Drug Therapy in Pregnancy

Thanh T. Hogan

Kristina E. Ward

Andrea L. McKeever

William Renfro

Linda Hastings

Ethical and legal limitations preclude drug studies in pregnant women, leaving the health care provider with little reliable information to base clinical decisions of drug use during pregnancy. As a result, some clinicians practice “therapeutic nihilism” where nothing is prescribed for the pregnant patient (1,2). However, avoiding medication use during pregnancy at all cost is not necessarily desirable. If left untreated, many conditions may jeopardize the health of the mother and/or the fetus. This chapter reviews the relative safety of common medications prescribed during pregnancy.

FOOD AND DRUG ADMINISTRATION PREGNANCY CATEGORIES

During the 1960s and 1970s, the tragedy of thalidomide use, which resulted in thousands of babies being born with severe limb defects, heightened awareness of medication use in pregnant women.

In 1980, the Food andDrug Administration (FDA) required that the labeling of prescription drugs include information about the use in pregnancy. Five categories were established to indicate a drug’s potential for causing birth defects. The category is assigned upon the drug’s initial approval by the FDA. As a result, information available to categorize the drugs is usually limited human data and animal studies. This information can be found in the precautions section of the package insert. A description of the current categories is summarized in Table 17.1 (3).

This classification system was an important step for assisting the clinician in identifying potential teratogenic prescription drugs. However, the categories lack specific details to assist clinicians in prescribing to pregnant women and does not address timing of pregnancy, appropriate dosage of the drugs, or use during lactation. Additionally, health care professionals often mistakenly believe that there is a gradation of risk across the categories, assuming that a drug in category B is safer than one in category C which is safer than one in category D. However, by definition, category C drugs generally have the least data (Table 17.2) and can represent risks of unknown magnitude. A new labeling system has been under development at the FDA since 1977. However, the proposed regulation, which would provide more information on fertility, pregnancy, and breastfeeding, has not yet been finalized. In the meantime, health care professionals cannot assume relative safety for category C drugs. All available information must be carefully reviewed and the risks and benefits of each drug evaluated.

TERATOGENESIS

Although initially designed to provide guidance, the current labeling system is often used to estimate teratogenic risk. Teratogenesis is defined as the dysgenesis of fetal organs as evidenced either structurally or functionally (e.g., brain functions) (4). Whether a given agent can induce congenital malformations in animals or humans is based on three fundamental principles of teratogenesis first described in 1959 (5). These include the particular dose of the substance, the susceptibility of the species, and the embryo’s stage of development at the time of exposure.

TABLE 17.1 FDA Pregnancy Categories (3)

Category A
	Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities.
Category B
	Animal studies have revealed no evidence of harm to the fetus; however, there are no adequate and well-controlled studies in pregnant women.
	or
	Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus.
Category C
	Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women.
	or
	No animal studies have been conducted, and there are no adequate and well-controlled studies in pregnant women.
Category D
	Studies, adequate, well-controlled, or observational, in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk.
Category X
	Studies, adequate, well-controlled, or observational, in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. The use of the product is contraindicated in women who are or may become pregnant.

TABLE 17.2 Animal and Human Risk Exposure and Pregnancy Categories

Pregnancy Category	Animal Exposure	Human Exposure
A	–	–
B	+	–
	–	Unknown
C	+	Unknown
	Unknown	Unknown
D (benefit may outweigh risk)	+	+
X (contraindicated)	+	+
Note: -, no risk; +, known risk.

The timing of fetal exposure is the most important determinant of teratogenesis. There are four critical periods in human development in which drugs may adversely affect the fetus (6). Days 0 to 7 represent the preimplantation phase, in which fertilization and zygote formation occur. Exposure to teratogens during this period usually results either in death of the embryo or in replacement of damaged cells by undifferentiated cells that go on to develop normally. During organogenesis (days 14 to 60), the embryo is at its peak sensitivity to teratogens. Most morphologic congenital abnormalities are thought to be produced during this interval. As organogenesis ends, susceptibility to anatomic abnormalities declines. Minor structural malformation may still occur throughout histogenesis. Exposures during the fetal development period are associated with a much lower risk of major birth defects because most major organ systems are well developed by this time (7,8). Problems that do occur usually involve growth or functional deviations.

