Phenytoin Fetal hydantoin syndrome, growth retardation, CNS deficits

Streptomycin and kanamycin Hearing loss, eighth cranial damage; no ototoxicity reported with gentamicin,

tobramycin, amikacin

Systemic retinoids (isotretinoin

and etretinate)

CNS, craniofacial, cardiovascular defects

Tetracycline Permanent discoloration of deciduous teeth

Thalidomide Limb and skeletalshortening defects, internal organ defects

Topiramate Cleft lip and cleft palate

35

Trimethoprim NTDs and cardiac defects

Vaccines (live) Live attenuated vaccines can potentially cause fetal infection

Valproic acid NTDs, developmental delay, and deficits

Vitamin A Microtia, anotia, thymic aplasia, cardiovascular defects (high dose)

Warfarin Fetal warfarin syndrome with nasal hypoplasia, stippled epiphyses, and skeletal

and CNS defects

Teratogenic effects include the four major manifestations of abnormal fetal development which include growth

Teratogenic effects include the four major manifestations of abnormal fetal development which include growth

alterations, functional deficits, structural malformations, and fetal death.

Only drugs that are teratogenic when used at clinically recommended doses are listed. List is not all-inclusive.

CNS, central nervous system; IUGR, intrauterine growth restriction.

Source: Briggs G et al. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. 11th

ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2017; Koren G et al. Drugs in pregnancy. N Engl J Med.

1998;338:1128.

PLACENTAL TRANSFER OF DRUGS

At one time, the placenta was thought to present a barrier to the passage of drugs and

noxious chemicals to the fetus. It is now known, however, that most medications

cross the placenta to the fetus and, in general, what the mother consumes also is

consumed by the fetus. Although the placenta acts as a biologic membrane, it initially

is composed of four layers effectively separating two distinct individuals.

41 These

layers are (a) the endothelial lining of the fetal vessels, (b) the connective tissue in

the core of the villus, (c) the cytotrophoblast layer, and (d) the covering syncytium.

During gestation, the placenta’s surface area increases while its thickness decreases

from approximately 25 μm during the first trimester to 2 to 6 μm at term. Both

processes tend to favor the transfer of chemicals to the fetus.

Drugs, nutrients, and other substances cross the placenta by five mechanisms: (a)

simple diffusion (e.g., most drugs), (b) facilitated diffusion (e.g., glucose), (c) active

transport (e.g., some vitamins, amino acids), (d) pinocytosis (e.g., immune

antibodies), and (e) breaks between cells (e.g., erythrocytes).

41,42,39 The latter two

mechanisms are of no practical importance in the transfer of drugs.

Several factors influence the rate of drug transfer across the placenta, including

molecular weight, lipid solubility, ionization, protein binding, uterine and umbilical

blood flow, and maternal diseases.

39 Drugs with molecular weights of less than 600

cross easily, whereas those of greater than 1,000 (e.g., heparin) cross with difficulty

or not at all. Because most drugs have molecular weights of less than 600, it is safe

to assume that most drugs reaching the mother’s circulatory system also will reach

the fetus. As with other biologic membranes, lipid-soluble substances are transferred

rapidly, with the rate of entry primarily governed by the lipid solubility of the

nonionized molecule. Conversely, those molecules that are ionized at physiologic pH

(e.g., the cholinergic quaternary amines) cross slowly, whereas weak acids and

bases with dissociation constant (pKα

) values between 4.3 and 8.5 are transferred

rapidly to the fetus. The penetration of highly protein-bound drugs also is inhibited;

only the free, unbound drugs cross the placenta.

41,38,39

p. 973

p. 974

Figure 49-2 Criticalstages of human development. (Adapted with permission from Moore KL, Persaud TVN.

The Developing Human: Clinically Oriented Embryology. 7th ed. Philadelphia, PA: Saunders; 2003.)

