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Drugs in Pregnancy

by Ravindu Gunatilake, MD, Avinash S. Patil, MD

Drugs are used in over half of all pregnancies and prevalence of use is increasing. The most commonly used drugs include antiemetics, antacids, antihistamines, analgesics, antimicrobials, diuretics, hypnotics, tranquilizers, and social and illicit drugs. Despite this trend, evidence-based guidelines for drug use during pregnancy are still lacking.

The FDA classifies drugs into 5 categories of safety for use during pregnancy (see FDA Categories of Drug Safety During Pregnancy). However, few well-controlled studies of therapeutic drugs have been conducted in pregnant women. Most information about drug safety during pregnancy is derived from animal studies and uncontrolled studies in people (eg, postmarketing reports). During pregnancy, drugs are often required to treat certain disorders. Despite widespread concern about drug safety, exposure to therapeutic drugs accounts for only 2 to 3% of all fetal congenital malformations; most malformations result from genetic, environmental, or unknown causes.

FDA Categories of Drug Safety During Pregnancy

Category

Description

A

Controlled human studies show no fetal risks; these drugs are the safest.

B

Animal studies show no risk to the fetus but no controlled human studies have been conducted, or animal studies show a risk to the fetus but well-controlled human studies do not.

C

No adequate animal or human studies have been conducted, or adverse fetal effects have been shown in animals but no human data are available.

D

Evidence of human fetal risk exists, but benefits may outweigh risks in certain situations (eg, life-threatening disorders, serious disorders for which safer drugs cannot be used or are ineffective).

X

Proven fetal risks outweigh any possible benefit.

Not all maternal drugs cross the placenta to the fetus. Drugs that cross the placenta may have a direct toxic effect or a teratogenic effect. Drugs that do not cross the placenta may still harm the fetus by

  • Constricting placental vessels and thus impairing gas and nutrient exchange

  • Producing severe uterine hypertonia that results in anoxic injury

  • Altering maternal physiology (eg, causing hypotension)

For a list of some drugs with adverse effects during pregnancy, see Table: Some Drugs With Adverse Effects During Pregnancy.

Drugs diffuse across the placenta similarly to the way they cross other epithelial barriers (see Drug Absorption). Whether and how quickly a drug crosses the placenta depend on the drug’s molecular weight, extent of its binding to another substance (eg, carrier protein), area available for exchange across the placental villi, and amount of drug metabolized by the placenta. Most drugs with a molecular weight of < 500 daltons readily cross the placenta and enter the fetal circulation. Substances with a high molecular weight (eg, protein-bound drugs) usually do not cross the placenta. The exception is immune globulin G, which is occasionally used to treat disorders such as fetal alloimmune thrombocytopenia. Generally, equilibration between maternal blood and fetal tissues takes at least 30 to 60 min.

A drug’s effect on the fetus is determined largely by fetal age at exposure, drug potency, and drug dosage. Fetal age affects the type of drug effect:

  • Before the 20th day after fertilization : Drugs given at this time typically have an all-or-nothing effect, killing the embryo or not affecting it at all. Teratogenesis is unlikely during this stage.

  • During organogenesis (between 20 and 56 days after fertilization): Teratogenesis is most likely at this stage. Drugs reaching the embryo during this stage may result in spontaneous abortion, a sublethal gross anatomic defect (true teratogenic effect), or covert embryopathy (a permanent subtle metabolic or functional defect that may manifest later in life), or the drugs may have no measurable effect.

  • After organogenesis (in the 2nd and 3rd trimesters): Teratogenesis is unlikely, but drugs may alter growth and function of normally formed fetal organs and tissues. As placental metabolism increases, doses must be higher for fetal toxicity to occur.

Some Drugs With Adverse Effects During Pregnancy

Examples

Adverse Effects

Pregnancy Safety Category*

Antibacterials

Aminoglycosides

Ototoxicity (eg, damage to fetal labyrinth), resulting in deafness

D

Chloramphenicol

Gray baby syndrome

In women or fetuses with G6PD deficiency, hemolysis

C

Fluoroquinolones

Possibly arthralgia; theoretically, musculoskeletal defects (eg, impaired bone growth), but no proof of this effect

C

Nitrofurantoin

In women or fetuses with G6PD deficiency, hemolysis

B

Primaquine

In women or fetuses with G6PD deficiency, hemolysis

C

Streptomycin

Ototoxicity

D

Sulfonamides (except sulfasalazine, which has minimal fetal risk)

When the drugs are given after about 34 wk gestation, neonatal jaundice and, without treatment, kernicterus

