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Treatment of Chronic Diseases During Pregnancy
TREATMENT OF CHRONIC DISEASES DURING
Drugs used to treat pregnant WOfflen with diabetes) asthma) epilepsy) and hypertension must be carefully selected to ensure the best possible care for both mother and child.
I
developing at that time, such as the heart or central nervous system. Toward the end of the classic teratogenic phase, the ear and hard palate are forming and may be affected by a teratogen. If drugs are not urgently needed, drug therapy should be avoided until this critical time of organ development is completed. Exposure to dnlgs during the frrst two to three weeks of pregnancy usually results in either no adverse fetal effects or the induction of spontaneous abortion. Fetal development continues in the second and third trimesters, and the brain develops throughout pregnancy and the neonatal period. Even after the first trimester, certain substances can have adverse effects, although their effects may not be noticed lmtil later in life when physical or behavioral changes occur. For example, some anomalies that have been linked to diethylstilbestrol exposure in the second trimester have not been identifiable until puberty. To help health care professionals determine the extent to which a dnlg or chemical is capable of causing fetal harm, in 1980, the Food and Drug Administration proposed the current regulations for labeling medications about use during pregnancy (Table 1). These classifications should be considered when selecting any dnlg for women who might be or become pregnant while using the drug.
Table 1
FDA Categories of Fetal Risk Category A Controlled studies in pregnant women fail to demonstrate a risk to the fetus in the first trimester (and there is no risk in later trimesters), and the possibility of fetal harm seems remote. Category B Animal studies have not demonstrated a fetal risk, but there are no controlled stud ies in pregnant women . Or animal studies have shown an adverse effect that has not been confirmed in women in the first trimester (there is no evidence of risk in later trimesters) . ' Category C Either studies in an i mals have revealed adverse effects on the fetus and there are no controlled studies in pregnant women, o r studies in women and animals are not available. Drugs shou ld be given only if potential benefit outweighs the risk to the fetus. Category D Positive evidence of human f etal ri s k exists, but the benefits f rom use in pregnant women may be acceptable . Category X Animal and human stu dies h ave demonstrated fetal abnormalities, or there is evidence of fetal risk based on human experience, or both, and the risk of drug use in p r egnant women clearly outwe i ghs any pot ential benefit. These d rug s are contraind icated i n women who are o r may become pregnant.
FDA = Food and Drug Admin ist rat ion . Modified from: Reference 2.
AMERICAN PHARMACY
Chronic Disease Management During Pregnancy D iabetes Mellitus Three to four percent of all pregnancies are complicated by diabetes. 3,4 Most pregnant women who are diabetic devel· op the condition during pregnancy (gestational diabetes). A smaller subset of pregnant diabetic women have preexisting diabetes. Although obstetricians are beginning to use the common descriptions of "type I" and "type II" diabetes for their pregnant patients, they more often tend to use the White classification of diabetes during pregnancy (Table 2). This system classifies patients on the basis of their history of diabetes and the presence of its complications. An increased rate of neonatal mortality has been reported in patients who have poor control of their blood glucose levels. Most morbid adverse effects to the fenls and neonate are exac· erbated by less than optimal control. These include congenital defects of the heart, kidneys, and central nervous system. The risk of these malformations in fetuses callied by mothers whose diabetes is poorly controlled is 6-8%, which is two to three times the risk of these problems in the general population. Biochemical problems such as hypocalcemia, hyperbilirubinemia, and hypoglycemia also may occur in the fetus. Hypoglycemia results from glucose diffusing freely across the placental barrier. This increase in fetal plasma glucose stimulates the pancreas to produce insulin. When the infant is born and the exogenous supply of glucose is removed, the infant continues to produce enhanced levels of insulin, resulting in hypoglycemia. Finally, macrosomia (premature development) of the infant can occur as a result of cellular hypertrophy and hyperplasia of the fetal fat, heart, liver, and adrenal glands. Because of excessive maternal production and underuse of glucose, amino acids, lipids, and ketones, these substances cross the placenta. They stimulate fetal insulin and growth factor production, which results in enhanced fetal growth. Risks exist not only for the fetus, but also for the mother whose diabetes is not appropriately controlled. Because of increased metabolic needs, pregnant patients with preexisting insulin-dependent diabetes are more prone to ketoacidosis. Pregnancy-induced hypertension also is more common in women with diabetes. Complications seen in women who do not demonstrate "tight" control of their diabetes may be exacerbated in pregnancy. These problems , which include microvascular, ophthalmic, neurologic, and renal complica· tions, can be diminished in severity by better control of the insulin regimen. The landmark Diabetes Control and Complications Trial6 demonstrated that tight control of diabetes can reduce renal and ophthalmic damage associated with diabetes. Several older studies in the obstetric literature have revealed similar fmdings for pregnant women who control their diabetes appropriately.7 June 1995
Vol. NS35, No.6
A therapeutic goal for blood glucose levels should be established with the patient. This goal should take into account normal blood glucose values during pregnancy, as well as the need to maintain control of blood glucose to reduce risk of complications to the mother and the fetus. Recommended goals for blood glucose levels are fasting values of 60-90 mg/ dL, preprandial values of less than 105 mg/dL, and postprandial values of not greater than 120 mg/dL. Whether or not the patient's diabetes develops during pregnancy or is related to previous standing disease, diabetes in a pregnant woman should be treated with insulin. Sulfonylureas are generally contraindicated during pregnancy because of the potential for teratogenicity, possibly resulting from hyperglycemia that often occurs in women using oral hypoglycemics, rather than from the drug itself. Insulin therapy must often be intensified during pregnancy. Several hormones are increased in pregnancy that affect insulin's ability to bind to its receptor sites. The most important of these hormones is human placental lactogen (HPL). HPL decreases the affinity of insulin for its receptor sites and therefore increases the insulin dose required. as gestation advances. When dosing insulin, keep in mind that insulin requirements vary over the course of the pregnancy (Table 3). To avoid the development of insulin antibodies, human insulin should be used during pregnancy. Insulin regimens should be adjusted on the basis of the insulin's duration of activity and the results of plasma glucose monitoring.
Table 2
White Classification of Diabetes During Pregnancy Class
Criteria
A1
Abnormal oral glucose tolerance test. Normal fasting blood glucose concentration. Diet controlled.
A2
Abnormal oral glucose tolerance test. Abnormal fasting blood glucose concentration. Insulin required.
B
Insulin dependent. Onset> 20 years old, duration < 10 years. Absence of vascular disease or retinopathy.
