontaneous errors of development may account for some of the malformations that occur without apparent abnormalities of the genome or environmental influence. We postulate that there is some probability for error during embryonic development, based on the fact that embryonic development is such a complicated process. It is estimated that 75% of all conceptions are lost before term; 50% within the first 3 weeks of development (1,2). The World Health Organization estimated that 15% of all clinically recognizable pregnancies end in a spontaneous abortion, 50% to 60% of which are as a result of chromosomal abnormalities (6,7,8,9,10). Finally, 3% to 6% of offspring are malformed, which represents the background risk for human maldevelopment. This means that, as a conservative estimate, 1,176 clinically recognized pregnancies will result in approximately 176 miscarriages, and 30 to 60 of the infants will have congenital anomalies in the remaining 1,000 live births. The true incidence of pregnancy loss is much higher, because undocumented pregnancies are not included in this risk estimate.

Based on his review of the literature, Wilson (11) provided a format of theoretical teratogenic mechanisms: mutation; chromosomal aberrations; mitotic interference; altered nucleic acid synthesis and function; lack of precursors, substrates, or coenzymes for biosynthesis; altered energy sources; enzyme inhibition; osmolar imbalance, alterations in fluid pressures, viscosities, and osmotic pressures; and altered membrane characteristics. We suggest a revised list of mechanisms for teratogenesis (Table 14.5).

Even though an agent can produce one or more of these pathologic processes, exposure to such an agent does not mean that
maldevelopment will occur. Furthermore, it is likely that a drug, chemical, or other agent can have more than one effect on the pregnant woman and the developing conceptus and, therefore, the nature of the drug or its biochemical or pharmacologic effects will not in themselves predict a teratogenic effect in the human. In fact, the discovery of human teratogens has come primarily from human epidemiologic studies. Animal studies and in vitro studies can be very helpful in determining the mechanism of teratogenesis and the pharmacokinetics related to teratogenesis (12). However, even if one understands the pathologic effects of an agent, one cannot predict the teratogenic risk of an exposure without taking into consideration the developmental stage, the magnitude of the exposure, and the reparability of the embryo.








TABLE 14.1 Frequency of Reproductive Risks in the Human












































Reproductive Risk

Frequency


Immunologically and clinically diagnosed spontaneous abortions per 106 conceptions

350,000


Clinically recognized spontaneous abortions per 106 pregnancies

150,000


Genetic diseases per 106 births

110,000


Multifactorial or polygenic (genetic-environmental interactions)

90,000


Dominantly inherited disease

10,000


Autosomal and sex-linked genetic disease

1,200


Cytogenetic (chromosomal abnormalities)

5,000


New mutations

3,000


Major congenital malformations per 106 births

30,000


Prematurity per 106 births

40,000


Fetal growth restriction per 106 births

30,000


Stillbirths per 106 pregnancies (>20 wk)

20,900


Modified from Brent RL. Environmental factors: miscellaneous. In: Brent RL, Harris ML, eds. Prevention of embryonic fetal and perinatal disease. Bethesda, MD: DHEW (NIH), 1976:211-218, with permission.









TABLE 14.2 Estimated Outcome of 100 Pregnancies versus Time from Conception







































































Time from Conception

Percent Survival to Term

Last Time for Induction of Selected Malformationsa


Preimplantation

0-6 d

25


Postimplantation

7-13 d

55

14-20 d

73

3-5 wk

79.5

22-23 d; cyclopia; sirenomelia, microtia 26 d; anencephaly 28 d; meningomyelocele 34 d; transposition of great vessels

6-9 wk

90

36 d; cleft lip, 6 wk; diaphragmatic hernia, rectal atresia, VSD, syndactyly 9 wk; cleft palate

10-13 wk

92

10 wk; omphalocele

14-17 wk

96.26

12 wk; hypospadias

18-21 wk

97.56

22-25 wk

98.39

26-29 wk

98.69

30-33 wk

98.98

34-37 wk

99.26

38+ wk

99.32

38+ wk; central nervous system (CNS) cell depletion


a Modified from Schardein JL, ed. Chemically induced birth defects. New York: Marcel Dekker, 1993.









TABLE 14.3 Etiology of Spontaneous Abortion in the Human








































Chromosomal Abnormalities

Chromosomal abnormalities from either the maternal or paternal gonadocytes account for 50%-70% of abortions


Abortions with Normal Chromosomes (Euploidy)

Genetic abnormalities: dominant mutations (lethal), polygenic genetic abnormalities, recessive disease from the maternal, paternal, or both parents gonadocytes.

Severe maternal disease states: diabetes, hypothyroidism, hepatitis, collagen diseases, untreated hyperthyroidism, severe malnutrition Corpus luteum or placental progesterone deficiency (luteal phase deficiency)

Maternal infection which results in fetal infection: Treponema pallidum, Plasmodium falciparum, Toxoplasma gondii, herpes simplex virus, parvovirus B19, or cytomegalovirus

Antiphospholipid antibodies: lupus anticoagulant, anticardiolipin antibodies

Maternal-fetal histocompatibility

Overmature gametes

Mechanical or physical problems: uterine abnormalities, multiple pregnancies, very rarely trauma

Cervical incompetence

Abnormal placentation: hypoplastic trophoblast, circumvallate implantation

Embryos and fetuses with severe malformations or growth restriction









TABLE 14.4 Etiology of Human Congenital Malformations Observed during the First Year of Life
























































Suspected Cause

Percent of Total


Unknown

65-75

Polygenic

Multifactorial (gene-environment interactions)

Spontaneous errors of development

Synergistic interactions of teratogens


Genetic

15-25

Autosomal and sex-linked inherited genetic disease

Cytogenetic (chromosomal abnormalities)

New mutations


Environmental

10

Maternal conditions: alcoholism; diabetes; endocrinopathies; phenylketonuria; smoking and nicotine; starvation; nutritional deficits

4

Infectious agents: rubella, toxoplasmosis, syphilis, herpes simplex, cytomegalovirus, varicella-zoster, Venezuelan equine encephalitis, parvovirus B19

3

Mechanical problems (deformations): amniotic band constrictions; umbilical cord constraint; disparity in uterine size and uterine contents

1-2

Chemicals, drugs, high-dose ionizing radiation, hyperthermia

<1


Modified from Brent RL. Environmental factors: miscellaneous. In: Brent RL, Harris ML, eds. Prevention of embryonic fetal and perinatal disease. Bethesda, MD: DHEW (NIH), 1976:211-218; Brent RL. Definition of a teratogen and the relationship of teratogenicity to carcinogenicity [Editorial]. Teratology 1986;34:359-360.










TABLE 14.5 Mechanisms of Teratogenesis







  1. Cell death or mitotic delay beyond the recuperative capacity of the embryo or fetus.



  2. Inhibition of cell migration, differentiation, and cell communication.



  3. Interference with histogenesis by processes such as cell depletion, necrosis, calcification, or scarring.



  4. Biologic and pharmacologic receptor-mediated developmental effects.



  5. Metabolic inhibition or nutritional deficiencies.



  6. Physical constraint, vascular disruption, inflammatory lesions, amniotic band syndrome.


Various maternal viral, bacterial, and parasitic infections are known to cause maldevelopment in humans including cytomegalovirus, fetal herpes virus infections (type 1 or 2), parvovirus B19 (erythema infectiosum), rubella virus, congenital syphilis (Treponema pallidum), T. gondii infection, varicella-zoster virus, and Venezuelan equine encephalitis (13). The incidence of serum antibody to human immunodeficiency virus (HIV) in pregnant women is increasing from the 1991 estimate of 1.5 per 1,000 women delivering in the United States (14); the incidence is as high as 31% in pregnant women in some African cities (15). Several studies support the conclusion that asymptomatic HIV pregnancies are not associated with an increased risk of congenital malformations, low birth weight, or abortion (16,17,18,19). It is likely that sexually transmitted diseases, opportunistic maternal infections, and symptomatic HIV pregnancies may increase the risk of low birth weight and morbidity in noninfected offspring.

