Gastroesophageal reflux disease during pregnancy

Gastroenterol Clin N Am 32 (2003) 235–261

Gastroesophageal reflux disease during pregnancy Joel E. Richter, MD Center for Swallowing and Esophageal Disorders, Department of Gastroenterology/Hepatology, The Cleveland Clinic Foundation, 9500 Euclid Avenue A30, Cleveland, OH 44195, USA

Incidence and epidemiology Heartburn is estimated to occur in 30% to 50% of pregnancies, with the incidence approaching 80% in some populations [1]. Uncommonly, it represents an exacerbation of preexisting disease. Usually, symptomatic gastroesophageal reflux disease (GERD) begins during pregnancy and ceases soon after delivery [2]. Marchand [3] found that most women first experience reflux symptoms after 5 months of gestation; however, Castro [4] suggested that many women report the onset of symptoms only when they become very troublesome, long after the symptoms actually began. After detailed interviews of 60 patients, he noted that 52% first experienced heartburn in the first trimester of pregnancy, 24% in the second trimester, and 9% in the third trimester. Heartburn was more frequent and more severe in the latter months of gestation. Almost all the women had experienced heartburn during previous pregnancies that had improved rapidly after delivery. In a study of 607 pregnant women by Marrero and colleagues [5], the prevalence and severity of heartburn also progressively increased during pregnancy; 22% complained of heartburn in the first trimester, 39% in the second trimester, and 72% in the third trimester. Regression analysis of this large database found that the risk of heartburn increased directly with gestational age, heartburn antecedent to the pregnancy, and parity and correlated inversely with maternal age. Body mass index before pregnancy, weight gain during pregnancy, or race did not predict heartburn frequency or severity. On the other hand, one study [1] noted a higher incidence of heartburn in whites than in Nigerians (78.8% versus 9%, respectively), but Banbridge et al [6] found no difference in the incidence of heartburn between

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white Europeans and Asians. Banbridge also suggested that multiparity and a history of heartburn in the first pregnancy were risk factors for heartburn in subsequent pregnancies. Thus, heartburn is so common during pregnancy that patients and obstetricians both view it as a normal occurrence during a healthy pregnancy.

Pathogenesis of gastroesophageal reflux disease during pregnancy The cause of GERD during pregnancy is controversial. The exact mechanisms promoting gastroesophageal reflux primarily involve decreased LES tone, but mechanical factors may also be important. Lower esophageal sphincter pressure In an early study, Nagler and Spiro [7] performed esophageal manometry on 20 pregnant women with symptoms of heartburn and on 19 pregnant women without symptoms. In serial studies 55% of the symptomatic women and 20% of the asymptomatic women demonstrated a hypotonic LES. Sphincter pressures progressively decreased as the pregnancy advanced, returning to normal values soon after delivery. The investigators suggested that the loss of the intraabdominal portion of the LES combined with an elevated intragastric pressure secondary to the gravid uterus contributed to GERD. Lind et al [8] further studied LES pressure during pregnancy. Ten nonpregnant women, serving as controls, were compared with 9 pregnant patients with heartburn and 11 pregnant patients without heartburn. Intragastric pressure, mean LES pressure, and LES pressure in response to abdominal compression were analyzed. Both groups of pregnant patients had intragastric pressures higher than those of controls. The maximal LES pressure increased normally in response to abdominal compression in the asymptomatic pregnant patients but not in the symptomatic patients, who in fact had a lower LES resting tone than did controls. The LES pressures returned to control levels postpartum. The investigators concluded that pregnancy increases intragastric pressure, but the LES pressure did not concomitantly increase in symptomatic patients. This phenomenon, combined with a decrease in resting LES tone, allows gastroesophageal reflux (GER) to occur. The decrease in LES pressure during pregnancy has been attributed to elevated serum levels of sex hormones, specifically estrogen and progesterone. Van Thiel et al [9] sequentially studied four previously asymptomatic pregnant patients at 12, 24, and 36 weeks of gestation, and at 1 to 4 weeks postpartum. In all study periods during pregnancy, LES pressure was below the lower limits of normal for women in their motility laboratory (Fig. 1). Pressures reached a nadir at 36 weeks and returned to normal postpartum. All four patients had symptomatic GER by 36 weeks. Serum levels of

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Fig. 1. Lower esophageal sphincter (LES) pressures in mm Hg recorded in four women during pregnancy and postpartum. Shaded area represents the range of normal LES pressures in nonpregnant women. Horizontal bars and stippled areas represent mean^SEM. Mean LES pressure declined progressively during pregnancy but returned to normal postpartum. (From Van Thiel DH, Gavaler JS, Joshi SN, et al. Lower esophageal sphincter pressure in women using sequential oral contraceptives. Gastroenterology 1977;72:668–78; with permission.)

estrogen, estradiol, and progesterone increased progressively throughout the pregnancy. These investigators hypothesized that progesterone, either alone or in combination with estrogen, probably produced the reduction in LES pressure. Fisher et al [10] studied eight women during early pregnancy (mean 16 weeks of gestation) and 6 weeks after elective abortion. The mean LES pressure before abortion of 22.1^2.4 mm Hg (^SEM) was unchanged from the postabortion mean LES pressure of 22.6^2.3 mm Hg. Despite a normal resting LES pressure during early pregnancy, the LES responded abnormally to challenges of injection with pentagastrin, edrophonium chloride, methacholine, or a protein meal, in that the LES pressure increased significantly less during early pregnancy than after abortion (Fig. 2). Serum levels of estrogen and progesterone were significantly higher during early pregnancy than after abortion. The investigators speculated that the blunted pressure responses to various physiologic stimuli suggested that, despite normal resting pressure, LES function was reversibly inhibited during early pregnancy, when serum concentrations of total estrogens and progesterone are elevated. Animal experiments have demonstrated a pivotal role for sex hormones in modulating LES pressure. The effect of these hormones on the doseresponse curves of LES smooth muscle to acetylcholine and gastrin was studied in muscle strips from the opossum [11]. The maximal LES muscle response was decreased by either estrogen or progesterone alone but was

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Fig. 2. Lower esophageal sphincter (LES) pressure response to maximal doses of edrophonium and methocholine in eight women. Early in the second trimester of pregnancy, LES responses to either drug were significantly blunted but returned to normal strength after abortion. Each bar represents the mean^SE. (From Fisher RS, Robert GS, Grabowski CJ, et al. Altered lower esophageal sphincter function during early pregnancy. Gastroenterology 1978;74:1233–7; with permission.)

