Teratogens in Pregnancy

Testosterone and Anabolic Steriods

Androgen exposure in reproductive-aged women typically stems from anabolic steroid use to accrue lean body mass and muscular strength. Exposure of a female fetus may cause varying degrees of virilization and may result in ambiguous genitalia similar to that encountered in congenital adrenal hyperplasia. Findings can include labioscrotal fusion with first-trimester exposure and phallic enlargement from later fetal exposure.

Selective SSRI and SNIR Inhibitors

As a class, these medications are not considered major teratogens. The one exception is paroxetine, which has been associated with a higher risk for cardiac anomalies, particularly atrial and ventricular septal defects. For these reasons, the American College of Obstetricians and Gynecologists (2016) recommends that paroxetine be avoided in women planning pregnancy. Fetal echocardiography should be considered for those with first-trimester paroxetine exposure. Neonatal effects have been associated with prenatal exposure to selective serotonin-reuptake inhibitors (SSRIs) and selective norepinephrine-reuptake inhibitors (SNRIs). Approximately 25 percent of neonates exposed to SSRIs in late pregnancy manifest one or more nonspecific findings considered to represent poor neonatal adaptation. Collectively termed the neonatal behavioral syndrome, findings can include jitteriness, irritability, hyper- or hypotonia, feeding abnormalities, vomiting, hypoglycemia, thermoregulatory instability, and respiratory abnormalities. Fortunately, these neonatal behaviors are typically mild and self-limited and last approximately 2 days. Rarely, neonates exposed to SSRIs in late pregnancy demonstrated more severe adaptation abnormalities (Ornoy, 2017). Another concern with late-pregnancy exposure is the possible association of SSRI medications with persistent pulmonary hypertension of the newborn (PPHN). The baseline incidence approximates 2 cases per 1000 term newborns. PPHN is characterized by elevated pulmonary vascular resistance with right-to-left shunting and resultant hypoxemia.

Sex hormones

Some of the functions and effects of male and female hormones on the developing fetus are discussed in Chapter 3 (Sexual Differentiation). It is intuitive that exposure of female fetuses to excessive male sex hormones—and vice versa—might be detrimental.

Immunosuppressant Medications

Some of the immune functions necessary for pregnancy maintenance. Given these important interactions, immunosuppressant drugs logically might affect pregnancy.

Aminoglycosides

Some preterm neonates treated with gentamicin or streptomycin have developed nephrotoxicity and ototoxicity. Despite theoretical concern for potential fetal toxicity, no adverse effects have been demonstrated, and no congenital defects resulting from prenatal exposure have been identified.

Most frequently reported fetal malformation for epilepsy medications

The most frequently reported anomalies are orofacial clefts, cardiac malformations, and neural-tube defects.

Antiviral agents

The number of drugs used to treat viral infections has increased rapidly during the past 20 years. For most, experience in pregnant women is limited.

Teratology

The study of birth defects and their etiology. It comes from the Greek teratos, meaning monster

Vitamin A

There are two natural forms of vitamin A. Beta-carotene, which is a precursor of provitamin A, is found in fruits and vegetables and has never been shown to cause birth defects. Retinol is preformed vitamin A, which has been associated with cranial neural-crest defects when more than 10,000 IU per day is consumed in the first trimester. It seems reasonable to avoid doses of preformed preparations that exceed the recommended 3000 IU daily allowance (American Academy of Pediatrics, 2017).

Tropical Retinoids

These compounds, initially used to treat acne, have become so popular for the treatment of sun damage that they are called cosmeceuticals. The most commonly used topical agents are tretinoin, isotretinoin, and adapalene. Systemic absorption is low, and this argues against plausible teratogenicity. Isolated case reports have described malformations following topical tretinoin, and it is unknown whether this is due to variability in absorption or perhaps potential individual susceptibility. The European Network of Teratology Information Services found no higher rates of birth defects or spontaneous losses, and no case of retinoid embryopathy. Investigators similarly identified no higher risk for congenital malformations, spontaneous abortion, stillbirth, low birthweight, or preterm delivery. These results may be reassuring to pregnant women with inadvertent exposure.

Tetracyclines

These drugs are no longer commonly used in pregnant women. They are associated with yellowish-brown discoloration of deciduous teeth when used after 25 weeks' gestation. The risk for subsequent dental caries does not appear greater. In contrast, a recent systematic review of doxycycline in pregnancy identified no higher rates of either birth defects or staining of deciduous teeth.

