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Effects of pregnancy on specific diseases
Effects of Pregnancy on Specific Diseases Larry C. Gilstrap III
Of the numerous physiological changes associated with pregnancy that may have effects on various diseases, the marked increase in blood volume probably exerts the most pronounced effect. This increase may affect the serum level of many medications, as well as affecting various laboratory tests. Other important changes occur in the renal and hepatic system, which in turn may affect the clearance and metabolism of certain drugs and medications. Moreover, the response to and treatment of various diseases during pregnancy may be affected by the "attitude" o f the health care providers who are often reluctant to perform certain diagnostic tests and procedures on the pregnant woman.
Copyright 9 2001 by W.B. Saunders Company here are numerous anatomical and physiothat occur during pregnancy that can affect specific diseases differently in the pregnant compared to the nonpregnant woman. Many of these changes begin early in pregnancy, soon after implantation and continue throughout gestation. A complete review of these changes and all of the possible disease states, which may be affected by these changes are beyond the scope of this presentation. Only the major changes along with examples of pregnancy effects by these changes will be discussed in detail. The reader should refer to major textbooks in obstetrics, such as the 20th edition of Williams Obstetrics 1, for a more thorough review on this subject. There are a few general principles, however, that are worthy of mention. Paramount among these is the fact that there are "two patients" involved-- mother and fetus (Table 1). Moreover, in addition to the effects on various diseases by pregnancy secondary to the many physiologic and anatomic changes, pregnancy per se may also affect the "attitude" of healthcare providers in their approach to the treatment of illness during pregnancy. For example, there is often great reluctance by clinicians to use certain diagnostic tests (ie, x-rays) and indicated medications during pregnancy. As~ summarized in the 20th edition of Williams Obstetrics, "a women should not be penalized because she is pregnant. "1 In other words, pregnant women should receive appropriate medications, tests, and surgery as indicated. Some of the organ systems most affected by the anatomical and physiological changes of pregnancy are summarized in Table 2.
T logical changes
H e m a t o l o g i c Changes in P r e g n a n c y There are pronounced changes in the hematologic system during pregnancy including changes in blood volume, hemoglobin concentration, hematocrit, iron requirements, immunological and leukocyte function, and blood coagulation (Table 3). 1 Effects on Diseases The increase in blood volume may affect numerous diseases and their treatment during pregnancy. The most pronounced effect of pregnancy-induced hypervolemia is the "dilutional effect" with regards to serum levels of various therapeutic agents. The serum level of many of the beta-lactam antibiotics, such as ampicillin, and aminoglycosides, such as gentamicin, may be decreased in pregnancy compared to nonpregnancy. 2-4The serum levels in anticonvulsant medications may also be lower or "subtherapeutic" during pregnancy. This latter group of medications may be affected not only by the dilutional effect of pregnancy hypervolemia but also by an increase in hepatic microsomal activity leading to an increase in drug clearance (ie, phenytoin). 5 Phenytoin may also be associated From the Department of Obstetrics, Gynecology and Reproductive Scienees, The University of Texas-Houston Medical School, Houston, TX. Address reprint requests to Larry C. Gilstrap, MD, Department of Obstetrics, Gynecologyand Reproductive Sciences, The University of Texas-Houston Medical School, 6431 Fannin, Suite 3.286, Houston, TX 77030; e-mail: [email protected]. Copyright 9 2001 by W..B. Saunders Company 0146-0005/01/2503-0005~35.00/0 doi:l O.1053/sper.2001.245 70
Seminars in Perinatology, Vol 25, No 3 (June), 2001: pp 139-144
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Table 1. General Principles
Table 3. Hematologic Changes in Pregnancy
