Drugs And Pregnancy Part 25

2.1.

6.Riboflavin (mg) 1.1.

1.5.

1.6.

Thiamin (mg) 1.3.

1.6.

1.8.

Minerals Calcium (mg) 1200.

1200.

1200.

Iodine (g) 150.

175.

200.

Iron (mg) 15.30.15.Magnesium (mg) 280.

320.

355.

Phosphorus (mg) 1200.

1200.

1200.

Zinc (mg) 12.15.19.aFor nonpregnant females age 1518 years.

b1 g retinol = 1 retinol equivalent (RE).

cTE, tocopherol equivalent.

From the National Academy of Science, 1989; current as of January 2006.

at high risk of inadequate protein-calorie nutrition. Special action from the clinician to ensure an adequate intake of the essential amino acids and folate must be taken. A professional nutritionist should be involved to help manage meal plans during pregnancy for the strict vegetarian. Nonlacto-ovo vegetarians may also suffer from various other nutrient deficiencies, specifically of vitamins of the A and B group.

VITAMINS.

'Super-vitamin' preparations or megadose regimens, such as Centrum, should not be used during pregnancy for reasons discussed below.

Vitamin A Vitamin A is an essential nutrient, and the recommended supplement of vitamin A (approximately 8000 IU per day; Table 12.1) is usually consumed. The risk of birth defects and adverse fetal effects is probably nil with maternal intake of 10 000 IU or less 218 218 Nutritional and dietary supplementation during pregnancy of vitamin A daily. However, megadoses of vitamin A, taken by some individuals for undoc.u.mented health advantages, are often encountered in practice. No data to support large-dose vitamin A are published in the scientific literature. Investigators a.n.a.lyzed the teratogenicity of high vitamin A intake of pregnant women and found that one in about 57 children had a malformation in cranial neural crest formation a.s.sociated with high dose vitamin A (> 10 000 IU supplements per day) (Rothman of vitamin A daily. However, megadoses of vitamin A, taken by some individuals for undoc.u.mented health advantages, are often encountered in practice. No data to support large-dose vitamin A are published in the scientific literature. Investigators a.n.a.lyzed the teratogenicity of high vitamin A intake of pregnant women and found that one in about 57 children had a malformation in cranial neural crest formation a.s.sociated with high dose vitamin A (> 10 000 IU supplements per day) (Rothman et al. et al. , 1995). The prevalence of malformations among infants born to mothers who ingested 5000 IU or less of food and supplements of vitamin A per day was significantly lower than the high-dose group (Rothman , 1995). The prevalence of malformations among infants born to mothers who ingested 5000 IU or less of food and supplements of vitamin A per day was significantly lower than the high-dose group (Rothman et al et al., 1995). The vitamin A dose a.s.sociated with an increased risk for congenital anomalies is unknown; however, more than 10 000 IU daily may significantly increase that risk.

Important note: Current RDA of 10 000 IU of vitamin A includes dietary intakes, not just supplementation.

Water-soluble vitamin A supplements are beta-carotene derived from vegetables.

Other vitamin A supplements (retinoic acid, discussed above) are fat soluble, and usually fish liver derived. Beta-carotene vitamin A probably has a higher clearance rate than retinoic acid because it is water soluble. Beta-carotene presumably poses much less, if any, teratogenic risk compared to similar amounts of retinoid acid-derived vitamin A (or Retinol). Anecdotal data (case reports) support the hypothesized a.s.sociation of birth defects with high-dose retinoic acid-derived vitamin A. Case reports describe urinary tract and craniofacial complex congenital anomalies among infants whose mothers who took > 40 000 IU or more of vitamin A during pregnancy (Bernhardt and Dorsey, 1974; Mounoud et al et al., 1975; Pilotti and Scorta, 1965). Findings among infants whose mothers used megadoses of vitamin A a.n.a.logs (isotretinoin, etretinate) support the existence of a retinoic acid embryopathy (see Chapter 14).