Sulfonamides

These drugs are often combined with trimethoprim and used to treat infections during pregnancy. One indication is treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection. The NBDPS, which included 107 pregnancies with periconceptional trimethoprim-sulfamethoxazole exposure and birth defects, identified a fivefold greater risk to have offspring with esophageal atresia or diaphragmatic hernia. ACOG says they're fine in 1st trimester as long as there aren't other alternatives Sulfonamides displace bilirubin from protein-binding sites. Thus, if given near the time of preterm delivery, these agents theoretically might worsen neonatal hyperbilirubinemia. However, a population-based review of more than 800,000 births from Denmark found no association between exposure to sulfamethoxazole in late pregnancy and neonatal jaundice.

Corticosteroids (immunosuppressant medications)

These medications include glucocorticoids and mineralocorticoids, which have antiinflammatory and immunosuppressive actions. They are frequently used to treat serious disorders such as asthma and autoimmune disease. Corticosteroids have been associated with clefts in animal studies. Unlike other corticosteroids, the active metabolite of prednisone, which is prednisolone, is inactivated by the placental enzyme 11β-hydroxysteroid dehydrogenase 2. Thus, it may not effectively reach the fetus.

Retinoids

These vitamin A derivatives are among the most potent human teratogens. Three retinoids available in the United States are highly teratogenic when orally administered—isotretinoin, acitretin, and bexarotene. By inhibiting neural-crest cell migration during embryogenesis, they create a pattern of cranial neural-crest defects—termed retinoic acid embryopathy—that involve the CNS, face, heart, and thymus (Fig. 12-5). Specific anomalies may include ventriculomegaly, maldevelopment of the facial bones or cranium, microtia or anotia, micrognathia, cleft palate, conotruncal heart defects, and thymic aplasia or hypoplasia.

NSAIDS in pregnancy

They exert their effects by inhibiting prostaglandin synthesis. When taken in late pregnancy, indomethacin may cause constriction of the fetal ductus arteriosus and subsequent pulmonary hypertension. Fetal ductal constriction is more likely when the drug is taken in the third trimester for longer than 72 hours. The risk is 15-fold higher among indomethacin-exposed pregnancies. The drug also may decrease fetal urine production and amnionic fluid volume. With aspirin, a low dosage of 100 mg daily or less does not confer a greater risk for constriction of the ductus arteriosus or for adverse infant outcomes. As with other NSAIDs, however, high-dose aspirin use should be avoided, particularly in the third trimester. In a report from the NBDPS, at least 20 percent of pregnant women recall first-trimester NSAID use, particularly ibuprofen and aspirin, and such exposure is not a major risk factor for birth defects (Hernandez, 2012)

Cyclophosphamide

This alkylating agent inflicts a chemical insult on developing fetal tissues and leads to cell death and heritable DNA alterations in surviving cells. Pregnancy loss rates are increased, and reported malformations include skeletal abnormalities, limb defects, cleft palate, and eye abnormalities. Surviving infants may have growth abnormalities and developmental delays. Environmental exposure among health-care workers is associated with a higher risk for spontaneous abortion.

Warfarin

This anticoagulant is a vitamin K antagonist with a long half-life. Because of its low molecular weight, it readily crosses the placenta and may cause embryotoxic and fetotoxic effects. Warfarin analogues, such as Coumadin, are considered contraindicated in pregnancy. An exception is treatment of women with mechanical heart valves who are at high risk for thromboembolism. Warfarin embryopathy is characterized by stippled epiphyses and nasal hypoplasia (Fig. 12-6). Warfarin exposure displayed characteristic findings, which include depressed nasal bridge with nasal hypoplasia and choanal atresia, along with stippled epiphyses of the femur, humerus, calcanei, and distal phalanges. It may result from exposure between the 6th and 9th weeks' gestation.

Chloramphenicol

This antimicrobial is not considered teratogenic and is no longer routinely used in the United States. Preterm newborns were unable to conjugate and excrete the drug and manifested abdominal distention, respiratory abnormalities, an ashen-gray color, and vascular collapse. Chloramphenicol was subsequently avoided in late pregnancy due to theoretical concerns.