more severely decreased by estrogen and progesterone in combination (Fig. 3). In another study using opossums [12], estrogen was intramuscularly administered on days 1 and 7 and estrogen and progesterone on days 7 to 12. The LES pressure was unchanged from baseline on days 1 and 7 but decreased on day 12 when combination therapy was administered. Unique studies in humans have confirmed the importance of progesterone preceded by estrogen priming in the decline of LES pressure during pregnancy. Filipone et al [13] studied resting LES pressure and the response of the LES to a protein meal in five transsexual patients during periods of no hormonal administration, estrogen administration, progesterone administration, and combined estrogen and progesterone administration. The LES resting pressure was significantly lower during periods of combined estrogen and progesterone therapy (5.0^0.1 mm Hg) than during periods of no hormonal therapy (11.2^2.1 mm Hg). The LES pressure did not decrease during administration of either estrogen or progesterone alone. The adaptive LES pressure response to protein was diminished by progesterone alone or by combination therapy but not by estrogen alone. Van Thiel and colleagues [9] made similar observations in normal menstruating women taking birth control pills containing sequential estrogen and progesterone compounds. The LES pressure was not significantly lower on days 18 to 20, when estrogens were administered alone, than on days 1 to 3 of the menstrual cycle, when neither hormone was administered, but the LES pressure decreased significantly on days 23 to 28, when both estrogen and progesterone were administered (Fig. 4).

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Fig. 3. Dose-response curves for acetylcholine alone and in the presence of estradiol, progesterone, or combination therapy. Active tension is expressed as a percentage of maximal response to acetylcholine alone. Each data point represents mean^SE in 10 experiments. In the presence of these sex hormones, the dose response to acetylcholine was shifted to higher concentrations, and the maximal response was significantly decreased. (From Fisher RS, Robert GS, Grabowski CJ, et al. Inhibition of lower esophageal sphincter circular muscle by female sex hormones. Am J Physiol 1978;234:E243–7; with permission.)

In summary, LES resting pressure is abnormally low during pregnancy, with a decrease in physiologic function. Progesterone seems to mediate LES relaxation, but estrogen is a necessary primer. Unfortunately, the effect of pregnancy on transient LES relaxation is poorly understood. Mechanical factors Increased abdominal pressure secondary to the enlarged gravid uterus is another potential mechanism for the reflux during pregnancy. In 1967, Spence and coworkers [14] studied intragastric pressures during anesthesia in pregnant women compared with men, nonpregnant women, and children. Intragastric pressure in pregnancy averaged twice that of the other groups. Because pressures decreased immediately postpartum, the authors concluded that the gravid uterus was responsible for the increased gastric pressure. To simulate the clinical setting of a gravid uterus, Van Thiel and Wald [15] studied cirrhotic patients with tense ascites (a clinical situation in which intraabdominal pressure is likely to be increased) before and after vigorous diuresis. Before diuresis, the mean LES pressure in 10 adult men was 30.9^1.7 mm Hg, just above the upper limits of normal for their laboratory. After the diuresis, the LES pressure fell significantly to 24^1.6 mm Hg.

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Fig. 4. Resting lower esophageal sphincter (LES) pressure in mm Hg during the menstrual cycle on a sequential oral contraceptive. Subjects taking both ethinyl estradiol and dimethisterone had significantly lower LES pressures than those measured at other times in the menstrual cycle (P<0.01). Data represent individual subjects and mean^SEM. Shaded area signifies normal laboratory range. (From Van Thiel DH, Gavaler JS, Joshi SN, et al. Lower esophageal sphincter pressure in women using sequential oral contraceptives. Gastroenterology 1977;72:668–78; with permission.)

These studies suggested that the barrier between the high abdominal pressure and the low pressure in the esophagus was maintained during tense ascites by a compensatory increase in LES pressure. These results supported the finding by Lind et al [8] that the LES pressure rose in response to abdominal compression in pregnant women without heartburn. Thus, other factors in addition to an increase in abdominal pressure must play a role in promoting GER during pregnancy. Other factors Other possibly contributing factors include an alteration in gastrointestinal transit. For example, some have suggested that ineffective esophageal motility (decreased amplitude of distal esophageal contractions) is the most common motility abnormality in GERD [16]. In early studies, Nagler and Spiro [7] found an increase in nontransmitted contractions in the distal esophagus. Ulmsten and Sundstrom [17] studied six nonpregnant women and six pregnant women, only one of whom had symptomatic heartburn. As with previous studies, pregnant women had lower LES pressures than nonpregnant women. In addition, the pregnant women had a slower wave velocity and lower amplitude of esophageal peristalsis. These changes in esophageal peristalsis could decrease acid clearance and compound the problems from reflux in pregnant women. Others have suggested that abnormal gastric emptying or small bowel transit might contribute to heartburn in pregnancy. Wald et al [18] studied

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the orocecal transit time in 15 women in the third trimester of pregnancy and 4 weeks postpartum by monitoring expiratory breath hydrogen concentrations at 10-minute intervals after lactulose ingestion. The time from ingestion to the first detectable sustained rise in breath hydrogen was calculated. Nine of the 15 subjects had prolonged transit times during pregnancy, and the average transit time was significantly longer during pregnancy (131^14 minutes) than postpartum (93^7 minutes). Schade et al [19] subsequently measured gastric emptying of liquids in 10 women during the second trimester of pregnancy by isotopic scans of technetium sulfur colloid. Four of the patients had repeat measurements 6 weeks after therapeutic abortion. Subjects had no difference in gastric emptying of liquids during pregnancy as compared with after pregnancy or as compared with normal menstruating controls. Unfortunately, neither of these studies addresses whether emptying of solids is delayed in normal pregnancy and contributes to GER. There are no data showing that pregnancy alters gastric acidity, bile reflux, or cytoprotective factors in the esophageal mucosa. Unfortunately, the latter two factors have not been studied during pregnancy. Clinical presentation during pregnancy The clinical features of GERD during pregnancy do not differ from those in the general adult population. Heartburn is the predominant symptom and worsens as pregnancy advances. Regurgitation occurs in about the same frequency as heartburn. Not unexpectedly, Castro [4] found that 77% of his patients reported exacerbation of symptoms with food ingestion. Some patients ate only one meal per day because of intense postprandial heartburn. Likewise, recumbency aggravated the heartburn in 82% of his patients and required some patients to sleep upright in a chair. The frequency of extraesophageal manifestations of GERD, including hoarseness, chronic cough, chronic laryngitis, and asthma, have not been studied during pregnancy. Complications of GERD during pregnancy include esophagitis, bleeding, and stricture formation. Castro [4] reported approximately two thirds of pregnant women with heartburn had histologic esophagitis; however, the endoscopic appearance of the esophagus usually showed only mild esophagitis. Only one subject had mucosal erosions. This finding is not surprising, because the reflux in pregnancy is generally of short duration without a background of chronic GERD. A lack of severe esophagitis may also explain the infrequent complications of dysphagia and bleeding associated with heartburn during pregnancy. Diagnosis in the pregnant patient During pregnancy, the initial diagnosis and treatment of GERD is based on symptoms. This reliance on clinical symptoms is reasonable, because the