PREGNANCY REGISTRIES

Beyond the current pregnancy categories, relevant clinical data on medications during pregnancy are found through a modest group of anecdotal case reports, case studies, observational studies, and retrospective chart reviews. Despite this lack of information about the effects of medications on the fetus, medication use during pregnancy appears to be increasing. A study conducted by the FDA in 1995 found that women under 35 years of age consumed on average three prescriptions during the course of their pregnancy (9). For those over 35 years of age, the number of prescriptions increased to five. A 2003 study estimates 80% of pregnant women taking some over-the-counter (OTC) or prescription medications (10). Known use of prescription and OTC medications in pregnant women, along with inadvertent exposures to medications during pregnancy (i.e., woman is unaware she is pregnant while taking a medication), provide another opportunity to collect relevant clinical data, through pregnancy registries.

A pregnancy registry is a surveillance study that enrolls pregnant women after they have been exposed to a medication and follows the women until the birth of the baby (11). Although regulations continue to be reviewed, pregnancy registries are currently voluntary with most administered through pharmaceutical companies and a few administered through specific organizations (i.e., hospitals, universities). Data from babies born to women taking a particular medication are compared to those born to women not taking the medicine. Patients may enroll directly to some but the majority require physician enrollment. A listing of available pregnancy registries is available on the FDA webpage.

To date, very few drugs are known to cause fetal harm (Table 17.3). Nonetheless, it is virtually impossible to prove drugs safe for use in pregnancy because no well-designed long-term studies can be ethically conducted. This leaves a huge void between known teratogenesis and known safety. Although this void is difficult to fill with our current labeling system and available literature, some clinically relevant conclusions can be reached (Table 17.4).

Anti-infectives

Although penicillins and penicillin derivatives cross the placenta, they are considered safe for use in the nonallergic patient during pregnancy (12,13,14). A large study involving 3,546 fetal exposures to penicillin derivatives (primarily penicillin G) during the first trimester of pregnancy found no link to major or minor malformations (15). Other reports and the wide use of this class of drugs during pregnancy support this finding (14,16). Data on the newer penicillins (i.e., ticarcillin and piperacillin) are lacking. However, the FDA places each of these agents in risk category B with the other penicillins. It is known that ticarcillin and piperacillin rapidly cross the placenta, but no reports of congenital defects with these agents have been located (14). Beta-lactamase inhibitors (i.e., clavulanate, sulbactam, tazobactam) are added to penicillin derivatives to broaden their spectrum of activity. Several studies have failed to find a teratogenic effect associated with exposure to clavulanate; however, the Michigan Medicaid Surveillance Study found a possible association with spina bifida (14,17,18,19). Limited data exist regarding sulbactam and tazobactam; however, available data suggest no evidence for concern (14,20).

TABLE 17.3 Medications Absolutely Contraindicated in Pregnancy (Category X)

Acetretin

Androgens

Estrogens

Dihydroergotamine

Finasteride

Goserelin

HMG-CoA Reductase Inhibitors (Atorvastatin, Fluvastatin, Lovastatin, Pravastatin, Simvastatin)

Leuprolide

Megestrol

Progesterone

Ribavirin

Thalidomide

Warfarin

Yohimbine

The majority of cephalosporins readily cross the placenta and have pharmacokinetic parameters very similar to the penicillins. In the retrospective Michigan Medicaid Surveillance Study, increased numbers of birth defects were found for cefaclor, cephalexin, and cephradine, but not other cephalosporins (14,19). However, a large, population-based, case-control study assessing the incidence of birth defects with seven cephalosporins found no association (21). Generally, the cephalosporins are considered safe for use during pregnancy and are the preferred alternative in patients with nonanaphylactic penicillin sensitivity (14,20,21). Where it covers the appropriate microbial spectrum, erythromycin base should be used in penicillin-allergic patients demonstrating immediate-type sensitivity.

The macrolide, erythromycin, has been used during pregnancy with no known increased risk to the mother or the fetus (14,20). Although the drug crosses the placenta, plasma levels are low in the fetus (22). One salt of erythromycin, the estolate form, is considered contraindicated during pregnancy because of a reported 10% reversible incidence of hepatotoxicity (increases in serum aspartate aminotransferase) occurring in the mother (14,20). Less evidence is available for clarithromycin and azithromycin. While teratogenic in animals, clarithromycin has, thus far, failed to demonstrate birth defects in small, epidemiologic studies of human pregnancy (14,23,24,25). Similar rates of major malformations and spontaneous abortions were observed with azithromycin and matched controls in a small study (26).