Uterine blood flow, a major factor in determining the rate of drug transfer,

increases throughout gestation. Several variables can affect uterine blood flow and

the rate of drug transfer, including maternal blood pressure (BP), cord compression,

and drug therapy. Maternal hypotension reduces uterine blood flow and the rate at

which substances are delivered to the membrane. Cord compression reduces the

blood flow on the fetal side of the membrane. The use of drugs with α-adrenergic

property (e.g., epinephrine) may constrict uterine vessels and thereby reduce blood

flow.

27 Maternal diseases, such as pregnancy-induced hypertension, erythroblastosis,

and diabetes, change the permeability of the placenta and may reduce or increase

transfer.

36

Food and Drug Administration (FDA) Risk Factors

In 1979, the US FDA introduced a system of rating pregnancy risks associated with

pharmacologic agents. This system categorizes all drugs approved after 1983 into

one of five pregnancy risk categories, A, B, C, D, and X. It establishes the level of

risks to the fetus based on available animal and human data and recommends the

degree of caution that should be undertaken with each drug.

38,40–42 This system had

many limitations. Effective in June 2015, the FDA introduced pregnancy labeling and

category system to include narrative text to provide more clinical management advice

that includes consideration of both animal and human data (Fig. 49-1).

43 The

structured narratives will include the following sections for each drug: a) pregnancy

(including considerations during labor and delivery), b) lactation (includes nursing

mother considerations), and c) females and males of reproductive potentionl.

43 For

specific information on the FDA pregnancy labeling

43

:

http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/labeling/The old FDA pregnancy classification structure states that levothyroxine is a

pregnancy category A drug, but does not give any further specific information. The

new FDA-structured narrative states “Levothyroxine (T4

) is compatible with all

stages of pregnancy. Untreated or undertreated maternal hypothyroidism is associated

with low birth weight secondary to medically indicated preterm delivery,

preeclampsia or placental abruption, and with lower neuropsychological

development of their offspring.”

38 S.C. should be counseled that levothyroxine can

safely be used during all trimesters of pregnancy including the period of

organogenesis, which she is currently in at 8 weeks’ gestation. She should not

discontinue her levothyroxine. Thyroxine insufficiency has been shown to impair

fetal and neonatal development. Levothyroxine therapy has not been observed to

increase the risk of congenital malformations beyond the reported background risk of

3%.

38

p. 974

p. 975

MANAGEMENT OF CONDITIONS IN

PREGNANCY

Nausea and Vomiting

CASE 49-1, QUESTION 6: S.C. is now 10 weeks pregnant and complains of nausea throughout the day with

occasional emesis occurring 2 to 3 times daily. She is able to tolerate at least two meals a day and oral liquids.

She reports very little weight gain since she became pregnant. Her current weight is 72 kg. S.C. states that

certain smells such as fish, eggs, and beans cause her to gag. How long is her nausea and vomiting likely to

last?

According to American College of Obstetricians and Gynecology, nausea and

vomiting during pregnancy (NVP) is a common condition occurring in approximately

70% to 85% of pregnancies, during weeks 5 to 12 of gestation.

44 For most women,

NVP is a self-limiting condition that usually resolves after the first trimester with no

long-term detrimental effect on the fetus.

47 About 91% of cases will resolve by 20

weeks of gestation.

45 The effects of NVP can have an impact on a woman’s daily

activities, work productivity, and quality of life. Studies estimate $130 million/year

is spent on the hospitalization for severe NVP.

46 The cause of NVP is unknown, but is

most likely multifactorial including hormonal, psychological, and neurologic factors.

Changes in hormonal levels of estrogen, progesterone, and hCG have been implicated

as a possible cause of NVP. Mild-to-moderate NVP has been associated with lower

rates of miscarriage, preterm delivery, and stillbirth.

47

NONPHARMACOLOGIC MANAGEMENT FOR NAUSEA AND VOMITING

CASE 49-1, QUESTION 7: What nonpharmacologic approaches should S.C. try for her nausea and

vomiting?

