Nutritional and dietary supplementation during pregnancy Antiemetics Antiemetics Most pregnant women experience at least some degree of nausea during the first trimester; most can be managed without medication. A variety of medications can be used in women requiring therapy for protracted vomiting or vomiting resulting in dehydration.

Phenothiazides Phenothiazides are used for several medical indications (nausea, vomiting, psychotic disorders, mild pain). This drug cla.s.s is also effective as an antidyskinetic and a mild sedative. Prochlorperazine, chlorpromazine, and promethazine are the most commonly used phenothiazine derivatives used to treat nausea and vomiting during pregnancy.

Phenothiazine use during pregnancy may be a.s.sociated with extrapyramidal symptoms in the mother as well as the fetus, but these adverse effects are uncommon (Hill et al et al., 1966; Levy and Wiseniewski, 1974). The phenothiazide cla.s.s does not seem to be a.s.sociated with an increased frequency of congenital anomalies when used during gestation.

Promethazine Promethazine is sold under several proprietary names, but Phenergan is the known brand. It is also used with meperidine during labor and for post-Caesarean section pain.

Among over a hundred infants whose mothers took promethazine in the first trimester, the frequency of malformations was not increased (Heinonen et al et al., 1977). Neither was the frequency of malformations increased in two other studies that included several-hundred women who used the drug during their first trimester (Aselton et al et al., 1985; Farkas and Farkas, 1971). The frequency of malformations was also not increased in the offspring of animals exposed to this agent (King et al et al., 1965).

Chlorpromazine The frequency of birth defects was not increased among infants of more than 400 women who took chlorpromazine during embryogenesis (Farkas and Farkas, 1971; Heinonen et al et al., 1977). The frequency of congenital anomalies was not increased among rodents whose mothers were given large doses of the drug during embryogenesis (Beall, 1972; Jones-Price et al et al., 1983; Robertson et al et al., 1980).

Prochlorperazine Published studies include over 3000 women who took prochlorperazine during pregnancy, involving over 1000 exposed during the first trimester (Heinonen et al et al., 1977; Jick et al et al., 1981; Kullander and Kallen, 1976; Milkovich and van den Berg, 1976). The frequency of congenital anomalies was not increased in the offspring of women who took the drug in the first trimester.

The frequency of cleft palate was increased in the offspring of pregnant animals given large doses of prochlorperazine during embryogenesis (Roux, 1959; Szabo and Brent, 1974). The significance of this finding in humans is unknown.

Gastrointestinal medications during pregnancy 227.

Piperazine derivatives Cyclizine, buclizine, and meclizine are piperazine derivatives used for their antiemetic and antihistamine properties. The frequency of congenital anomalies was not increased in a.s.sociation with the exposure to cyclizine or meclizine during the first trimester in the Collaborative Perinatal Project in more than 1000 infants (Heinonen et al et al., 1977). Among 111 infants whose mothers took cyclizine in the first trimester, no increase in congenital anomalies was found (Milkovich and van den Berg, 1976). More detailed discussion of these agents is given in Chapter 11. No studies have been published on buclizine during pregnancy.

Doxylamine-pyridoxine The combination of doxylaminepyridoxine (Bendectin) has received considerable attention over the past decade as a possible teratogen. Until it was taken off the market, Bendectin was the most commonly prescribed antiemetic for hyperemesis during pregnancy. There have been reports of an a.s.sociation of Bendectin use with diaphragmatic hernias (Bracken and Berg, 1983) and with congenital heart disease and pyloric stenosis (Aselton et al et al., 1985; Esken.a.z.i and Bracken, 1982). Reports refuting such an a.s.sociation (Mitch.e.l.l et al et al., 1981, 1983; Zierler and Rothman, 1985) have also been published. Among more than 1100 infants exposed to doxylamine (Bendectin) during the first trimester of pregnancy, the frequency of congenital anomalies was not increased (Heinonen et al et al., 1977). No statistically significant a.s.sociation was found between doxylamine and congenital heart disease in a large casecontrol study (Zierler and Rothman, 1985). Animal teratology studies are also negative (Gibson et al et al., 1968).