C
Insulin dependent. Onset between ages 10 and 20. Duration between 10 and 20 years. Background retinopathy noted.
D
Insulin dependent. Onset before age 10. Duration> 20 years. Background retinopathy noted.
F
Presence of diabetic nephropathy.
H
Presence of cardiac disease.
R
Presence of proliferative retinopathy.
T
Pancreatic and/or renal transplant.
Source: Reference 5.
Epilepsy binding of any highly protein-bound dnlg and an increase in the free or pharmacologically active portion of the drug. The effect of pregnancy on epileptiC seizure frequency If possible, free drug levels should be monitored. varies; approximately 50% of patients show no change in freChanges that occur in drug pharmacokinetics are not quency, 25% experience a decreased number of seizures, and restricted to the pregnancy period. During the 3 to 12 25% have an increase in seizure activity. Hormonal and weeks following delivery, the patient will gradually return metabolic factors, respiratory changes, psychological probto her prepregnancy level of drug assimilation. Blood levels lems, and noncompliance with medication regimen~ can should also be followed closely during this period to preinfluence seizure frequency. vent toxicity. Pharmacokinetic alterations of anticonvulsant agents can The problem of birth defects in children of epileptic be dramatic in pregnancy. Pregnancy is associated with an women can be attributed both to drug exposure and to increase in clearance and volume of distribution of most anticonvulsants. UnfortuTable 3 nately, the changes in pharmacokinetics are not consisGeneral Insulin Dosing Guidelines During Pregnancy tent within a particular patient. Because of pharmaInsulin Gestational cokinetic changes, serum Regimen Dose Age (units/kg) (weeks) Concentrations should be monitored regularly during Regimens should be divided as for nonpregnant 0.7 6-18 patients (i.e., % of total daily dose in morning pregnancy to ensure theraand ~ of daily dose in evening). Of the O.B 18-26 peutic efficacy. A dilutional morning portion, % should be of moderate hypoalbuminemia occurs duration (e.g., NPH or lente), and ~ should be 26-36 0.9 of short duration (e.g., regular, semilente). during pregnancy, which 1.0 >36 causes a decrease in protein
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Vol. NS35, No.6
June 1995
AMERICAN PHARMACY
Table 4
placentae (detachment of the placenta from attachDrugs Used in Chronic Disease Processes ment points) , pregn ancyDuring Pregnancy induced h ypertension, premature labor, complicated Pregnancy labor and deliv ery, stillGeneric Drug Products Disease Category birth, small fetal size, and (Trade Name-Manufacturer) low intelligence are also of Albuterol Asthma C concern. Theophylline C All anticonvulsants h ave Cromolyn (Intal-Fisons) B Nedocromil (Tilade-Fisons) B teratogenic potential (see Corticosteroids B/C Table 4). The best known of these problems was originalInsulin Diabetes B Oral sulfonylureas C/D ly referred to as the fetal hydantoin syndrome. This Antacids Gastrointestinal B syndrome may occur in up H 2 -antagonists disorders B Metoclopramide (Reglan-Robins) B to 11 % of fetuses exp osed to Cisapride (Propulsid-Janssen) C phenytoin and includes conSucralfate (Carafate-Marion Merrell Dow) B genital heart defects, cleft lip D Hypertension Angiotensin-converting enzyme inhibitors and palate , microce p haly, Beta-blockers C and learning diffi c ulties. Clonidine (Catapres-Boehringer Ingelheim) C Recent research shows that Diltiazem (Cardizem-Marion Merrell Dow; this problem is not unique to Dilacor-Rhone-Poulenc Rorer) C use of the anticonv ulsant C Furosemide (Lasix-Hoechst-Roussel) Hydralazine (Apresoline-Ciba) C agent phenytoin (DilantinD Hydrochlorothiazide Parke-Davis) , as was previLabetalol (Normodyne-Schering; ously thought , and may Trandate-Allen & Hanburys) C appear with any of the comMethyldopa (Aldomet-Merck) C monly used anticonvulsants. Nifedipine (Procardia- Pfizer; Adalat-Miles) C Prazosin (Minipress-Pfizer) C Phenytoin and phenobarVerapamil (Calan-Searle; bital remain the anticonvulIsoptin-Knoll; Verelan-Wyeth-Ayerst) D sants most commonly used Hyperthyroidisn1 D Propylthiou racil by obstetricians. Fetal hydanMethimazole (Tapazole-Lilly) D toin syndrome may occur with use of either drug. Folic Hypothyroidisn1 Levothyroxine (Synthroid-Boots; acid is commonly provided Levothroid-Forest; Levoxyl-Daniels; A Thyrar-Rh6ne-Poulenc Rorer) to pregnant women to ensure appropriate developMigraine D Ergotamine with caffeine Sumatriptan (lmitrex-Cerenex) B ment of the fetus 'S central nervous system. Women Seizure Carbamazepine (Tegretol-Ciba) C receiving anticonvulsants disorders D Phenobarbital D Phenytoin (Dilantin-Parke-Davis) may be more likely to develD Valproic acid (Depakene-Parke-Davis) op folic acid deficiency. Folic acid therapy may need to be Thron1boen1bolic Heparin C D adjusted to provide for adeWarfarin (Coumadin-DuPont) disease quate therapy. Note: See Table 1 for definition of pregnancy categories. Both phenytoin and p heModified from: Reference 2. nobarbital may be associated with a potential for depression of vitamin K -dependent clotting factors in the neonatal effects secondary to seizure activity. Generalized motor liver. This problem is especially notable in the premature seizures, especially when prolonged , carry the risk of infant and may result in increased risk of intracranial hemorcompromising the fetus. Possible effects include hypoxia rhage and/or death of the neonate. To help keep vitamin and, subsequently, acidosis in the unborn child. In addiK-dependent clotting factors from falling too low, suppletion, increased incidence of vaginal bleeding, abruptio AMERICANPHARMACY
June 1995
Vol. NS35, No. 6
ments of phytonadione (vitamin K 1) can be given to the mother during late pregnancy and to the neonate at delivery. Carbamazepine has been considered by some as the drug of choice for managing generalized seizure disorders. As with phenytOin and phenobarbital, carbamazepine metabolism may be increased in pregnancy and require dosage adjustments. Spina bifida has been reported in children born of mothers who received carbamazepine (1 %) and in those who received valproic acid (2%) . In addition, a fetal carbamazepine syndrome has been reported that may be similar to that reported with phenytoin. Therefore, when an anticonvulsant agent is being selected for a pregnant patient with epilepsy, her past experience with a given drug must be considered. In addition, the incidence and overall teratogenic risk of each of the four major agents should be considered in selecting appropriate therapy for the pregnant woman. Fetal dysmorphic syndromes have been reported with exposure to each of the major anticonvulsants. If a patient is well controlled on one agent, switching to a second drug may bring no benefits to the fetus.