TABLE 17.4 Pregnancy Categories for Disease-Specific Medications

Condition			FDA Pregnancy Category	Comments
Acne
	Adapalene		C	No malformations seen in animal studies, but no well-controlled human trials available
	Isotretinoin		X	Absolute contraindication, no safe dose, monthly pregnancy testing and two forms of contraception are required throughout therapy
	Tazarotene		X	Absolute contraindication, negative pregnancy test should be obtained 2 weeks before therapy initiation
	Tretinoin		C	Case reports of malformations with topical administration during the first trimester
Anti-infectives
	Aminoglycosides		D	Streptomycin and kanamycin have been reported to cause congenital deafness. Serious side effects in the fetus have not been reported with other aminoglycosides
	Azithromycin		B	No evidence of congenital defects
	Cephalosporins		B	Less data than with penicillins, but generally considered safe in pregnancy
	Daptomycin		B	Unknown risk to the fetus because of limited safety data
	Erythromycin		B	The base is considered safe for use during pregnancy. No significant evidence of congenital defects reported. The estolate salt has been reported to cause hepatotoxicity in pregnant women
	Linezolid		C	Unknown risk to the fetus because of limited safety data
	Metronidazole		B	No compelling evidence of fetal harm. Recommended by CDC for treatment of trichomoniasis and bacterial vaginosis during pregnancy. Manufacturer lists first trimester use as a contraindication
	Nitrofurantoin		B	Considered safe. Theoretically, could cause hemolytic anemia in newborn. Avoid in bacteremia, urosepsis, and pyelonephritis
	Penicillins		B	Generally considered safe in pregnancy. Most safety experience with penicillin G
	Quinupristin/dalfopristin		C	Unknown risk to the fetus due to limited safety data
	Quinolones		C	Avoid use during pregnancy. Have been associated with arthropathies in animals and children
	Tetracyclines		D	Avoid if possible, especially during last half of pregnancy
	Trimethoprim/Sulfamethoxazole		C	Trimethoprim inhibits folic acid synthesis. Sulfonamides can induce kernicterus in the newborn if used late in pregnancy
	Vancomycin		C	Generally not thought to be teratogenic. Links to ototoxicity and nephrotoxicity not established
Analgesia
	Acetaminophen		B	Analgesic and antipyretic of choice in pregnancy
	Aspirin		C	May produce adverse effects in the mother and the fetus. Can inhibit labor if used late in pregnancy. Avoid if possible
	Codeine		C/D	High doses or long term use is not recommended. Likely to cause neonatal respiratory depression and withdrawal if used near term
	Nonsteroidal anti-inflammatories		B/C/D	No association to date with congenital malformations. Can theoretically inhibit labor if used late in pregnancy. May cause constriction or closure of the ductus arteriosus if used near term
	Hydromorphone		B/D	Not associated with congenital defects. High doses or long-term use is not recommended. Likely to cause neonatal respiratory depression and withdrawal if used near term
	Fentanyl		C/D	Not associated with congenital defects. Likely to cause neonatal respiratory depression and withdrawal if used near term
	Morphine		C/D	Not associated with congenital defects. High doses or long-term use is not recommended. Likely to cause neonatal respiratory depression and withdrawal if used near term
	Oxycodone		B/D	Not associated with teratogenic effects. High doses or long-term use is not recommended. Likely to cause neonatal respiratory depression and withdrawal if used near term
Asthma
	β-Agonists		C	Safety differences between agents have not been identified. Oral/parenteral agents may delay delivery based on alternative indications (i.e., preterm labor)
	Corticosteroids		C	Inhaled budesonide is preferred. ACOG does not mandate change from prior inhaled steroid agent despite category
	Inhaled anticholinergics		B	No reports of teratogenicity in animals exposed to ipratropium, but few human investigations. No well-controlled studies in humans with tiotropium
	Leukotriene receptor antagonists		B	No long-term data for this newer therapeutic class
	Theophylline		C	Does not appear teratogenic. Drug clearance may be altered in pregnancy, monitor dose
Coagulation
	Coumarin derivatives (warfarin)		X	Generally considered contraindicated. Risks include embryopathy, spontaneous abortion, stillbirth, prematurity, and hemorrhage
	Heparin		C	Generally considered the agent of choice in pregnancy. Long-term therapy has been linked to maternal osteopenia