Teratogen

any agent that acts during embryonic or fetal development to produce a permanent alteration of form or function. Thus, a teratogen may be a medication or other chemical substance, a physical or environmental factor such as heat or radiation, a maternal metabolite as in diabetes or phenylketonuria, or an infection such as cytomegalovirus

malformations were twofold higher among children exposed to which epileptic medication?

carbamazepine or phenytoin

What are the risks of using fluconazole as an antifungal medication?

congenital malformations resembling the autosomal recessive Antley-Bixler syndrome. Abnormalities include oral clefts, abnormal facies, and cardiac, skull, long-bone, and joint abnormalities. Such findings have been reported only with chronic, first-trimester, high-dose treatment at doses of 400 to 800 mg daily. Regarding low-dose treatment of vulvovaginal candidiasis, the Motherisk Program recently conducted a systematic review of pregnancies with first-trimester fluconazole exposure of 150 or 300 mg in total . The overall risk for birth defects was not greater, although a small increase in rates of cardiac malformations could not be excluded.

Antineoplastic agents

Cancer management in pregnancy includes many chemotherapeutic agents generally considered to be at least potentially toxic to the embryo, fetus, or both. For the many novel polyclonal antibody therapies designated as antineoplastics, there are few data concerning their safety. A few of the more common agents for which experience in pregnancy has accrued are considered below.

The Embryonic period

extends from the second through the eighth week postconception. It encompasses organogenesis and is thus the most crucial period with regard to structural malformations

Nitrofurantoin

first-trimester nitrofurantoin exposure is linked to a twofold risk for cleft lip. Considering that the birth prevalence of clefts approximates 1 case per 1000, the likelihood that a nitrofurantoin-exposed fetus would not have a cleft would thus be 998 per 1000. For other birth defects, initial associations with this antibiotic did not persist in the final NBDPS cohort. ACOG has concluded that first-trimester nitrofurantoin use is appropriate if no suitable alternatives are available.

malformations were threefold higher among those exposed to phenobarbital, and fourfold higher among those exposed to which epileptic medication?

topiramate as monotherapy

!! Fetotoxic

used to describe agents, such as tobacco, that have toxic effects on the fetus and adversely affect growth or development. The fetus is most likely to be exposed to teratogenic agents in the first trimester and to fetotoxic agents in the second and third trimesters.

Which epileptic medication has the greatest risk?

valproic acid confers the greatest risk. The North American Antiepileptic Drug (NAAED) Pregnancy Registry reported that major malformations developed in 9 percent of fetuses with first-trimester valproate exposure. This included a 4-percent risk for neural-tube defects. School-aged children within utero exposure to valproic acid have poorer cognitive development—including significantly lower intelligence quotient (IQ) scores—than children exposed to other antiepileptic drugs.

The Fetal period

which is beyond eight weeks postconception, is characterized by continued maturation and functional development. During this time, certain organs remain vulnerable

Isotretinoin

13-cis-Retinoic acid is a vitamin A isomer that stimulates epithelial cell differentiation and is used for dermatological disorders, especially cystic nodular acne. First-trimester exposure is associated with a high rate of pregnancy loss, and up to a third of fetuses have malformations. The iPLEDGE program is an FDA-mandated REMS for isotretinoin and is found at: www.ipledgeprogram.com. This web-based, restricted-distribution program requires participation for all patients, physicians, and pharmacies to help eliminate embryonic-fetal exposure. Although other countries have instituted similar programs, inadvertent exposure remains a global concern.

Endothelin-Receptor Antagonist

Bosentan, ambrisentan, and macitentan are three endothelin-receptor antagonists used to treat pulmonary arterial hypertension (Chap. 49, Cardiomyopathies). The endothelin-receptor signaling pathway is important for neural-crest development. Mice deficient in endothelin receptors develop neural-crest cell defects that include craniofacial and cardiac outflow tract abnormalities. Each of these three agents has been found to cause similar birth defects in multiple animal species. No human data are available. Endothelin-receptor antagonists may be obtained only through restricted access programs, each of which has stringent requirements that include contraception and monthly pregnancy testing.

Mercury

Environmental spills of methyl mercury in Minamata Bay, Japan, and rural Iraq demonstrated that the developing nervous system is particularly susceptible to this heavy metal. Prenatal exposure causes disturbances in neuronal cell division and migration. This leads to a range of defects from developmental delay to microcephaly and severe brain damage. The principal concern for prenatal mercury exposure is the consumption of certain species of large fish. The FDA (2017a) advises that pregnant women and breastfeeding mothers avoid consumption of king mackerel, marlin, orange roughy, shark, swordfish, tilefish, and bigeye tuna.