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classic presentation of substernal burning occurring after meals or in the supine position has a 90% sensitivity and specificity for the diagnosis of GERD in adults [20]. Barium radiogram studies are not necessary and should be avoided because of radiation teratogenicity. Esophageal manometry and pH studies are rarely necessary during pregnancy but can be safely performed (J.E. Richter, personal experience). Data are, however, lacking on the definition of normal and pathologic reflux during pregnancy. Esophagogastroduodenoscopy (EGD) is the procedure of choice to evaluate intractable reflux symptoms or complications. Esophagogastroduodenoscopy can be safely performed without harm to the mother or fetus by carefully monitoring blood pressure and oxygenation and with judicious use of conscious sedation. Meperidine, midazolam, or diazepam is probably safe, particularly after the first trimester, although the drugs are not approved for these indications by the Food and Drug Administration (FDA). Fetal monitoring may increase the safety of EGD during pregnancy [21]. Several studies have confirmed the safety of EGD during pregnancy. Castro [4] performed endoscopy and esophageal biopsies in 43 pregnant women at different stages of pregnancy with no complications. In the largest endoscopic study, Cappell et al [22] in a case-controlled study assessed 83 consecutive pregnant patients undergoing EGD from 1980 to 1995. The mean gestational age was about 20 weeks. Esophagitis, usually mild, was noted in 62% of patients. The effect of EGD with sedation on vital signs and oxygen saturation was clinically and statistically insignificant. Esophagogastroduodenoscopy did not induce labor or cause any other complications. Ninety-five percent of women delivered healthy babies, a rate equal to that in age-matched controls. Birth weight, Apgar scores, and fetal heart rates were comparable with those in infants born to pregnant controls not undergoing EGD. Four poor outcomes (3 stillbirths and 1 involuntary abortion) occurred in high-risk pregnancies and were unrelated to endoscopy temporally and etiologically. Finally, in a mail survey conducted by the American Society of Gastrointestinal Endoscopy [23], no fetal or maternal complications were reported in 73 pregnant women undergoing EGD. Of this group, 35% had received meperidine or diazepam. Midazolam and diazepam are category D and meperidine and fentanyl are category C drugs during pregnancy (Table 1). Therefore, the author limits EGD to patients with medically refractory disease or severe complications and tries to defer EGD until after the first trimester of pregnancy. Treatment during pregnancy The challenge of treatment during pregnancy is the potential teratogenicity of common antireflux medications. For mild symptoms, lifestyle and dietary modifications may be all that are required. These modifications include avoiding eating late at night or before retiring to bed, raising the

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Table 1 FDA classification of drugs during pregnancy FDA classification

Definition

Category A Category B

Well-controlled studies in humans show no fetal risk. Animal studies show no risks, but human studies are inadequate or animal studies show some risk not supported by human studies. Animal studies show risk, but human studies are inadequate or lacking or no studies in humans or animals. Definite fetal abnormalities in human studies, but potential benefits may outweigh the risks. Contraindicated in pregnancy because of fetal abnormalities in animals or humans. Risks outweigh benefits.

Category C Category D Category X

Abbreviation: FDA, Food and Drug Administration.

head of the bed by 6 inches, and avoiding foods and medications that cause heartburn. Abstinence from drinking alcohol and smoking tobacco is encouraged to reduce reflux symptoms and to avoid fetal exposure to these harmful substances. For moderate to severe GERD symptoms, the physician must discuss with the patient the benefits versus the risks of drug therapy. Informed consent is appropriate. Medications for treating GERD are not routinely or rigorously tested in randomized, controlled trials in pregnant women because of ethical and medicolegal concerns. Most recommendations arise from case reports and cohort studies by physicians, pharmaceutical companies, or the FDA. Voluntary reporting by the manufacturers suffers from an unknown duration of follow up, absence of appropriate controls, and possible reporting bias [24]. Commonly used medications include antacids, sucralfate, histamine2 receptor antagonists (H2RAs), promotility drugs, and proton-pump inhibitors (PPIs). The incidence of major fetal malformations in the general population ranges between 1% and 3% [25]. The safety of drugs in pregnancy is divided by the FDA into five categories called A, B, C, D, or X, based on systemic absorption and reports of congenital defects in humans and animals (Table 1) [26]. The teratogenic period typically ranges from day 31 (in a 28-day menstrual cycle) to day 71 from the last menstrual period [25], essentially the first 10 weeks of gestation. This is the critical period of organogenesis. Before day 31, exposure to a teratogen usually causes an all-or-none effect in that the fetus either dies or survives without anomalies. Fetal cells are totipotential during this time period with respect to organogenesis; therefore, if a few cells die, the remaining cells can replace their function. Drugs that are not urgently required should be withheld until after the teratogenic period, although drugs can still affect the fetus in later gestation. Drugs used for GERD during pregnancy and their FDA categories are summarized in Table 2.

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Table 2 FDA classification of drug therapy for gastroesophageal reflux disease in pregnancy Drugs

FDA class

Comments

None

Most are safe during pregnancy and for aspiration prophylaxis during labor because of minimal absorption. Avoid long-term, high-dose therapy in pregnancy. Not safe during pregnancy because it causes fluid overload and metabolic alkalosis.

Antacids Aluminum-, calcium-, or magnesium-containing antacids Magnesium trisilicates

None

Sodium bicarbonate

None

Mucosal protectant Sucralfate

B

No teratogenicity in animals. Generally regarded as acceptable in humans because of minimal absorption.

H2RAs Cimetidine

B

Ranitidine

B

Famotidine

B

Nizatidine

B

A prospective, controlled study suggests acceptable safety in humans. Same as cimetidine. Ranitidine is the only H2RA whose efficacy during pregnancy has been established. Same as cimetidine, but paucity of safety data in humans. Not recommended during pregnancy. In animals, spontaneous abortion, congenital malformations, low birth weight, and fewer live births have been reported. Little data in humans.