Millions of women used Bendectin during the first trimester of pregnancy with no apparent epidemic of birth defects or adverse fetal effects. Therefore, it seems very unlikely that either doxylamine or pyridoxine is a significant human teratogen. It is generally accepted that neither Bendectin nor its components caused birth defects in human infants.

Unfortunately, it does appear that Bendectin was a significant 'litogen,' i.e., capable of inducing lawsuits (Brent, 1983, 1985; Holmes, 1983).

Other Ondansetron (Zofran) is a 5-hydroxytryptamine (5-HT ) receptor agonist and is a very 3 potent antiemetic. It is most often utilized for severe nausea and vomiting a.s.sociated with cancer chemotherapy. It has also been utilized for severe hyperemesis gravidarum (World, 1993; Guikontes et al et al., 1992), and the authors have also had experience with the successful use of this agent for severe hyperemesis gravidarum. Among 176 infants born to women who used ondansetron during pregnancy, six (3.6 percent) major malformations occurred, and this is no different from the control group (Einarson et al et al., 2004). In unpublished studies, this agent was not teratogenic in animal studies (information provided by the manufacturer). It is an FDA pregnancy risk category B drug.

Prokinetic agents Prokinetic agents stimulate upper gastrointestinal tract motility and are utilized primarily for the treatment of gastrointestinal reflux. Two agents are currently available in this 228 228 Nutritional and dietary supplementation during pregnancy cla.s.s: cisapride (Propulsid) and metoclopramide (Reglan). Among 88 infants born to women who used cisapride during the first trimester, the frequency of congenital anomalies was not increased (Bailey cla.s.s: cisapride (Propulsid) and metoclopramide (Reglan). Among 88 infants born to women who used cisapride during the first trimester, the frequency of congenital anomalies was not increased (Bailey et al et al., 1997). Metoclopramide is also used as an antiemetic, especially for postoperative nausea. Among 175 infants born to women who used metoclopramide during the first trimester, the frequency of congenital anomalies was 4.4 percent, which was no different from the control rate, 4.8 percent (Berkovitch et al et al., 2002). According to the manufacturer, metoclopramide was not teratogenic in rats or rabbits (unpublished data). Interestingly, cisapride is listed as a category C drug and metoclopramide as a category B drug. In view of the data, both prokinetic agents appear safe for use during pregnancy, keeping in mind that metoclopramide has a larger cohort size and more power.

Anticholinergics Anticholinergics are mainly used as antispasmodics and in the therapy of gastrointestinal diseases (ulcer disease, irritable bowel disease). Some of these medications are utilized for other nongastrointestinal indications, such as cardiac arrhythmias or urologic disorders. This cla.s.s of preparations (Table 12.3) is known to cross the placenta.

Table 12.3 Anticholinergics Anticholinergics Agents Brand names Atropine Belladonna Clidinium Quarzan Dicyclomine Bentyl, Byclomine, Dibent, Di-Spaz Glycopyrolate Robinul Hexocyclium Tral Filmtabs Homatropine Homapin Hyoscyamine Cystospaz, Levsinex, Levsin, Anaspaz, Neoquess, Bellafoline Isopropamide Darbid Mepenzolate Cantil Methantheline Banthine Methscopolamine Pamine Oxyphencyclimine Oxyphenonium Propantheline Norpanth, Pro-Banthine Scopolamine Tridihexethyl Pathilon ATROPINE.

Atropine is an anticholinergic that is utilized for a variety of indications, such as cardiac arrhythmias (especially bradycardia), Parkinsonism, asthma, biliary tract diseases, as an antidote for organophosphate insecticide poisoning, and as a preanesthetic agent. The frequency of congenital anomalies was not increased among more than 450 women who received this agent in early pregnancy (Heinonen et al et al., 1977; Jick et al et al., 1981). Skeletal Gastrointestinal medications during pregnancy Gastrointestinal medications during pregnancy 229.

anomalies were reported to be increased in one animal study (Arcuri and Gautieri, 1973). Such anomalies have not been reported to date in humans and the data suggest atropine is a safe drug for use during pregnancy.

SCOPOLAMINE.