Offspring of rats, mice, hamsters, pigs, and dogs whose mothers were given vitamin A (doses up to 5000 times RDA) during embryogenesis had increased frequencies of congenital anomalies that were dose related (Cohlan, 1951; Kalter and Warkany, 1961; Kochhar, 1964; Marin-Padrilla and Ferm, 1965; Palludan, 1966; Wiersig and Swenson, 1967; Willhite, 1984). As with human case reports, anomalies in animal studies were also heterogeneous (brain, cardiac, eye, and craniofacial anomalies) and not consistent with a syndrome.

Despite the purely anecdotal nature of direct information on large doses of vitamin A during early pregnancy, an increased risk of congenital anomalies seems highly likely.

On balance, the negative information regarding the a.s.sociation of birth defects and high-dose vitamin A is the apparent lack of a pattern of congenital anomalies observed (highly heterogeneous collection of defects). The high frequency of congenital anomalies with isotretinoin and etretinate vitamin A congeners exposure during embryogenesis offers evidence that vitamin A megadoses during pregnancy increase the risk of congenital anomalies (see Chapter 14).

Vitamin D Vitamin D is produced by skin exposed to ultraviolet light and is integral to normal calcium metabolism. Notably, vitamin D deficiency is a.s.sociated with rickets. Skeletal anomalies comparable to rickets in humans were found in rats born to mothers who were vitamin D deficient during gestation (Warkany, 1943). No congenital anomalies Vitamins Vitamins 219.

were observed in a clinical case series of 15 children born to hypoparathyroid women who took more than 200 times the RDA of vitamin D throughout pregnancy (Goodenday and Gordon, 1971).

Defects with high-dose vitamin D parallel those seen in Williams syndrome supravalvular aortic stenosis, unusual facies, and infantile hypercalcemia in the human (Chan et al et al., 1979; Friedman and Mills, 1969; Friedman and Roberts, 1966). Williams syndrome was speculated to be caused by the use of megadoses of vitamin D during pregnancy (Friedman, 1968), but the available data do not support this (Forbes, 1979; Warkany, 1943). Interestingly, rats and rabbits born to mothers given several thousands of times the human RDA of vitamin D during gestation had cardiovascular and craniofacial anomalies (Friedman and Mills, 1969).

Vitamin B group NIACIN.

Vitamin B , niacin, is naturally present in many foods. Prescriptions for vitamin B are usu-3 3.ally for doses 200400 times the RDA to treat hyperlipidemia. No studies have been published of congenital anomalies among infants born to mothers who took niacin during the first trimester. No increased frequency of congenital anomalies was found in rats and rabbits born to mothers given large doses of niacin during organogenesis (Takaori et al et al., 1973).

PANTOTHENATE.

Pantothenate is an essential cofactor in metabolism of carbohydrates, proteins, and fats.

It contributes to the composition of coenzyme A. Pantothenate is nearly ubiquitous in a well-balanced diet.

No reports have been published of infants born to women who took more than the RDA of pantothenate during pregnancy, or of the effects of megadoses of pantothenate on animals are not published. However, deficiency of pantothenate during pregnancy in rats, mice, and swine was a.s.sociated with an excess of intrauterine deaths and brain, eye, limb, and heart defects among offspring exposed during gestation (Kalter and Warkany, 1959; Kimura and Ariyama, 1961; Lefebvres, 1954; Nelson et al et al., 1957; Ullrey, et al et al., 1955).

PYRIDOXINE.

Pyridoxine (vitamin B ), another essential nutrient, is an enzyme cofactor. Dietary pyri-6 doxine requirements are increased among pregnant women (Table 12.1).

No investigations have been published on the frequency of congenital anomalies among infants born to women who took megadoses of pyridoxine during pregnancy. In one animal study, congenital anomalies were not increased in frequency among rats born to mothers given many times the RDA for pyridoxine during pregnancy (Khera, 1975).