Promotility agents Cisapride

C

Metoclopramide

B

Proton pump inhibitors Omeprazole

C

Lansoprazole

B

Rabeprazole

B

Pantoprazole

B

Esomeprazole

B

Embryotoxic and fetotoxic in animals. Recent prospective controlled study suggests acceptable safety in human pregnancy, but drugs recently removed by FDA for fatal cardiac arrhythmias. No reported teratogenic effects in animals or humans. Embryotoxic and fetotoxic in animals. Case reports in human suggest similar concerns. Acceptable for aspiration prophylaxis in labor. No fetal teratogenicity or harm. Limited data in human pregnancy. Use in acceptable for aspiration prophylaxis during pregnancy. No fetal teratogenicity or harm. Limited data in human pregnancy. Use is acceptable for aspiration prophylaxis during pregnancy. No fetal teratogenicity or harm. Limited data in human pregnancy. Use is acceptable for aspiration prophylaxis during pregnancy. No fetal teratogenicity or harm. Limited data in human pregnancy. Use is acceptable for aspiration prophylaxis during pregnancy.

Abbreviations: FDA, Food and Drug Administration; H2RA, histamine2 receptor antagonist.

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Antacids About 30% to 50% of women use antacids to relieve heartburn and other acid reflux symptoms during pregnancy. Only limited data exist concerning the effects of antacids on the fetus, with no controlled trials of efficacy during pregnancy included in many of the larger prospective drugsurveillance studies. Magnesium-, aluminum-, or calcium-containing antacids are not teratogenic in animal studies [27], although 15% to 30% of magnesium and a smaller percentage of aluminum preparations are absorbed after reacting with hydrochloric acid. One retrospective, case-controlled study in the 1960s [28] reported a significant increase in major and minor congenital abnormalities in infants exposed to antacids during the first trimester of pregnancy. Analysis of individual antacids (aluminum hydroxide, sodium bicarbonate, magnesium trisilicate, and calcium carbonate) found no association with increased congenital anomalies, however. Presently, most aluminum-, magnesium-, and calcium-containing antacids are considered acceptable in normal therapeutic doses during pregnancy [26]. Other antacids or antacid combinations typically come with caveats. Alginic acid (Gaviscon, SmithKline Beecham Consumer Healthcare, Pittsburg, PA) is used in combination with antacids for heartburn relief. This compound contains magnesium trisilicate, which can lead to fetal nephrolithiasis, hypotonia, respiratory distress, and cardiovascular impairment if used long-term and in high doses [26]. Increased serum levels of magnesium can cause further problems if undesirable compounds are formed. Magnesium sulfate can slow or arrest labor and may cause convulsions. All magnesium-containing antacids should be avoided during the last few weeks of pregnancy. Antacids containing sodium bicarbonate should not be used during pregnancy because they can cause maternal or fetal metabolic alkalosis and fluid overload. Pregnant women receiving iron for iron deficiency anemia should be monitored carefully when antacids are used, because normal gastric acid secretions facilitate the absorption of iron. Administering the antacids at a different time than the supplemental iron can circumvent this problem [24]. Sucralfate Sucralfate, an aluminum salt of a sulfated disaccharide, inhibits pepsin activity and protects against ulceration. The drug is a highly polar anion in a strongly acidic solution which probably accounts for its poor gastrointestinal absorption. It exerts mucosal protection and ulcer healing through local, rather than systemic, action. Each gram of sucralfate contains 207 mg of aluminum [29]. The potential fetal toxicity of sucralfate relates to its aluminum content. Sucralfate is the only nonabsorbable drug that has been assessed by a randomized, controlled study during pregnancy. Ranchet et al [30]

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evaluated 66 patients with heartburn during pregnancy. Forty-two women administered 1 g of sucralfate three times daily were compared with 24 women who were given information on dietary and lifestyle modifications. Symptoms of heartburn were evaluated before and 15 or 30 days after treatment. Sucralfate-treated patients had a higher frequency of remission of symptoms of heartburn and regurgitation than controls (90% versus 43% and 83% versus 27%, respectively). One patient experienced diarrhea during treatment. No other adverse effects were reported. In mice, rats, and rabbits, sucralfate did not affect fertility and was not teratogenic with doses up to 50 times those used in humans [29]. Excessive accumulation of aluminum, especially in animals with renal impairment, can cause increased perinatal mortality, osteopenia, and impaired learning and memory, however [31]. Although aluminum toxicity is well documented, the normal doses of aluminum-containing medications, such as sucralfate, do not apparently present a risk to the fetus of pregnant women with normal renal function because only negligible amounts are absorbed from the gastrointestinal tract. For example, in a surveillance study of 229,101 pregnancies in Michigan Medicaid patients evaluated between 1985 and 1992, 185 newborn babies were exposed to sucralfate during the first trimester. Five birth defects were observed, whereas eight were expected [29]. Therefore, sucralfate is an FDA category B drug. Histamine2 receptor antagonist Although recently replaced by the PPIs to treat GERD in nonpregnant adults, the H2RAs are the most commonly used and safest medications for pregnant patients with heartburn not responding to lifestyle modifications and nonabsorbable medications. All four drugs (cimetidine, ranitidine, famotidine, and nizatidine) are FDA category B during pregnancy. Cimetidine Cimetidine, the first FDA-approved H2RA, has been available in the United States since 1975. Cimetidine has a weak antiandrogenic effect in animals, as evidenced by a reduction in the size of testes, prostate glands, and seminal vesicles [32]. The manufacturer reports that dosages as high as 950 mg/kg/day in pregnant rats and rabbits produced no adverse effects on litters or on early pup development, despite plasma cimetidine concentrations in the offspring approximately 300-fold higher than those concentrations needed to produce a 50% inhibition of basal acid secretion [26]. In contrast, others report that the sexual development and behavior of male rat pups was impaired after exposure of the pregnant dams to dosages of cimetidine as low as 17.1 mg/kg/day, equivalent to a 70-kg human taking 1200 mg/day. The observed effects persisted for 35 days after drug discontinuation suggesting that both central and end-organ androgen receptor activity or responsiveness had been modified [33,34]. Despite these