	Low molecular weight heparins		B	Alternative therapy to UFH. Use of enoxaparin in pregnant women with a mechanical heart valve is controversial due to valvular clotting and deaths reported in clinical trial and post-marketing surveillance
	Fondaparinux		B	Synthetic factor Xa inhibitor used in patients with heparin allergy or heparin
Depression
	Monoamine oxidase inhibitors		C	Limited human data for pregnancy. Maybe increased risk for malformations; risk of use must be weighed against benefits
	Selective serotonin reuptake inhibitors (SSRIs) (Paroxetine = D)		C	Most experience with fluoxetine with no associated teratogenicity. Neonatal withdrawal syndrome has been estimated to occur in 30% of infants. Paroxetine use has been linked to cardiac malformations and PPHN
	Tricyclic antidepressants (TCAs) Imipramine = D		C	This drug class may be associated with neonatal withdrawal (colic, cyanosis, tachypnea, and irritability). Animal trials and human case reports have documented congenital abnormalities with imipramine
	Newer Antidepressants Bupropion = B Duloxetine = C Mirtazapine = C Nefaxodone = C Trazodone = Venlafaxine = C		B/C	Limited human data available for more recently approved agents. May consider for women refractory to other agents
Diabetes
	Glyburide		C	One large prospective study has found that glyburide is as effective as insulin in women after the first trimester with gestational diabetes. Glyburide is a reasonable alternative to insulin in certain patients (e.g., fear of needles/injections)
	Insulin (human), short-acting			Regular insulin is the agent of choice in pregnancy. Insulin aspart and lispro are alternatives for better postprandial glucose control. No human data available for glulisine
		Regular	B
		Aspart	B
		Lispro	B
		Glulisine	C
	Insulin (human), long-acting			NPH insulin is the basal insulin agent of choice in pregnancy. Limited pregnancy data available for insulin glargine and detemir (peak-less insulins); clinical implications of their increase in IGF-1 receptor affinity unknown
		NPH	Not available
		Detemir	C
		Glargine	C
	Metformin		B	No morphological abnormalities observed in animals but some conflicting human data; results of one large clinical trial found metformin (with supplemental insulin) to be as effective and safe as insulin alone for gestational diabetes (after first trimester). PCOS clinical trials demonstrate safety. More research needed
Gastrointestinal Reflux
	Aluminum-containing antacids		Not available	Use is controversial. Severe developmental retardation reported in a child after high-dose use during pregnancy; normal doses during pregnancy may be acceptable. Co-ingestion of acidic foods or beverages should be avoided due to potential for increased GI absorption of aluminum
	Calcium/Magnesium-containing antacids		Not available	Generally considered first-line therapy for GERD in pregnancy; 10%-30% of calcium, 15%-30% of magnesium is absorbed
	H₂ Receptor Antagonists
		Cimetidine	B	Antiandrogenic effects observed in animals and nonpregnant humans; Limited data in humans suggest no association with increased risk of malformations
		Ranitidine	B	Only H2RA with documented efficacy in pregnancy; available evidence suggests no congenital malformations or neonatal toxicity
		Famotidine	B	Limited safety data in humans
		Nizatidine	B	Caution recommended during pregnancy due to reports of abortions, low fetal weights, and fewer live fetuses in rabbits at doses significantly higher than recommended human doses
	Magnesium trisilicates		Not available	Avoid long-term, high-dose use due to potential for fetal nephrolithiasis, hypotonia, respiratory distress, and cardiovascular effects
	Proton Pump Inhibitors
	Omeprazole		C	Reports regarding use in pregnancy are conflicting; use of safer alternatives preferred whenever possible (especially in the first trimester)
		Lansoprazole	B	Limited clinical experience available in humans. Use of safer alternatives preferred whenever possible (especially in the first trimester)
		Rabeprazole
		Pantoprazole
		Esomeprazole
	Metoclopromide		B	Available evidence suggests no congenital malformations or neonatal toxicity
	Sodium bicarbonate		Not available	Avoid in pregnancy due to potential for maternal/fetal fluid overload and potential for metabolic alkalosis
	Sucralfate		B	No data in animals, generally considered acceptable in pregnancy due to low absorption; Potential for fetal toxicity linked to aluminum content (1 g sucralfate = 207 mg aluminum)