Two patients involved Few medications have fetal/teratogenic potential Most medications can be used safely during pregnancy Prepregnancy period is an ideal time for assessing risk, counseling, and adjusting medications Serum levels of medications may have to be 1` Pregnancy may worsen some medical conditions--h e m disease, diabetes, hypertension
Blood volume--- 1` 40%-50% Most rapid in 2nd trimester Plateau in late 3rd trimester Higher in multifetal gestations Hemoglobin/Hematocrit Plasma volume 1` greater than RBCs ~, Whole blood viscosity from dilutional effect "Physiologic anemia" Hemoglobin averages 12 g/dL Iron requirements 1' During pregnancy by total of 1,000 mg 500 mg for maternal RBCs 300 mg for fetal RBCs (active transport) 200 mg "lost" Amount from diet/stores often inadequate Immunological/leukocyte function ? Suppression of humeral/cellular immunological function Depression of leukocyte chemotaxis and adherence Relative leukocytosis--14 to 16,000 during labor and puerperium Coagulation Fibrinogen 1' 50% (average 40 mg/dL) Factors VII, VIII, IX, X also 1` Factors XI, XlII
with folic acid deficiency or anemia. 6 O t h e r classes o f drugs may also be affected. The increase in b l o o d volume usually results in an average increase in plasma volume of 1,000 m L a n d red b l o o d cell volume of 500 mL. This in turn may lead to a decrease in h e m a t o c r i t that may be i n t e r p r e t e d as anemia. T h e increased iron requirements during p r e g n a n c y may lead to iron deficiency a n e m i a during pregnancy, especially in medically indig e n t w o m e n a n d in w o m e n of all socioeconomic classes who are deficient in iron stores. Although iron s u p p l e m e n t a t i o n / t h e r a p y results in a satisfactory response in m o s t of these women, therapy may be difficult in some w o m e n because o f nausea a n d vomiting associated with p r e g n a n c y and o t h e r side effects such as e x t r e m e constipation associated with iron therapy. T h e actual response in h e m a t o c r i t may be somewhat slower in the p r e g n a n t w o m a n than in the n o n p r e g n a n t w o m a n because o f the dilutional effect f r o m the increased plasma volume. Megaloblastic a n e m i a secondary to folic acid deficiency, a l t h o u g h u n c o m m o n , is n o t rare during p r e g n a n c y - - especially in w o m e n with multifetal gestations who do not take prenatal vitamins or c o n s u m e dietary folate. These w o m e n may n o t e x p a n d their b l o o d volume to the same degree as n o r m a l p r e g n a n t w o m e n a n d may develop t r o u b l e s o m e nausea and vomiting, f u r t h e r aggravating the anemia. Moreover, the h e m a t o Table 2. Specific Organ System That may be Affected by Pregnancy Hematologic Cardiovascular Renal Respiratory Metabolic Gastrointestinal
Data from ref 1. crit may actually d r o p after folate r e p l a c e m e n t because o f the n o r m a l b l o o d volume expansion that follows such therapy.
Cardiovascular Changes During Pregnancy T h e heart undergoes several anatomical changes d u r i n g pregnancy, which have litde, if any, significant effects on cardiovascular disease d u r i n g pregnancy. T h e m a j o r change is a shift upward a n d to the left secondary to evaluation o f the d i a p h r a g m (apex is m o r e lateral). T h e r e may be an exaggerated splitting o f the first h e a r t s o u n d a n d a p r o m i n e n t systolic m u r m u r present in the majority o f p r e g n a n t women. T h e r e are several significant h e m o d y n a m i c changes associated with pregnancy, which in turn may affect cardiovascular diseases. T h e m o s t significant o f these changes is cardiac output, which increases by 40% to 50% at term. T h e various changes induced by p r e g n a n c y are summarized in Table 4.1,7,8 Moreover, the various changes of pregnancy may actually mimic cardiac disease. For example, in addition to a comm o n systolic m u r m u r , most n o r m a l p r e g n a n t
Effects of Pregnancy on Specific Diseases
Table 4. Hemodynamic Changes in Term Pregnancies Cardiac output Heart rate Left ventricular stroke work index Systemic vascular resistance Pulmonary vascular resistance Colloid osmotic pressure Pulmonary capillary wedge pressure
'~ 40-50% 1' 10-15 bpm 1' 17% $ 21% ,1, 30-35% .l, 14% 1' 18%
Data from refs 1, 7, and 8.