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animal data, there are no reports of human sexual defects in infants exposed to cimetidine. The manufacturer has received a number of reports of women taking cimetidine during pregnancy, including three isolated instances of congenital defects, apparently unrelated to cimetidine therapy, of congenital heart disease, mental retardation, and club foot [29]. One case of a cimetidinerelated hepatitis was reported in a newborn exposed to the drug during the last month of gestation [35]. In a surveillance study of 229,101 pregnancies in Michigan Medicaid recipients between 1985 and 1992, 460 newborns were exposed to cimetidine during the first trimester [29]. Twenty (4.3%) major birth defects were observed, a rate similar to that reported in women taking no medications. Several studies have assessed the safety of H2RAs in early pregnancy. In the Swedish Medical Birth Registry in 1998, 553 babies (including six sets of twins) were delivered by 547 women using various acid-suppressing medications in early pregnancy [36]. Seventeen infants with congenital defects were identified (3.1%, confidence interval [CI] 1.8%–4.9%) compared with the crude malformation rate of 3.9% in the Registry among women who did not take these medications. Of the 17 infants with congenital defects, 10 had been exposed to PPIs, 6 to H2Ras, and 1 to both classes of drugs. In the entire study, cimetidine was the only acidsuppressing drug exposure in 35 infants. The odds ratio for malformations after H2RAs was 0.46 (95% CI, 0.17–1.20) in contrast to 0.91 (95% CI, 0.45–1.84) for patients exposed to PPIs early during pregnancy. Two birth defects (5.7%) were observed among patients who only used cimetidine. The defects were an encephalocele and an unstable hip. Two databases, one from England and another from Italy, were combined in a study published in 1999 that compared the incidence of congenital malformations in women administered cimetidine, ranitidine, or omeprazole during the first trimester of pregnancy with unexposed control women [37]. Cimetidine was taken in 333 pregnancies, resulting in 234 live births, three stillbirths, and 1 neonatal death. Eleven of the newborns (4.7%) had a congenital malformation, compared with a 4.1% malformation rate in controls. The relative risk of malformations (adjusted for maternal age and prematurity) associated with cimetidine was 1.3 (95% CI, 0.7–2.6), with ranitidine was 1.5 (95% CI, 0.9–2.6) and with omeprazole was 0.9 (95% CI, 0.4–2.4). In summary, cimetidine has not been associated with an increased risk of congenital malformations. Some authorities have recommended that cimetidine not be used during pregnancy because of possible feminization as observed in some animals and in nonpregnant humans [38]. Ranitidine Ranitidine efficacy has been specifically studied during pregnancy. In a double-blind, placebo-controlled, triple-crossover study, Larson et al [39]

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compared the efficacy of ranitidine taken once or twice daily with placebo in pregnant women with GER symptoms not responding to lifestyle changes and antacids. Twenty women after 20 weeks’ gestation were randomly assigned to receive ranitidine, 150 mg, two times per day, ranitidine one time per day in the evening, or placebo. The number of antacid tablets and symptomatic assessments from patient diaries were compared. In the 18 patients completing the study, only twice-daily doses of ranitidine reduced symptoms and antacid usage, when compared with baseline (P<0.001), or with placebo (P<0.01). The average reduction of heartburn was 55.6% (95% CI, 34.8%–76.5%) in patients receiving twice-daily ranitidine therapy when compared with baseline and was 44.2% (95% CI, 15.4%–72.9%) when compared with placebo. No adverse pregnancy outcomes or drug reactions were noted. One patient reported continued heartburn after delivery that responded to antacids and ranitidine therapy. Reproduction studies with ranitidine in rats and rabbits at doses up to 160 times the recommended human dose revealed no evidence of impaired fertility or fetal toxicity [40]. Unlike cimetidine, ranitidine apparently has no antiandrogenic activity in animals or humans [34]. In anecdotal reports of 10 women taking ranitidine while pregnant, no maternal or fetal abnormalities occurred [41,42]. A single case report describes ranitidine use throughout pregnancy without any adverse fetal outcome [43]. In another report 14 women were exposed to ranitidine during the first trimester, including 1 woman exposed to both ranitidine and cimetidine. Follow up revealed the birth of 10 healthy infants, 2 spontaneous abortions, and an eyelid hemangioma in 1 infant. In the previously mentioned surveillance study of 229,101 pregnancies in Michigan Medicaid recipients [29], 23 (4.5%) of 560 newborns exposed to ranitidine during the first trimester had major birth defects compared with the expected prevalence of major birth defects of 22 (4.3%). Several studies addressed the safety of ranitidine during the first trimester of pregnancy. In a 1996 prospective cohort study, 178 women exposed during pregnancy to H2RAs were matched with 178 control women with no exposure but with similar maternal age and smoking and alcohol history [44]. Among these subjects, 71% took ranitidine, 16% cimetidine, 8% famotidine, and 5% nizatidine. The outcomes of subjects and controls were not significantly different in terms of live births, spontaneous or elective abortions, gestational age at delivery, birth weight, infants small for gestational age, or major malformations. The congenital malformation rate was 2.l% in subjects exposed to H2RAs versus 3.0% in the nonexposed cohorts. Similarly, in the Swedish Medical Birth Registry Study in 1998, 6 birth defects (3.8%) occurred among 156 infants exposed to ranitidine during pregnancy [36]. As mentioned previously, the combined database from England and Italy [37] reported a relative risk of malformations of 1.5 associated with ranitidine (95% CI, 0.9–2.6).

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In summary, the absence of teratogenicity or toxicity in animals and the available human pregnancy data indicate that ranitidine is safe during pregnancy, even during the first trimester. Ranitidine is the only H2RA with documented efficacy in pregnancy. Ranitidine may be the preferred H2RA during pregnancy because of its efficacy and lack of antiandrogenic activity in animals. Famotidine There are few data on famotidine use during human pregnancies. Studies in rabbits and rats administered oral doses of 200 and 500 mg/kg/day and intravenous dosages of 200 mg/kg/day revealed no impaired fertility, fetal toxicity, teratogenicity, or changes in postnatal behavior [45]. In the surveillance study of Michigan Medicaid recipients [29], 2 (6.1%) of 33 fetuses exposed to famotidine during the first trimester developed major birth defects compared with an expected prevalence of 1. The sample size was too small to draw firm conclusions, however. The antiandrogenic effects of cimetidine administered to male rat pups have not been found in male humans treated with famotidine [46]. Nizatidine Although safety data are limited, adverse effects of nizatidine during pregnancy have been reported. In animal studies, pregnant rabbits treated with the equivalent of 300 times the recommended human dose encountered abortions, low fetal weights, and fewer live fetuses [47]. Studies of pregnant rats given oral dosages up to 506 mg/kg/day reported no adverse effects on fertility, however. Unlike cimetidine, male rats treated with nizatidine suffered no antiandrogenic effects [48]. Likewise, no teratogenicity was observed in rabbits and rats with dosages up to 1500 mg/kg/day, although some abortions occurred in rabbits at the higher dose [47]. The only human report in the literature is of a woman who delivered a healthy baby weighing 7 pounds, 13 ounces at 37 weeks’ gestation after taking nizatidine during the 14th through the 16th weeks of gestation [29]. Although nizatidine was previously classified as category C, the FDA recently reclassified nizatidine as a category B drug. The conflicting animal data are troublesome, however, and suggest that other H2RAs may be safer during pregnancy. Promotility drugs Promotility drugs, metoclopramide and cisapride, provide symptomatic relief equivalent to H2RAs in mild GERD but are less effective in healing esophagitis. Metoclopramide is designated a category B drug during pregnancy. It is used infrequently for treating GERD, however, because of frequent side effects. Cisapride, a better promotility agent, is designated a category C drug in pregnancy because of toxicity in animals. This drug has