Antimicrobial drugs

Medications used to treat infections are among those most frequently administered during pregnancy. Over the years, experience has accrued regarding their general safety. With a few exceptions cited below, most of the commonly used antimicrobial agents are considered safe for the embryo-fetus.

Antipsychotic medications

No antipsychotic medications are considered teratogenic. Exposed neonates can manifest abnormal extrapyramidal muscle movements and withdrawal symptoms that include agitation, abnormally enhanced or diminished muscle tone, tremor, sleepiness, feeding difficulty, and respiratory abnormalities. These findings are nonspecific and transient, similar to the neonatal behavioral syndrome that can follow SSRI exposure. An FDA (2011) alert cites all medications in this class. These include older drugs such as haloperidol and chlorpromazine, as well as newer medications such as aripiprazole, olanzapine, quetiapine, and risperidone.

Are ACE inhibitors and angiotensin receptor-blocking drugs recommended in pregnancy?

No, there are many therapeutic options for treating hypertension during pregnancy other than these. First choice is labetolol.

Placental transfer components

Placental transfer depends on maternal metabolism; on specific characteristics of the drug, such as protein binding and storage, molecular size, electrical charge, and lipid solubility; and on placental metabolism, such as by the cytochrome P450 enzyme system. In early pregnancy, the placenta also has a relatively thick membrane that slows diffusion.

Thalidomide and Lenalidomide

Possibly the most notorious human teratogen, thalidomide causes malformations in 20 percent of fetuses exposed between 34 and 50 days menstrual age. The characteristic malformation is phocomelia—an absence of one or more long bones. As a result, hands or feet are attached to the trunk, occasionally by a small rudimentary bone. Cardiac malformations, gastrointestinal abnormalities, external ear malformations, eye anomalies, and other limb-reduction defects are also common following thalidomide exposure. The manufacturer reports that up to 40 percent of affected newborns do not survive the neonatal period. Thalidomide was first approved in the United States in 1999 and currently is used to treat erythema leprosum nodosum and multiple myeloma. The FDA has mandated a web-based, restricted-distribution program for thalidomide, called THALOMID REMS, which is required before patients, physicians, and pharmacies can access the medication. Lenalidomide is an analogue of thalidomide that is used to treat some types of myelodysplastic syndrome and multiple myeloma. It crosses the placenta in multiple animal species, and it causes thalidomide-like limb abnormalities in monkeys (Celgene, 2017b). Because of obvious teratogenicity concerns, a restricted-distribution program similar to that used for thalidomide has been developed

Lead

Prenatal lead exposure is associated with fetal-growth abnormalities and with childhood developmental delay and behavioral abnormalities. According to the CDC (2010), no level of lead exposure is considered safe in pregnancy.

Radioiodine

Radioactive iodine-131 is used for treatment of thyroid cancer and thyrotoxicosis and for diagnostic thyroid scanning. It is also a component of iodine-131 tositumomab therapy, which is employed to treat a type of non-Hodgkin lymphoma. Radioiodine is contraindicated during pregnancy because it readily crosses the placenta and is then concentrated in the fetal thyroid gland by 12 weeks' gestation. It may cause severe or irreversible fetal and neonatal hypothyroidism, which can lead to decreased mental capacity and delayed skeletal maturation. Pregnancy testing should be performed before administration of radioiodine-131.

angiotensin-receptor blockers and Ace inhibitors effect on the fetus

Reduced perfusion can result in fetal-growth restriction and calvarium maldevelopment, and oligohydramnios may lead to pulmonary hypoplasia and limb contractures

Danazol

This ethinyl testosterone derivative has weak androgenic activity. It is used to treat endometriosis, immune thrombocytopenic purpura, migraine headaches, premenstrual syndrome, and fibrocystic breast disease. Inadvertent exposure during early pregnancy, exposed female fetuses were virilized. There was a dose-related pattern of clitoromegaly, fused labia, and urogenital sinus malformation.

