The Motherisk Program, the Hospital for Sick Children,
Toronto, Ontario, Canada
Women of childbearing age with chronic medical conditions are often concerned about hazards from drug exposure during pregnancy and lactation. The number of mothers who take drugs during pregnancy is not known, but a U.S. survey showed that about 45% of women may use at least one drug on prescription, and many more use drugs bought over the counter.1 A British prospective study suggested that only about 10% of women take drugs in early pregnancy.2 The avoidance of any medication after conception may often be unwise for maternal well-being. Proper prescribing of drugs in pregnancy is a challenge and should provide maximal safety to the foetus as well as therapeutic benefit to the mother. Double-blind, randomized, prospective drug trials are generally impossible to perform during pregnancy. Certain medical disorders occur infrequently at any one medical centre or cannot be studied during pregnancy for ethical or regulatory reasons. Major congenital defects occur in 1-3% of the general population at birth. Careful follow-up increases the number detected to up to 5% later in life. Major birth defects cause 20% of infant mortality and are responsible for a substantial number of childhood hospitalizations. Of those defects about 25% are of genetic origin (genetically inherited diseases, new mutations and chromosomal abnormalities) and 65% are of unknown etiology (multifactorial, polygenic, spontaneous errors of development and synergistic interactions of teratogens). Only 2-3% of defects are thought to arise in association with drug treatment.3 The remaining defects are associated with other environmental exposures during pregnancy including infectious agents, maternal disease states, mechanical problems and irradiation.
Maternal physiologic changes in pregnancy may alter the pharmacokinetics of drugs. There is large variability in maternal metabolism and elimination of drugs during pregnancy. Clearance rates of many drugs increase during late pregnancy due to increases in both hepatic and renal elimination processes (e.g., digoxin, phenytoin), while in some cases clearance rates decrease (e.g., theophylline).
Teratology is the study of environmentally induced congenital anomalies. A teratogen is an agent, which by acting on the developing embryo or foetus, can cause a structural anomaly. To date, very few drugs are proven teratogens. However, malformations induced by drugs are important because they are potentially preventable.
Teratogens act with specificity in that they produce specific abnormalities at specific times during gestation. For example, thalidomide produces limb phocomelia, while valproic acid and carbamazepine produce neural tube defects. Other teratogens are associated with recognizable patterns of malformations, for example, phenytoin with foetal hydantoin syndrome and coumarin anticoagulants with foetal warfarin syndrome (see proven teratogenic drugs in humans for description of the above). Teratogenic specificity also applies to species, for example, aspirin and corticosteroids have been found to be teratogenic in mice and rats but appear to be safe in humans.4 Thalidomide, on the other hand, was not shown to be teratogenic in rats, a tragic fact that resulted in significant human morbidity.
Teratogens may demonstrate a dose-effect relationship. At low doses there can be no effect, at intermediate doses the characteristic pattern of malformations will result, and at high dose the embryo will be killed.
A dose-response may be considered essential in establishing teratogenicity in animals, but is uncommonly demonstrated in sufficient data among humans. A threshold dose is the dosage below which the incidence of adverse effects is not statistically greater than that of controls. With most agents, a dose threshold for teratogenic effects has not been determined; however they are usually well below levels required to cause toxicity in adults.
Teratogens must reach the developing conceptus in sufficient amounts to cause their effects. Large molecules with molecular weights greater than 1,000 do not easily cross the placenta into the embryonic-foetal bloodstream to exert potential teratogenic effect. Other factors influencing the rate and extent of placental transfer of xenobiotics include polarity, lipid solubility and the existence of a specific protein carrier.
The effect produced by a teratogenic agent depends upon the developmental stage in which the foetus is exposed to the agent. Several important phases in human development are recognized:
Many organ systems continue structural and functional maturation long after birth. Most of the adenocarcinomas associated with first trimester exposure to the synthetic estrogen, diethylstilbestrol, occurred many years after the exposure.
All new drug applications filed with the United States Food and Drug Administration (FDA) include data from animal developmental and reproductive-toxicologic studies. Although major new teratogenic drugs in humans have been predicted from animal studies, there are problems in extrapolating animal data to humans. Animals have a different "gestational clock" to humans, there is marked interspecies variability in susceptibility to teratogens and no experimental animal is metabolically and physiologically identical to humans. Animal studies are important because, in some instances, they have shed light on mechanisms of teratogenicity and because when an agent causes similar patterns of anomalies in several species, human teratogenesis should also be suspected.