w o m e n also experience shortness of breath, fatigue, and e d e m a - - all c o m m o n symptoms of heart disease. Effects on Cardiovascular Diseases The various physiologic and h e m o d y n a m i c changes associated with pregnancy may have p r o f o u n d effects on cardiovascular diseases during pregnancy. Pregnancy is a significant "stress" to the pregnant women with cardiovascular disease. T h e hypervolemia associated with exp a n d e d blood volume and the increased "cardiovascular workload" associated with pregnancy, labor and delivery subjects the p r e g n a n t women with heart disease to an increased risk o f cardiac decompensation and failure. O t h e r complications such as hypertension, preeclampsia, blood loss from delivery, and infection f u r t h e r increase the risk o f cardiac decompensation in these women and further complicate therapy. As previously alluded to, the serum levels of various cardiovascular medications may be lower in p r e g n a n t women c o m p a r e d to n o n p r e g n a n t women at "usual dosages" (ie, digoxin). Alt h o u g h most cardiovascular medications can be used safely during pregnancy, there are some notable exceptions, such as angiotensin-converting enzyme (ACE) inhibitors and coumarin derivatives. ACE inhibitors may be associated with congenital hypocalvaria, renal anomalies, oligohydramnios and fetal death. 9-1~ Some antihypertensive agents, although not teratogenic, may be associated with fetal growth restriction. Finally, there are a few types o f heart disease such as pulmonary hypertension, aortic coarctation with valvular involvement, and Mar'fan syndrome with aortic involvement that are associated with significant maternal mortality (50% or higher). 13 Pregnancy also creates special problems for the treatment o f thromboembolic disease dur-
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ing pregnancy. For example, coumarin readily crosses the placenta may be associated with a "fetal warfarin syndrome" or even fetal death. 14 It is generally contraindicated during pregnancy. Thus, p r e g n a n t women with thromboembolic disease or with mechanical heart valves should be treated with heparin instead of coumatin derivatives. Low molecular weight heparin may also be used in these women. T h e course and therapy for chronic or essential hypertension may be significantly affected by pregnancy. These women are at significant risk of developing superimposed preeclampsia (25% or higher), fetal growth restriction, premature delivery, and placental abruption. Antihypertensive medications may n e e d to be increased during pregnancy and multiple agents may he required to control blood pressure during pregnancy. With the exception of ACE inhibitors previously mentioned, most antihypertensive agents may be used during pregnancy. Unfortunately, antihypertensive medications do not appear to improve pregnancy o u t c o m e or prevent preeclampsia but are used for maternal reasons. In fact, antihypertensive medications may he associated with fetal growth restriction in some pregnant women. Antihypertensive medications should therefore be used only in pregnant women with severe hypertension or those with mild hypertension complicated by renal or heart disease. 15 The acute use o f diuretics may be associated with a decrease in uteroplacental blood flow (especially in conditions associated with compromised blood volume such as preeclampsia),16 although data from a recent metaanalysis would indicate that diuretics can be used safely in select women without compromised blood volume. 17 Renal C h a n g e s D u r i n g P r e g n a n c y T h e r e are several anatomic and physiologic changes in the renal system during pregnancy. T h e kidneys increase in size by approximately 1 cm. T h e r e is also m a r k e d increase in dilation of the ureter and renal calyces resulting in "physiologic hydronephrosis." T h e r e is also a relative urinary tract obstruction secondary to h o r m o n a l effects and the growing uterus. T h e functional and physiologic changes occurring in the renal system are summarized in Table 5.
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Table 5. Physiological/Functional Changes in Renal Function During Pregnancy Renal plasma flow Glomerular filtration rate Creatinine clearance Blood urea nitrogen/serum creatinine Glucosuria Protein excretion
1' 1' 50% 1' Common Increases slightly
Data from ref 1.