In women or fetuses with G6PD deficiency, hemolysis

C

Tetracycline

Slowed bone growth, enamel hypoplasia, permanent yellowing of the teeth, and increased susceptibility to cavities in offspring

Occasionally, liver failure in pregnant women

D

Trimethoprim

Increased risk of neural tube defects due to folate antagonism

C

Anticoagulants

Low molecular weight heparin

Thrombocytopenia and maternal bleeding

B

Unfractionated heparin

Thrombocytopenia and maternal bleeding

C

Warfarin

When warfarin is given during the 1st trimester, fetal warfarin syndrome (eg, nasal hypoplasia, bone stippling, bilateral optic atrophy, various degrees of intellectual disability)

When the drug is given during the 2nd or 3rd trimester, optic atrophy, cataracts, intellectual disability, microcephaly, microphthalmia, and fetal and maternal hemorrhage

X

Anticonvulsants

Carbamazepine

Hemorrhagic disease of the newborn

Some risk of congenital malformations including neural tube defects

D

Lamotrigine

No appreciable increased risk with dosage up to 600 mg/day

C

Levetiracetam

Minor skeletal malformations in animal studies, but no appreciable increased risk in humans

C

Phenobarbital

Hemorrhagic disease of the newborn

Some risk of congenital malformations

D

Phenytoin

Congenital malformations (eg, cleft lip, GU defects such as a narrowed or an incompletely formed urethra, cardiovascular defects)

Hemorrhagic disease of the newborn

D

Trimethadione

High risk of congenital malformations (eg, cleft palate; cardiac, craniofacial, hand, and abdominal defects) and risk of spontaneous abortion

Almost always contraindicated during pregnancy

D

Valproate

Major congenital malformations (eg, neural tube defects such as meningomyelocele; cardiac, craniofacial, and limb defects)

D

Antihistamine/anticholinergic drug

Meclizine

Teratogenic in rodents, but no proof of this effect in humans

B

Antihypertensives

When the drugs are given during the 2nd or 3rd trimester, fetal hypocalvaria and hypoperfusion (which can cause renal defects), renal failure, and the oligohydramnios sequence (oligohydramnios, craniofacial deformities, limb contractures, and hypoplastic lung development)

D

β-Blockers

Fetal bradycardia, hypoglycemia, and possibly fetal growth restriction

C

Ca channel blockers

When the drugs are given during the 1st trimester, possibly phalangeal deformities

When the drugs are given during the 2nd or 3rd trimester, fetal growth restriction

C

Thiazide diuretics

Prevention of normal maternal volume expansion, reducing placental perfusion and contributing to fetal growth restriction

Neonatal hyponatremia, hypokalemia, and thrombocytopenia

D

Antineoplastic drugs

Actinomycin

Teratogenic in animals, but no proof of this effect in humans

D

Busulfan

Congenital malformations (eg, fetal growth restriction, mandibular hypoplasia, cleft palate, cranial dysostosis, spinal defects, ear defects, clubfoot)

D

Chlorambucil

Same as those for busulfan

D

Colchicine

Possibly congenital malformations and sperm abnormalities

D

Cyclophosphamide

Same as those for busulfan

D

Doxorubicin

Teratogenic in animals

Potential for dose-dependent cardiac dysfunction

D

Mercaptopurine

Same as those for busulfan

D

Methotrexate

Same as those for busulfan

X

Vinblastine

Teratogenic in animals, but no proof of this effect in humans

D

Vincristine

Teratogenic in animals, but no proof of this effect in humans

D

Anxiolytics

Benzodiazepines

When benzodiazepines are given late in pregnancy, respiratory depression or a neonatal withdrawal syndrome that can cause irritability, tremors, and hyperreflexia

D

Hypoglycemic drugs (oral)

Chlorpropamide

Neonatal hypoglycemia

C

Glyburide

Neonatal hypoglycemia

C

Metformin

Neonatal hypoglycemia

B

Tolbutamide

Neonatal hypoglycemia

D

Lithium

Lithium

Possibly teratogenic

Neonatal lethargy, hypotonia, poor feeding, hypothyroidism, goiter, and nephrogenic diabetes insipidus

D

Opioids

Codeine

Meperidine

Morphine

In neonates of women addicted to opioids, withdrawal symptoms possibly occurring 6 h to 8 days after birth

With high doses given in the hour before delivery, possibly neonatal CNS depression and bradycardia

C

Retinoids

Isotretinoin

High teratogenic risk (eg, multiple congenital malformations), spontaneous abortion, and intellectual disability