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recently been removed from the United States market because of an association with life-threatening cardiac arrhythmias. Metoclopramide Metoclopramide, an antidopaminergic agent, improves gastroesophageal reflux by increasing LES pressure, improving esophageal acid clearance, and promoting gastric emptying. Its major use in pregnancy is for the treatment of nausea and vomiting. Reproductive studies in mice, rats, and rabbits at doses up to 250 times the recommended human dose have revealed no evidence of impaired fertility or fetal toxicity [49]. No congenital malformations or other neonatal toxicity attributed to metoclopramide have been reported in humans. In the Michigan Medicaid Surveillance study [29], 10 (5.2%) major birth defects were reported in 192 newborns exposed to metoclopramide during the first trimester (8 were expected). Cisapride Cisapride promotes acetylcholine release from the myenteric plexus, thereby increasing LES pressure, improving acid clearance, and promoting gastric emptying. The drug is toxic to the fetuses of rats and rabbits at doses 112 times the recommended human dose, resulting in lower birth weights of rat pups and decreased survival [50]. Until recently, human experience with cisapride during pregnancy was limited to case reports received by the manufacturer. Most of these reports documented the birth of healthy infants or therapeutic abortions, but there were a few reports of spontaneous abortions [51]. In a prospective, multicenter study, the outcomes of 129 Canadian women who took cisapride during pregnancy between November 1996 and November 1998 were compared with matched control groups [51]. Outcomes included major and minor malformations, birth weight including low birth weight babies, live births including premature births, spontaneous or induced abortions, fetal distress, and gestational age at birth. The mean daily cisapride dose was 25 mg (range, 5–120 mg,) and the mean length of exposure was 4.6 weeks (range, 0.14–41 weeks). Cisapride indications included gastroesophageal reflux (22.5%), motility problems (16.3%), gastrointestinal pain (56.6%), and duodenal ulcer (5%). Most of the women were also taking multiple other medications, including H2RAs, PPIs, and antacids. Most women took cisapride during the first trimester (87.6%); 3.1% of women took it throughout pregnancy. Investigators found no differences in rates of major or minor congenital malformations in the cisapride group compared with the controls. In 1998, a noninterventional observational cohort study described the outcomes of 12 pregnancies in women who took cisapride during the first trimester in England [52]. Data were obtained by questionnaires mailed to the prescribing physicians 1 month after the expected date of delivery. The

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outcomes included 2 elective abortions, 1 lost to follow up, and 10 normalterm babies. In two other cases, cisapride was taken during the second or third trimesters, and healthy babies were born. In July 2000, Janssen Pharmaceuticals removed cisapride from the market. Cisapride is now only available in a limited-access program. Cisapride is metabolized by the cytochrome P-450 3A4 enzyme. High cisapride blood levels from decreased metabolism can cause serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation. From July 1993 through May 1999, more than 341 cases of cisapride-associated arrhythmias were reported to the FDA, including 80 fatalities. In approximately 85% of cases, the toxicity occurred when cisapride was used in conjunction with drugs which interfere with the cytochrome P-450 system, including macrolide antibiotics (eg, erythromycin), certain antifungals (eg, fluconazole and ketoconazole), and protease inhibitors [53]. Proton-pump inhibitors The PPIs are the most effective medical therapy for symptom control and healing of esophagitis. All PPIs are more effective than placebo or H2RAs, with symptomatic relief in 70% to 80% of patients and healing of esophagitis in at least 80% of patients after 4 to 8 weeks of therapy [54]. The PPIs have not been as extensively used in pregnancy as the H2RAs, and the data about fetal safety are more limited. Omeprazole is categorized as a class C drug by the FDA because of fetal toxicity. The other PPIs are categorized as class B drugs but should be used during pregnancy only in individuals with well-defined complicated GERD who are not responding to H2RAs. Omeprazole Omeprazole, the first of the PPIs, is classified as a class C drug in pregnancy because at doses similar to those used in humans, omeprazole produced dose-related embryonic and fetal mortality in pregnant rats and rabbits [55]. No teratogenicity was observed. The FDA has received reports of at least 12 birth defects in pregnant women exposed to omeprazole, including 5 cases of anencephaly and 1 of hydranencephaly that developed after use of omeprazole starting in the thirteenth week of pregnancy [29]. Other reports, however, have noted omeprazole was safe during pregnancy. A woman with Zollinger-Ellison syndrome was treated during two pregnancies with omeprazole. In the first pregnancy, she received 120 mg/day of omeprazole beginning at 11 weeks of gestation and delivered a healthy baby. During the second pregnancy, she was treated throughout the pregnancy with 180 mg/day of omeprazole and 450 mg/day of cimetidine and delivered a healthy male infant [56]. In a study of nine women who took 20 to 60 mg/day of omeprazole during gestation, including four who took omeprazole during the first trimester, no