For obvious ethical considerations no studies of teratogenicity are conducted during embryogenesis in humans. The studies are, therefore, either retrospective in nature (case reports, case-series and case-control studies), or prospective cohort studies, where a specific maternal exposure in question is ascertained during pregnancy and the pregnancy outcome is evaluated and compared to a control group. Retrospective case-control studies are less costly and easier to conduct but they have other weaknesses such as the inaccuracy of data collected from medical records and recall bias. For the rare malformation/rare exposure, the case report method is commonly used to suggest association, but case reports are unable to prove or disprove teratogenicity, nor can they give estimation of teratogenic risk. Human teratogenicity is supported by:
In an attempt to provide the practitioner who is considering treatment of the pregnant woman with a better assessment of foetal risk, the FDA developed a classification of foetal risk in 1979 (Table 1). The subscript "m" denotes that it is a manufacturer's designation. These categories initially appeared logical, but were not found to be very helpful in counselling individual patients. The manufacturers may have legal rather than scientific reasons for their particular designations. The classification frequently resulted in ambiguity and even in false alarm. For example, the oral contraceptive hormones are denoted as X, despite failure of two meta-analyses to show increased teratogenic risk with their use. The Teratology Society stated in 1994 that the FDA ratings are inappropriate for the purpose of therapeutic guidance to physicians and that the risk of such abuse exceeds the benefits of the system.5 The Teratology Society recommended that the FDA ratings be deleted from drug labelling and replaced by narrative statements that summarize and interpret available data regarding hazards of developmental toxicity and provide estimates of teratogenic risk. Shepard summarized the criteria for establishing human teratogenicity (Table 2).6
In counselling the pregnant patient exposed to a potential human teratogen, it is important to emphasize the significance of exposure to the patient. Ascertaining the clinical facts regarding the nature of the exposure: the length, dosage, and timing of exposure during pregnancy, as well as other exposures of concern about which the patient may not ask (e.g., alcohol, cigarette smoking). All available current data regarding the agent are then collected, and conclusions regarding the risks of exposures are drawn. Counselling should include the background human baseline risk for major malformations, whether the foetus is at increased risk, which anomaly has been associated with the agent in question, a risk assessment, methods of prenatal detection, when available, limitations in our knowledge, and limitations of prenatal diagnostic capabilities. Additional aspects include the potential risk of the medical condition for which a drug is prescribed, known interactions (in both directions) between the disease state and the pregnancy and preventive measures, when applicable (e.g., folic acid supplementation in the case of carbamazepine exposure). Because more than 50% of pregnancies in North America are unplanned, teratogenic risk assessment should be started prior to pregnancy.
Alcohol
The foetal alcohol syndrome is a clinical pattern of anomalies characterized
by intrauterine growth retardation which commonly continues postnatally. These
include: microcephaly, developmental delay, and dysmorphic facies consisting
of low nasal bridge, midface hypoplasia, long featureless philtrum, small palpebral
fissures and thin upper lip. Cleft palate and cardiac anomalies may also occur.
Full expression of this syndrome occurs with chronic daily ingestion of at least
2 grams alcohol per kilogram (eight drinks per day). The full syndrome is present
in about one third of these mothers and partial effects occur in approximately
three quarters of offspring.
Angiotensin converting enzyme inhibitors (ACEI) (captopril, enalapril, lisinopril)
ACEI are potent anti-hypertensive drugs. Their use in late pregnancy has
been associated with foetal toxicity including intrauterine renal insufficiency.
Reports of neonatal hypotension, oliguria with renal failure, and hyperkalemia
have been reported with ACEI use in pregnancy. Complications of oligohydramnios
(i.e., foetal limb contractures, lung hypoplasia, and craniofacial anomalies),
prematurity, intrauterine growth retardation, and foetal death have also been
reported with the use of these agents late in pregnancy. The adverse effects
are related to the haemodynamic effects of ACEI on the foetus, teratogenic risk
with first trimester exposure to these agents appears to be low.
Carbamazepine
Exposure to carbamazepine in utero carries a 1% risk of neural tube defects
(10 times their baseline risk). A pattern of malformations similar to those
described with the foetal hydantoin syndrome has also been associated with carbamazepine
exposure in pregnancy.
Cocaine
Cocaine use during pregnancy has been associated with abruptio placentae,
prematurity, foetal loss, decreased birth weight, microcephaly, limb defects,
urinary tract malformations, and poorer neurodevelopmental performance. The
contribution of cocaine to the incidence of congenital malformations is difficult
to assess because of methodological problems, which make the results difficult
to interpret. Cocaine abuse is often associated with poly-drug abuse, alcohol
consumption, smoking, malnutrition, and poor prenatal care. Experimental animal
studies and human epidemiology indicate that the risk of major malformation
from cocaine is probably low, but the anomalies may be severe.