Most mild forms of NVP can be managed with psychological support and lifestyle

and dietary changes. Advising S.C. to eat smaller frequent meals consisting of a lowfat, bland, and dry diet (e.g., bananas, crackers, rice, toast), to avoid spicy and highly

aromatic foods, and to take prenatal vitamins with iron at night may alleviate some of

the symptoms. Meals high in protein are more likely to alleviate NVP than

carbohydrate-laden or fatty meals. Rest and avoidance of the sensory stimuli

occurring from foods, and lotions that may contribute to the effects of NVP can also

be helpful.

47 Advise S.C. to avoid the foods (i.e., fish, beans, eggs, spaghetti sauce)

that specifically trigger her gag reflex, which may induce emesis.

PHARMACOLOGIC MANAGEMENT FOR NAUSEA AND VOMITING

CASE 49-1, QUESTION 8: S.C. has tried crackers and avoiding the foods that trigger her gag reflex but

does not respond to nonpharmacologic treatment of her nausea and vomiting. What pharmacologic agent would

be appropriate for her?

Antiemetics are indicated for the treatment of moderate-to-severe nausea and

vomiting that fails to respond to nonpharmacologic interventions or when the nausea

or vomiting threatens the mother’s metabolic or nutritional status (e.g., hyperemesis

gravidarum). Traditionally, medications for NVP have been avoided during the first

trimester because of fear of the possible teratogenic effects. Most antiemetic

therapies (e.g., antihistamines, multivitamins, phenothiazines) can be taken during

pregnancy safely. Table 49-23

8,46,48,50,51 shows the most common antiemetics used

during pregnancy. The goal of antiemetic therapy is to choose an effective medication

to improve a woman’s quality of life by maintaining her nutrition and hydration

needs, while ensuring fetal safety.

The FDA-recently-approved and prescription delayed-release formulation of 10

mg doxylamine with 10mg of pyridoxine (vitamin B6

) called Diclegis can be

considered first-line therapy for the treatment of NVP. Several randomized,

controlled trials have demonstrated its effectiveness in reducing NVP. Because of its

safety and efficacy profile, doxylamine and pyridoxine are still considered a firstline therapy and are available in combination as prescription or separately as overthe-counter products.

48,52–54

Other antihistamine H1

receptor blockers (e.g., diphenhydramine, hydroxyzine,

meclizine, dimenhydrinate) have been studied for NVP. The safety of antihistamines

was supported in a meta-analysis including more than 200,000 first-trimester

exposures, which did not find an increase in teratogenic risk.

49 Sedation is the main

side effect that limits the use of this class of antiemetics.

Phenothiazines or metoclopramide is usually prescribed if antihistamines fail.

50,51

Phenothiazines (e.g., promethazine, prochlorperazine) are generally considered safe

for both the mother and fetus if used occasionally in low doses. A recent randomized

trial compared IV metoclopramide versus IV promethazine in the treatment of

hyperemesis gravidarum and found both agents have similar efficacy. However,

metoclopramide caused less drowsiness and dizziness.

50 Metoclopramide, a

dopaminergic antagonist with prokinetic abilities, can control vomiting and gastric

reflux associated with pregnancy. Oral metoclopramide can be added to an

antihistamine (e.g., hydroxyzine) or a regimen of doxylamine and pyridoxine.

50,51 A

large cohort study of 3,458 women exposed to metoclopramide in the first trimester

failed to show an increase in congenital malformations. Metoclopramide issued a

black box warning concerning the risk of rare incidences of tardive dyskinesia.

50,51

Risk of tardive dyskinesia increases with longer duration of treatment and total

cumulative doses; thus, length of therapy beyond 12 weeks should be avoided.

50,51

Due to the use of ondansetron, a 5-hydroxytryptamine type 3 antagonist during

pregnancy has increased due to more experiences with its use. It is increasingly used

for NVP and hyperemesis owing to ease of administration with oral disintegrating

tablets and tolerability with minimal sedating side effects or poor fetal outcomes.