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complications or congenital malformations were observed in the infants with follow up ranging from 2 to 12 years [57]. Several prospective database studies have assessed the safety of PPIs, especially omeprazole, in pregnancy. In the Swedish Medical Birth Registry [36], omeprazole was the only acid-suppressing maternal drug in 262 infants. Eight birth defects (3.1%) were observed in the omeprazole group compared with the crude malformation rate of 3.9% in the registry. Five of the birth defects were cardiac (ie, ventricular septum defect, patent ductus arteriosus), whereas only one such cardiac defect occurred in those exposed to H2RAs. In another prospective cohort study, the pregnancy outcome of 113 women exposed to omeprazole during pregnancy was compared with 113 diseasematched controls exposed to H2RAs and 113 untreated controls during pregnancy [58]. No significant differences between the three groups were observed in terms of live births, spontaneous or elective abortions, preterm delivery, cesarean section, or birth weight. The incidence of major congenital abnormalities in the women exposed to omeprazole in the first trimester was 4 of 78 (5.1%), as compared with 3 of 98 (3.1%), and 2 of 66 (3.0%) in the two other groups. A high rate of cardiac abnormalities was not confirmed in this study. Other observation database studies suggest that omeprazole is safe during pregnancy. In a 1998 noninterventional observational cohort study, five pregnant women took omeprazole during the first trimester [52]. Four women had healthy full-term infants, and one had an elective abortion. The previously described combined databases from England and Italy reported that 134 pregnant patients taking omeprazole had 139 live births (11 premature), including 5 (3.7%) who had congenital malformations, 2 of which were cardiac septal defects [37]. The relative risk of malformations adjusted for maternal age and neonatal prematurity associated with omeprazole was 0.9 (95% CI, 0.4–2.4), as compared with 1.3 (95% CI, 0.7–2.6) for cimetidine and 1.5 (95% CI, 0.9–2.6) for ranitidine. Omeprazole seems to be relatively safe in human pregnancies. The increased fetal toxicity in animal studies and the suggestion of a high risk of cardiac malformations in some human studies support the class C categorization by the FDA, however. Lansoprazole Reproductive studies in pregnant rats and rabbits, at oral doses of lansoprazole up to 40 and 16 times, respectively, of the recommended human dose, have found no evidence of impaired fertility or fetal toxicity [59]. Human data on the safety of lansoprazole in pregnancy are limited. In one nonobservational cohort study [52], six pregnant patients taking lansoprazole during the first trimester delivered seven healthy newborns, including one premature birth and one set of twins. In the Swedish Medical Birth Registry lansoprazole was the only acid-suppressing drug exposure in 13 infants. The two birth defects observed in this group were an atrial

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septum defect and an undescended testicle [36]. In a Danish study published in 1999, 38 patients had taken PPIs during the interval between 30 days before conception and the end of the first trimester. Thirty-five of these women had taken omeprazole, and 3 had taken lansoperazole. The prevalence of major birth defects was 7.9% in the PPI patients as compared with 5.2% in pregnant controls not receiving any medications [60]. The relative risk for the outcome of congenital malformation was 1.6 (95% CI, 0.1–5.2), of low birth weight was 1.8 (95% CI, 0.2–13.1), and of preterm delivery was 2.3 (95% CI, 0.9–6.0). In summary, the lack of teratogenicity in animal studies is reassuring, but the data on safety in human pregnancies are limited. Avoidance of lansoprazole during pregnancy, especially during the first trimester, is the safest course. If lansoprazole is required or if inadvertent exposure occurs early in gestation, the fetal risk seems to be low. Newer proton-pump inhibitors: rabeprazole, pantoprazole, and esomeprazole Based on product information from the individual manufacturers, the newer PPIs have been shown safe in various animal studies. Intraveneous doses up to 13 and eight times the recommended human dose of rabeprazole in pregnant rats and rabbits, respectively, were not associated with impaired fertility or fetal harm [61]. Pantoprazole and esomeprazole were also safe in these pregnant animal models. No reports describing the use of these newer PPIs during human pregnancies are available [29]. Therefore, avoidance of these PPIs in the pregnant patient with complicated GERD is suggested. Summary of gastroesophageal reflux disease treatment algorithm in pregnant patients The recommended antireflux therapy during pregnancy follows a step-up algorithm (Fig. 5). In mild cases, reassurance that heartburn frequently accompanies pregnancy and lifestyle modifications are recommended. In more symptomatic cases, drug treatment should begin with antacids after meals and at bedtime, or sucralfate, 1 g, three times per day. In refractory cases, the patient should be informed about the risk and benefits of proposed systemic medications so that informed decisions can be made. It is best to avoid systemic drugs, if possible, during the first trimester of pregnancy. Histamine2 receptor antagonists should be used before PPIs in a once-a-day regimen, especially after the evening meal when symptoms may be worse. The dose can be increased to twice a day if necessary. The author prefers ranitidine, 150 mg, because of its documented efficacy in pregnancy and its favorable safety profile, even during the first trimester. Proton-pump inhibitors are reserved for the intractable patient or the pregnant woman with complicated reflux disease. Before initiating PPI therapy, the author suggests performing EGD. Lansoprazole, 30 mg before breakfast, may be the preferred PPI because of its safety profile in animals and case reports of safety in human

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Fig. 5. Algorithm for the treatment of gastroesophageal reflux disease in the pregnant patient. Abbreviations: H2Ras, histamine2 receptor antagonists.

pregnancies. Antireflux surgery should be avoided during pregnancy because the disease is usually self-limited and resolves with delivery. Aspiration prevention during delivery Pregnant women are at a higher risk for aspirating gastric contents, especially if they receive anesthesia during delivery. Mendelson’s syndrome, or aspiration during labor, is the most common cause of obstetric morbidity