Coumarin anticoagulants
First trimester exposure to coumarin derivatives is associated with a characteristic
pattern of malformations termed the foetal warfarin syndrome. Clinical features
consist of nasal hypoplasia and calcific stippling of the epiphyses. Intrauterine
growth retardation and developmental delay due to central nervous system damage,
eye defects, and hearing loss have also been described. The critical period
of exposure for the foetal warfarin syndrome appears to be between 6 and 9 weeks
of gestation. A prospective study found evidence of warfarin embryopathy in
about one third of the cases where a coumarin derivative was given throughout
pregnancy. Oral anticoagulants are also associated with a high rate of miscarriage.
Exposure to oral anticoagulants after the first trimester presents a risk of
central nervous system damage due to haemorrhage. Unlike heparin, oral anticoagulants
readily cross the placental barrier.
Diethylstilbestrol
Diethylstilbestrol was used in the 1950s and 1960s for the diagnosis of
recurrent miscarriage. Clear cell adenocarcinoma of the vagina was found to
be associated with diethylstilbestrol treatment of the patient's mother during
the first trimester of pregnancy. Over 90% of the cancers occurred after 14
years of age. Clear cell carcinoma has not occurred in women exposed in utero
after the 18th week of gestation. A high incidence of benign adenosis of the
vagina was found in women prenatally exposed to this nonsteroidal estrogen analogue.
In a prospective study, exposure starting at 4 weeks was associated with adenosis
in 56% of the offspring, decreasing later to 30% at 16 weeks and 10% at 20 weeks.
Miscarriage rate and preterm delivery were significantly more common in women
exposed in utero to diethylstilbestrol compared to matched controls. In 134
males exposed in utero to the agent no signs of malignancy were found but 27%
had genital lesions (epididymal cysts, hypotrophic testes, or capsular induration
of the testes). In 29%, pathologic changes were found in spermatozoa.
Folic acid antagonists: Aminopterin and methotrexate
Aminopterin has been known since 1950 to result in foetal death, which led
to its use as a human abortifacient. The foetal aminopterin syndrome was described
based on anomalies observed in aborted foetuses and infants born following unsuccessful
abortions. Malformations include central nervous system defects (hydrocephalus,
meningomyelocele), facial anomalies (cleft palate, high arched palate, micrognathia,
ocular hypertelorism, external ear anomalies), abnormal cranial ossification,
abnormalities in first branchial arch derivatives, intrauterine growth retardation
and mental retardation. Infants have been born with features of the aminopterin
syndrome after pregnancy exposure to methotrexate (methylaminopterin). It was
suggested that the maternal dose necessary to induce defects is above 10 mg
per week with a critical period of 6 to 8 weeks post conception being postulated.
Hydantoins (phenytoin and trimethadione)
Hydantoins have been associated with a recognizable pattern of malformation
termed the foetal hydantoin syndrome. The clinical features include craniofacial
dysmorphology (wide anterior fontanelle, ocular hypertelorism, metopic ridge,
broad depressed nasal bridge, short anteverted nose, bowed upper lip, cleft
lip, cleft palate), as well as variable degrees of hypoplasia of the distal
phalanges, nail hypoplasia and low arch dermal ridge patterning. Growth retardation,
mental deficiency and cardiac defects are additional features of the syndrome.
Isotretinoin (13-cis-retinoic acid)
Isotretinoin is a synthetic vitamin A derivative, prescribed for severe
cystic acne, that has been proven to be a potent human teratogen as well as
a behavioural teratogen when given systemically. A pattern of anomalies termed
retinoic acid embryopathy has been associated with isotretinoin (and other retinoic
acid derivatives such as etretinate and megadoses of vitamin A) exposure in
pregnancy. The clinical features include craniofacial anomalies (microtia or
anotia, accessory parietal sutures, narrow sloping forehead, micrognathia, flat
nasal bridge, cleft lip and palate, and ocular hypertelorism), cardiac defects
(primarily conotruncal malformations), abnormalities in thymic development,
and alterations in central nervous system development. The risk for associated
miscarriage was 40%.