Hypertension
	Angiotensin-converting enzyme inhibitors (ACEIs)		D	Contraindicated in pregnancy. Can cause fetal toxicity and death
	Angiotensin II receptor antagonists		D	Contraindicated. Similar to ACEIs
	β-Blockers		C	Generally considered safe, but may be associated with fetal growth retardation
	Calcium antagonists nifedipine		C	Limited data. No increase in major teratogenicity noted, but generally not used due to its association with cardiovascular events. Nifedipine use is controversial
	Diuretics		B/C	Probably safe, but not first-line agents. Furosemide is embryotoxic. Thiazide diuretics considered safest in this class
	Hydralazine		C	May be used as first or second line for acute hypertensive crisis, but second line after methyldopa for chronic treatment during pregnancy
	Labetalol		C	May be used as first or second line for acute hypertensive crisis, but second line after methyldopa for chronic treatment during pregnancy. Should not be used in those with asthma or congestive heart failure
	Methyldopa		B	Preferred agent for chronic hypertension during pregnancy. No adverse effects noted in long term follow-up study
Migraine/Headache
	Dihydroergotamine		X	Contraindicated. Has been linked to perinatal deaths and abnormalities
	Ergotamine		X	Contraindicated. Has been linked to perinatal deaths and abnormalities
	Sumatriptan		C	Not thought to be a human teratogen. Exposures, including those in the first trimester, linked to preterm labor and low birth weight infants
Nausea and Vomiting
	Dimenhydrinate		B	Limited data available. Congenital defects were not found to be associated with dimenhydrinate
	Diphenhydramine		B	Avoid near delivery
	Doxylamine		A	Effective in combination with pyridoxine
	Hydroxyzine		C	Given orally or IM. Possible congenital defects when given in first trimester
	Meclizine		B	Several studies show safety in pregnancy
	Metoclopramide		B	Enhances upper GI tract motility, increases lower esophageal sphincter tone, and in high doses, blocks serotonin in CTZ. EPS may be seen
	Ondansetron		B	Blocks serotonin peripherally and in the CTZ
	Promethazine		C	Safety data are conflicting. Use in labor is common, however, limited data regarding its use for NVP
	Pyridoxine		A	Effective in combination with doxylamine
Psychosis and Bipolar Disorder
	Benzodiazepines		C	Sedation and withdrawal seen in the neonate. Floppy infant syndrome (hypotonia, low Apgar scores, and neurological depression)
			D (near term)
	Low-potency antipsychotics Chlorpromazine Thioridazine		C	Tachycardia, GI dysfunction, sedation, and hypotension seen at birth and up to several days after delivery. Exposure during weeks 4-10 of gestation associated with increased risk of malformations. Chlorpromazine may cause insulin resistance in mother and respiratory depression in the newborn exposed during the third trimester. Dose reduction near term can be considered to reduce risk of toxicity in infant
	High-potency antipsychotics Fluphenazine Perphenazine Trifluoperazine Thiothixine Haloperidol		C	Extrapyramidal side effects (hyperactivity, tremor, hyperactive deep tendon reflexes, restlessness, abnormal movements, increased muscle tone, vigorous rooting or sucking, arching of back, and shrill crying) seen in newborn (especially if mother is given high doses). Exposure during weeks 4-10 of gestation associated with increased risk of malformations. Dose reduction near term can be considered to reduce risk of toxicity in the infant. Two case reports of limb reduction when haloperidol was administered in the first trimester; however, other studies have not confirmed this association
	Atypical Antipsychotics Clozapine		B	No defects seen in animals; one case report of intrauterine fetal death; accumulation of clozapine in neonate theoretically linked to floppy infant syndrome, neonatal seizures, gastrointestinal reflux disease, and agranulocytosis. Monitoring of white blood cells in newborns can be considered. Potential risk for gestational diabetes in mother
		Olanzapine	C	Potential risk for gestational diabetes in mother; Limited data suggest olanzapine does not increase fetal teratogenic risk or rates of spontaneous abortion, however, more data are needed
		Risperidone, Quetiapine, Ziprasidone	C	Data for these agents are limited or absent; ziprasidone is associated with developmental delays, possible teratogenic effects, and increased stillbirths in animals; however, limited human data are available