The lethal or developmental effects of infectious agents are the result of mitotic inhibition, direct cytotoxicity, or necrosis. Repair processes may result in metaplasia, scarring, or calcification, which causes further damage by interfering with histogenesis. Infectious agents appear to be exceptions to some of the principles of teratogenesis, because the relevance of dose and time of exposure cannot be demonstrated as readily for replicating teratogenic agents. Transplacental transmission of an infectious agent does not necessarily result in congenital malformations, growth restriction, or lethality.

Vascular disruption is a rare event associated with intrauterine death and a wide range of structural anomalies, including cerebral infarctions, certain types of visceral and urinary tract malformations, congenital limb amputations of the nonsymmetrical type; and orofacial malformations such as mandibular hypoplasia, cleft palate, and Möbius syndrome, which vary too widely to constitute a recognized syndrome. Some anomalies associated with twin pregnancies can be explained by vascular disruption resulting from placental anastomoses in the shared placenta of monozygotic twins, anastomoses in a small percentage of dichorionic placentas in the case of dizygotic twins, or death of one twin resulting in emboli, intravascular coagulation, and altered fetal hemodynamics in the cotwin (20,21). Vascular disruption may also result from physical trauma causing chorion bleeding, such as chorionic villous sampling, and exposure to some developmental toxicants, such as cocaine and misoprostol. Although uterine bleeding during the first trimester may result in fetal anomalies, the malformations associated with vascular disruption can also occur later in gestation. This topic, illustrated with specific drugs, is discussed in greater detail below.


Adverse Effects Produced Later in Pregnancy

The fetal period is characterized by histogenesis involving cell growth, differentiation, and migration. Drugs that produce permanent cell depletion, vascular disruption, necrosis, specific tissue or organ pathology, physiologic decompensation, or severe growth restriction have the potential to cause deleterious effects throughout gestation. Sensitivity of the fetus for induction of mental retardation and microcephaly is greatest at the end of the first and the beginning of the second trimester. Other permanent neurologic effects can be induced in the second and third trimesters.

The classic example of a drug that presents little risk to the developing embryo during organogenesis but can affect the near-term fetus if high doses are used is aspirin. It is possible that other anti-inflammatory drugs present a similar risk.


▪ FACTORS THAT AFFECT SUSCEPTIBILITY TO THE DELETERIOUS EFFECTS OF DRUGS

A basic tenet of environmentally produced embryo- and fetotoxicity is the effect of teratogenic or abortigenic milieu that has certain characteristics in common and follows certain basic principles. These principles determine the quantitative and qualitative aspects of developmental toxicity (Table 14.6).


Stage of Development

The induction of developmental toxicity by environmental agents usually results in a spectrum of morphologic anomalies or intrauterine death, which varies in incidence depending on stage of exposure and dose. The developmental period at which an exposure occurs will determine which structures are most susceptible to the deleterious effects of the drug or chemical and to what extent the embryo can repair the damage. The period of sensitivity may be narrow or broad, depending on the environmental agent and the malformation in question. Limb defects, produced by thalidomide, have a very short period of susceptibility (Table 14.7) although microcephaly produced by radiation has a long period of susceptibility. Our knowledge of the susceptible stage of the embryo to various environmental influences is continually expanding and is vital to evaluating the significance of individual exposures or epidemiologic studies.

During the first period of embryonic development, from fertilization through the early postimplantation stage, the embryo is most sensitive to the embryolethal effects of drugs and chemicals. Surviving embryos have malformation rates similar to the controls, not because malformations cannot be produced at this stage but because significant cell loss or chromosome abnormalities at these early stages have a high likelihood of killing the embryo. Also, because of the omnipotentiality of early embryonic cells, surviving
embryos have a much greater ability to normalize developmental potential. Wilson et al. (22) demonstrated that the all-or-none phenomenon, or marked resistance to teratogens, disappears over a period of a few hours in the rat during early organogenesis utilizing ionizing X-irradiation as the experimental teratogen. The term all-or-none phenomenon has been misinterpreted by some investigators to indicate that malformations cannot be produced at this stage. On the contrary, it is likely that certain drugs, chemicals, or other insults during this stage of development can result in malformed offspring, but the nature of embryonic development at this stage will still reflect the basic characteristic of the all-or-none phenomenon, which is a propensity for embryo lethality rather than surviving malformed embryos.








TABLE 14.6 Factors that Influence Susceptibility to Developmental Toxicants

















Stage of development: The developmental period at which an exposure occurs will determine which structures are most susceptible to the adverse effects of chemicals and drugs and to what extent the embryo can repair the damage.


Magnitude of the exposure: Both the severity and incidence of toxic effects increase with dose.


Threshold phenomena: The threshold dose is the dose below which the incidence of death, malformation, growth restriction, or functional deficit is not statistically greater than that of nonexposed subjects.


Pharmacokinetics and metabolism: The physiologic changes in the pregnant woman and during fetal development and the bioconversion of compounds can significantly influence the developmental toxicity of drugs and chemicals by affecting absorption, body distribution, active metabolites, and excretion.


Maternal diseases: A maternal disease may increase the risk of fetal anomalies or abortion with or without exposure to a chemical or drug.


Placental transport: Most drugs and chemicals cross the placenta. The rate and extent to which a drug or chemical crosses the placenta are influenced by molecular weight, lipid solubility, polarity or degree of ionization, plasma protein binding, receptor mediation, placental blood flow, pH gradient between the maternal and fetal serum and tissues, and placental metabolism of the chemical or drug.


Genotype: The maternal and fetal genotypes may result in differences in cell sensitivity, placental transport, absorption, metabolism, receptor binding and distribution of an agent, and account for some variations in toxic effects among individual subjects and species.









TABLE 14.7 Developmental Stage Sensitivity to Thalidomide-Induced Limb Reduction Defects in the Human



































Days from Conception for Induction of Defects

Limb Reduction Defects


21-26

Thumb aplasia


22-23

Microtia


23-34

Hip dislocation


24-29

Amelia, upper limbs


24-33

Phocomelia, upper limbs


25-31

Preaxial aplasia, upper limbs


27-31

Amelia, lower limbs


28-33

Preaxial aplasia, lower limbs; phocomelia, lower limbs; femoral hypoplasia; girdle hypoplasia


30-36

Triphalangeal thumb


Modified from Brent RL, Holmes LB. Clinical and basic science lessons from the thalidomide tragedy: what have we learned about the causes of limb defects? Teratology 1988;38: 241-251, with permission.


The period of organogenesis (from day 18 through about day 40 of postconception in the human) is the period of greatest sensitivity to teratogenic insults and the period when most gross anatomic malformations can be induced. Most environmentally produced major malformations occur before the 36th day of gestation in the human. The exceptions are malformations of the genitourinary system, the palate, and the brain or deformations as a result of problems of constraint, disruption, or destruction. Severe growth restriction in the whole embryo or fetus may also result in permanent deleterious effects in many organs or tissues.

The fetal period is characterized by histogenesis involving cell growth, differentiation, and migration. Teratogenic agents that produce permanent cell depletion, vascular disruption, necrosis, specific tissue or organ pathology, physiologic decompensation, and/or severe growth restriction have the potential to cause deleterious effects throughout gestation. Additionally, sensitivity of the fetus for induction of mental retardation and microcephaly is greatest at the end of the first and the beginning of the second trimester. Other permanent neurologic effects can be induced in the second and third trimesters. Effects such as cell depletion or functional abnormalities, not readily apparent at birth, may give rise to changes in behavior or fertility that are apparent only later in life. The approximate last gestational day on which certain malformations may be induced in the human is presented in Table 14.2.


