Part 26 (1/2)
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.