Lithium
By 1983, the International Registry of Lithium Babies had collected retrospective
information on 225 babies exposed to lithium during the first trimester. Despite
the lack of a control group and the likely over-reporting of abnormal outcome,
the data suggested a higher risk for major anomalies than in the general population
and a specific risk for cardiac teratogenesis in early gestation. The number
of cases of Ebstein's anomaly, a rare malformation of the tricuspid valve, by
far exceeded its spontaneous rate of occurrence.6
In a prospective study of 148 women who took lithium during the first trimester
of pregnancy, three infants were born with major malformations, a rate comparable
to that found in the control group. One pregnancy was terminated following prenatal
diagnosis of Ebstein's anomaly. Foetal echocardiography is recommended in the
management of pregnancies exposed to lithium in the first trimester.
Misoprostol
Misoprostol is a synthetic prostaglandin E1 analogue, prescribed for duodenal
and gastric ulceration, also used as an abortifacient by women in Brazil. A
Brazilian case-series suggested an association between first trimester exposure
to misoprostol and limb defects with or without Moebius' sequence. The association
was further supported by a case-control study comparing the frequency of misoprostol
use during the first trimester by mothers of 96 infants with Moebius' syndrome
and mothers of infants with neural tube defects. Among the mothers of infants
with Moebius' syndrome, 49% had used misoprostol, as compared with 3% of the
mothers of infants with neural tube defects (odds ratio, 29.7; 95% confidence
interval 11.6 to 76.0). Despite the strong association between misoprostol exposure
during the first trimester and Moebius' syndrome, its absolute teratogenic risk
is probably not high.
Tetracyclines
Yellow-brown discolouration of teeth may occur due to deposition of the
antibiotic in calcifying teeth with tetracycline use in late pregnancy. The
risk is apparent only after 17 weeks of gestation when the deciduous teeth begin
to calcify. Generally, only the deciduous teeth are involved, although with
administration of the drug close to term the crowns of the permanent teeth may
be stained. Oxytetracycline and doxycycline are associated with a lower incidence
of enamel staining.
Thalidomide
More than any other event, the thalidomide tragedy alerted the world to
the teratogenic potential of drugs. Thalidomide was marketed in 1956 and was
available for four years before its teratogenicity was recognized. Thalidomide
produced malformations limited to tissues of mesodermal origin, primarily limbs,
ears, cardiovascular system, and gut musculature. The types of malformations
could be related to the developmental stage of the embryo at the time of ingestion.
Malformations resulted from repeated use as well as from single ingestions during
the critical period from the 27th day to the 40th day of gestation. In women,
a single dose of less than 1 milligram per kilogram has produced the syndrome.
Abnormal development of long bones produced a variety of limb reduction defects.
Typically the upper limbs were more severely involved than the lower limbs.
However, any of the bones could be defective or, in severe cases, totally absent.
Phocomelia, polydactyly, syndactyly, oligodactyly were all reported. Lower extremities
could be similarly affected, although less frequently and less severely. Defects
of the external ears ranging from agenesis to preauricular tags occurred in
20% of cases and were the earliest of the recognized thalidomide anomalies.
Other anomalies associated with phocomelia are facial capillary haemangiomas,
and palsies of cranial nerves VI or VII. A wide variety of cardiovascular defects
were seen, affecting about 10% of infants. Visceral anomalies included agenesis
of kidneys, spleen, gallbladder and appendix and atresias or stenoses of the
esophagus, duodenum, and anus. Cleft palate was a rare complication and the
central nervous system was not adversely affected as reflected by normal intelligence.
It has been estimated that the embryopathy was found in about 20% of the pregnancies
with exposure to thalidomide in the critical period.
Valproate
First trimester exposure to valproate is associated with neural tube defects
and carries a 1-2% risk of meningomyelocele, primarily lumbar or lumbosacral.
A number of investigators have delineated an associated pattern of malformations,
which they termed the foetal valproate syndrome. The clinical features include
narrow bifrontal diameter, high forehead, epicanthal folds, infra-orbital creases,
telecanthus, low nasal bridge, short nose with anteverted nares, midfacial hypoplasia,
long philtrum, thin vermillion border, small mouth, cardiovascular defects,
long fingers and toes, hyperconvex fingernails, and cleft lip.
D-penicillamine
Based on several case reports, high dose treatment of the pregnant woman
with D-penicillamine has been associated with connective tissue disorders (cutis
laxa).
Methimazole
Methimazole treatment during pregnancy has been associated with scalp defects
(aplasia cutis congenita) based on case reports and on an epidemiological study
in which methimazole had been added to animal feeds as a weight enhancer, and
in those areas a higher incidence of cutis aplasia congenita was found.
Diazepam
First trimester exposure to diazepam has been associated in small studies
with a small increase in the incidence of cleft lip and palate. Larger studies
did not confirm the association.
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