Pyridoxine deficiency during pregnancy was a.s.sociated with digital defects and cleft palate in mice and rats (Davis et al et al., 1970; Miller, 1972).

THIAMINE.

Vitamin B (thiamine) is an essential dietary component because it is a coenzyme. No 1 studies of high doses of thiamine during human pregnancy have been published.

Congenital anomalies were not increased in frequency among offspring of rats given up to 140 times the RDA of thiamine during pregnancy (Morrison and Sarett, 1959; 220 220 Nutritional and dietary supplementation during pregnancy Schumacher Schumacher et al et al., 1965) or about 50 times the rat daily requirement. Thiamine deficiency was a.s.sociated with an increased frequency of fetal death and decreased fetal weight gain among pregnant rats (Nelson and Evans, 1955; Roecklein et al et al., 1985).

CYANOCOBALAMIN.

Vitamin B , also known as cyanocobalamin, is also an essential nutrient. Megadose 12 cyanocobalamin (about 260 times RDA) is used to treat pernicious anemia. The frequency of congenital anomalies among infants whose mothers took megadoses of vitamin B dur-12 ing pregnancy has not been published. Malformations were not increased in frequency among the offspring of mice treated during pregnancy with 525010 500 times the RDA of cyanocobalamin (Mitala et al et al., 1978). Cyanocobalamin deficiency among offspring of rats treated with megadoses of cyanocobalamin had increased frequencies of hydrocephalus, eye defects, and skeletal anomalies (Grainger et al et al., 1954; Woodard and Newberne, 1966).

VITAMIN C.

Vitamin C (as...o...b..c acid) is an essential nutrient. Deficiency of vitamin C causes scurvy.

No increase in the use of vitamin C was found in a casecontrol study of the use of vitamin C during the first trimester by mothers of 175 infants with major congenital anomalies and 283 with minor anomalies compared to the control group (Nelson and Forfar, 1971). Embryofetal effects of megadoses of vitamin C during pregnancy have not been published. Two infants born to women who took more than six times the RDA of vitamin C during pregnancy had scurvy (Cochrane, 1965).

The frequency of congenital anomalies was not increased among mice and rats born to mothers treated with hundreds to several thousand times the RDA of vitamin C during embryogenesis (Frohberg et al et al., 1973). An increased frequency of fetal death was found in offspring of mice fed 4800 times the RDA of as...o...b..c acid during embryogenesis (Pillans et al et al., 1990). Increased dietary requirements for vitamin C was found in guinea pigs born to mothers who were given several hundred times the RDA throughout pregnancy; increased clearance apparently caused the need for more vitamin C (Cochrane, 1965; Norkus and Rosso, 1975, 1981).

VITAMIN E.

Vitamin E is another essential nutrient. If caloric intake is adequate, vitamin E deficiency is extremely rare. No studies of vitamin E use during human pregnancy have been published. Among rats and mice born to mothers given vitamin E in doses up to thousands of times the RDA, the frequency of congenital anomalies was not increased (Hook et al et al., 1974; Hurley et al et al., 1983; Krasavage and Terhaar, 1977; Sato et al et al., 1973). In contrast, the frequency of cleft palate was increased among mice born to mothers given several-hundred times the human RDA of vitamin E during embryogenesis (Momose et al et al., 1972).

OTHER ESSENTIAL NUTRIENTS.

Folic acid Folic acid is an essential nutrient and acts as a coenzyme. It has been shown that folic acid is extremely important in normal embryonic development, specifically the neural tube complex. Pregnancy elevates the RDA for folic acid.

Other essential nutrients 221.