X

NSAIDs

Aspirin and other salicylates

Fetal kernicterus

With high doses, possibly 1st-trimester spontaneous abortions, delayed onset of labor, premature closing of the fetal ductus arteriosus, jaundice, occasionally maternal (intrapartum and postpartum) and/or neonatal hemorrhage, necrotizing enterocolitis, and oligohydramnios

With low doses (81 mg) of aspirin, no significant teratogenic risk

D

Nonsalicylate NSAIDs

Same as those for salicylate NSAIDs

Contraindicated in the 3rd trimester

C

D for some drugs if given after 30 wk

Sex hormones

Danazol

When these drugs are given during the first 14 wk, masculinization of a female fetus’s genitals (eg, pseudohermaphroditism), sometimes requiring surgery to correct

X

Synthetic progestins (but not the low doses used in oral contraceptives)

Same as those for danazol

X

Thyroid drugs

Methimazole

Fetal goiter and neonatal scalp defects (aplasia cutis)

D

Propylthiouracil

Fetal goiter and maternal hepatotoxicity and agranulocytosis

D

Radioactive iodine ( 131 I)

Destruction of the fetal thyroid gland or, when the drug is given near the end of the 1st trimester, severe fetal hyperthyroidism

D

Saturated solution of K iodide

Large fetal goiter, which may obstruct breathing in neonates

Triiodothyronine

Fetal goiter

D

Vaccines

Live-virus vaccines such as those for measles, mumps, rubella, polio, chickenpox, and yellow fever

With rubella and varicella vaccines, potential infection of the placenta and developing fetus

With other vaccines, potential but unknown risks

Others

Corticosteroids

When these drugs are used during the 1st trimester, possibly orofacial clefts

B

Hydroxychloroquine

No increased risk at usual doses

C

Loratadine

Possible hypospadias

B

Ondansetron

No significant teratogenic risk

B

Pseudoephedrine

Placental vasoconstriction and possible risk of gastroschisis

C

Vitamin K

In women or fetuses with G6PD deficiency, hemolysis

C

*FDA pregnancy categories:

  • A: Studies in pregnant women show no risk.

  • B: Animal studies show no risk, but human data are insufficient; or animal studies show toxicity, but human studies show no risk.

  • C: Animal studies show toxicity, human data are insufficient, but clinical benefit may exceed risk.

  • D: There is evidence of human risk, but clinical benefits may outweigh risk.

  • X: There is evidence of fetal abnormalities in humans, and risk exceeds benefits.

G6PD = glucose-6-phosphate dehydrogenase.

Vaccines

Immunization is as effective in women who are pregnant as in those who are not. Influenza vaccine is recommended for all pregnant women in the 2nd or 3rd trimester during influenza season. Other vaccines should be reserved for situations in which the woman or fetus is at significant risk of exposure to a hazardous infection and risk of adverse effects from the vaccine is low. Vaccinations for cholera, hepatitis A and B, measles, mumps, plague, poliomyelitis, rabies, tetanus-diphtheria, typhoid, and yellow fever may be given during pregnancy if risk of infection is substantial.

Live-virus vaccines should not be given to women who are or may be pregnant. Rubella vaccine, an attenuated live-virus vaccine, may cause subclinical placental and fetal infection. However, no defects in neonates have been attributed to rubella vaccine, and women vaccinated inadvertently during early pregnancy need not be advised to terminate pregnancy based solely on theoretical risk from the vaccine. Varicella is another attenuated live-virus vaccine that can potentially infect the fetus; risk is highest between 13 wk and 22 wk gestation. This vaccine is contraindicated during pregnancy.

Vitamin A

In the amount typically present in prenatal vitamins (5000 IU/day), vitamin A has not been associated with teratogenic risk. However, doses > 10,000 IU/day during early pregnancy may increase risk of congenital malformations.

Antidepressants

Antidepressants, particularly SSRIs, are commonly used during pregnancy because an estimated 7 to 23% of pregnant women have perinatal depression. Physiologic and psychosocial changes during pregnancy can affect depression (possibly worsening it) and possibly reduce the response to antidepressants. Ideally, a multidisciplinary team that includes an obstetrician and a psychiatric specialist should manage depression during pregnancy.

If a pregnant woman takes paroxetine, echocardiography should be done to evaluate the fetus's heart because paroxetine appears to be associated with an increased incidence of congenital cardiac anomalies.