Effects on Renal Disease
Chronic renal disease per se is generally not affected by pregnancy and may actually appear to improve somewhat secondary to the increase in renal plasma flow and glomerular filtration rate associated with pregnancy. However, pregnant women with significant renal disease (ie, sert~.m creatinine --> 2.5 m g / d L ) and those with associated hypertension may be at significant risk for pregnancy complications, such as severe preeclampsia, fetal growth restriction, and premature delivery.x,a5 The treatment of chronic renal disease and associated hypertension is generally not altered by pregnancy, with the possible exception of medication dosage. However, the pregnant woman is especially susceptible to the development of acute pyelonephritis, especially in the presence of untreated bacteriuria (present in up to 6% to 12% of asymptomatic pregnant women). 1 Acute pyelonephritis is a serious complication during pregnancy and may be associated with sepsis, shock, and multiorgan system dysfunction, such as hematologic (anemia), pulmonary (adult respiratory distress syndrome), renal (decreased creatinine clearance), and hypothalamic (wide temperature ranges). 1,18 With the exception of the tetracyclines, most antibiotics (especially the beta-lactams) can be used safely during pregnancy. However, because of a marked reduction in the endogenous creatinine clearance in up to 20% of pregnant women with acute pyelonephritis, special attention must be given to medications excreted primarily by the kidneys. 1,19 Importantly, up to one third of pregnant women with acute pyelonephritis will develop another urinary tract infection if not given suppressive antibiotic therapy. Ureteral stones are relatively u n c o m m o n during pregnancy and are frequently asymptomatic
during pregnancy because of the ureteral dilatation.
Carbohydrate Metabolism
Pregnancy has been said to be "diabetogenic" secondary to the various changes in carbohydrate metabolism. In normal pregnancy there is usually a fasting hypoglycemia associated with a postprandial hyperglycemia. Hyperinsulinemia is also present (Table 6). 1 Although the exact physiology of these changes is not completely understood, they appear to be secondary to the interaction of estrogen, progesterone and especially, h u m a n placental lactogen. Effects on Disease
Pregnant women are at increased risk of "carbohydrate intolerance" and may develop overt diabetes. Women with insulin d e p e n d e n t diabetes may require more insulin during pregnancy. During the first trimester, such women may experience increasing episodes of hypoglycemia secondary to nausea and vomiting, while in the late trimester they may be more prone to hyperglycemia. Pregnant women with insulin depend e n t diabetes often require frequent hospitalization for diet and insulin adjustment. These women are also at increased risk for preeclampsia, fetal macrosomia, fetal growth restriction (if they have significant vascular disease), fetal congenital anomalies, and prematurity. Tight or rigid glucose control before becoming pregnant and during pregnancy may significantly reduce the risk of these complications. Special attention must also be given to the use of corticosteroids for fetal maturation during pregnancy as they may significantly affect glucose control and even lead to ketoacidosis.
Table 6. Changes in Carbohydrate Metabolism in Pregnancy Fasting hypoglycemia--a.m, ketosis Postprandial hyperglycemia Insulin resistance Hyperinsulinemia Lipolysis and I' circulating fatty acids Inhibition of maternal uptake of glucose and gluconeogenesis (sparing of glucose and protein) Data from ref 1.
Effects of Pregnancy on Specific Diseases
Table 7. Functional Changes in the Respiratory System During Pregnancy Tidal volume--- I' Minute volume---Minute 02 uptake-- 1' Residual volume-- $ Lung volume---unchanged Mild respiratory alkalosis from $ pCO 2 with compensatory 1" in plasma bicarbonate (22 mmol/L) Data from refs 1 and 8.
Respiratory Changes T h e m a j o r anatomical change in the respiratory system during p r e g n a n c y is a rise in the level o f the d i a p h r a g m of approximately 4 cm. T h e r e are several functional changes that may affect p u l m o n a r y illness during p r e g n a n c y (Table 7).
Effects on Disease T h e r e is controversy as to w h e t h e r p u l m o n a r y diseases such as p n e u m o n i a a n d asthma are worse during p r e g n a n c y c o m p a r e d to n o n p r e g n a n t state secondary to the decreased functional residual capacity a n d "relative i m m u n o s u p pression" during pregnancy. Most p u l m o n a r y diseases are the same in p r e g n a n t a n d nonp r e g n a n t women. Most antimicrobials a n d antiasthmatic medications can be used during pregnancy, although the dosage may have to be adjusted. It is i m p o r t a n t to note the usual lower p C O 2 and plasma bicarbonate level during pregnancy when m a n a g i n g w o m e n with an acute asthmatic attack.