Scopolamine is an anticholinergic agent similar to atropine, and like atropine, may be utilized as a preoperative medication. It may also be used as an antiemetic and for motion sickness. The frequency of congenital anomalies was no different from control in the offspring of the almost 400 women who received this medication in early pregnancy (Heinonen et al et al., 1977). The frequency of birth defects was not increased among the offspring of rodents given doses much larger than the human dose during embryogenesis (George et al et al., 1987).

HOMATROPINE AND METHSCOPOLAMINE.

No information has been published regarding the use of the anticholinergics homatropine (an ophthalmic preparation) or methscopolamine (used for cardiac arrhythmias, functional bowel disease, and ulcer disease) during pregnancy for experimental animals or humans.

BELLADONNA.

Belladonna is a naturally occurring anticholinergic and is used to treat several conditions: functional bowel disorders, motion sickness, dysmenorrhea. Among more than 500 infants born to women who took belladonna during the first trimester, the frequency of major congenital anomalies was not increased (Heinonen et al et al., 1977). There was an a.s.sociation with minor malformations, but the meaning of this finding is unknown. No animal teratology studies of this agent have been published.

GLYCOPYROLATE.

Glycopyrolate is used for several indications: ulcer disease, functional bowel syndrome, and as a preanesthetic agent. No publications on human or animal exposure to this agent during pregnancy have been published.

DICYCLOMINE.

Used primarily for the treatment of spastic or irritable colon, dicyclomine was at one time used in combination with doxylamine and pyridoxine in the popular antiemetic preparation, Bendectin. No increase in the frequency of congenital anomalies was found in the offspring of about 100 women who used this agent in early pregnancy (Aselton et al et al., 1985). The frequency of malformations was not increased in the offspring of animals given dicyclomine in doses several times that of the human dose during embryogenesis (Gibson et al et al., 1968).

HYOSCYAMINE.

Hyoscyamine is used to treat spasmodic bowel diseases and asthma. Over 300 women were exposed to hyoscyamine in early pregnancy, and their infants did not have an increased frequency of birth defects (Heinonen et al et al., 1977). No animal teratology studies have been published on hyoscyamine.

230.

Nutritional and dietary supplementation during pregnancy ISOPROPAMIDE ISOPROPAMIDE This agent is used as an adjunct to treat ulcer disease and is also used for the treatment of spastic bowel disorders. Congenital anomalies were not increased in frequency in the offspring of 180 women who took the drug during early pregnancy (Heinonen et al et al., 1977). No published animal teratology studies are available regarding isopropamide.

PROPANTHELINE.

Very little information is available regarding the use of this agent during early pregnancy. Only 33 women who took this drug during early pregnancy are included in the Collaborative Perinatal Project database, and the frequency of congenital anomalies in their infants was not increased (Heinonen et al et al., 1977).

OTHER AGENTS.

No epidemiological studies of congenital anomalies in infants born to women who took clidinium, hexocyclium, mepenzolate, tridihexethyl, oxyphencyclimine, or methantheline during pregnancy have been published. No animal teratology studies of these agents have been published.

Appet.i.te suppressants Appet.i.te suppressants are not indicated during pregnancy. It is not unusual to encounter pregnant women who used these medications during early pregnancy before they knew that they were pregnant, because these agents are commonly used by women of reproductive age. Numerous available commercial preparations and some common appet.i.te suppressants are listed (Box 12.1).

Box 12.1 Appet.i.te suppressants Amphetamine Fenfluramine Phendimetrazine Benzphetamine Mazindol Phenmetrazine Diethylpropion Methamphetamine Phentermine AMPHETAMINES, DEXTROAMPHETAMINES, AND METHAMPHETAMINES.

These controlled substances are used in a variety of medications for the treatment of hyperactivity, short attention span syndrome, narcolepsy, and as an appet.i.te suppressant for morbid obesity. They are not recommended for use during pregnancy or in breastfeeding mothers because of potential adverse effects. These stimulants are discussed in further detail in Chapter 16.

BENZPHETAMINE.

No information has been published on teratogenicity of the use of benzphetamine (Didrex) in pregnant women.

Antiflatulents, laxatives, and antidiarrheals 231.