		Lithium	D	Based on voluntary Register of Lithium Babies: higher rate of cardiovascular malformation (Ebstein’s Anomaly); “floppy baby” syndrome (cyanosis and hypotonicity) common with exposure during labor; hypothyroidism and nephrogenic diabetes insipidus have been observed
Seizure
	Carbamazepine		D	Estimated 1% risk of spina bifida; craniofacial defects, developmental delay (rate may be as high as 20%), may lessen effectiveness of contraceptives
	Gabapentin		C	Gabapentin: No pattern of malformations reported to date, but often used with other agents, making causal determination difficult
	Lamotrigine		C	Lamotrigine: may cause nervous system, heart, craniofacial, skeletal and urinary tract defects (Australian Birth Registry data)
	Levetiracetam		C	Levatiracetam: no malformations or developmental delay reported in limited human evaluations
	Oxcarbazepine		C	Oxcarbazepine: no major malformations reported to date; however, similar structure to carbamazepine which may cause neuronal tube defects; may lessen effectiveness of contraceptives
	Phenobarbital		D	Congenital heart defects, facial clefts, dysmorphic features, fetal withdrawal syndrome, may lessen effectiveness of contraceptives
	Phenytoin		D	Cleft palate, dysmorphic features, and craniofacial abnormalities; may lessen effectiveness of contraceptives
	Primidone		D	Neonatal hemorrhagic syndrome, neural tube defects, may lessen effectiveness of contraceptives
	Topiramate		C	Topiramate: developmental delay and teratogenicity in animal studies, may lessen effectiveness of contraceptives
	Valproic Acid and salt derivatives		D	Doses >1,000 mg/d may heighten risk for spina bifida; other effects: dysmorphic features, developmental delay, cardiovascular and urogenital malformations
Herbal Products
	Ginkgo biloba		Not applicable	Ginkgo not recommended for use during pregnancy due to lack of standardization of products and need for further studies. No published evidence of major birth defects; however, more studies needed
	Mugwort, Blue Cohash, Tansy, Black Cohosh, Scotch Broom, Goldenseal, Juniper Berry, Pennyroyal Oil, Rue, Mistletoe, and Chaste Berry		Not applicable	All are considered uterine stimulants or abortifacients and therefore contraindicated in pregnancy
	Echinacea		Not applicable	Echinacea cannot be recommended for use during pregnancy, due to lack of standardization of products and need for further studies
	St. John’s wort		Not applicable	No studies regarding reproductive toxicity; animal studies suggest slight uterotonic activity. Due to lack of standardization of products and need for further studies, St. John’s wort cannot be recommended for use during pregnancy
	Ginger		Not applicable	Use could affect testosterone receptor binding in the fetus; use is controversial and not recommended
	Ginseng		B	Associated with hypertension and hypoglycemia in the mother

Tetracyclines are known to cause numerous potential problems to the mother and the fetus and should be avoided during pregnancy (14,20). Nearly all tetracyclines readily cross the placenta (14). Tetracycline is well-known to cause yellow-brown discoloration of the teeth after in utero exposure because of its ability to chelate calcium orthophosphate, which becomes incorporated into bones and teeth during calcification (14,20). Severe dysplasia of the teeth and inhibition of bone growth also have been demonstrated. These effects are more common when the drug is taken in the second and the third trimesters, when bone mineralization occurs (14,20). Tetracycline has also been reported to induce limb anomalies, inguinal hernia, and hypospadias (14). Potentially fatal maternal liver and renal toxicities, although rare, have been attributed to tetracycline (14,20).

Sulfonamides cross the placenta and accumulate in significant quantities in the fetus (14,20). Teratogenicity has been shown in some animal species, but a link to human malformations has not been demonstrated even in large trials (15,19). Sulfonamides should not be administered close to delivery as they can causejaundice and kernicterus in the newborn through displacement of bilirubin from albumin-binding sites. Earlier in pregnancy, the placenta is capable of clearing the free unconjugated bilirubin; however, the clearing mechanism is no longer available at birth (14

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