Asthma Asthma is estimated to occur in 1-2% of all pregnancies. The objectives for asthma management in pregnant women are to gain effective control of asthma symptoms, avoid exacerbation of symptoms, avoid fetal hypoxia resulting from impaimIent of maternal and fetal oxygenation secondary to maternal airway obstruction, and minimize risk to the fetus from drug therapy. The treatment of asthma in the pregnant woman is similar to treatment of the disease in the nonpregnant woman. As in the nonpregnant woman, beta2-adrenergic bronchodilators (e .g. , albuterol , bitolterol [Tornalate-Sanofi Winthrop], terbutaline) are the drugs of choice for treating a pregnant woman with mild asthma. In addition, these agents form the basis of a stepped-care approach to treating more severe asthma. The drugs should be given on an as-needed basis with a metered-dose inhaler (MDl) for optimal efficacy. An inhalation device (e.g., Aerochamber-Forest, InspirEaseSchering) can make administration of these products easier. For the patient with wheezing, coughing, shortness of breath, and/or nocturnal coughing and wheezing more than three times a week, anti-inflammatory therapy should be considered. Anti-inflammatory therapy for this group of patients may include inhaled corticosteroids or a mast-cell degranulation inhibitor (e.g., cromolyn sodium [Intal-Fisonsl, nedocromil [Tilade-FisonsD. Any of the currently available corticosteroid MDIs (e.g. , beclomethasone, triamcinolone, flunisolide) can be used. Dosages usually begin at two inhalations every six hours and increase to as many as five to six puffs every six hours in more severe cases. The patient must understand that the full benefit may not be achieved until after two to four weeks of corticosteroid therapy. Vol. NS35, No.6 June 1995
A relative lack of adverse effects in the fetus from systemic as well as inhaled corticosteroids has been noted. Decreased birth weight and a slight increase in the incidence of premature deliveries and infants of low birth weight have been noted with use of oral corticosteroids. Some patients and health care practitioners may be concerned about the risk of facial clefting with use of corticosteroids in pregnancy. Facial clefting does occur with corticosteroid use in aninIals who are very sensitive to this defect. In humans, however, no increase in the number of infants born with facial clefts or other birth defects has been seen.2 The mast-cell inhibitors cromolyn and nedocromil are also safe in pregnancy, especially for patients whose asthma is exacerbated by exercise. For some patients, these agents can be used as alternatives to corticosteroids to provide anti-inflammatory activity. Dosing of mast-cell degranulation inhibitors should be two puffs four times daily. Patients should be counseled that four to six weeks of therapy may be required before full benefit is seen from a trial of these agents , as with corticosteroids. Continued use of an inhaled beta 2-agonist should also be encouraged to provide relief of intermittent bronchospasm not controlled by the anti-inflammatory medication. One way of explaining this to patients is to describe the beta 2-agonist MDI as their "rescue medication" for an acute attack. Current recommendations for use of theophylline in pregnancy are similar to those in the general population. Theophylline should be considered only for those patients whose asthma is not readily controlled with the combination of an anti-inflammatory agent and a betaz-agonist. A once-a.{\ay dose of theophylline in the evening may be especially helpful for treating nocturnal asthma. Neonates exposed to theophylline in utero have shown transient jitteriness, vomiting, and tachycardia.
Hypertension Hypertensive diseases, occurring in 6% to 30% of all pregnancies, represent one of the most common medical complications of pregnancy. Elevated blood pressure can be differentiated as existing before pregnancy or occurring secondary to pregnancy. The impact and management of these two conditions can differ, depending on the perspective being considered: the mother'S or the fetus's. The American College of Obstetricians and Gynecologists has devised a system for classifying women with elevated blood pressure during pregnancy. Women who have hypertension that predates pregnancy or that is diagnosed before the 20th week of gestation are considered to have chronic hypertension. Hypertension diagnosed for the first time during pregnancy and that persists beyond seven weeks postpartum is considered to be new-onset chronic hypertension. These diagnoses encompass most pregnant patients who are hypertensive. AMERICAN PHARMACY
Pregnant women whose elevated blood pressure presents after conception may have preeclampsia. Preeclampsia also is referred to as pregnancy-induced hypertension or toxemia of pregnancy. Women may also present with preeclampsia superimposed on preexisting chronic hypertension. Only the pharmacotherapy of chronic hypertension in pregnancy will be discussed in tllis section. As a result of decreased peripheral vascular resistance, increased renal blood flow, and a higher glomerular filtration rate, mean blood pressure decreases in early pregnancy. Diastolic blood pressure levels in the second trimester may be as much as 10-15 mm Hg lower than those noted before pregnancy. Blood pressure values increase slowly throughout the third trimester and approach prepregnancy values shortly before delivery. Because of a lowered value for "normal" blood pressure, the standards for diagnosing hypertension in pregnant women are slightly different from those for diagnosing hypertension in nonpregnant women. Hypertension is defmed as a diastolic blood pressure of ~ 90 mm Hg or a rise of ~ 15 mm Hg from a base line in early pregnancy, or a systolic blood pressure of ~ 140 mm Hg or a rise of ~ 30 mm Hg from base line. Physiologic changes in blood pressure in the expectant mother will affect pharmacologic treatment. The vasodilation noted with pregnancy may allow for decreased dosing of some antihypertensive agents. It is not uncommon for some patients to discontinue some or all antihypertensive medications during pregnancy. Chronic hypertension that is not well controlled can be detrimental to the fetus. Mothers with chronic hypertension are more prone to superimposed preeclampsia. Fetal outcome seems to be related to the extent of end-organ damage noted before conception and to the severity of preeclampsia, if it occurs. Fetal growth in utero depends on maternal blood pressure, weight, and overall weight gain. If hypertension occurs, blood pressure should be reduced gradually to avoid compromise of uteroplacental perfusion and help prevent poor fetal outcome. The pregnancy
Women's Health Series "Treatment of Chronic Diseases During Pregnancy" is part of American Pharmacy's series on women's health, guest edited by Maura A. Kraynak, PharmD, assistant professor, Department of Pharmacology, and assistant director, Drug Information Services, University of Texas Health Science Center at San Antonio. The series is supported by an educational grant from WyethAyerst Laboratories.