Gastrointestinal Changes D u r i n g Pregnancy T h e r e are also several changes in the gastrointestinal, hepatic, and biliary system during pregnancy that can affect various diseases. 1 Anatomically, the stomach and intestines are displaced-resulting in altered physical findings for certain diseases (ie, appendicitis). Gastric emptying and intestinal transit time are also altered during pregnancy. T h e r e is also altered gallbladder function during p r e g n a n c y with decreased e m p tying a n d increase in biliary sludge. Hepatic changes include a decrease in s e r u m a l b u m i n (which in turn may affect s e r u m levels o f medications a n d decrease the colloid oncotic pres-
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sure), increase in alkaline phosphatase, increase in transferring a n d b i n d i n g proteins (which may alter various laboratory tests a n d serum levels of various substances a n d medications), a n d an increase in hepatic microsomal activity (which as previously m e n t i o n e d , may affect drug clearance).
Effects of Gastrointestinal Changes on Disease Because o f the changes in gastric emptying, there may be an increase in pyrosis, as well as an increased risk o f regurgitation a n d aspiration. Biliary sludge may lead to an increase in cholelithiasis and cholecystitis. Certain diseases, such as ulcerative colitis may worsen in up to o n e third o f p r e g n a n t women.
Summary In summary, there are n u m e r o u s physiological changes associated with p r e g n a n c y that can have an effect on various diseases. O f p a r a m o u n t importance is the m a r k e d increase in blood volume, which may affect the s e r u m levels of m a n y medications. Equally i m p o r t a n t is the change in renal function d u r i n g pregnancy, as well as the increase in hepatic microsomal activity, which in turn may result in an increase in clearance or metabolism of certain drugs a n d medications. Finally, the increase in workload associated with pregnancy may result in a significant increase in stress to the cardiovascular system.
References 1. Cunningham FG, MacDonald PC, Gant NF,et al: Williams Obstetrics (ed 20). Appleton & Lange, Stamford, CT, 1997 2. DuffP, JorgensenJH, Gibbs RS, et al: Serum gentamicin levels in patients with post-cesarean endomyometritis. Obstet Gynecol 61:723-727, 1983 3. Zaske DE, Cipolle RJ, Strate RG, et al: Rapid gentamicin elimination in obstetric patients. Obstet Gynecol 56:559564, 1980 4. Gilstrap LC III, Little BB: Antimicrobial agents during pregnancy, in Gilstrap LC III, Little BB (eds): Drugs and Pregnancy (ed 2). Chapman & Hall, NewYork, NY, 1998, pp 45-75 5. LevyRH, Yerby MS: Effects of pregnancy on antiepileptic drug utilization. Epilepsia 26 (Suppl):S52-57, 1985 6. Cantrell DTC, Gilstrap LC III, Little BB: Anticonvulsant drugs during pregnancy. Drugs and Pregnancy, 2nd Edi-
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7.
8.
9.
10.
11.
12.
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don. Eds Gilstrap LC III and Little BB.Chapman & Hall. New York. 1997, pp137-147 Clark SL, Cotton DB, Lee W, Bishop C, et al: Central hemodynamic assessment of normal term pregnancy. A m J Obstet Gynecol 161:1439-1442, 1989 Clark SL, Cotton DB, Hankins GDV, Phelan JP: Pregnancy-induced physiologic alterations. Critical Care Obstetrics. 3rd Edition. Eds Clarke SL, Cotton DV, Hankins GDV, PhelanJP. Blackwell Science. Malden, Mass, 1997, pp 1- 32 BaIT M, Cohen MM: ACE inhibitor fetopathy and hypocalvaria: the kidney-skull connection. Teratology 44: 485-495, 1991 Brent RL, Beckman DA: Angiotensin-converting enzyme inhibitors, an embryopathic class of drugs with unique properties: information for clinical teratology counselors. Teratology 43:543-546, 1991 PiperJM, Ray WA, Rosa FW: Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors. Obstet Gynecol 80:429-432, 1992 Pryde PG, Sedman AB, Nugent CE, et al: Angiotensinconverting enzyme inhibitor fetopathy. J Am Soc Nephrol 3:1575-1582, 1993