Methotrexate

This folic-acid antagonist is a potent teratogen.It is used for cancer chemotherapy, immunosuppression of autoimmune diseases and psoriasis, nonsurgical treatment of ectopic pregnancy, and medical abortion. It is similar in action to aminopterin, which is no longer used clinically, and can cause defects known collectively as the fetal methotrexate-aminopterin syndrome. This includes craniosynostosis with a "clover-leaf" skull, wide nasal bridge, low-set ears, micrognathia, and limb abnormalities. The embryo is thought to be most vulnerable at 8 to 10 weeks postconception and at dosages of at least 10 mg/week. The standard 50 mg/m2 dose given to treat ectopic pregnancy or to induce elective abortion exceeds this threshold dose. Some reports have suggested an association with cardiac anomalies, particularly conotruncal defects, in intrauterine pregnancies inadvertently treated with methotrexate for suspected ectopic pregnancy. Thus, ongoing pregnancies after treatment with methotrexate—especially if used in conjunction with misoprostol—raise serious concerns for fetal malformations.

Mycophenolate Mofetil

This inosine monophosphate dehydrogenase inhibitor, and a related agent, mycophenolic acid, are immunosuppressants. They are used to prevent rejection in organ-transplant recipients and to treat autoimmune disease. Mycophenolate is a potent teratogen. From the National Transplantation Pregnancy Registry, of pregnancies in which mycophenolate was not discontinued until after the first trimester, birth defects complicated 30 percent, and another 30 percent spontaneously aborted. Many affected infants have a pattern of defects termed mycophenolate embryopathy. This includes microtia, auditory canal atresia, clefts, coloboma and other eye anomalies, short fingers with hypoplastic nails, and cardiac defects. A Risk Evaluation and Mitigation Strategy (REMS) has been developed for mycophenolate prescribers who treat women with reproductive potential. REMS are safety strategies mandated by the FDA to help manage known risks associated with a medicine yet still allow patients to have access to the benefits of a given drug.

Efavirenz

This is a nonnucleoside reverse transcriptase inhibitor used to treat HIV infection- discussed more in High risk Obstetrics. CNS and ocular abnormalities have been reported in cynomolgus monkeys treated with doses comparable to those used in humans. Several case reports also describe neural-tube defects following human exposure to efavirenz. Reassuringly, the Antiretroviral Pregnancy Registry has identified no increased birth defect rates in more than 800 pregnancies with first-trimester exposure.

Leflunomomide

This is a pyrimidine-synthesis inhibitor used to treat rheumatoid arthritis but is contraindicated in pregnancy. In several animal species, it results in fetal hydrocephalus, eye anomalies, skeletal abnormalities, and embryo death when given at or below human-equivalent doses. The active metabolite, teriflunomide, is detectable in plasma for up to 2 years following discontinuation of the medication. Women who become pregnant while taking leflunomide, and even those of childbearing potential who have discontinued it, are recommended to undergo an accelerated drug elimination procedure with either cholestyramine or activated charcoal.

Trastuzumab

This is a recombinant monoclonal antibody directed to the human epidermal growth factor receptor 2 (HER2) protein. Used to treat breast cancers that express HER2 protein, this drug has not been associated with fetal malformations. However, cases of oligohydramnios sequence resulting in pulmonary hypoplasia, renal failure, skeletal abnormalities, and neonatal deaths have been reported. Surveillance for these complications is recommended for exposed pregnancies and for those treated at any time in the 7 months prior to conception. A trastuzumab pregnancy exposure registry and a pregnancy pharmacovigilance program have been established to monitor pregnancy outcomes. These warnings also apply to those treated with ado-trastuzumab emtansine.

Lithium

This medication has been associated with Ebstein anomaly, a rare cardiac abnormality that otherwise complicates only 1 per 20,000 births. Ebstein anomaly is characterized by apical displacement of the tricuspid valve, often resulting in severe tricuspid regurgitation and marked right atrial enlargement that confer significant morbidity. A report from the Lithium Baby Registry initially suggested that the risk for Ebstein anomaly was as high as 3 percent. However, subsequent series have identified an attributable risk for Ebstein anomaly and co-occurring right-sided cardiac anomalies of only 1 to 4 per 1000 exposed pregnancies. Neonatal lithium toxicity stems from exposure near delivery. The manufacturer recommends that if possible, the dosage should be decreased or drug discontinued 2 to 3 days prior to delivery to reduce this risk. Findings typically persist for 1 to 2 weeks and may include neonatal hypothyroidism, diabetes insipidus, cardiomegaly, bradycardia, electrocardiogram abnormalities, cyanosis, and hypotonia (American College of Obstetricians and Gynecologists, 2016).