Dose-Response Relationship

The dose-response relationship is extremely important when comparing effects among different species because mg/kg doses are, at most, rough approximations. Dose equivalence among species can only be accomplished by performing pharmacokinetic studies, metabolic studies, and dose-response investigations in the human and the species being studied. Furthermore, the response should be interpreted in a biologically sound manner. One example is that a substance given in large enough amounts to cause maternal toxicity is likely to also have deleterious effects on the embryo such as death, growth restriction, or retarded development. Another example is that because the steroid receptors that are necessary for naturally occurring and synthetic progestin action are absent from nonreproductive tissues early in development, this is evidence against the involvement of progesterone or its synthetic analogs in nongenital teratogenesis (23,24).

An especially anxiety-provoking concept is that the interaction of two or more drugs or chemicals may potentiate their developmental effects. Although this is an extremely difficult hypothesis to test in the human, it is an especially important consideration because multichemical or multitherapeutic exposures are common. Fraser (25) warns that the actual existence of a threshold phenomenon when nonteratogenic doses of two teratogens are combined could easily be misinterpreted as potentiation or synergism. Potentiation or synergism should be assumed only when exposure to two or more drugs is just below their individual thresholds for toxicity.

Several considerations affect the interpretation of dose-response relationships:


Active metabolites: Metabolites may be the proximate teratogen rather than the administered chemical; that is, the metabolites phosphoramide mustard and acrolein may produce maldevelopment resulting from exposure to cyclophosphamide (26).

Duration of exposure: A chronic exposure to a prescribed drug can contribute to an increased teratogenic risk, for example, anticonvulsant therapy; in contrast, an acute exposure to the same drug may present little or no teratogenic risk.

Fat solubility: Fat-soluble substances such as polychlorinated biphenyls (27) can produce fetal maldevelopment for an extended period after the last maternal ingestion or exposure because they have an unusually long half-life.


Threshold Phenomenon

The threshold dose is the dosage below which the incidence of death, malformation, growth restriction, or functional deficit is not statistically greater than that of controls. The threshold level of exposure is usually from less than one to three orders of magnitude below the teratogenic or embryopathic dose for drugs and chemicals that kill or malform half the exposed embryos. A teratogenic agent therefore has a no-effect dose, as compared to mutagens or carcinogens that have a stochastic dose-response curve. Threshold phenomena are compared to stochastic phenomena in Table 14.8. The severity and incidence of malformations produced by every exogenous teratogenic agent that has been appropriately tested have exhibited threshold phenomena during organogenesis (11).


Pharmacokinetics of the Maternal-Placental-Fetal Unit

Most drugs taken in pregnancy cross the placenta and expose the developing fetus to their potential pharmacologic and teratogenic effects. Critical factors affecting placental drug transfer and drug effects on the fetus include (a) the physicochemical properties of the drug; (b) the rate and extent of drug crossing; (c) the duration of exposure; (d) distribution in different fetal tissues; (e) the stage of development at the time of exposure; and (f) the effects of drugs used in combination (28).


Physiochemical Properties

Drug transfer across the placenta is dependent on lipid solubility and the degree of drug ionization. Lipophilic drugs tend to diffuse readily across the placenta to enter the fetal circulation. Highly ionized drugs such as succinylcholine and tubocurarine, used for cesarean sections, cross the placenta slowly and achieve very low
concentrations in the fetus, compared to the lipid-soluble thiopental. Impermeability of the placenta to polar compounds is relative rather than absolute. If sufficiently high maternal-fetal concentration gradients are achieved, polar compounds cross the placenta in measurable amounts. Salicylate, which is almost completely ionized at physiologic pH, crosses the placenta rapidly. This occurs because the small amount of salicylate that is not ionized is highly lipid soluble.








TABLE 14.8 Stochastic and Threshold Dose-Response Relationships of Diseases Produced by Environmental Agents


























Relationship

Pathology

Site

Diseases

Risk

Definition


Stochastic phenomena

Damage to a single cell may result in disease

Deoxyribonucleic acid DNA

Cancer, mutation

Some risk exists at all dosages; at low exposures the risk is below the spontaneous risk

Incidence of disease increases but severity and nature of the disease remain the same


Threshold phenomena

Multicellular injury

High variation in etiology, affecting many cell and organ processes

Malformation, growth restriction, death, chemical toxicity, etc.

No increased risk below the threshold dose

Both severity and incidence of the disease increase with dose


Modified from Brent RL. Definition of a teratogen and the relationship of teratogenicity to carcinogenicity [Editorial]. Teratology 1986;34:359-360, with permission.


The molecular weight of the drug affects the rate of transfer and the amount of drug transferred across the placenta. Drugs with molecular weights of 250 to 500 can cross the placenta easily, depending upon their lipid solubility and degree of ionization; those with molecular weights of 500 to 1,000 cross the placenta with more difficulty; and those with molecular weights greater than 1,000 cross very poorly. A classical application of this property is the choice of heparin as an anticoagulant in pregnant women. Because it is a large (and polar) molecule, heparin does not cross the placenta. Unlike warfarin, which is teratogenic and should be avoided during the first trimester, heparin is safely given to pregnant women in need for anticoagulation. Yet the placenta contains drug transporters, which can carry larger molecules to the fetus. For example, a variety of maternal IgG antibodies cross the placenta and may cause fetal morbidity, as in Rh incompatibility, and as is the fact with some of the new biologic drugs.

Because maternal blood has a pH of 7.4, compared to fetal blood pH of 7.3, drugs with pKa above 7.4 will be more ionized in the fetal compartment, leading to ion trapping and, hence, to higher fetal levels.


Placental Drug Transporters

During the last two decades, numerous drug transporters have been identified in the placenta, with increasing recognition of their potential effects on drug transfer to the fetus. For example, the P-glycoprotein transporters encoded by the MDR1 gene efflux into the maternal circulation a variety of drugs, including cancer drugs (e.g., doxorubicin) and other agents. Similarly, viral protease inhibitors, which are substrates to P-glycoprotein, achieve only low fetal concentrations—an effect that may increase the risk of vertical HIV infection from the mother to the fetus. The hypoglycemic drug glyburide has much lower concentrations in the fetus as compared to the mother. Recent work has documented that this agent is effluxed from the fetal circulation by the BCRP transporter, as well as by the MRP3 transporter located in the placental brush border membrane. In addition, very high maternal protein binding of glyburide (>98.8%) contributes to lower fetal levels as compared to maternal concentrations. This can partially explain the apparent fetal safety of glyburide (29,30).


Drug-Protein Binding

The degree to which a drug is bound to plasma proteins (particularly albumin) may also affect the rate of transfer and the amount transferred. However, if a compound is very lipid soluble (e.g., some anesthetic gases), it will not be affected greatly by protein binding. Transfer of these more lipid-soluble drugs and their overall rates of equilibration are more dependent on (and proportionate to) placental blood flow. This is because very lipid-soluble drugs diffuse across placental membranes so rapidly that their overall rates of equilibration do not depend on the free drug concentrations becoming equal on both sides. In contrast, if a drug is poorly lipid soluble and is ionized, its transfer is slow and will probably be affected by its binding to maternal plasma proteins. Differential protein binding is also important, since some drugs exhibit greater protein binding in maternal plasma than in fetal plasma because of a lower binding affinity of fetal proteins. This phenomenon has been demonstrated for sulfonamides, barbiturates, phenytoin, and local anesthetic agents.