13. American College of Obstetricians and Gynecologists. Cardiac Disease in Pregnancy. Technical bulletin no. 168, June 1992 14. Hall JG, Pauli RM, Wilson KM: Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 68:122-140, 1980 15. Anonymous. Nadonal High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 183:81-$22, 2OOO 16. Sibai BM, Grossman RA, Grossman HG: Effects of diuretics on plasma volume in pregnancies with longterm hypertension. Am J Obstet Gynecol 150:831-835, 1984 17. Collins R, Yusuf S, Peto R: Overview of randomized trials of diuretics in pregnancy. BMJ 290:1%23, 1985 18. Gilstrap LC III, Cunningham FG, Whalley PJ: Acute pyelonephritis in pregnancy: An anterospective study. Obstet Gynecol 57:409-413, 1981 19. Whalley PJ, Cunningham FG, Martin FG: Transient renal dysfunction associated with acute pyelonephritis of pregnancy. Obstet Gynecol 46:174-177, 1975
Of the numerous physiological changes associated with pregnancy that may have effects on various diseases, the marked increase in blood volume probably exerts the most pronounced effect. This increase may affect the serum level of many medications, as well as affecting various laboratory tests. Other important changes occur in the renal and hepatic system, which in turn may affect the clearance and metabolism of certain drugs and medications. Moreover, the response to and treatment of various diseases during pregnancy may be affected by the "attitude" o f the health care providers who are often reluctant to perform certain diagnostic tests and procedures on the pregnant woman.
Copyright 9 2001 by W.B. Saunders Company here are numerous anatomical and physiothat occur during pregnancy that can affect specific diseases differently in the pregnant compared to the nonpregnant woman. Many of these changes begin early in pregnancy, soon after implantation and continue throughout gestation. A complete review of these changes and all of the possible disease states, which may be affected by these changes are beyond the scope of this presentation. Only the major changes along with examples of pregnancy effects by these changes will be discussed in detail. The reader should refer to major textbooks in obstetrics, such as the 20th edition of Williams Obstetrics 1, for a more thorough review on this subject. There are a few general principles, however, that are worthy of mention. Paramount among these is the fact that there are "two patients" involved-- mother and fetus (Table 1). Moreover, in addition to the effects on various diseases by pregnancy secondary to the many physiologic and anatomic changes, pregnancy per se may also affect the "attitude" of healthcare providers in their approach to the treatment of illness during pregnancy. For example, there is often great reluctance by clinicians to use certain diagnostic tests (ie, x-rays) and indicated medications during pregnancy. As~ summarized in the 20th edition of Williams Obstetrics, "a women should not be penalized because she is pregnant. "1 In other words, pregnant women should receive appropriate medications, tests, and surgery as indicated. Some of the organ systems most affected by the anatomical and physiological changes of pregnancy are summarized in Table 2.
T logical changes
H e m a t o l o g i c Changes in P r e g n a n c y There are pronounced changes in the hematologic system during pregnancy including changes in blood volume, hemoglobin concentration, hematocrit, iron requirements, immunological and leukocyte function, and blood coagulation (Table 3). 1 Effects on Diseases The increase in blood volume may affect numerous diseases and their treatment during pregnancy. The most pronounced effect of pregnancy-induced hypervolemia is the "dilutional effect" with regards to serum levels of various therapeutic agents. The serum level of many of the beta-lactam antibiotics, such as ampicillin, and aminoglycosides, such as gentamicin, may be decreased in pregnancy compared to nonpregnancy. 2-4The serum levels in anticonvulsant medications may also be lower or "subtherapeutic" during pregnancy. This latter group of medications may be affected not only by the dilutional effect of pregnancy hypervolemia but also by an increase in hepatic microsomal activity leading to an increase in drug clearance (ie, phenytoin). 5 Phenytoin may also be associated From the Department of Obstetrics, Gynecology and Reproductive Scienees, The University of Texas-Houston Medical School, Houston, TX. Address reprint requests to Larry C. Gilstrap, MD, Department of Obstetrics, Gynecologyand Reproductive Sciences, The University of Texas-Houston Medical School, 6431 Fannin, Suite 3.286, Houston, TX 77030; e-mail: [email protected]. Copyright 9 2001 by W..B. Saunders Company 0146-0005/01/2503-0005~35.00/0 doi:l O.1053/sper.2001.245 70
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Table 1. General Principles