'On March 5, 1996, the US Food and Drug Administration (FDA) required that manufacturers fortify enriched cereal-grain products with 140 g of folic acid per 100 g of cereal-grain product by January 1, 1998' (Grosse et al et al., 2005). Subsequent a.n.a.lysis has shown a reduction in neural tube defects (NTDs) on a national scale of 2030 percent, and a resulting a.s.sociated monetary saving of $312425 million annually. Direct cost avoidance was $88145 million per year for an annual investment of $23 million. The return on investment (ROI) for the a.s.sociated economic impact and direct cost avoidance were minimally 13.6 and 3.8, respectively. What follows is the scientific background to an apparently very effective public health intervention to reduce birth defects (neural tube defects) through improved population level nutrition intervention, providing needed folic acid supplementation.

Folic acid supplementation and deficiency during pregnancy with infant outcome was investigated in a number of published studies, but results were inconsistent. No congenital anomalies were found among 44 treatment infants whose mothers took 15 times the RDA throughout pregnancy to prevent the recurrence of a NTD (Laurence et al et al., 1981).

However, there were two NTDs in the treatment noncompliance group and four in the placebo control group. Other studies have a.n.a.lyzed folic acid supplements at doses similar to the RDA, and the occurrence of neural tube defects was not more frequent than expected.

Folic acid supplements given in prospective studies to prevent NTDs have shown a decreased risk of neural tube defects (Bower and Stanley, 1989; Smith.e.l.ls et al et al., 1981, 1983, 1989). Daily intake of folic acid was found to reduce the occurrence and recurrence of NTDs in 5502 women in a randomized controlled study (Czeizel and Dudas, 1992; Czeizel et al et al., 1994). Folic acid antagonists, such as aminopterin, are well-known human and animal teratogens. Numerous teratology studies using rats and mice have consistently shown that folic acid deficiency is a.s.sociated with an increased frequency of various congenital anomalies (Shepard, 1995). Daily periconceptional intake of 0.4 mg of folic acid by women before and during early pregnancy in a casecontrol study decreased the risk of NTD occurrence in their infants by 50 percent (Werler et al et al., 1993).

Conversely, retrospective studies have not found a reduced risk of neural tube defects with folic acid supplementation during pregnancy (Mills et al et al., 1989; Milunsky et al et al., 1989). Folic acid deficiency was a.s.sociated with adverse pregnancy outcome in one study (Dansky et al et al., 1987), but not in two others (Pritchard et al et al., 1970, 1971).

In 1992, the US Centres for Disease Control (CDC) issued the recommendation that women of childbearing should consume 0.4 mg of folic acid per day. However, it was cautioned that women should consume less than 1.0 mg per day of the supplement. The untoward effects of hypervitaminosis B are not well studied, especially during preg-12 nancy. For this reason, folate intake among women who are of childbearing age should regulate their intake to 0.4 mg or less than 1 mg per day (MMWR, 1992). In 1996, the US FDA issued the requirement that manufacturers fortify enriched cereal-grain products with 140 g of folic acid per 100 g (Grosse et al et al., 2005).

Iron Iron is an essential dietary metal and its requirements during pregnancy increase as gestation age advances. Scholl et al et al. (1992) found that iron-deficiency anemia was related to low 222 222 Nutritional and dietary supplementation during pregnancy energy levels and a lower mean corpuscular volume among 800 pregnant women at their first prenatal care visit. Preterm delivery was doubled and the incidence of delivering a low-birth weight baby was tripled among the iron deficiency anemic women. Need for iron supplementation usually occurs 2028 weeks gestation. Iron supplementation (60100 mg daily) is needed because the normal diet cannot supply the required amounts. It is also recommended that the iron supplement be given alone and not as a component of prenatal vitamins because of lower absorption from multivitamin preparations (Cunningham energy levels and a lower mean corpuscular volume among 800 pregnant women at their first prenatal care visit. Preterm delivery was doubled and the incidence of delivering a low-birth weight baby was tripled among the iron deficiency anemic women. Need for iron supplementation usually occurs 2028 weeks gestation. Iron supplementation (60100 mg daily) is needed because the normal diet cannot supply the required amounts. It is also recommended that the iron supplement be given alone and not as a component of prenatal vitamins because of lower absorption from multivitamin preparations (Cunningham et al et al., 1989). Anecdotally, iron overdose is a common suicide attempt method during pregnancy.