Drug Metabolism

Several different types of aromatic oxidation reactions (e.g., hydroxylation, N-dealkylation, demethylation) have been shown to occur in placental tissue (31). Pentobarbital is oxidized in this way. Conversely, it is possible that the metabolic capacity of the placenta may lead to creation of toxic metabolites, and the placenta may therefore augment toxicity (e.g., ethanol, benzpyrenes) (2). Drugs that have crossed the placenta enter the fetal circulation via the umbilical vein. About 40% to 60% of umbilical venous blood flow enters the fetal liver; the remainder bypasses the liver and enters the general fetal circulation. A drug that enters the liver may be partially metabolized there before it enters the fetal circulation. In addition, a large proportion of drug present in the umbilical artery (returning to the placenta) may be shunted through the placenta back to the umbilical vein and into the liver again. It should be noted that metabolites of some drugs may be more active than is the parent compound and may affect the fetus adversely.


Fetal Pharmacodynamics

Fetal therapeutics is an emerging area in perinatology. This involves drug administration to the pregnant woman or directly into the fetus with the fetus as the target of the drug. As examples, corticosteroids are used to stimulate fetal lung maturation when preterm birth is expected. Phenobarbital, when given to pregnant women near term, has been shown to induce fetal hepatic enzymes responsible for the glucuronidation of bilirubin, and the incidence of jaundice is lower in newborns when mothers are given phenobarbital than when phenobarbital is not used. Before phototherapy became the preferred mode of therapy for neonatal indirect hyperbilirubinemia, phenobarbital was used for this indication. While administration of phenobarbital to the mother was suggested recently as a means of decreasing the risk of intracranial bleeding in preterm infants, large randomized studies failed to confirm this effect. Antiarrhythmic drugs have also been given to mothers for treatment of fetal cardiac arrhythmias. Although their efficacy has not yet been established by controlled studies, digoxin, flecainide, procainamide, verapamil, and other antiarrhythmic agents have been shown to be effective in case series.



Predictable Fetal Toxicity

The fetus often responds to drugs with adverse effects predictable from the adult response. Chronic use of opioids, selective serotonin reuptake inhibitors (SSRIs), alcohol, and sedative hypnotics by the mother may produce dependence in the fetus and newborn. This dependence may be manifested after delivery as a neonatal withdrawal syndrome. A less well understood fetal drug toxicity is caused by the use of angiotensin-converting enzyme (ACE) inhibitors during pregnancy. These drugs can result in significant and irreversible renal damage in the fetus and are, therefore, contraindicated in pregnant women. Adverse effects may also be delayed, as in the case of female fetuses exposed to diethylstilbestrol, who may be at increased risk for adenocarcinoma of the vagina after puberty.


Ex Vivo Predictive Studies with the Human Placenta

An important determinant in assessing the fetal risks of drugs is estimation of fetal exposure, which is accomplished by quantifying the amount of drug that crosses the human placenta. Evaluating the transplacental kinetics of drugs in humans has numerous ethical limitations that stem from concerns regarding fetal and maternal safety and from the fact that the fetoplacental unit is not easily accessible until delivery. Animal studies cannot be directly extrapolated to humans because the placenta is the most species-specific mammalian organ (32). Cell culture and membrane vesicle models are limited mostly to the investigation of specific mechanisms of transfer, such as active transport or passive diffusion, but they lack anatomic integrity and blood flow.

An ideal model, which circumvents the above limitations, is the ex vivo perfused human placental lobule. Unlike subcellular preparations or tissue homogenates, perfused, intact tissue that has structural integrity and maintains cell-cell organization generates data that reflect the in vivo situation. Moreover, confounding metabolic and physiologic influences of maternal and/or fetal origin are eliminated, and the experimental conditions can be controlled. The placenta is the only organ in the human body that can be harvested at birth and kept alive and functioning for the next 4 to 6 hours, allowing studies of drug transfer and metabolism and of direct placental toxicology in human rather than in animal species.

A placental lobule, or cotyledon, is regarded as the functional unit of the human placenta. On the fetal side, the umbilical vessels branch over the surface of the placenta and form 40 to 70 villous stems at term. These stems branch further to form villous trees or fetal cotyledons. The fetal villi are covered by a layer of syncytiotrophoblasts, which separate the maternal and fetal circulations and across which transplacental exchange occurs. The maternal side of the placenta consists of 10 to 40 irregularly shaped mounds, each of which is occupied by several lobules (33). The placental lobule is the structure perfused in this perfusion model.

The first perfusion of an isolated human placental lobule was described by Panigel et al. in 1967 (34,35) and was subsequently modified by Schneider and Miller (31,33). A fetal vein-artery pair that supplies a well-defined cotyledon is identified, and the corresponding maternal surface is confirmed to have no evident trauma and an intact basal plate. The fetal vessels are cannulated, and flow of perfusate is established. The lobule is clamped into a chamber with the fetal side downward, and the excess placental tissue is removed. Buffered saline in the chamber supports the weight of the lobule and is placed in a water bath to maintain physiologic temperature. Venous samples from the maternal circulation are collected from multiple venous openings in the decidual plate.

The experiments are performed in either a closed (recirculating) configuration or an open (single-pass or nonrecirculating) one. In the closed configuration, the perfusate is recycled to imitate physiologic conditions. Drug transfer, as well as the maternal-placental-fetal distribution, can be evaluated. The open configuration allows for the calculation of drug clearance at steady-state concentrations. The drug can also be added equally to both circulations in the closed configuration to quantify accumulation against a concentration gradient (34,35).


Adverse Fetal Effects of Maternal Disease (See also Chapter 13)

Maternal disease states such as diabetes mellitus, epilepsy, phenylketonuria, and endocrinopathies are associated with adverse effects on the fetus. In some cases, it may be difficult to determine whether a maternal disease or the treatment for the disease plays a role in the etiology of fetal malformations. For example, the genetic and environmental milieu that causes epilepsy may also contribute to the maldevelopment associated with exposure to diphenylhydantoin (36).

The role of maternal malnutrition is an important area for investigation because it may be a contributing factor to many teratogenic milieu. A series of investigations provided evidence suggesting that folic acid supplementation could reduce the incidence of recurrence of neural tube defects in the human (37,38,39,40). It was later shown convincingly that periconceptional supplementation with folic acid, 4 mg/d, reduces the risk of recurrence of neural tube defects in subsequent siblings of children with neural tube defects (41). Furthermore, low-dose folic acid supplementation, 0.8 mg/d, was reported to decrease the incidence of neural tube defects in a population not at increased risk for these defects (42). Although folate supplementation reduces the incidence of neural tube defects, folate supplementation will not prevent all neural tube defects, and it is not known whether folic acid supplementation corrects an undefined metabolic defect or a nutritional deficiency.


Genotype

The genetic constitution of an organism is an important factor in the susceptibility of a species to a drug or chemical. More than 30 disorders involving increased sensitivity to drug toxicity or effects have been reported in the human as a result of an inherited trait (43). The effect of a drug or chemical depends on both the maternal and fetal genotypes and may result in differences in cell sensitivity, placental transport, absorption, metabolism (activation, inactivation, active metabolites), receptor binding, and distribution of an agent. This accounts for some variations in teratogenic effects among species and in individual subjects.


▪ ESTIMATING THE DEVELOPMENTAL RISKS OF DRUGS DURING HUMAN PREGNANCY


Evaluation of Data Available for the Human

Although chemicals and drugs can be evaluated for fetotoxic potential by utilizing in vivo animal studies and in vitro systems, it should be recognized that these testing procedures are only one component in the process of evaluating the potential teratogenic risk of drugs and chemicals in the human. The evaluation of the teratogenicity of drugs and chemicals should include, when possible, (a) data obtained from human epidemiologic studies, (b) secular trend data in humans, (c) animal developmental toxicity studies, (d) the dose-response relationship for developmental toxicity and the relationship to the human pharmacokinetic equivalent dose in the animal studies, and (e) considerations of biologic plausibility (Table 14.9) (44,45). This approach is of greatest value when utilized for the evaluation of chemicals and drugs that have been in use for some time or for evaluating new drugs that have a similar mechanism of action, structure, pharmacology, and purpose to other, extensively studied agents. The ability to establish a causal relationship between
an environmental agent and abortigenic effect is more difficult, for the following reasons:








TABLE 14.9 Evidence for Potential Developmental Toxicity in the Human















Epidemiologic studies: Epidemiologic studies consistently demonstrate an increased incidence of pregnancy loss or of a particular spectrum of fetal effects in exposed human populations.