,.,4
WYETH ®~~ AYERST
AMERICAN PHARMACY
should be prolonged to the extent possible to avoid the hazards of premature birth. Avoiding hypertensive and hypotensive incidents can prevent morbidity in both the mother and the fetus. The goal should be reliable, long-term blood pressure control that allows for continued management at home. In accordance with this goal, most experts recommend avoiding pharmacotherapy until diastolic pressure reaches 100-110 mm Hg. Clinicians believe that drug therapy should be started at this point to prevent hypertensive vascular disease. Nondrug therapies are important in treating hypertension in pregnancy. Weight reduction, encouraged in nonpregnant women with hypertension, should be avoided during pregnancy. Exercise may help to reduce blood pressure. The vigorousness of exercise may need to be modified to prevent reduction of blood flow to the uterus and placenta. Bed rest helps encourage a gentle diuresis that may lower blood pressure in some women; it also encourages proper blood flow to the uterus and fetus. Salt restriction should be continued cautiously if it has shown past benefits. Selection of agents for treating hypertension in pregnant women remains controversial. Obstetricians have the most experience with use of older agents such as methyldopa and hydralazine. Newer agents, such as beta-adrenergic blockers, labetalol (Normodyne-Schering; Trandate-Allen & Hanburys) , and calcium-channel blockers, are safe and may be useful in this condition. Angiotensin-converting enzyme inhibitors are associated with increased risk of birth defects (e.g., oliguria, anuria) and should be avoided. Diuretic use in pregnancy is quite controversial and is generally avoided. Diuretics may lead to maternal hypovolemia and a decrease in placental perfusion. Additionally, diuretics have caused electrolyte imbalances, transplacental hyponatremia (especially if combined with salt restriction), and fetal thrombocytopenia. Methyldopa has long been used to treat chronic hypertension during pregnancy. Its history of safe use makes it the drug of choice for many practitioners. Children exposed to methyldopa have been followed to age 10, and their mental and physical development has shown no evidence of deformities. Methyldopa given to women with chronic hypertension in pregnancy has reduced the risk of midtrimester abortion, without affecting neonatal survival or fetal growth. Hydralazine is a vasodilator that is usually ineffective as a first-line agent because reflex tachycardia can result from the increased cardiac output associated with its use. Other adverse effects include dizziness and flushing. The drug's major use has been in combination with methyldopa for treating moderate-ta-severe hypertension. Use of beta-adrenergic blockers during pregnancy to treat hypertension is increasing. Propranolol, metoprolol, and atenolol are the agents used most often. Early concerns about use of beta-blockers in pregnancy had to do with the possibility of intrauterine growth retardation, neonatal hypoJune 1995
Vol. NS35, No.6
glycemia, and bradycardia. In most studies, the incidences of of complications and associated fetal loss increase with the numthese problems were small and involved pregnancies at ber of cigarettes smoked. Positive evidence has also shown an 29-33 weeks' gestation. Pre term infants are predisposed to association between smoking and sudden infant death syndrome many adverse events by virtue of their prematurity, and there(SIDS). Both maternal smoking during pregnancy and smoking fore the cause-and-effect relationship of drug therapy to an after delivery may playa role in SIDS. adverse event cannot be established. Recent experience with Alcohol use in pregnancy may be associated with fetal complications such as fetal alcohol syndrome (FAS). Although a these agents indicates good utility and safety in the pregnant, chronic hypertensive patient. Labetalol is a combined alpha- and beta-adrenergic Counseling Tips for Pregnant Women blocker that has been used with Chronic Conditions extensively for treating hypertension during pregnancy. • Inform your doctor and pharmacist about your pregnancy. Success with use of labetalol • Learn about your pregnancy and the developing baby. , • Question your doctor about the effects of any chronic or acute diseases on your has rivaled that seen with oldpregnancy. er agents such as methyldopa • Take only medicines that are prescribed or recommended by your doctor during your and hydralazine. Labetalol pregnancy. does not impair uteroplacen• Ask your pharmacist about the safety of any medication taken during your pregnancy. tal blood flow or cause con• You should not smoke, use illicit drugs, or drink alcohol during your pregnancy. genital malformations, and it may have a beneficial effect Diabetes mellitus on lung maturation. • Maintain a well-balanced diet and closely monitor your blood glucose during your Calcium-channel blockers, pregnancy. most notably nifedipine, have • Excellent control of blood glucose early in your pregnancy will decrease the chance of recently been used to treat major congenital malformations. chronic hypertension in preg• Your doctor may discontinue your oral hypoglycemic (if pertinent) and prescribe insulin nancy. Although most of the only during yout pregnancy. experience with nifedipine Epilepsy has been positive, some • Children of epileptic mothers have an increased risk of developing a congenital malforreports have indicated a mation, compared with those of nonepileptic mothers. decrease in uterine blood • Some women experience more seizures during pregnancy, but some are able to disconflow and fetal oxygenation. tinue antiepileptic medications altogether during pregnancy. This problem may be more • The lowest effective dose of your antiepileptic medication should be used, and blood acute in preeclampsia, levels should be monitored periodically. because altered uterine vascu• Folic acid therapy may be prescribed alone, or in combination with a prenatal vitamin. lar resistance is an integral part of the pathogenesis of this disease.
Smoking and Alcohol
Asthma
• In general, no special 'considerations regarding drug treatment apply during pregnancy. • Effective control of symptoms should be achieved in order to avoid decreased oxygen flow to your baby. A lack of oxygen supplied to your baby can result in adverse events. • You should ask your doctor for a short-acting inhaler (i.e., beta2-bronchodilator) to use during acute asthma episodes. Hypertension
Smoking and alcohol use can have adverse and/or teratogenic effects during pregnancy. Smoking has been assoCiated with decreased birth weight and increased prematurity. Spontaneous abortion OCcurs in smokers at twice the rate seen in nonsmokers. Risks VoL NS35, No.6
June 1995
• Increases in blood pressure can occur in normotensive and hypertensive women during pregnancy. • In women with chronic hypertension, doses of blood pressure medication may be decreased during pregnancy because of decreases in blood pressure that normally occur as the gestation continues. • Some medications that are acceptable for use early in pregnancy may have to be discontinued later in pregnancy, and vice versa. • If your increased blood pressure cannot be controlled with oral medicine, intravenous medicine may be required along with bed rest and/or hospitalization.