A prudent practice for high-risk patients is to provide only a 1-week supply at a time, which limits access to toxic doses of iron. Toxic doses are between 3 and 6 g of iron supplements.

Iron supplement megadoses are among the more commonly used medications in suicide gestures, which is discussed in Chapter 14, Drug overdoses during pregnancy.

Congenital anomalies were not increased in frequency among 66 infants born to women who received parental iron supplementation during the first trimester. No complications or malformations were found among more than 1800 infants whose mothers received iron supplementation at any time during pregnancy (Heinonen et al et al., 1977).

Similarly, the frequency of congenital anomalies or complications was no different than the general population among 1336 infants born to either women who received iron supplements when they were anemic or women who routinely received the supplement during the second and third trimester of pregnancy (Hemminki and Rimpela, 1991).

Therefore, it may be prudent to limit prescriptions to a 1-week course per refill in gravidas with a history of suicide gestures, although no abnormalities were observed in a group of 19 children whose mothers had ingested overdoses of iron during the last two trimesters of pregnancy (McElhatton et al et al., 1991).

Animal data regarding iron use during pregnancy are inconsistent. Rats born to mothers given up to 100 times the usual therapeutic dose of iron during embryogenesis showed frequency of congenital anomalies no different from controls (Flodh et al et al., 1977; Tadokoro et al et al., 1979). Central nervous system anomalies were increased in frequency above control levels among mice and rabbits whose mothers were given comparably large doses of iron during embryogenesis (Flodh et al et al., 1977; Kuchta, 1982).

Calcium Calcium is an essential nutrient required for normal physiological function and fetal growth. A balanced diet provides the required amount of calcium.

The frequency of congenital anomalies was not increased among more than 1000 infants born to women who received calcium supplements during the first trimester, or among more than 3500 infants whose mothers took supplements after the first trimester (Heinonen et al et al., 1977). A slight, but significant excess of nonspecific central nervous system abnormalities was reported. The heterogeneity of the defects suggests that the a.s.sociation may be a chance occurrence of multiple comparisons.

Among rats, rabbits, and mice whose mothers were given twice the RDA of calcium during embryogenesis, the frequency of congenital anomalies was no greater than controls (McCormack et al et al., 1979). Fetal death and growth r.e.t.a.r.dation occurred more frequently in the offspring of pregnant rats given about 1600 mg/kg.day of calcium chloride (Hayasaka et al et al., 1990).

Gastrointestinal medications during pregnancy 223.

Special considerations NEURAL TUBE DEFECTS.

There is highly compelling evidence that occurrence and recurrence of NTDs can be decreased by folic acid supplementation, as discussed earlier. Risk of NTD recurrence was decreased in several different studies in England when a combination vitamin regimen that contained folic acid and seven other vitamins was given to women who had given birth to a child with a NTD in a previous pregnancy (Smith.e.l.ls et al et al., 1981, 1983, 1989; MRC Vitamin Study Research Group, 1991). The group concluded that, 'Folic acid supplementation starting before pregnancy can now be firmly recommended for all women who have had an affected pregnancy and public health measures should be taken to ensure that the diet of all women who may bear children contains an adequate amount of folic acid,' (MRC Vitamin Study Research Group, 1991). This has led to a cost-effective and significant reduction in the occurrence of NTDs in the USA.

Nutritional summary In conclusion, iron supplements during pregnancy are definitely necessary. Folic acid supplements are also a universal necessity. The gravid vegetarian or one who is following a 'fad' diet is a special concern and a nutritional a.s.sessment should be undertaken to a.s.sure adequate intake. Prenatal vitamins should probably be given, although there is no consensus on whether they are necessary. At RDA doses, such preparations will not cause harm and may be of benefit. Following Hippocrates to above all do 'no harm,'

prenatal vitamins should be given. Megadose regimens are clearly contraindicated.