Secular trend data: Secular trends demonstrate a relationship between the incidence of pregnancy loss or a particular fetal effect and the changing exposures in human populations. The percent of the population exposed must be large for this analysis.


Animal developmental toxicity studies: An animal model mimics the human developmental effect at clinically comparable exposures. Since mimicry may occur in only one animal species, if it occurs at all, it would not necessarily be observed during an initial developmental toxicology study. Developmental toxicity studies are therefore indicative of a potential hazard in general rather than the potential for a specific adverse effect on the fetus.


Dose-response relationship: Developmental toxicity in the human increases with dose and the developmental toxicity in animals occurs at a dose that is pharmacokinetically equivalent to the human dose.


Biologic plausibility: The mechanisms of developmental toxicity are understood or the results are biologically plausible.


Modified from Brent RL. Method of evaluating alleged human teratogens [Editorial]. Teratology 1978;17:83; Brent RL. Definition of a teratogen and the relationship of teratogenicity to carcinogenicity [Editorial]. Teratology 1986;34:359-360, with permission.




  • Abortion is a very frequent reproductive event and, therefore, the incidence can vary considerably between different populations of women. Differences in the abortion incidence between two populations in a single study may be as a result of chance alone.


  • There are multiple causes of abortion and most epidemiologic studies dealing with abortion make no attempt to determine the etiology of the abortions. Since most abortions are as a result of preconceptual or periconceptual events, it is extremely difficult to match patients in case-control studies, and it would be necessary to have large increases in a particular etiologic category of environmentally induced abortion to demonstrate a statistically significant increase in the incidence of spontaneous abortion in an “exposed” population of pregnant women.


  • Confounding factors appear to be more significant in abortion studies than in birth defect studies (cocaine, smoking, alcohol, syphilis, narcotics, caffeine). This further decreases the possibility that the agent being studied has a direct abortigenic effect.


  • The incidence of therapeutic abortions is difficult to estimate or control for in most epidemiologic studies (46,47).

One of the advantages of reproductive effects is that there is frequently, but not always, concordance of effects involving more than one parameter (growth, malformations, abortion, stillbirth, prematurity, etc.). Isolated abortion studies that do not study the totality of reproductive effects are at a serious disadvantage, because spurious or nonetiologic results may be misinterpreted as being causally related to a drug or environmental toxicant.

Some investigators and regulatory agencies divide drugs and chemicals into developmentally toxic and nontoxic compounds. In reality, potential developmental toxicity can be evaluated only if one considers, as a minimum, the agent, the dose, the species, and the stage of gestation. Working definitions for developmental toxicity in the human are suggested in Table 14.10.

Potential human teratogens and abortifacients comprise a large group of drugs because they include all drugs and chemicals that can produce embryotoxic and fetotoxic effects at some exposure. Since these exposures are not utilized or attained in the human, they represent no or minimal risks to the human embryo.








TABLE 14.10 Definitions of Potential for Developmental Toxicity in the Human











Developmental toxicant: An agent or milieu that has been demonstrated to produce permanent alterations or death in the embryo or fetus following intrauterine exposures that usually occur or are attainable in the human.


Potential for developmental toxicity: An agent or milieu that has not been demonstrated to produce permanent alterations or death in the embryo or fetus following intrauterine exposures that usually occur or are attainable in the human but can affect the embryo or fetus if the exposure is raised substantially above the usual exposure. Most chemicals and drugs have the potential for interrupting a pregnancy or inducing developmental defects if the exposure is increased sufficiently.


Little or no potential for developmental toxicity: An agent or milieu that has been demonstrated to produce no embryo- or fetotoxicity at any attainable dose in the human. In contrast, an environmental agent may be so toxic that it has no developmental toxicity in the human because it kills the mother before or at the same dose that it begins to have adverse effects on the embryo.


Modified from Brent RL. Method of evaluating alleged human teratogens [Editorial]. Teratology 1978;17:83, with permission.



Misconceptions in Evaluating Developmental Toxicity in the Human

Misconceptions have lead to confusion regarding the potential effects of even proven teratogens. Examples of erroneous concepts include: if an agent can produce one type of malformation, it can produce any malformation; an agent presents a risk at any dose, once it can be proven to be teratogenic; and an agent that is teratogenic is likely to be abortigenic.

This concept is incorrect. The data clearly indicate that proven teratogens do not have the ability to produce every birth defect. Many teratogens can be identified on the basis of the malformations that are produced. Thus, the concept of the syndrome is probably more appropriate in clinical teratology than any other area of clinical medicine. Some symptoms or signs appear in many teratogenic syndromes, such as growth restriction or mental retardation, and therefore are not very discriminating. On the other hand, rare or specific effects, such as deafness, retinitis, or a pattern of cerebral calcifications, may point to a specific teratogen. It is also true that there is substantial overlap in malformation syndromes, which may not always be separable. Environmentally produced birth defects may be confused with genetically determined malformations. Using thalidomide as an example, a patient with bilateral radial aplasia and a ventricular septal defect (VSD) may have the Holt Oram syndrome or the thalidomide syndrome. It may or may not be possible to make a diagnosis with absolute certainty, even if one has a history of thalidomide ingestion during pregnancy. It is possible, however, to refute the suggestion that thalidomide was responsible for congenital malformations in an individual based on the nature of the limb malformation.

The specificity of some teratogens can sometimes point to the mechanism or site of action. For instance, the predominant central nervous system effects of methyl mercury are understood when one realizes the propensity for organic mercury to be stored in lipid.

Epidemiologists sometimes use poor judgment when grouping malformations. As an example, limb reduction defects are frequently studied regarding their association with environmental teratogens but, in some studies, limb defects that are clearly related to problems of organogenesis are lumped with congenital amputations even though it is very unlikely that any agent will be responsible for both types of malformations. It is clear that epidemiologic studies could be markedly improved if there was more input from clinical teratologists in planning and performing the studies.


Case-control studies concerning spontaneous abortion may contain serious errors unless the populations being studied are similar regarding the stage of pregnancy when abortion occurred. This study design diminishes the possibility that the abortion rate will differ on the basis of the selection process and not the drug or environmental agent being studied. Unfortunately, most epidemiologic studies dealing with drug- or environmentally induced abortion do not attempt to determine the etiology of the abortion.


▪ POTENTIAL EMBRYO- AND FETOTOXICITY OF SELECTED PRESCRIBED AND SELF-ADMINISTERED DRUGS

We evaluated the literature concerning selected drugs that cause or are suggested to cause deleterious effects during pregnancy in the human. The data included human epidemiologic studies, secular trend data in humans where appropriate, and animal developmental toxicity studies. In our analysis, we considered the dose-response relationship of teratogenicity, the relationship to the human pharmacokinetic equivalent dose in the animal studies and biologic plausibility (Table 14.9) (43,44). Table 14.11 focuses on these drugs, listing their potential adverse effects in the human. Although these drugs account for a small percentage of all malformations and abortions, they are important because these exposures may be preventable.


Alcohol (Ethanol)

Adverse effects in offspring from excessive alcohol consumption during pregnancy were recognized more than 200 years ago (48). It was Jones et al. (49), however, who defined the fetal alcohol syndrome (FAS) in children with intrauterine growth restriction, microcephaly, mental retardation, maxillary hypoplasia, flat philtrum, thin upper lip, and reduction in the width of palpebral fissures. Cardiac abnormalities were also seen. Many of the children of alcoholic mothers had FAS, and all of the affected children evidenced developmental delay (49,50).