AMERICAN PHARMACY
Drugs used to treat pregnant WOfflen with diabetes) asthma) epilepsy) and hypertension must be carefully selected to ensure the best possible care for both mother and child.
I
developing at that time, such as the heart or central nervous system. Toward the end of the classic teratogenic phase, the ear and hard palate are forming and may be affected by a teratogen. If drugs are not urgently needed, drug therapy should be avoided until this critical time of organ development is completed. Exposure to dnlgs during the frrst two to three weeks of pregnancy usually results in either no adverse fetal effects or the induction of spontaneous abortion. Fetal development continues in the second and third trimesters, and the brain develops throughout pregnancy and the neonatal period. Even after the first trimester, certain substances can have adverse effects, although their effects may not be noticed lmtil later in life when physical or behavioral changes occur. For example, some anomalies that have been linked to diethylstilbestrol exposure in the second trimester have not been identifiable until puberty. To help health care professionals determine the extent to which a dnlg or chemical is capable of causing fetal harm, in 1980, the Food and Drug Administration proposed the current regulations for labeling medications about use during pregnancy (Table 1). These classifications should be considered when selecting any dnlg for women who might be or become pregnant while using the drug.
Table 1
FDA Categories of Fetal Risk Category A Controlled studies in pregnant women fail to demonstrate a risk to the fetus in the first trimester (and there is no risk in later trimesters), and the possibility of fetal harm seems remote. Category B Animal studies have not demonstrated a fetal risk, but there are no controlled stud ies in pregnant women . Or animal studies have shown an adverse effect that has not been confirmed in women in the first trimester (there is no evidence of risk in later trimesters) . ' Category C Either studies in an i mals have revealed adverse effects on the fetus and there are no controlled studies in pregnant women, o r studies in women and animals are not available. Drugs shou ld be given only if potential benefit outweighs the risk to the fetus. Category D Positive evidence of human f etal ri s k exists, but the benefits f rom use in pregnant women may be acceptable . Category X Animal and human stu dies h ave demonstrated fetal abnormalities, or there is evidence of fetal risk based on human experience, or both, and the risk of drug use in p r egnant women clearly outwe i ghs any pot ential benefit. These d rug s are contraind icated i n women who are o r may become pregnant.
FDA = Food and Drug Admin ist rat ion . Modified from: Reference 2.
AMERICAN PHARMACY
Chronic Disease Management During Pregnancy D iabetes Mellitus Three to four percent of all pregnancies are complicated by diabetes. 3,4 Most pregnant women who are diabetic devel· op the condition during pregnancy (gestational diabetes). A smaller subset of pregnant diabetic women have preexisting diabetes. Although obstetricians are beginning to use the common descriptions of "type I" and "type II" diabetes for their pregnant patients, they more often tend to use the White classification of diabetes during pregnancy (Table 2). This system classifies patients on the basis of their history of diabetes and the presence of its complications. An increased rate of neonatal mortality has been reported in patients who have poor control of their blood glucose levels. Most morbid adverse effects to the fenls and neonate are exac· erbated by less than optimal control. These include congenital defects of the heart, kidneys, and central nervous system. The risk of these malformations in fetuses callied by mothers whose diabetes is poorly controlled is 6-8%, which is two to three times the risk of these problems in the general population. Biochemical problems such as hypocalcemia, hyperbilirubinemia, and hypoglycemia also may occur in the fetus. Hypoglycemia results from glucose diffusing freely across the placental barrier. This increase in fetal plasma glucose stimulates the pancreas to produce insulin. When the infant is born and the exogenous supply of glucose is removed, the infant continues to produce enhanced levels of insulin, resulting in hypoglycemia. Finally, macrosomia (premature development) of the infant can occur as a result of cellular hypertrophy and hyperplasia of the fetal fat, heart, liver, and adrenal glands. Because of excessive maternal production and underuse of glucose, amino acids, lipids, and ketones, these substances cross the placenta. They stimulate fetal insulin and growth factor production, which results in enhanced fetal growth. Risks exist not only for the fetus, but also for the mother whose diabetes is not appropriately controlled. Because of increased metabolic needs, pregnant patients with preexisting insulin-dependent diabetes are more prone to ketoacidosis. Pregnancy-induced hypertension also is more common in women with diabetes. Complications seen in women who do not demonstrate "tight" control of their diabetes may be exacerbated in pregnancy. These problems , which include microvascular, ophthalmic, neurologic, and renal complica· tions, can be diminished in severity by better control of the insulin regimen. The landmark Diabetes Control and Complications Trial6 demonstrated that tight control of diabetes can reduce renal and ophthalmic damage associated with diabetes. Several older studies in the obstetric literature have revealed similar fmdings for pregnant women who control their diabetes appropriately.7 June 1995
Vol. NS35, No.6
A therapeutic goal for blood glucose levels should be established with the patient. This goal should take into account normal blood glucose values during pregnancy, as well as the need to maintain control of blood glucose to reduce risk of complications to the mother and the fetus. Recommended goals for blood glucose levels are fasting values of 60-90 mg/ dL, preprandial values of less than 105 mg/dL, and postprandial values of not greater than 120 mg/dL. Whether or not the patient's diabetes develops during pregnancy or is related to previous standing disease, diabetes in a pregnant woman should be treated with insulin. Sulfonylureas are generally contraindicated during pregnancy because of the potential for teratogenicity, possibly resulting from hyperglycemia that often occurs in women using oral hypoglycemics, rather than from the drug itself. Insulin therapy must often be intensified during pregnancy. Several hormones are increased in pregnancy that affect insulin's ability to bind to its receptor sites. The most important of these hormones is human placental lactogen (HPL). HPL decreases the affinity of insulin for its receptor sites and therefore increases the insulin dose required. as gestation advances. When dosing insulin, keep in mind that insulin requirements vary over the course of the pregnancy (Table 3). To avoid the development of insulin antibodies, human insulin should be used during pregnancy. Insulin regimens should be adjusted on the basis of the insulin's duration of activity and the results of plasma glucose monitoring.
Table 2
White Classification of Diabetes During Pregnancy Class
Criteria
A1
Abnormal oral glucose tolerance test. Normal fasting blood glucose concentration. Diet controlled.
A2
Abnormal oral glucose tolerance test. Abnormal fasting blood glucose concentration. Insulin required.
B
Insulin dependent. Onset> 20 years old, duration < 10 years. Absence of vascular disease or retinopathy.