46,55

Methylprednisolone is an option for refractory cases; however, its use during the first

trimester is associated with a small but significant risk of fetal oral clefts.

Alternative therapies (e.g., vitamin B6

, ginger root, acupuncture, acupressure) have

improved NVP in a small number of patients.

38,45 S.C. may be started on doxylamine

10 mg and pyridoxine 10 mg 2 tablets by mouth at bedtime. S.C. may increase to 2

additional tablets in the afternoon if needed to a maximum of 4 tablets per day

because of its safety and efficacy profile. Drug selection for S.C. mostly depends on

the tolerability of adverse effects. If S.C. continues to have significant nausea and

emesis on these antiemetics and fails to tolerate any oral liquids or solids, she should

be advised to return to the clinic for evaluation and possibly be admitted for IV

hydration and IV antiemetic therapy.

CASE 49-1, QUESTION 9: S.C. returns to the clinic a few weeks later at 12 weeks’ gestation stating that

she has lost about 4 kg in the past 3 weeks, has been unable to tolerate any liquids or medication for 2 weeks,

and feels dehydrated and dizzy. S.C. is referred for admission to the hospital. What recommendations should be

given to S.C. to help control her nausea and vomiting?

Severe NVP can persist in less than 1% of pregnancies, leading to a condition

called hyperemesis gravidarum, which can lead to detrimental effects on the mother

and fetus. Weight loss of more than 5% of prepregnancy weight, ketonuria, and

electrolyte abnormalities are associated with this condition. Treatment of

hyperemesis gravidarum often requires hospitalization for parental fluid

administration, electrolyte replacement, vitamin supplementation, and antiemetic

therapy.

47 Metabolic acidosis, ketosis, hypovolemia, electrolyte disturbances, and

weight loss may ensue if patients are not treated.

47 Reductions in lower esophageal

pressure, gastric peristalsis, and gastric emptying may worsen nausea and vomiting.

p. 975

p. 976

Table 49-2

Common Antiemetics Used for Nausea and Vomiting During Pregnancy (NVP)

Drug Dose Comments

Vitamin B6

(pyridoxine) 10–25 mg PO TID First-line therapy

45

;

Documented safety in pregnancy

Vitamin B6

(pyridoxine)–

doxylamine combination

Pyridoxine 10–25 mg PO TID–

QID;

Doxylamine 12.5 mg PO TID–

QID

Doxylamine 10 mg/

Pyridoxine 10 mg PO

QHS, Max 4 tablets/day

First-line therapy;

Available OTC;

Well-documented safety in pregnancy through

large meta-analysis,

54

RX only

Antihistamines

Diphenhydramine

Meclizine

Hydroxyzine

Dimenhydrinate

25–50 mg PO every 8 hours

25 mg PO every 6 hours

25–50 mg PO every 4–6 hours

50–100 mg PO every 4–6 hours

First-line therapy;

Antihistamines have not been shown to be

teratogenic

49,50

Phenothiazines

Promethazine

Prochlorperazine

12.5–25 mg PO, PR every 6

hours

5–10 mg PO every 6–8 hours

Second line of therapy;

Available as suppositories;

Also suppositories and buccal tablets;

Usually add phenothiazine or metoclopramide to

therapy if antihistamines fail

45,51

;

Can cause EPS

Dopamine Antagonists

Metoclopramide 10 mg PO every 6 hours Usually add phenothiazine or metoclopramide to

therapy if antihistamines fail

45,51

;

Avoid treatment greater than 12 weeks’ duration,

risk of tardive dyskinesia;

Can cause EPS

Droperidol 1.25–2.5 mg IV/IM or

Continuous infusion 1 mg/h for

treatment of hyperemesis

gravidarum

50

Boxed warning regarding torsades de pointes,

may need ECG during administration.