A period of greatest susceptibility is not clearly established, but the risk for adverse effects increases with increased consumption, and binge drinking early in pregnancy may be associated with an increased risk of alcohol-related effects (51). The risk of decreased brain growth and differentiation that results from high alcohol consumption is greater during the second and third trimesters.



Chronic consumption of 6 oz of alcohol per day constitutes a high risk, although the FAS is not likely when the mother consumes fewer than two drinks (equivalent to 1 oz of alcohol) per day (52). Reduction of alcohol consumption or cessation of drinking early in pregnancy will reduce the incidence and severity of alcohol-related effects (51,53) but may not entirely eliminate the risk of some degree of physical or behavioral impairment. The human syndrome is likely to involve the direct effects of alcohol and the indirect effects of genetic susceptibility and poor nutrition. Alcoholism can have maternally deleterious effects on intermediary metabolism and nutrition, especially if alcoholic cirrhosis is present, which can contribute to an adverse milieu for the developing embryo.








TABLE 14.11 Effects and Estimated Risks of Selected Prescribed and Self-administered Drugs During Human Pregnancy

















































































































































































Selected Drugs

Reported Effects or Associations and Estimated Risks

Commentsa


Alcohol

Fetal alcohol syndrome: intrauterine growth restriction, maxillary hypoplasia, reduction in width of palpebral fissures, characteristic but not diagnostic facial features, microcephaly, and mental retardation. An increase in spontaneous abortion has been reported but since mothers who abuse alcohol during pregnancy have multiple other risk factors, it is difficult to determine whether this is a direct effect on the embryo. Consumption of 6 oz of alcohol or more per day constitutes a high risk, but it is likely that detrimental effects can occur at lower exposures.

Quality of available information: good to excellent. Direct cytotoxic effects of ethanol and indirect effects of alcoholism. While a threshold teratogenic dose is likely, it will vary in individuals because of a multiplicity of factors.


Aminopterin, methotrexate

Microcephaly, hydrocephaly, cleft palate, meningomyelocele, intrauterine growth restriction, abnormal cranial ossification, reduction in derivatives of first branchial arch, mental retardation, postnatal growth restriction. Aminopterin can induce abortion within its therapeutic range; it is used for this purpose to eliminate ectopic embryos. Risk from therapeutic doses is unknown but appears to be moderate to high.

Quality of available information: good. Anticancer, antimetabolic agents; folic acid antagonists that inhibit dihydrofolate reductase, resulting in cell death.


Androgens

Masculinization of female embryo: clitoromegaly with or without fusion of labia minora. Nongenital malformations are not a reported risk. Androgen exposures that result in masculinization have little potential for inducing abortion. Based on animal studies, behavioral masculinization of the female human will be rare.

Quality of available information: good. Effects are dose and stage dependent; stimulates growth and differentiation of sex steroid receptor-containing tissue.


ACE inhibitors

The therapeutic use of ACE inhibitors has neither a teratogenic effect nor an abortigenic effect in the first trimester. Since this group of drugs does not interfere with organogenesis, they can be used in a woman of reproductive age; if the woman becomes pregnant, therapy can be changed during the first trimester without an increase in the risk of teratogenesis. Later in gestation, these drugs can result in fetal and neonatal death, oligohydramnios, pulmonary hypoplasia, neonatal anuria, intrauterine growth restriction, and skull hypoplasia. Risk is dependent on dose and length of exposure.

Quality of available information: good. Antihypertensive agents; adverse fetal effects are related to severe fetal hypotension over a long period of time during the second or third trimester.


Antibiotics

Streptomycin: Streptomycin and a group of ototoxic drugs can affect the eighth nerve and interfere with hearing; it is a relatively low-risk phenomenon. There are not enough data to estimate the abortigenic potential of streptomycin. Because the deleterious effect of streptomycin is limited to the eighth nerve, it is unlikely to affect the incidence of abortion.

Quality of available information: fair to good. Long duration maternal therapy during pregnancy is associated with hearing deficiency in offspring.

Tetracycline: Bone staining and tooth staining can occur with therapeutic doses. Persistent high doses can cause hypoplastic tooth enamel. The risk of other congenital malformations is not increased. The usual therapeutic doses present no increased risk of abortion to the embryo or fetus.

Quality of available information: good. Effects seen only if exposure is late in the first or during second or third trimester, since tetracyclines have to interact with calcified tissue.

Penicillin G benzathine used for the treatment of syphilis produces no adverse fetal effects in the usual therapeutic regimens:


Ceftriaxone and doxycycline used for the treatment of gonorrhea produces no adverse fetal effects in the usual therapeutic regimens.


Erythromycin base or stearate used for the treatment of Chlamydia involves a possible increased risk of cholestatic hepatitis in the usual therapeutic regimens.

These antibiotics are used in late pregnancy for the treatment of sexually transmitted diseases.


Antihypertensive (excluding ACE inhibitors)

Clonidine: a direct alpha adrenergic agonist that appears to be relatively safe during pregnancy, but there are few available data.


Hydralazine: a vasodilator often used in combination with methyldopa and is considered to be safe.


Methyldopa: a centrally acting adrenergic antagonist and currently the safest antihypertensive drug available for use during pregnancy with no reported adverse effects on the fetus or on mental and physical development.


Nifedipine: a calcium channel blocker whose potential for adverse effects with long-term use in the treatment of hypertension is unknown.


Propranolol: a β-blocker whose prolonged use may increase the risk of intrauterine growth restriction.


Antituberculosis therapy

Drugs prescribed for the treatment of tuberculosis include aminoglycosides, ethambutol, isoniazid, rifampin, and ethionamide. The ototoxic effects of streptomycin (discussed above) are the only proven adverse effects of these drugs on the fetus. Therapeutic exposures to other tuberculostatic drugs appear to present a very small risk of teratogenesis and even less risk of abortion.


Aspirin

No increased risk for malformations or abortion low-dose regimen (60-150 mg/d). Aspirin should be discontinued 1 week before anticipated delivery, to reduce the risk for maternal or neonatal bleeding.

Used for treatment of preeclampsia, idiopathic placental insufficiency, systemic lupus erythematosus, increased platelet aggregation


Benzodiazepines

Benzodiazepines appear to carry minimal or no increased risk of malformations, at therapeutic ranges; higher exposures may increase the risk. The risk for abortion is unknown.


Chlordiazepoxide (Librium) appears to carry a minimal risk for congenital anomalies and no increased risk for abortion, at therapeutic doses. Higher exposures are likely to increase the risk of adverse effects on the fetus, but the magnitude of the increase is not known.


Diazepam (Valium): third-trimester exposure can reversibly affect the fetus and neonate; there is minimal increased risk of congenital malformations and no demonstrated increased risk of abortions from therapeutic exposures.


Meprobamate: weakly associated with a variety of congenital malformations, but the data are not sufficient to confirm or rule out a small increased risk of malformations due to exposures early in pregnancy.

The benzodiazepines are widely used as tranquilizers during pregnancy.


Caffeine

Caffeine is teratogenic in rodent species with doses of 150 mg/kg. There are no convincing data that moderate or usual exposures (300 mg/d or less) present a measurable risk in the human for any malformation or group of malformations. On the other hand, excessive caffeine consumption (exceeding 300 mg/d) during pregnancy is associated with growth restriction and embryonic loss.

Quality of available information: fair to good. Behavioral effects have been reported and appear to be transient or temporary; more information is needed concerning the population with higher exposures.