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and mortality from anesthesia [62]. Pregnant women at term must be protected during general anesthesia against the risks of regurgitation and aspiration pneumonitis. Vanner and Goodman [63] reported that pregnant women at term, even if asymptomatic, have more gastroesophageal reflux during provocative tests than nonpregnant individuals. The predisposing factors are the same as those promoting gastroesophageal reflux during pregnancy but are compounded by the recumbent position and administration of anesthesia, which decreases LES pressure and slows gastric emptying [64]. The deleterious effects of aspiration during pregnancy depend upon gastric acidity. For example, Lewis et al [65], in a study of 18 patients with aspiration pneumonitis, reported that all patients with a gastric pH less than 1.75 died, whereas only 1 patient with a gastric pH greater than 2.4 died. Therefore, the key to preventing mortality is increasing the pH level of the gastric contents to greater than 2.5 during labor and delivery. Prophylactic ingestion of antacids before anesthesia is commonly recommended, but the choice of antacids is important. Insoluble antacids, such as aluminum and magnesium hydroxides, carbonates, and trisilicates can cause significant pulmonary damage if aspirated because of their particulate composition [66]. Soluble antacids, such as sodium citrate and sodium bicarbonate, produce a less severe and more transient pulmonary lesion and are the antacids of choice in this setting [67]. Histamine2 receptor antagonists elevate gastric pH levels comparable with antacids and have the advantage of also reducing intragastric volume as shown by Hodgkinson et al [68] in a study comparing cimetidine versus antacid administration for elective cesarean section under general anesthesia. The investigators found that either regimen raised the mean gastric pH level at induction of labor to greater than 5.5. The mean volume of gastric contents in the cimetidine-treated group was one third the volume measured in the antacid-treated group, however (P<0.01). Multiple case reports have documented the safety of H2RAs administered before vaginal delivery or cesarean section to prevent gastric acid aspiration [29]. No effect was observed on the frequency and strength of uterine contractions, fetal heart rate pattern, or infant Apgar scores [69]. Newborns who received H2RAs at the time of cesarean section have had no problems. In particular, neonatal gastric acidity at 24 hours was not affected. Several investigators have studied the effects of omeprazole for prophylaxis against aspiration pneumonitis in emergency cesarean section. Moore et al [70] reported that the average intragastric pH immediately following endotracheal intubation and before extubation was 5.0 in women receiving omeprazole, 80 mg, orally on the evening before surgery. In a similar study, the addition of metoclopramide to omeprazole produced a trend towards smaller intragastric volume that did not reach statistical significance [71]. Yau et al [72] compared ranitidine, 150 mg every 6 hours, with sodium citrate at induction of anesthesia, omeprazole, 40 mg every 12 hours, with sodium citrate, or omeprazole, 40 mg every 12 hours alone. Ten

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patients (17%) in the omeprazole-only group, 3 (6%) in the omeprazole and citrate group, and 1 (2%) in the ranitidine group had an intragastric pH less than 2.5 and volume greater than 25 mL. Ranitidine and sodium citrate were the most cost-effective regimens. The safety of medical treatments for gastroesophageal reflux disease during lactation Although gestational GERD symptoms typically resolve shortly after delivery, women may still experience reflux symptoms postpartum that require ongoing medical therapy. Many antireflux medications are excreted into breast milk and could harm the infant. Therapeutic options must be explained and discussed with women who require treatment but who want to breastfeed. Drug safety during lactation has been assessed in animal studies and human case reports (Table 3). Aluminum and magnesium hydroxide antacids do not concentrate in breast milk and are thus considered safe during lactation. Gaviscon has not been studied during lactation but is considered to be safe because of limited maternal absorption; the same is true for sucralfate. All H2RAs are excreted in human breast milk. Cimetidine and ranitidine reach concentrations in breast milk four to seven times the doses present in maternal serum [23,73]. On the other hand, 6 hours after ingestion, famotidine only reaches a mean milk:plasma concentration of 1.78 [74]. Small amounts (0.1%) of nizatidine are also excreted into human breast milk [75]. Pups reared by lactating rats treated with nizatidine have experienced growth retardation [76]. Animal data are unavailable for the other H2RAs. The effects of H2RAs in breast milk on the nursing infant are Table 3 Safety of GERD medications during lactation Drugs

Safety

Comments

Antacids Sucralfate H2RAs Cimetidine

Yes Yes

Not concentrated in breast milk Minimal, if any, excretion in breast milk

Yes

Ranitidine

Yes

Famotidine Nizatidine

Yes No

Classified as compatible with breastfeeding by the American Academy of Pediatrics Excreted in breast milk in concentrations similar to cimetidine Lowest concentrations in breast milk of all H2RAs Growth depression in pups of lactating rats receiving nizatidine Little known about excretion in breast milk. Growth depression in pups of lactating rats receiving omeprazole and rebeprazole

Proton-pump inhibitors

No

Abbreviations: GERD, gastroesophageal reflux disease; H2RAs, histamine2 receptor antagonists.

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not known. Theoretically, these drugs could adversely affect the infant’s gastric acidity, inhibit drug metabolism, and stimulate the central nervous system, but these effects have not been reported. In 1994, the American Academy of Pediatrics classified cimetidine as compatible with breastfeeding [77]. The author’s review also suggests that ranitidine and famotidine are safe during breastfeeding. Famotidine, in fact, may be the preferred H2RA because of a lower tendency to concentrate in breast milk. Nizatidine should be avoided in the breastfeeding mother because of the single animal study [76]. Little is known about PPI excretion in breast milk or infant safety in lactating women. Proton-pump inhibitors probably are excreted in human milk because they have a relatively low molecular weight, as confirmed in the only report of PPI use during human lactation [78]. A woman was treated with 20 mg per day of omeprazole during pregnancy and during breastfeeding for refractory GERD. During the day, she fed her infant son just before taking omeprazole at 8:00 AM, refrained from nursing for 4 hours, and then expressed and discarded her breast milk at 12:00 noon. At 3 weeks’ postpartum, blood and milk samples were obtained at 8:00 AM and then every 30 minutes for 4 hours. Breast milk levels of omeprazole began to rise at 9:30 AM and peaked at 11:00 AM at 58 mM but were considerably lower than the simultaneous maternal level of 950 mM. The infant was doing well at 1 year of age. In rats, however, omeprazole administered at doses 35 to 345 times the recommended human dose and rabeprazole administered at a dose of 195 times the recommended human dose during late pregnancy and lactation resulted in decreased body weight gain of the pups [55,61]. Because of these limited data, PPIs are not recommended for use by lactating women. Women who must take therapy to control severe reflux symptoms can either take PPIs and discontinue nursing or use a GERD medication from another drug class.

Summary Approximately two thirds of pregnant patients develop heartburn. The origin is multifactorial, but the predominant factor is a decrease in LES pressure caused by female sex hormones, especially progesterone. Mechanical factors play a small role. Serious reflux complications during pregnancy are rare; therefore EGD and other diagnostic tests are infrequently needed. Symptomatic GERD during pregnancy should be managed with a step-up algorithm beginning with lifestyle modifications and dietary changes. Antacids or sucralfate are considered the first-line medical therapy. If symptoms persist, H2RAs should be used. Ranitidine is probably preferred because of its documented efficacy and safety profile in pregnancy, even in the first trimester. Proton-pump inhibitors are reserved for the woman with intractable symptoms or complicated reflux disease. Lansoprazole may be

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the preferred PPI because of its safety profile in animals and case reports of safety in human pregnancies.

Acknowledgments The author thanks Peg Krivac for excellent secretarial assistance in the preparation of this manuscript and the Borra Family Endowment for Esophageal and Swallowing Disorders for supporting the research and education program.

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