Table 3. Hematologic Changes in Pregnancy
Two patients involved Few medications have fetal/teratogenic potential Most medications can be used safely during pregnancy Prepregnancy period is an ideal time for assessing risk, counseling, and adjusting medications Serum levels of medications may have to be 1` Pregnancy may worsen some medical conditions--h e m disease, diabetes, hypertension
Blood volume--- 1` 40%-50% Most rapid in 2nd trimester Plateau in late 3rd trimester Higher in multifetal gestations Hemoglobin/Hematocrit Plasma volume 1` greater than RBCs ~, Whole blood viscosity from dilutional effect "Physiologic anemia" Hemoglobin averages 12 g/dL Iron requirements 1' During pregnancy by total of 1,000 mg 500 mg for maternal RBCs 300 mg for fetal RBCs (active transport) 200 mg "lost" Amount from diet/stores often inadequate Immunological/leukocyte function ? Suppression of humeral/cellular immunological function Depression of leukocyte chemotaxis and adherence Relative leukocytosis--14 to 16,000 during labor and puerperium Coagulation Fibrinogen 1' 50% (average 40 mg/dL) Factors VII, VIII, IX, X also 1` Factors XI, XlII
with folic acid deficiency or anemia. 6 O t h e r classes o f drugs may also be affected. The increase in b l o o d volume usually results in an average increase in plasma volume of 1,000 m L a n d red b l o o d cell volume of 500 mL. This in turn may lead to a decrease in h e m a t o c r i t that may be i n t e r p r e t e d as anemia. T h e increased iron requirements during p r e g n a n c y may lead to iron deficiency a n e m i a during pregnancy, especially in medically indig e n t w o m e n a n d in w o m e n of all socioeconomic classes who are deficient in iron stores. Although iron s u p p l e m e n t a t i o n / t h e r a p y results in a satisfactory response in m o s t of these women, therapy may be difficult in some w o m e n because o f nausea a n d vomiting associated with p r e g n a n c y and o t h e r side effects such as e x t r e m e constipation associated with iron therapy. T h e actual response in h e m a t o c r i t may be somewhat slower in the p r e g n a n t w o m a n than in the n o n p r e g n a n t w o m a n because o f the dilutional effect f r o m the increased plasma volume. Megaloblastic a n e m i a secondary to folic acid deficiency, a l t h o u g h u n c o m m o n , is n o t rare during p r e g n a n c y - - especially in w o m e n with multifetal gestations who do not take prenatal vitamins or c o n s u m e dietary folate. These w o m e n may n o t e x p a n d their b l o o d volume to the same degree as n o r m a l p r e g n a n t w o m e n a n d may develop t r o u b l e s o m e nausea and vomiting, f u r t h e r aggravating the anemia. Moreover, the h e m a t o Table 2. Specific Organ System That may be Affected by Pregnancy Hematologic Cardiovascular Renal Respiratory Metabolic Gastrointestinal
Data from ref 1. crit may actually d r o p after folate r e p l a c e m e n t because o f the n o r m a l b l o o d volume expansion that follows such therapy.
Cardiovascular Changes During Pregnancy T h e heart undergoes several anatomical changes d u r i n g pregnancy, which have litde, if any, significant effects on cardiovascular disease d u r i n g pregnancy. T h e m a j o r change is a shift upward a n d to the left secondary to evaluation o f the d i a p h r a g m (apex is m o r e lateral). T h e r e may be an exaggerated splitting o f the first h e a r t s o u n d a n d a p r o m i n e n t systolic m u r m u r present in the majority o f p r e g n a n t women. T h e r e are several significant h e m o d y n a m i c changes associated with pregnancy, which in turn may affect cardiovascular diseases. T h e m o s t significant o f these changes is cardiac output, which increases by 40% to 50% at term. T h e various changes induced by p r e g n a n c y are summarized in Table 4.1,7,8 Moreover, the various changes of pregnancy may actually mimic cardiac disease. For example, in addition to a comm o n systolic m u r m u r , most n o r m a l p r e g n a n t
Effects of Pregnancy on Specific Diseases
Table 4. Hemodynamic Changes in Term Pregnancies Cardiac output Heart rate Left ventricular stroke work index Systemic vascular resistance Pulmonary vascular resistance Colloid osmotic pressure Pulmonary capillary wedge pressure
'~ 40-50% 1' 10-15 bpm 1' 17% $ 21% ,1, 30-35% .l, 14% 1' 18%
Data from refs 1, 7, and 8.