C
Insulin dependent. Onset between ages 10 and 20. Duration between 10 and 20 years. Background retinopathy noted.
D
Insulin dependent. Onset before age 10. Duration> 20 years. Background retinopathy noted.
F
Presence of diabetic nephropathy.
H
Presence of cardiac disease.
R
Presence of proliferative retinopathy.
T
Pancreatic and/or renal transplant.
Source: Reference 5.
Epilepsy binding of any highly protein-bound dnlg and an increase in the free or pharmacologically active portion of the drug. The effect of pregnancy on epileptiC seizure frequency If possible, free drug levels should be monitored. varies; approximately 50% of patients show no change in freChanges that occur in drug pharmacokinetics are not quency, 25% experience a decreased number of seizures, and restricted to the pregnancy period. During the 3 to 12 25% have an increase in seizure activity. Hormonal and weeks following delivery, the patient will gradually return metabolic factors, respiratory changes, psychological probto her prepregnancy level of drug assimilation. Blood levels lems, and noncompliance with medication regimen~ can should also be followed closely during this period to preinfluence seizure frequency. vent toxicity. Pharmacokinetic alterations of anticonvulsant agents can The problem of birth defects in children of epileptic be dramatic in pregnancy. Pregnancy is associated with an women can be attributed both to drug exposure and to increase in clearance and volume of distribution of most anticonvulsants. UnfortuTable 3 nately, the changes in pharmacokinetics are not consisGeneral Insulin Dosing Guidelines During Pregnancy tent within a particular patient. Because of pharmaInsulin Gestational cokinetic changes, serum Regimen Dose Age (units/kg) (weeks) Concentrations should be monitored regularly during Regimens should be divided as for nonpregnant 0.7 6-18 patients (i.e., % of total daily dose in morning pregnancy to ensure theraand ~ of daily dose in evening). Of the O.B 18-26 peutic efficacy. A dilutional morning portion, % should be of moderate hypoalbuminemia occurs duration (e.g., NPH or lente), and ~ should be 26-36 0.9 of short duration (e.g., regular, semilente). during pregnancy, which 1.0 >36 causes a decrease in protein
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AMERICAN PHARMACY
Table 4
placentae (detachment of the placenta from attachDrugs Used in Chronic Disease Processes ment points) , pregn ancyDuring Pregnancy induced h ypertension, premature labor, complicated Pregnancy labor and deliv ery, stillGeneric Drug Products Disease Category birth, small fetal size, and (Trade Name-Manufacturer) low intelligence are also of Albuterol Asthma C concern. Theophylline C All anticonvulsants h ave Cromolyn (Intal-Fisons) B Nedocromil (Tilade-Fisons) B teratogenic potential (see Corticosteroids B/C Table 4). The best known of these problems was originalInsulin Diabetes B Oral sulfonylureas C/D ly referred to as the fetal hydantoin syndrome. This Antacids Gastrointestinal B syndrome may occur in up H 2 -antagonists disorders B Metoclopramide (Reglan-Robins) B to 11 % of fetuses exp osed to Cisapride (Propulsid-Janssen) C phenytoin and includes conSucralfate (Carafate-Marion Merrell Dow) B genital heart defects, cleft lip D Hypertension Angiotensin-converting enzyme inhibitors and palate , microce p haly, Beta-blockers C and learning diffi c ulties. Clonidine (Catapres-Boehringer Ingelheim) C Recent research shows that Diltiazem (Cardizem-Marion Merrell Dow; this problem is not unique to Dilacor-Rhone-Poulenc Rorer) C use of the anticonv ulsant C Furosemide (Lasix-Hoechst-Roussel) Hydralazine (Apresoline-Ciba) C agent phenytoin (DilantinD Hydrochlorothiazide Parke-Davis) , as was previLabetalol (Normodyne-Schering; ously thought , and may Trandate-Allen & Hanburys) C appear with any of the comMethyldopa (Aldomet-Merck) C monly used anticonvulsants. Nifedipine (Procardia- Pfizer; Adalat-Miles) C Prazosin (Minipress-Pfizer) C Phenytoin and phenobarVerapamil (Calan-Searle; bital remain the anticonvulIsoptin-Knoll; Verelan-Wyeth-Ayerst) D sants most commonly used Hyperthyroidisn1 D Propylthiou racil by obstetricians. Fetal hydanMethimazole (Tapazole-Lilly) D toin syndrome may occur with use of either drug. Folic Hypothyroidisn1 Levothyroxine (Synthroid-Boots; acid is commonly provided Levothroid-Forest; Levoxyl-Daniels; A Thyrar-Rh6ne-Poulenc Rorer) to pregnant women to ensure appropriate developMigraine D Ergotamine with caffeine Sumatriptan (lmitrex-Cerenex) B ment of the fetus 'S central nervous system. Women Seizure Carbamazepine (Tegretol-Ciba) C receiving anticonvulsants disorders D Phenobarbital D Phenytoin (Dilantin-Parke-Davis) may be more likely to develD Valproic acid (Depakene-Parke-Davis) op folic acid deficiency. Folic acid therapy may need to be Thron1boen1bolic Heparin C D adjusted to provide for adeWarfarin (Coumadin-DuPont) disease quate therapy. Note: See Table 1 for definition of pregnancy categories. Both phenytoin and p heModified from: Reference 2. nobarbital may be associated with a potential for depression of vitamin K -dependent clotting factors in the neonatal effects secondary to seizure activity. Generalized motor liver. This problem is especially notable in the premature seizures, especially when prolonged , carry the risk of infant and may result in increased risk of intracranial hemorcompromising the fetus. Possible effects include hypoxia rhage and/or death of the neonate. To help keep vitamin and, subsequently, acidosis in the unborn child. In addiK-dependent clotting factors from falling too low, suppletion, increased incidence of vaginal bleeding, abruptio AMERICANPHARMACY
June 1995
Vol. NS35, No. 6
ments of phytonadione (vitamin K 1) can be given to the mother during late pregnancy and to the neonate at delivery. Carbamazepine has been considered by some as the drug of choice for managing generalized seizure disorders. As with phenytOin and phenobarbital, carbamazepine metabolism may be increased in pregnancy and require dosage adjustments. Spina bifida has been reported in children born of mothers who received carbamazepine (1 %) and in those who received valproic acid (2%) . In addition, a fetal carbamazepine syndrome has been reported that may be similar to that reported with phenytoin. Therefore, when an anticonvulsant agent is being selected for a pregnant patient with epilepsy, her past experience with a given drug must be considered. In addition, the incidence and overall teratogenic risk of each of the four major agents should be considered in selecting appropriate therapy for the pregnant woman. Fetal dysmorphic syndromes have been reported with exposure to each of the major anticonvulsants. If a patient is well controlled on one agent, switching to a second drug may bring no benefits to the fetus.