GASTROINTESTINAL MEDICATIONS DURING PREGNANCY.

Gastrointestinal disorders occur frequently during pregnancy, often in response to the pregnancy-related physiological changes. Nausea, with or without vomiting is the most common gastrointestinal disorder of early pregnancy. In the extreme form (i.e., hyperemesis gravidarum), vomiting may result in significant weight loss and dehydration.

Pyrosis or 'heartburn' is a very common symptom in pregnancy and is related to increased gastroesophageal reflux secondary to decreased muscular tone in the lower esophagus. Gastrointestinal disorders that may be a.s.sociated with pregnancy, but occur with about the same frequency in nongravid women, include peptic ulcer disease, inflammatory bowel disease, and gallbladder disease cholelithiasis and cholecyst.i.tis (Cunningham, 1994). Medications to treat gastrointestinal disorders, including antacids, anticholinergics, antiemetics, antiflatulents, and laxatives, are discussed in this section. Corticosteroids, which may be useful in the therapy of inflammatory bowel disease, are discussed in Chapter 4.

Antacids Antacids are cla.s.sified based on their content: aluminum, calcium, magnesium, magal-drate, sodium bicarbonate, and combinations of any of these. Antacids are the most common over-the-counter and prescribed gastrointestinal medications used by pregnant 224 224 Nutritional and dietary supplementation during pregnancy women. Combinations of aluminum hydroxide and magnesium hydroxide are used in popular commercial preparations (e.g., Maalox, Mylanta, Riopan, and Gelusil). women. Combinations of aluminum hydroxide and magnesium hydroxide are used in popular commercial preparations (e.g., Maalox, Mylanta, Riopan, and Gelusil).

Calcium carbonate is also a very popular antacid (e.g., Tums, t.i.tralac, Rolaids, and Chooz).

No human or animal teratology studies have been published regarding antacids.

Antacids are a.s.sociated with little, if any, significant risk for congenital anomalies or fetal risk when used in moderation. Chronic use of high-dose antacids has been a.s.sociated with adverse effects such as hypercalcemia, hypermagnesemia, or hypocalcemia.

Histamine receptor antagonists Histamine receptor antagonists are systemic agents used to reduce gastric acidity.

Currently available preparations include cimetidine, ranitidine, famotidine, and nizatidine (Table 12.2). A primary use of these agents in pregnant women before general anesthesia is as a prophylaxis against aspiration. Histamine receptor antagonists are also used to treat peptic ulcer disease, which is uncommon in pregnant women. H -receptor 2 antagonists (i.e., inhibitors of gastric acid production) are also useful in pregnant women with severe forms of reflux esophagitis unresponsive to the usual antacids (Cunningham, 1994). These agents are known to cross the placenta (Howe et al et al., 1981; Schenker et al et al., 1987).

Among 237 infants born to women who took cimetidine during the first trimester of pregnancy, the frequency of congenital anomalies was not increased (Ruigomez et al et al., 1999). In another study the frequency of congenital anomalies was increased among 113 infants exposed to cimetidine during the first trimester (Garbis et al et al., 2005). First-trimester ranitidine exposure was reported in 335 infants and the frequency of congenital anomalies was not increased above controls (Garbis et al et al., 2005). Similarly, congenital anomalies in infants born to 300 women who took ranitidine during embryogenesis were not increased over controls (Ruigomez et al et al., 1999). Among infants born to 58 women who used famotidine in the first trimester, the frequency of congenital anomalies was no higher than that expected in the general population (Kallen, 1998). In one study of 75 infants whose mothers took famotidine during the first trimester, the frequency of congenital anomalies detected at birth was no higher than would be expected in the general population (Garbis et al et al., 2005). However, two elective terminations occurred in the famotidine group because they had NTDs. The relevance of these data is unknown because of the small sample size; the authors felt that timing of famotidine exposure excluded a causal a.s.sociation with the neural tube defects (Garbis et al et al., 2005). Data have been published on a small number of first-trimester exposures to nizatidine Table 12.2 Table 12.2 Histamine receptor antagonists Histamine receptor antagonists Agent Brand name Cimetidine Tagamet Famotidine Pepcid Nizatidine Axid Ranitidine Zantac Rozatidine Gastrointestinal medications during pregnancy 225.