DIETHYLPROPION.

Use of diethylpropion (M-Orexic, n.o.besine, Tenuate) in early pregnancy was not a.s.sociated with an increased frequency of congenital anomalies among infants born to several-hundred women (Bunde and Leyland, 1965; Heinonen et al et al., 1977). Diethylpropion was not teratogenic in one animal study (Cohen et al et al., 1964).

Although appet.i.te suppressants are generally not recommended for use during pregnancy, this agent is listed as an FDA category B.

PHENDIMETRAZINE.

At least 36 different commercial preparations of this agent are available in the USA, but no epidemiological studies have been published of human infants born following its use during pregnancy. No animal teratology studies of phendimetrazine (Prelu-2) have been published. It should be listed as a category C drug because of lack of information.

PHENTERMINE AND FENFLURAMINE.

Among 98 infants born to women who took phentermine/fenfluramine during the first trimester, the frequency of both minor and major congenital anomalies was comparable to the control group frequency (Jones et al et al., 2002).

MAZINDOL.

No human reproduction studies with mazindol (Mazanor) have been published.

DEXFENFLURAMINE.

Dexfenfluramine is a dextroisomer of fenfluramine, a serotoninergic agent. Information on dexfenfluramine and exposure during pregnancy have not been published.

ANTIFLATULENTS, LAXATIVES, AND ANTIDIARRHEALS.

Gastric motility is decreased during pregnancy (Little, 1999) and constipation is a relatively common complaint in pregnant women. Various iron preparations may also contribute to constipation in the pregnant patient. Laxatives are frequently used during pregnancy. The majority of such agents are absorbed very little, if at all, from the gastrointestinal tract. Overall, they should have no systemic effects or pose any serious threat to the fetus.

Antiflatulents SIMETHICONE.

Simethicone (Phazyme, Myliam, Gas-X, Gas Relief) is the most commonly used antiflatulent. There are no human or animal reproductive studies available. Simethicone is logically not expected to cause systemic effects or have access to the fetalplacental unit, because simethicone is not absorbed from the gastrointestinal tract. It is contained in several antacid preparations.

232.

Nutritional and dietary supplementation during pregnancy CHARCOAL CHARCOAL No information has been published regarding the use of charcoal during pregnancy, although activated charcoal capsules and tablets are used for relief of gas. Notably, it is not absorbed systemically.

From a practical standpoint, it has no clear indications for use during pregnancy, neither does this agent offer any advantage over simethicone. However, it should be used without hesitation when it is needed in the treatment of acute poisoning.

CALCIUM CARBONATE.

This agent in combination with magnesium hydroxide (Mylanta) is utilized as both an antacid and an antiflatulent. This combination can be used safely in pregnancy, avoiding chronic high doses which pose a risk (hypercalcemia, etc).

Laxatives and purgatives Laxatives/purgatives can generally be divided into several cla.s.ses depending on the mode of action: (1) emollients and softeners; (2) bulk-forming agents; (3) stimulants; and (4) saline, hyperusmetic, or lubricant agents (Box 12.2). Fortunately, there are few side effects a.s.sociated with the use of these agents. Allergic reactions are rare. Chronic use of the agents should be avoided because diarrhea and electrolyte imbalances may occur.

Box 12.2 Laxatives and purgatives Emollients and softeners Docusate sodium (Colace plus numerous others) plus combinations Docusate calcium (Surfak, Pro-Cal-Sof) plus combinations Docusate pota.s.sium (Dialose, Diocto-K, Kasof) Bulk-forming agents Psyllium (Metamucil, Konsyl-D, Pro-Lax, Serutan, plus several others) Methylcellulose (Citrucel, Cologel) Malt soup extract (Maltsupex) Polycarbophil (Fibercan, Equalactin, Mitrolan) Stimulants Castor oil Bisacodyl (Dulcolax plus others) plus combinations Casanthrunol (Black-Draught) plus combinations Cascara sagrada plus combinations Phenolphthalen (Ex-Lax plus others) plus combinations Senna (Senokot plus others) plus combinations Saline, hyperosmotic, or lubricant agents Mineral oil (Kondremul plus others) plus combinations Glycerin Lactulose (Chronulac plus others) Magnesium citrate (Citroma; Citro-Nesia) Magnesium hydroxide (Milk of Magnesia) plus combinations Antiflatulents, laxatives, and antidiarrheals Antiflatulents, laxatives, and antidiarrheals 233.