Tamoxifen

This nonsteroidal selective estrogen-receptor modulator (SERM) is used as an adjuvant to treat breast cancer. No pattern of birth defects has been described in limited case reports and series. However, tamoxifen has been associated with malformations similar to those caused by diethylstilbestrol (DES) exposure in rodents, including vaginal adenosis. Consequently, women who become pregnant on therapy or within 2 months of its discontinuation should be apprised of the potential long-term risks of a DES-like syndrome.

Ribavirin

This nucleoside analogue is a component of therapy for hepatitis C infection, discussed in Chapter 55 (Hepatitis D). Ribavirin causes birth defects in multiple animal species at doses significantly lower than those recommended for human use. Reported malformations include skull, palate, eye, skeleton, and gastrointestinal abnormalities. The drug has a half-life of 12 days and persists in extravascular compartments following therapy discontinuation. Treated women must use two forms of contraception and have monthly pregnancy tests while on therapy and for 6 months following drug discontinuation. Ribavirin use is also contraindicated in men whose partners are pregnant.

Bexarotene

This retinoid is used to treat cutaneous T-cell lymphoma. When given to rats in doses comparable to those for human therapy, fetuses developed eye and ear abnormalities, cleft palate, and incomplete ossification. For a woman to receive this medication, the manufacturer requires two forms of contraception that are initiated 1 month before therapy and are continued for 1 month after bexarotene discontinuation. This is coupled with monthly pregnancy testing during treatment (Valeant Pharmaceuticals, 2015). Males who have partners who could become pregnant are advised to use condoms during sexual intercourse while taking bexarotene and for 1 month after discontinuing therapy.

Acitretin

This retinoid is used to treat severe psoriasis and was introduced to replace etretinate. The latter is a lipophilic retinoid with such a long half-life (120 days) that birth defects resulted more than 2 years after therapy was discontinued. Although acitretin has a short half-life, it is metabolized to etretinate, and thus remains in the body for prolonged periods (Stiefel Laboratories, 2015). To obviate exposure, the manufacturer of acitretin has developed a pregnancy risk management program. Called "Do Your P.A.R.T"—Pregnancy prevention Actively Required during and after Treatment, this program promotes a delay of conception for at least 3 years following therapy discontinuation

Psychiatric Medication

Treatment of psychiatric illness in pregnancy, including a discussion of the risks and benefits of various psychiatric medications, is described in Chapter 61 (Psychological Adjustments to Pregnancy). Selected birth defects and adverse effects associated with specific medications are presented her

ACE-inhibitor medication may cause fetal...

hypotension and renal hypoperfusion, with subsequent ischemia and anuria.

!! Teratology

is essentially the study of congenital anomalies and teratogens or any agent that irreversibly alters growth, structure, or function in a developing embryo or fetus. Teratogens include viruses such as rubella, chemicals such as mercury, and drugs such as diethylstilbestrol (DES).

!!Unique fact about teratogenic medications

is that avoiding the teratogen can prevent the associated congenital anomaly. For this reason, knowledge of teratogenic drugs is essential for the practicing midwife. Fortunately, the number of teratogenic agents is relatively small, and even fewer are in common use.

The preimplantation period

is the two weeks between fertilization and implantation and is known as the "all or none" period. As the zygote undergoes cleavage, an insult damaging a large number of cells typically causes embryonic death.

!! Birth Defects

occur in approximately 1% to 3% of all births. This percentage is often called the "background risk" upon which additional risks are calculated based on family history, past history, and environmental exposure. Only 10% of birth defects can be associated with environmental factors, and the majority of environmental factors are not pharmaceutical. Drugs and chemical agents such as mercury and pesticides account for approximately 45% of the environmental teratogens involved in congenital anomalies. Drugs alone account for only 2% to 3% of all birth defects.

!! the preimplantation periods is considered...

the "all or nothing" period. If a small number of cells are damaged during this time period, the fetus usually compensates without any damage. Conversely, if a large number of cells are damaged, the embryo will be lost and a spontaneous abortion will occur. The period of organogenesis—between two and eight weeks postfertilization or four to 10 gestational weeks—is the most critical period wherein teratogenic exposures can cause fetal malformations.