Asthma Asthma is estimated to occur in 1-2% of all pregnancies. The objectives for asthma management in pregnant women are to gain effective control of asthma symptoms, avoid exacerbation of symptoms, avoid fetal hypoxia resulting from impaimIent of maternal and fetal oxygenation secondary to maternal airway obstruction, and minimize risk to the fetus from drug therapy. The treatment of asthma in the pregnant woman is similar to treatment of the disease in the nonpregnant woman. As in the nonpregnant woman, beta2-adrenergic bronchodilators (e .g. , albuterol , bitolterol [Tornalate-Sanofi Winthrop], terbutaline) are the drugs of choice for treating a pregnant woman with mild asthma. In addition, these agents form the basis of a stepped-care approach to treating more severe asthma. The drugs should be given on an as-needed basis with a metered-dose inhaler (MDl) for optimal efficacy. An inhalation device (e.g., Aerochamber-Forest, InspirEaseSchering) can make administration of these products easier. For the patient with wheezing, coughing, shortness of breath, and/or nocturnal coughing and wheezing more than three times a week, anti-inflammatory therapy should be considered. Anti-inflammatory therapy for this group of patients may include inhaled corticosteroids or a mast-cell degranulation inhibitor (e.g., cromolyn sodium [Intal-Fisonsl, nedocromil [Tilade-FisonsD. Any of the currently available corticosteroid MDIs (e.g. , beclomethasone, triamcinolone, flunisolide) can be used. Dosages usually begin at two inhalations every six hours and increase to as many as five to six puffs every six hours in more severe cases. The patient must understand that the full benefit may not be achieved until after two to four weeks of corticosteroid therapy. Vol. NS35, No.6 June 1995
A relative lack of adverse effects in the fetus from systemic as well as inhaled corticosteroids has been noted. Decreased birth weight and a slight increase in the incidence of premature deliveries and infants of low birth weight have been noted with use of oral corticosteroids. Some patients and health care practitioners may be concerned about the risk of facial clefting with use of corticosteroids in pregnancy. Facial clefting does occur with corticosteroid use in aninIals who are very sensitive to this defect. In humans, however, no increase in the number of infants born with facial clefts or other birth defects has been seen.2 The mast-cell inhibitors cromolyn and nedocromil are also safe in pregnancy, especially for patients whose asthma is exacerbated by exercise. For some patients, these agents can be used as alternatives to corticosteroids to provide anti-inflammatory activity. Dosing of mast-cell degranulation inhibitors should be two puffs four times daily. Patients should be counseled that four to six weeks of therapy may be required before full benefit is seen from a trial of these agents , as with corticosteroids. Continued use of an inhaled beta 2-agonist should also be encouraged to provide relief of intermittent bronchospasm not controlled by the anti-inflammatory medication. One way of explaining this to patients is to describe the beta 2-agonist MDI as their "rescue medication" for an acute attack. Current recommendations for use of theophylline in pregnancy are similar to those in the general population. Theophylline should be considered only for those patients whose asthma is not readily controlled with the combination of an anti-inflammatory agent and a betaz-agonist. A once-a.{\ay dose of theophylline in the evening may be especially helpful for treating nocturnal asthma. Neonates exposed to theophylline in utero have shown transient jitteriness, vomiting, and tachycardia.
Hypertension Hypertensive diseases, occurring in 6% to 30% of all pregnancies, represent one of the most common medical complications of pregnancy. Elevated blood pressure can be differentiated as existing before pregnancy or occurring secondary to pregnancy. The impact and management of these two conditions can differ, depending on the perspective being considered: the mother'S or the fetus's. The American College of Obstetricians and Gynecologists has devised a system for classifying women with elevated blood pressure during pregnancy. Women who have hypertension that predates pregnancy or that is diagnosed before the 20th week of gestation are considered to have chronic hypertension. Hypertension diagnosed for the first time during pregnancy and that persists beyond seven weeks postpartum is considered to be new-onset chronic hypertension. These diagnoses encompass most pregnant patients who are hypertensive. AMERICAN PHARMACY
Pregnant women whose elevated blood pressure presents after conception may have preeclampsia. Preeclampsia also is referred to as pregnancy-induced hypertension or toxemia of pregnancy. Women may also present with preeclampsia superimposed on preexisting chronic hypertension. Only the pharmacotherapy of chronic hypertension in pregnancy will be discussed in tllis section. As a result of decreased peripheral vascular resistance, increased renal blood flow, and a higher glomerular filtration rate, mean blood pressure decreases in early pregnancy. Diastolic blood pressure levels in the second trimester may be as much as 10-15 mm Hg lower than those noted before pregnancy. Blood pressure values increase slowly throughout the third trimester and approach prepregnancy values shortly before delivery. Because of a lowered value for "normal" blood pressure, the standards for diagnosing hypertension in pregnant women are slightly different from those for diagnosing hypertension in nonpregnant women. Hypertension is defmed as a diastolic blood pressure of ~ 90 mm Hg or a rise of ~ 15 mm Hg from a base line in early pregnancy, or a systolic blood pressure of ~ 140 mm Hg or a rise of ~ 30 mm Hg from base line. Physiologic changes in blood pressure in the expectant mother will affect pharmacologic treatment. The vasodilation noted with pregnancy may allow for decreased dosing of some antihypertensive agents. It is not uncommon for some patients to discontinue some or all antihypertensive medications during pregnancy. Chronic hypertension that is not well controlled can be detrimental to the fetus. Mothers with chronic hypertension are more prone to superimposed preeclampsia. Fetal outcome seems to be related to the extent of end-organ damage noted before conception and to the severity of preeclampsia, if it occurs. Fetal growth in utero depends on maternal blood pressure, weight, and overall weight gain. If hypertension occurs, blood pressure should be reduced gradually to avoid compromise of uteroplacental perfusion and help prevent poor fetal outcome. The pregnancy
Women's Health Series "Treatment of Chronic Diseases During Pregnancy" is part of American Pharmacy's series on women's health, guest edited by Maura A. Kraynak, PharmD, assistant professor, Department of Pharmacology, and assistant director, Drug Information Services, University of Texas Health Science Center at San Antonio. The series is supported by an educational grant from WyethAyerst Laboratories.