DOCUSATE.

This agent is an emollient-type laxative used either singly as a stool softener or in combination with other laxatives. Congenital anomalies were not increased in frequency among the offspring of over 800 women who utilized this agent in early pregnancy (Aselton et al et al., 1985; Heinonen et al et al., 1977; Jick et al et al., 1981). Docusate is not absorbed systemically.

CASANTHRANOL AND CASCARA SAGRADA.

The anthraquinone cathartics belong to the stimulant cla.s.s of laxatives. They are used as monotherapy or in combination with other laxatives. Congenital anomalies were not increased in frequency among offspring of mothers who utilized either casanthranol (21 patients) or cascara sagrada (53 patients) in early pregnancy (Heinonen et al et al., 1977).

SENNA.

Senna is also an anthraquinone laxative. No human reproduction studies have been published. It is very unlikely that it poses any risk to the fetus because this agent is minimally absorbed from the gastrointestinal tract.

PHENOLPHTHALEIN.

Phenolphthalein (Ex-Lax, Feen-A-Mint, Atophen, Medilax, Modone, Espotabs) is a commonly utilized agent in commercial preparations. In one mouse study, decreased litter size and fertility were observed, but no somatic effects (Anonymous, 1997).

LACTULOSE.

This agent is utilized as a laxative and for lowering serum ammonia in cases of hepatic encephalopathy. Although there are no human reproduction studies, this agent is not absorbed from the gastrointestinal tract for the most part, and thus is unlikely to be a.s.sociated with adverse fetal effects.

MINERAL OIL.

Mineral oil is a lubricant laxative. There are no published human epidemiological or animal teratology studies with this agent. However, chronic use of mineral oil as a laxative might interfere with the absorption of fat-soluble vitamins such as vitamin K and D, and thus theoretically could have adverse fetal effects.

CASTOR OIL.

There are no published human epidemiological or animal teratology studies with this agent. There are also no reports of an a.s.sociation of adverse fetal effects with the use of castor oil during pregnancy. It has been a commonly held belief that this agent would stimulate labor and it is often utilized for this purpose in women close to term. However, little scientific data support the use of this agent as a potent stimulant of labor.

Antidiarrheal agents Unlike constipation, diarrhea is an uncommon complaint of pregnancy and is usually secondary to medications (especially antibiotics), infections (bacterial, viral, and para-234 Nutritional and dietary supplementation during pregnancy Box 12.3 Antidiarrheal medications Box 12.3 Antidiarrheal medications Bulk agents Absorbents Kaolin and pectin (Kaopectate) Opioid agents site), and abuse of laxatives or lactose intolerance. Fortunately, most cases of acute diarrhea are self-limited and require no specific therapy. Patients should maintain adequate hydration. Antidiarrheals can generally be divided into three major categories bulk-forming agents, absorbents, and opiates (Box 12.3).

BULK-FORMING AGENTS.

These agents are utilized primarily for chronic diarrhea and are listed in Box 12.3. None of these agents are absorbed systemically. Therefore, embryofetal exposure does not occur and there is no a.s.sociated risk.

ABSORBENTS.

The combination of kaolin and pectin (Kaopectate) is probably the antidiarrheal agent most commonly used, including during pregnancy. Its main mode of action is reported to be via absorbent action. There are no epidemiological studies regarding the use of this agent in pregnant women. However, since very little, if any, of it is absorbed from the gastrointestinal tract, it seems very unlikely that this antidiarrheal poses a significant risk to either mother or fetus.

OPIOID AGENTS.