Antidepressants taken by a pregnant woman can cause withdrawal symptoms in the neonate. To reduce this risk, clinicians can consider tapering the dose of all antidepressants during the 3rd trimester. However, the potential benefits of tapering must be balanced against the risk of worsening symptoms and postpartum depression. Postpartum depression is common, often unrecognized, and should be treated promptly (see Postpartum Care and Associated Disorders).

Social and Illicit Drugs

Cigarette smoking is the most common addiction among pregnant women. Also, percentages of women who smoke and of those who smoke heavily appear to be increasing. Only 20% of smokers quit during pregnancy. Carbon monoxide and nicotine in cigarettes cause hypoxia and vasoconstriction, increasing risk of spontaneous abortion (fetal loss or delivery < 20 wk), fetal growth restriction, abruptio placentae, placenta previa, premature rupture of the membranes, preterm birth, chorioamnionitis, and stillbirth. Neonates whose mothers smoke are also more likely to have anencephaly, congenital heart defects, orofacial clefts, sudden infant death syndrome, deficiencies in physical growth and intelligence, and behavioral problems. Smoking cessation or limitation reduces risks.

Alcohol is the most commonly used teratogen. Drinking alcohol during pregnancy increases risk of spontaneous abortion. Risk is probably related to amount of alcohol consumed, but no amount is known to be risk-free. Regular drinking decreases birth weight by about 1 to 1.3 kg. Binge drinking in particular, possibly as little as 45 mL of pure alcohol (equivalent to about 3 drinks) a day, can cause fetal alcohol syndrome. This syndrome occurs in 2.2/1000 live births; it includes fetal growth restriction, facial and cardiovascular defects, and neurologic dysfunction. It is a leading cause of intellectual disability and can cause neonatal death due to failure to thrive.

Cocaine use has indirect fetal risks (eg, maternal stroke or death during pregnancy). Its use probably also results in fetal vasoconstriction and hypoxia. Repeated use increases risk of spontaneous abortion, fetal growth restriction, abruptio placentae, preterm birth, stillbirth, and congenital malformations (eg, CNS, GU, and skeletal malformations; isolated atresias).

Although marijuana’s main metabolite can cross the placenta, recreational use of marijuana use does not consistently appear to increase risk of congenital malformations, fetal growth restriction, or postnatal neurobehavioral abnormalities.

Bath salts refers to a group of designer drugs made from a variety of amphetamine-like substances; these drugs are being increasingly used during pregnancy. Although effects are poorly understood, fetal vasoconstriction and hypoxia are likely, and there is a risk of stillbirth, abruptio placentae, and possibly congenital malformations.

Whether consuming caffeine in large amounts can increase perinatal risk is unclear. Consuming caffeine in small amounts (eg, 1 cup of coffee/day) appears to pose little or no risk to the fetus, but some data, which did not account for tobacco or alcohol use, suggest that consuming large amounts (> 7 cups of coffee/day) increases risk of stillbirths, preterm deliveries, low birth weight, and spontaneous abortions. Decaffeinated beverages theoretically pose little risk to the fetus.

Use of aspartame (a dietary sugar substitute) during pregnancy is often questioned. The most common metabolite of aspartame, phenylalanine, is concentrated in the fetus by active placental transport; toxic levels may cause intellectual disability. However, when ingestion is within the usual range, fetal phenylalanine levels are far below toxic levels. Thus, moderate ingestion of aspartame (eg, no more than 1 liter of diet soda per day) during pregnancy appears to pose little risk of fetal toxicity. However, in pregnant women with phenylketonuria (see Phenylketonuria (PKU)), intake of phenylalanine and thus aspartame is prohibited.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • FURADANTIN, MACROBID, MACRODANTIN
  • CYTOXAN (LYOPHILIZED)
  • ACHROMYCIN V
  • DIABINESE
  • No US brand name
  • MARQIBO KIT
  • PLAQUENIL
  • DIABETA, GLYNASE
  • ANTIVERT
  • PURINETHOL
  • MYLERAN
  • DEMEROL
  • AFRINOL, SUDAFED
  • LEUKERAN
  • KEPPRA
  • LAMICTAL
  • ALAVERT, CLARITIN
  • PANHEPRIN
  • COLCRYS
  • AZULFIDINE
  • TAPAZOLE
  • GLUCOPHAGE
  • COUMADIN
  • DURAMORPH PF, MS CONTIN
  • OTREXUP
  • DILANTIN
  • SOTRET
  • ZOFRAN
  • LITHOBID
  • TEGRETOL
  • PAXIL
  • COMMIT, NICORETTE, NICOTROL

* This is a professional Version *