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WYETH ®~~ AYERST
AMERICAN PHARMACY
should be prolonged to the extent possible to avoid the hazards of premature birth. Avoiding hypertensive and hypotensive incidents can prevent morbidity in both the mother and the fetus. The goal should be reliable, long-term blood pressure control that allows for continued management at home. In accordance with this goal, most experts recommend avoiding pharmacotherapy until diastolic pressure reaches 100-110 mm Hg. Clinicians believe that drug therapy should be started at this point to prevent hypertensive vascular disease. Nondrug therapies are important in treating hypertension in pregnancy. Weight reduction, encouraged in nonpregnant women with hypertension, should be avoided during pregnancy. Exercise may help to reduce blood pressure. The vigorousness of exercise may need to be modified to prevent reduction of blood flow to the uterus and placenta. Bed rest helps encourage a gentle diuresis that may lower blood pressure in some women; it also encourages proper blood flow to the uterus and fetus. Salt restriction should be continued cautiously if it has shown past benefits. Selection of agents for treating hypertension in pregnant women remains controversial. Obstetricians have the most experience with use of older agents such as methyldopa and hydralazine. Newer agents, such as beta-adrenergic blockers, labetalol (Normodyne-Schering; Trandate-Allen & Hanburys) , and calcium-channel blockers, are safe and may be useful in this condition. Angiotensin-converting enzyme inhibitors are associated with increased risk of birth defects (e.g., oliguria, anuria) and should be avoided. Diuretic use in pregnancy is quite controversial and is generally avoided. Diuretics may lead to maternal hypovolemia and a decrease in placental perfusion. Additionally, diuretics have caused electrolyte imbalances, transplacental hyponatremia (especially if combined with salt restriction), and fetal thrombocytopenia. Methyldopa has long been used to treat chronic hypertension during pregnancy. Its history of safe use makes it the drug of choice for many practitioners. Children exposed to methyldopa have been followed to age 10, and their mental and physical development has shown no evidence of deformities. Methyldopa given to women with chronic hypertension in pregnancy has reduced the risk of midtrimester abortion, without affecting neonatal survival or fetal growth. Hydralazine is a vasodilator that is usually ineffective as a first-line agent because reflex tachycardia can result from the increased cardiac output associated with its use. Other adverse effects include dizziness and flushing. The drug's major use has been in combination with methyldopa for treating moderate-ta-severe hypertension. Use of beta-adrenergic blockers during pregnancy to treat hypertension is increasing. Propranolol, metoprolol, and atenolol are the agents used most often. Early concerns about use of beta-blockers in pregnancy had to do with the possibility of intrauterine growth retardation, neonatal hypoJune 1995
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glycemia, and bradycardia. In most studies, the incidences of of complications and associated fetal loss increase with the numthese problems were small and involved pregnancies at ber of cigarettes smoked. Positive evidence has also shown an 29-33 weeks' gestation. Pre term infants are predisposed to association between smoking and sudden infant death syndrome many adverse events by virtue of their prematurity, and there(SIDS). Both maternal smoking during pregnancy and smoking fore the cause-and-effect relationship of drug therapy to an after delivery may playa role in SIDS. adverse event cannot be established. Recent experience with Alcohol use in pregnancy may be associated with fetal complications such as fetal alcohol syndrome (FAS). Although a these agents indicates good utility and safety in the pregnant, chronic hypertensive patient. Labetalol is a combined alpha- and beta-adrenergic Counseling Tips for Pregnant Women blocker that has been used with Chronic Conditions extensively for treating hypertension during pregnancy. • Inform your doctor and pharmacist about your pregnancy. Success with use of labetalol • Learn about your pregnancy and the developing baby. , • Question your doctor about the effects of any chronic or acute diseases on your has rivaled that seen with oldpregnancy. er agents such as methyldopa • Take only medicines that are prescribed or recommended by your doctor during your and hydralazine. Labetalol pregnancy. does not impair uteroplacen• Ask your pharmacist about the safety of any medication taken during your pregnancy. tal blood flow or cause con• You should not smoke, use illicit drugs, or drink alcohol during your pregnancy. genital malformations, and it may have a beneficial effect Diabetes mellitus on lung maturation. • Maintain a well-balanced diet and closely monitor your blood glucose during your Calcium-channel blockers, pregnancy. most notably nifedipine, have • Excellent control of blood glucose early in your pregnancy will decrease the chance of recently been used to treat major congenital malformations. chronic hypertension in preg• Your doctor may discontinue your oral hypoglycemic (if pertinent) and prescribe insulin nancy. Although most of the only during yout pregnancy. experience with nifedipine Epilepsy has been positive, some • Children of epileptic mothers have an increased risk of developing a congenital malforreports have indicated a mation, compared with those of nonepileptic mothers. decrease in uterine blood • Some women experience more seizures during pregnancy, but some are able to disconflow and fetal oxygenation. tinue antiepileptic medications altogether during pregnancy. This problem may be more • The lowest effective dose of your antiepileptic medication should be used, and blood acute in preeclampsia, levels should be monitored periodically. because altered uterine vascu• Folic acid therapy may be prescribed alone, or in combination with a prenatal vitamin. lar resistance is an integral part of the pathogenesis of this disease.
Smoking and Alcohol
Asthma
• In general, no special 'considerations regarding drug treatment apply during pregnancy. • Effective control of symptoms should be achieved in order to avoid decreased oxygen flow to your baby. A lack of oxygen supplied to your baby can result in adverse events. • You should ask your doctor for a short-acting inhaler (i.e., beta2-bronchodilator) to use during acute asthma episodes. Hypertension
Smoking and alcohol use can have adverse and/or teratogenic effects during pregnancy. Smoking has been assoCiated with decreased birth weight and increased prematurity. Spontaneous abortion OCcurs in smokers at twice the rate seen in nonsmokers. Risks VoL NS35, No.6
June 1995
• Increases in blood pressure can occur in normotensive and hypertensive women during pregnancy. • In women with chronic hypertension, doses of blood pressure medication may be decreased during pregnancy because of decreases in blood pressure that normally occur as the gestation continues. • Some medications that are acceptable for use early in pregnancy may have to be discontinued later in pregnancy, and vice versa. • If your increased blood pressure cannot be controlled with oral medicine, intravenous medicine may be required along with bed rest and/or hospitalization.
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