Kaolin and pectin have also been combined with opium and belladonna (Amogel-PG, Donnagel-PG, Donnapectolin-PG, Quiagel-PG) and with paregoric (kapectolin with paregoric, parepectolin). The addition of belladonna and opioid agents results in decreased gastrointestinal mobility. There is little available information regarding the use of opium-containing agents in pregnant women. There were only 36 women with early pregnancy exposure included in the Collaborative Perinatal Project database, but there was no evidence of a significant increase in the frequency of congenital anomalies (Heinonen et al et al., 1977). Almost 100 women were exposed to paregoric in early pregnancy with no significant increase in frequency of congenital anomalies (Aselton et al et al., 1985). There is, however, the possibility of addiction and withdrawal syndrome in neonates whose mothers use this agent on a chronic basis.

Another commonly used antidiarrheal is the combination of diphenoxylate and atropine (Lomotil and others). Diphenoxylate is a compound similar to meperidine and acts primarily to reduce intestinal motility. Of interest is the fact that atropine is included in this preparation in an effort to prevent abuse. Although there is a case report of an infant born with congenital heart disease whose mother used this agent during pregnancy (Ho et al et al., 1975), there are no large epidemiologic studies regarding its use during pregnancy. Moreover, there were less than 10 patients who utilized this agent in early pregnancy included in the Collaborative Perinatal Project (Heinonen et al et al., 1977).

None of the offspring of these women had malformations.

Special considerations 235.

LOPERAMIDE.

This antidiarrheal agent works by decreasing intestinal motility. No human reproduction studies have been published. According to its manufacturer, loperamide was not teratogenic in rats and rabbits. It is an FDA category B drug.

Teratogen Information System (TERIS) and FDA risk ratings for congenital anomalies congenital anomalies The TERIS and FDA risk ratings for drugs in this chapter provide a reasonable summary of risks that are supported by the medical literature. Most of the supporting literature for Table 12.4 has been discussed above.

SPECIAL CONSIDERATIONS.

Most agents utilized for gastrointestinal disease can be safely used in pregnant women, especially after the first trimester.

Nausea and vomiting All pregnant women probably experience nausea to some degree in early pregnancy.

Nausea and vomiting or 'morning sickness' are common symptoms of pregnancy during the first trimester, but most pregnant women do not require antiemetic therapy. Frequent small meals may prove a beneficial way to manage nausea without medical intervention.

Fortunately, hyperemesis gravidarum, the most severe form of pregnancy-a.s.sociated nausea and vomiting occurs in only a small percentage of gravidas. Women with hyperemesis gravidarum may require hospitalization and intravenous hydration, and antiemetic therapy. One of the most effective antiemetic agents for nausea and vomiting a.s.sociated with pregnancy was doxylamine plus pyridoxine (Bendectin). However, this agent is no longer available because of the fear of litigation. When antiemetics are indicated, promethazine suppositories (or occasionally orally) in doses of 25 mg should be used. Other agents which may prove useful for hyperemesis gravidarum are described in Box 12.4.

Such agents as prochlorperazine, promethazine, chlorpromazine, and thiethylperazine may be a.s.sociated with extrapyramidal side effects manifested by dystonia, torticollis, and oculogyric crisis. If it occurs, this unusual syndrome of adverse effects can be treated with diphenhydramine (Benadryl). Importantly, chlorpromazine may be a.s.sociated with significant hypotension when given intravenously. Therefore, suppositories are the preferred route of administration.

In severe cases of hyperemesis gravidarum in which other agents are largely ineffective, ondansetron (Zofran) 32 mg intravenously as a single dose may be effective. It is also available in oral form (8 mg twice a day), but this is much less likely to be effective in cases of hyperemesis gravidarum where almost everything taken orally is vomited.

Reflux esophagitis Reflux esophagitis resulting in heartburn or pyrosis is very common in pregnancy and is thought to be secondary to decreased gastroesophageal sphincter tone with resultant 236 236 Nutritional and dietary supplementation during pregnancy Table 12.4 Table 12.4 Teratogen Information System (TERIS) risk rating for congenital anomalies and Food and Drug Administration (FDA) pregnancy risk: category rating for nutritional supplements and gastrointestinal drugs Teratogen Information System (TERIS) risk rating for congenital anomalies and Food and Drug Administration (FDA) pregnancy risk: category rating for nutritional supplements and gastrointestinal drugs Drugs TERIS risk FDA pregnancy risk rating Aminopterin Moderate to high X.