Continuous infusion of droperidol requires

concomitant diphenhydramine 50 mg IV every 6

hours

5-HT3 Receptor Antagonists

Ondansetron 4–8 mg IV/PO every 6–8 hours Available as ODT tablets;

Does not cause sedation;

Studies suggest low risk in pregnancy

38,55

Glucocorticoids

Methylprednisolone 16 mg PO every 8 hours × 3

days, then taper over 2 weeks

For refractory cases, last line of therapy;

Avoid use before 10th week of gestation,

associated with oral cleft and palate

38,45

Ginger extract 125–250 mg PO every 6 hours Available OTC as food supplement

ECG, electrocardiogram; EPS, extrapyramidal symptoms; IM, intramuscular; IV, intravenous; ODT, oral

disintegrating tablet; OTC, over-the-counter; PO, by mouth; QID, 4 times a day; TID, 3 times a day.

Source: Briggs G et al. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. 11th

ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2017; Niebyl JR. Clinical practice. Nausea and vomiting in

pregnancy. N EnglJ Med. 2010;363:1544; McKeigue PM et al. Bendectin and birth defects: I. A meta-analysis of

the epidemiologic studies. Teratology. 1994;50:27; Seto A et al. Pregnancy outcome following first trimester

exposure to antihistamines: meta-analysis. Am J Perinatol. 1997;14:119.

In addition to ondansetron as mentioned above used for NVP, droperidol, an IV

dopamine antagonist, has been used extensively for many years in the treatment of

hyperemesis and the prevention and treatment of postoperative nausea and vomiting.

38

Although the FDA has mandated electrocardiographic monitoring for concern about

the risk of prolonged QTc interval, large meta-analysis studies have failed to show

an increased risk of arrhythmias when using droperidol at the low doses used for

nausea and vomiting.

45 Limited experience with droperidol use in hyperemesis

gravidarum has been documented in a small controlled trial.

52 Human and

p. 976

p. 977

animal data suggest droperidol carries a low risk of teratogenicity to the

fetus.

38,50,51

S.C. should be hydrated with IV fluids with electrolyte replacement therapy and

multivitamins including pyridoxine. If hydration with multivitamins does not quell her

nausea, IV ondansetron 4 to 8 mg every 4 to 6 hours should be given. IV droperidol

therapy should be considered if ondansetron does not work. She should also be

evaluated for other causes of nausea and vomiting if her symptoms persist (e.g.,

gastroenteritis, cholecystitis, pancreatitis, hepatitis, peptic ulcer disease,

pyelonephritis, and fatty liver of pregnancy).

47 Enteral nutrition may be needed in the

treatment of hyperemesis gravidarum if S.C. cannot tolerate oral liquid and solid

intake despite continuous IV antiemetics and hydration. Total parental nutrition

should be reserved after multiple antiemetic regimens and enteral therapies have

failed because of the substantial risks of catheter sepsis (25%) and thromboembolic

clots.

45,46,50

REFLUX ESOPHAGITIS

CASE 49-1, QUESTION 10: S.C. is now 30 weeks pregnant and no longer complains of nausea or vomiting.

However, now she has heartburn that worsens when she lies down. What causes reflux esophagitis in

pregnancy, and how should S.C. manage this problem?

Reflux esophagitis or heartburn is a normal occurrence in pregnancy affecting

approximately two-thirds of women. The enlarging uterus increases intra-abdominal

pressure, and estrogen and progesterone relax the esophageal sphincter. These two

factors cause the reflux of stomach acid into the lower esophagus, producing

symptoms of substernal burning worsened by eating, lying down, or bending over.

Lifestyle and dietary modifications, such as eating smaller meals, avoiding late meals

close to bedtime, and elevation of the head of the bed, should be tried first.

Avoidance of salicylates, caffeine, alcohol, and nicotine are encouraged to reduce

the symptoms of reflux and fetal exposure to these harmful substances.

If these modifications are not successful, S.C. should try a calcium carbonate

antacid. Animal studies have not shown antacids to have teratogenic effects.