( n n = 15) and roxatidine ( = 15) and roxatidine ( n n = 15) and there were no congenital anomalies (Garbis = 15) and there were no congenital anomalies (Garbis et al et al., 2005). Nizatidine is closely related to cimetidine.

Histamine receptor antagonists were not a.s.sociated with an increased frequency of malformations or adverse fetal effects in several animal teratology studies involving rodents (Brimblecombe et al et al., 1985; Higas.h.i.+da et al et al., 1983; Hirakawa et al et al., 1980; Tamura et al et al., 1983). Several reports regarding the use of these agents as premedications prior to Caesarean section found an increased frequency of complications (Gillett et al et al., 1984; Hodgkinson et al et al., 1983; Mathews et al et al., 1986; Thorburn and Moir, 1987), but these exposures are not relevant to the risk for congenital anomalies.

Therefore, data suggest that histamine receptor antagonists may be used safely in the first trimester of pregnancy in humans and with apparent safety for both mother and fetus in the latter half of pregnancy.

Proton pump inhibitors OMEPRAZOLE, LANSOPRAZOLE, AND ESOMEPRAZOLE.

Omeprazole (Prilosec) is a proton pump inhibitor (PPI) and blocks the production of gastric acid. Among 295 infants whose mothers were exposed to omeprazole during embryogenesis, the frequency of congenital anomalies was no greater than among controls (Kallen, 1998). Ninety-one infants were born to women who took omeprazole during the first trimester and the frequency of congenital anomalies was no greater than expected (Lalkin et al et al., 1998). Among 233 infants exposed during the first trimester to omeprazole, the frequency of congenital anomalies was not significantly greater than unexposed controls (Diav-Citrin et al et al., 2005). A case report of an omeprazole overdose during pregnancy that resulted in a normal infant has been published (Ferner and Allison, 1993). Also, there is a small case series ( n n = 3) in which mothers were treated with omeprazole chronically, and all three infants were healthy in the neonatal period (Harper = 3) in which mothers were treated with omeprazole chronically, and all three infants were healthy in the neonatal period (Harper et al et al., 1995). No congenital anomalies were found among rat pups born to mothers given many times the usual human dose of omeprazole during embryogenesis, although growth r.e.t.a.r.dation was present (s.h.i.+mazu et al et al., 1988).

Among 55 infants exposed to lansoprazole during the first trimester, the frequency of congenital anomalies was not increased. In the same investigation, the frequency of congenital anomalies among infants exposed to pantoprazole during the first trimester was no greater than controls (Diav-Citrin et al et al., 2005).

No epidemiological studies of esomeprazole during first trimester of pregnancy have been published. Notably, esomeprazole is the sinister racemate of omeprazole. Clinically, the advantage of esomeprazole over omeprazole is that the S S-racemate isomer is cleared from the body more slowly, decreasing dose frequency (Kendall, 2003). It is tempting to deduce that esomeprazole is safe because a closely related drug (omeprazole) is apparently safe based upon 538 first-trimester exposures. However, it is imperative that we bear in mind that an isomer of thalidomide, the most notorious human teratogen ever discovered, was not a.s.sociated with birth defects.

Proton pump inhibitors seem to be safe for use during pregnancy. Omeprazole (Prilosec) is the best studied and should be the drug of choice. Esomeprazole (Nexium) has not been adequately studied to a.s.sess its safety for use during pregnancy.

226.