Carbamazepine

Minor craniofacial defects (upslanting palpebral fissures, epicanthal folds, short nose with long philtrum), fingernail hypoplasia, and developmental delay. Teratogenic risk is not known but likely to be significant for minor defects. There are too few data to determine whether carbamazepine presents an increased risk for abortion. Since embryos with multiple malformations are more likely to abort, it would appear that carbamazepine presents little risk because an increase in these types of malformations has not been reported.

Quality of available information: fair to good. Anticonvulsant; little is known concerning mechanism. Epilepsy may itself contribute to an increased risk for fetal anomalies.


Cocaine

Preterm delivery; fetal loss; placental abruption; intrauterine growth restriction; microcephaly; neurobehavioral abnormalities; vascular disruptive phenomena resulting in limb amputation, cerebral infarctions and certain types of visceral and urinary tract malformations. There are few data to indicate that cocaine increases the risk of first-trimester abortion. The low but increased risk of vascular disruptive phenomena due to vascular compromise of the pregnant uterus would more likely result in midgestation abortion or stillbirth. It is possible that higher doses could result in early abortion. Risk for deleterious effects on fetal outcome is significant; risk for major disruptive effects is low but can occur in the latter portion of the first trimester as well as the second and third trimesters.

Quality of available information: fair to good. Cocaine causes a complex pattern of cardiovascular effects due to its local anesthetic and sympathomimetic activities in the mother. Fetopathology is likely to be due to decreased uterine blood flow and fetal vascular effects. Because of the mechanism of cocaine teratogenicity, a well-defined cocaine syndrome is not likely. Poor nutrition accompanies drug abuse and multiple drug abuse is common.


Coumarin derivatives

Nasal hypoplasia; stippling of secondary epiphysis; intrauterine growth restriction; anomalies of eyes, hands, neck; variable central nervous system anatomical defects (absent corpus callosum, hydrocephalus, asymmetrical brain hypoplasia). Risk from exposure 10% to 25% during 8th to 14th week of gestation. There is also an increased risk of pregnancy loss. There is a risk to the mother and fetus from bleeding at the time of labor and delivery.

Quality of available information: good. Anticoagulant; bleeding is an unlikely explanation for effects produced in the first trimester. CNS defects may occur anytime during second and third trimesters and may be related to bleeding.


Cyclophosphamide

Growth restriction, ectrodactyly, syndactyly, cardiovascular anomalies, and other minor anomalies. Teratogenic risk appears to be increased, but the magnitude of the risk is uncertain. Almost all chemotherapeutic agents have the potential for inducing abortion. This risk is dose related; at the lowest therapeutic doses, the risk is small.

Quality of available information: fair. Anticancer, alkylating agent; requires cytochrome P450 monooxidase activation; interacts with DNA, resulting in cell death.


Diethylstilbestrol (DES)

Clear cell adenocarcinoma of the vagina occurs in about 1:1,000 to 10,000 females who were exposed in utero. Vaginal adenosis occurs in about 75% of females exposed in utero before the 9th week of pregnancy. Anomalies of the uterus and cervix may play a role in decreased fertility and an increased incidence of prematurity although the majority of women exposed to DES in utero can conceive and deliver normal babies. In utero exposure to DES increased the incidence of genitourinary lesions and infertility in males. DES can interfere with zygote survival, but it does not interfere with embryonic survival when given in its usual dosage after implantation. Offspring who were exposed to DES in utero have an increased risk for delivering prematurely but do not appear to be at increased risk for first-trimester abortion.

Quality of available information: fair to good. Synthetic estrogen; stimulates estrogen receptor-containing tissue, may cause misplaced genital tissue that has a greater propensity to develop cancer.


Digoxin

No adverse fetal effects reported with usual therapeutic regimens.

Used for treatment of fetal dysrhythmia.


Diphenylhydantoin

Hydantoin syndrome: microcephaly, mental retardation, cleft lip/palate, hypoplastic nails and distal phalanges; characteristic, but not diagnostic facial features. Associations documented only with chronic exposure. Wide variation in reported risk of malformations but appears to be not >10%. The few epidemiologic data indicate a small risk of abortion for therapeutic exposures for the treatment of epilepsy. For short-term treatment, phosphoramide mustard, prophylactic therapy for a head injury, there is no appreciable risk.

Quality of available information: fair to good. Anticonvulsant; direct effect on cell membranes, folate, and vitamin K metabolism. Metabolic intermediate (epoxide) has been suggested as the teratogenic agent.


Glucocorticoids

Dexamethasone, Betamethasone, Hydrocortisone, Methylprednisolone: Glucocorticoids have not been shown to be teratogenic but chronic glucocorticoid therapy may result in prematurity and intrauterine growth restriction.

Glucocorticoids are used late in pregnancy to reduce respiratory distress in premature infants and to treat congenital adrenal hyperplasia. They are also used in the treatment of rheumatic diseases, other acute and chronic inflammatory diseases, and organ transplantation.


Indomethacin

Can prolong labor and may predispose neonate to necrotizing enterocolitis when used as a tocolytic.

Used for the prevention or reduction of intraventricular hemorrhage in premature infant and for treatment of polyhydramnios.


Lithium carbonate

Although animal studies have demonstrated a clear teratogenic risk, the effect in humans is uncertain. Early reports indicated an increased incidence of Ebstein anomaly, other heart and great vessel defects, but as more studies are reported the strength of this association has diminished. Lithium levels within the therapeutic range (<1.2 mg%) do not increase the risk of abortion.

Quality of available information: fair to good. Antidepressant; mechanism has not been defined.


Methylene blue

Hemolytic anemia and jaundice in neonatal period after exposure late in pregnancy. There may be a small risk for intestinal atresia but this is not yet clear. No indication of increased risk of abortion.

Quality of available information: poor to fair. Used to mark amniotic cavity during amniocentesis.


Misoprostol

Misoprostol is a synthetic prostaglandin analog that has been used by millions of women for illegal abortion. A low incidence of vascular disruptive phenomenon, such as limb reduction defects and Möbius syndrome, has been reported.

Quality of available information: fair classical animal teratology studies would not be helpful in discovering these effects, because vascular disruptive effects occur after the period of early organogenesis.


Oxazolidine-2,4-diones (trimethadione, paramethadione)

Fetal trimethadione syndrome: V-shaped eye brows, low-set ears with anteriorly folded helix, high-arched palate, irregular teeth, CNS anomalies, severe developmental delay. Wide variation in reported risk. Characteristic facial features are documented only with chronic exposure. The abortifacient potential has not been adequately studied but appears to be minimal.

Quality of available information: good to excellent. Anticonvulsants; affects cell membrane permeability. Actual mechanism of action has not been determined.


D-Penicillamine

Cutis laxa, hyperflexibility of joints. Condition appears to be reversible and the risk is low. There are no human data on the risk of abortion.

Quality of available information: fair to good. Copper chelating agent; produces copper deficiency inhibiting collagen synthesis and maturation.


Phenobarbital

No adverse fetal effects reported for usual therapeutic regimens.

May be used for the prevention or reduction of intraventricular hemorrhage in premature infant.


Progestins

Masculinization of female embryo exposed to high doses of some testosterone-derived progestins and may interact with progesterone receptors in the liver and brain later in gestation. The dose of progestins present in modern oral contraceptives presents no masculinization or feminization risks. Progestins present no risk for nongenital malformations. Many synthetic progestins and natural progesterone have been used to treat luteal phase deficiency, embryos implanted via in vitro fertilization (IVF) threatened abortion or bleeding in pregnancy with variable results. Conversely, synthetic progestins that interfere with progesterone function may cause early pregnancy loss; RU-486 is presently used specifically for this purpose.

Quality of available information: good. Stimulates or interferes with sex steroid receptor-containing tissue.