38

Sodium bicarbonate can cause metabolic alkalosis and fluid overload and should be

avoided. Despite evidence of fetal toxicity with aluminum, available data suggest that

usual doses of aluminum-containing medications are not harmful to the fetus of a

pregnant woman with normal renal function. Sucralfate, which contains aluminum,

appears to be safe in pregnancy. The American College of Gastroenterology has

classified sucralfate as a medication with benefits that outweigh the risks when used

in pregnant women.

38

H2

-receptor antagonists can be used safely during pregnancy because most studies

in animals and humans have not found fetal harm with cimetidine, ranitidine,

famotidine, or nizatidine.

38

If H2

-receptor antagonists fail to control symptoms,

proton-pump inhibitors (PPIs) should be used as the next treatment option. Recent

studies have shown that PPI use during the first trimester and throughout pregnancy is

not associated with a significant increase in the risk of congenital anomalies. These

studies suggest that PPIs can be safely used at any gestational age.

56,57

URINARY TRACT INFECTIONS

CASE 49-1, QUESTION 11: S.C. is now 31 weeks pregnant, and a routine urine dip was positive for

leukocyte esterase and nitrates. Her urine was sent for urinalysis at her most recent prenatal visit and was

positive for 10

5 colony-forming units (CFU) of Escherichia coli. She does not complain of any frequency and

urgency when urinating and denies any fevers. Her temperature is currently 98.9°F. She denies any allergies to

medications. What are the risks of having a urinary tract infection during pregnancy, and how should S.C. be

treated?

Pathogenesis

Urinary tract infections are one of the most common complications of pregnancy

owing to hormonal and mechanical changes that increase the likelihood of

bacteriuria. During pregnancy, increases in progesterone cause relaxation of ureteral

smooth muscle, promoting urinary stasis. The enlarging gravid uterus can also

mechanically compress the ureters, which may lead to urinary retention.

Approximately 90% of pregnant women may exhibit ureteral dilation or

hydronephrosis, which can decrease bladder tone and ureteral tone. These

physiologic changes along with increases in the GFR, urine alkalization, and

glucosuria help to promote bacterial growth.

Asymptomatic Bacteriuria and Acute Cystitis

Urinary tract infections during pregnancy can present as either asymptomatic

bacteriuria (ASB) or acute cystitis. ASB is defined as the presence of significant

bacteria, greater than 10

5 CFU of bacteria, obtained by two consecutive clean-catch

samples in the absence of any urinary symptoms.

58

In contrast, acute cystitis involves

an infection of the bladder and manifests with signs and symptoms of frequency,

urgency, dysuria, and hematuria without fever or evidence of systemic illness along

with significant presence of bacteria of at least 10

5 CFU. Counts of less than 10

5 CFU

with two or more organisms likely represent contamination and not true bacteriuria.

ASB is estimated to occur in 2.5% to 15% of pregnant women with about 80,000

to 400,000 cases occurring each year in the United States.

58,59

If ASBs are left

untreated, they can lead to complications such as pyelonephritis, low-birth-weight

infants, and premature delivery.

60 During pregnancy, treatment of ASB reduces the

risk of developing pyelonephritis dramatically down from 20% to 35% to only 1% to

4%.

60 The US Preventive Services Task Force recommends screening for ASB with

a urine culture for all pregnant women between 12 and 16 weeks of gestation or at

the first prenatal visit if it occurs later.

61 The American College of Obstetrics and

Gynecology (ACOG) further recommends repeating a urine culture during the third

trimester.

62

Risk factors for ASB during pregnancy include diabetes, sickle cell disease,

immunosuppression, HIV or acquired immunodeficiency syndrome, urinary tract

anatomic anomalies, and spinal cord injuries.

63 The primary sources of organisms

that cause bacteriuria originate from existing vaginal and perineal flora and migrate

up the urethra to cause ASB and cystitis; they include E. coli (most common pathogen

isolated), Klebsiella pneumoniae, Proteus mirabilis, Enterobacter species,

Enterococcus, Staphylococcus saprophyticus, and group B β-hemolytic

Streptococcus.