Retinoids, systemic (isotretinoin, etretinate)

Increased risk of CNS, cardioaortic, ear, and clefting defects. Microtia, anotia, thymic aplasia and other branchial arch, aortic arch abnormalities, and certain congenital heart malformations. Exposed embryos are at greater risk for abortion. This is plausible since many of the malformations, such as neural tube defects, are associated with an increased risk of abortion.

Quality of available information: fair. Used in treatment of chronic dermatoses. Retinoids can cause direct cytotoxicity and alter programmed cell death; affect many cell types but neural crest cells are particularly sensitive.


Retinoids, topical (tretinoin)

Epidemiologic studies, animal studies, and absorption studies in humans do not suggest a teratogenic risk. Regardless of the risks associated with systemically administered retinoids, topical retinoids present little or no risk for intrauterine growth restriction, teratogenesis, or abortion because they are minimally absorbed and only a small percentage of skin is exposed.

Quality of available information: poor. Topical administration of tretinoin in animals in therapeutic doses is not teratogenic, although massive exposures can produce maternal toxicity and reproductive effects. More importantly, topical administration in humans results in nonmeasurable blood levels.


Rh immune globulin

No adverse fetal effects have been associated with Rh-Ig prophylaxis against Rh immunization.


Smoking and nicotine

Placental lesions; intrauterine growth restriction; increased postnatal morbidity and mortality. While there have been some studies reporting increases in anatomical malformations, most studies do not report an association. There is no syndrome associated with maternal smoking. Maternal or placental complications can result in fetal death. Exposures to nicotine and tobacco smoke are a significant risk for pregnancy loss in the first and second trimesters.

Quality of available information: good to excellent. While tobacco smoke contains many components, nicotine can result in vascular spasm and vasculitis that has resulted in a higher incidence of placental pathology.


Thalidomide

Limb reduction defects (preaxial preferential effects, phocomelia), facial hemangioma, esophageal or duodenal atresia, anomalies of external ears, eyes, kidneys, and heart, increased incidence of neonatal and infant mortality. The thalidomide syndrome, while characteristic and recognizable, can be mimicked by some genetic diseases. Although there are fewer data pertaining to its abortigenic potential, there appears to be an increased risk of abortion.

Quality of available information: good to excellent. Sedative-hypnotic agent. The etiology of thalidomide teratogenesis has not been definitively determined.


Thyroid: iodides, antithyroid drugs (thioamides)

Fetal hypothyroidism or goiter with variable neurologic and aural damage. Maternal hypothyroidism is associated with an increase in infertility and abortion. Maternal intake of 12 mg of iodide per day or more increases the risk of fetal goiter. Thioamides may cause fetal goiter but dose can be adjusted to minimize this effect.

Quality of available information: good. Fetopathic effect of iodides and antithyroid drugs involves metabolic block, decreased thyroid hormone synthesis and gland development.


Tocolytics

There are no reports of adverse fetal outcome resulting from exposure to therapeutic doses of terbutaline, ritodrine, or magnesium sulfate.


Toluene

Intrauterine growth restriction; craniofacial anomalies; microcephaly. It is likely that high exposures from abuse or intoxication increase the risk of teratogenesis and abortion. Occupational exposures should present no increase in the teratogenic or abortigenic risk. The magnitude of the increased risk for teratogenesis and abortion in abusers is not known, because the exposure in abusers is too variable.

Quality of available information: poor to fair. Neurotoxicity is produced in adults who abuse toluene; a similar effect may occur in the fetus.


Valproic acid

Malformations are primarily neural tube defects and facial dysmorphology. The facial characteristics associated with this drug are not diagnostic. Small head size and developmental delay have been reported with high doses. The risk for spina bifida is about 1%, but the risk for facial dysmorphology may be greater. Because therapeutic exposures increase the incidence of neural tube defects, one would expect a slight increase in the incidence of abortion.

Quality of available information: good. Anticonvulsant; little is known about the teratogenic action of valproic acid.


Vitamins

Biotin: No adverse fetal effects for the usual therapeutic regimen

Used for treatment of multiple carboxylase deficiency

Cyanocobalamin: No adverse fetal effects for the usual therapeutic regimen.

Used for treatment of vitamin B12-responsive methylmalonic acidemia

Folic acid: The efficacy of folic acid supplementation for reducing the risk of neural tube defect recurrence may be limited to a select portion of the population. There are no adverse fetal effects for the usual therapeutic regimen.

Used for reduction in recurrence of neural tube defects

Vitamin A: The same malformations that have been reported with the retinoids have been reported with very high doses of vitamin A (retinol). Exposures below 10,000 IU present no risk to the fetus. Vitamin A in its recommended dose presents no increased risk for abortion.

Quality of available information: good. High concentrations of retinoic acid are cytotoxic; it may interact with DNA to delay differentiation and/or inhibit protein synthesis.

Vitamin D: Large doses given in vitamin D deficiency are possibly involved in the etiology of supravalvular aortic stenosis, elfin faces, and mental retardation. There are no data on the abortigenic effect of vitamin D.

Quality of available information: poor. Mechanism is likely to involve a disruption of cell calcium regulation with excessive doses.


a Modified from Friedman JM, Prolifka JE. Teratogenic effects of drugs (TERIS), 2nd ed. Baltimore, MD: Johns Hopkins University Press, 2000.


Although alcoholic mothers frequently smoke and consume other drugs, there is little doubt from the human and animal data that alcohol ingestion alone can have a disastrous effect on the developing embryo or fetus. The reported incidence of FAS varies widely in different studies but appears to be approximately 6% in offspring of women who drink heavily during pregnancy (54). Fetal alcohol syndrome may be the most commonly recognized cause of environmentally induced mental deficiency; there are at least several hundred children born each year with full FAS and probably many more with more subtle fetal alcohol effects (52,55).

In the last decade, the term FAS was replaced by fetal alcohol spectrum disorder, which better describes the wide range of potential pathology to the developing brain.


Aminopterin and Methotrexate

Aminopterin and methotrexate (methylaminopterin) are folic acid antagonists that inhibit dihydrofolate reductase, resulting in cell death during the S phase of the cell cycle (56). Aminopterin-induced therapeutic abortions have resulted in malformations (hydrocephalus, cleft palate, meningomyelocele, and growth restriction) in some of the abortuses (57,58,59). Three case reports of children exposed to aminopterin in utero included observations of growth restriction, abnormal cranial ossification, high-arched palate, and reduction in derivatives of the first branchial arch (60). The pattern of malformations associated with exposure to either compound has been referred to as the fetal aminopterin/methotrexate syndrome (61). Key features of this pattern of malformations include prenatal growth deficiency, abnormal cranial ossification, micrognathia, small low-set ears, and limb abnormalities. There have also been three case reports to date of severe developmental delay in children with methotrexate syndrome (62,63,64). Methotrexate is used therapeutically as an abortifacient, for treatment of rheumatoid arthritis and other autoimmune disorders, and as an antineoplastic agent. Skalko and Gold demonstrated a threshold effect and a dose-dependent increase in malformations in mice exposed to methotrexate in utero (65). Although malformations were induced in rats at doses exceeding those used in humans (66), smaller doses than those used in humans have resulted in malformation in rabbits (67). Analysis of human data indicate a critical period of exposure to methotrexate from 6 to 8 weeks from conception, at a dose above 10 mg/week, for the development of aminopterin/methotrexate syndrome (68). The risk of adverse effects caused by aminopterin in the usual therapeutic range is not known precisely but appears to be moderate to high (59). A recent multicenter prospective cohort study has shown increased teratogenic risk from the small dose of methotrexate used to treat rheumatic disease, if taken during the first trimester (69).


Androgens

Masculinization of the external genitalia of the female has been reported following in utero exposure to large doses of testosterone, methyltestosterone, and testosterone enanthate (70

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May 30, 2016 | Posted by in PEDIATRICS | Comments Off on Maternal Drugs and the Developing Fetus

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