w o m e n also experience shortness of breath, fatigue, and e d e m a - - all c o m m o n symptoms of heart disease. Effects on Cardiovascular Diseases The various physiologic and h e m o d y n a m i c changes associated with pregnancy may have p r o f o u n d effects on cardiovascular diseases during pregnancy. Pregnancy is a significant "stress" to the pregnant women with cardiovascular disease. T h e hypervolemia associated with exp a n d e d blood volume and the increased "cardiovascular workload" associated with pregnancy, labor and delivery subjects the p r e g n a n t women with heart disease to an increased risk o f cardiac decompensation and failure. O t h e r complications such as hypertension, preeclampsia, blood loss from delivery, and infection f u r t h e r increase the risk o f cardiac decompensation in these women and further complicate therapy. As previously alluded to, the serum levels of various cardiovascular medications may be lower in p r e g n a n t women c o m p a r e d to n o n p r e g n a n t women at "usual dosages" (ie, digoxin). Alt h o u g h most cardiovascular medications can be used safely during pregnancy, there are some notable exceptions, such as angiotensin-converting enzyme (ACE) inhibitors and coumarin derivatives. ACE inhibitors may be associated with congenital hypocalvaria, renal anomalies, oligohydramnios and fetal death. 9-1~ Some antihypertensive agents, although not teratogenic, may be associated with fetal growth restriction. Finally, there are a few types o f heart disease such as pulmonary hypertension, aortic coarctation with valvular involvement, and Mar'fan syndrome with aortic involvement that are associated with significant maternal mortality (50% or higher). 13 Pregnancy also creates special problems for the treatment o f thromboembolic disease dur-
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ing pregnancy. For example, coumarin readily crosses the placenta may be associated with a "fetal warfarin syndrome" or even fetal death. 14 It is generally contraindicated during pregnancy. Thus, p r e g n a n t women with thromboembolic disease or with mechanical heart valves should be treated with heparin instead of coumatin derivatives. Low molecular weight heparin may also be used in these women. T h e course and therapy for chronic or essential hypertension may be significantly affected by pregnancy. These women are at significant risk of developing superimposed preeclampsia (25% or higher), fetal growth restriction, premature delivery, and placental abruption. Antihypertensive medications may n e e d to be increased during pregnancy and multiple agents may he required to control blood pressure during pregnancy. With the exception of ACE inhibitors previously mentioned, most antihypertensive agents may be used during pregnancy. Unfortunately, antihypertensive medications do not appear to improve pregnancy o u t c o m e or prevent preeclampsia but are used for maternal reasons. In fact, antihypertensive medications may he associated with fetal growth restriction in some pregnant women. Antihypertensive medications should therefore be used only in pregnant women with severe hypertension or those with mild hypertension complicated by renal or heart disease. 15 The acute use o f diuretics may be associated with a decrease in uteroplacental blood flow (especially in conditions associated with compromised blood volume such as preeclampsia),16 although data from a recent metaanalysis would indicate that diuretics can be used safely in select women without compromised blood volume. 17 Renal C h a n g e s D u r i n g P r e g n a n c y T h e r e are several anatomic and physiologic changes in the renal system during pregnancy. T h e kidneys increase in size by approximately 1 cm. T h e r e is also m a r k e d increase in dilation of the ureter and renal calyces resulting in "physiologic hydronephrosis." T h e r e is also a relative urinary tract obstruction secondary to h o r m o n a l effects and the growing uterus. T h e functional and physiologic changes occurring in the renal system are summarized in Table 5.
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Table 5. Physiological/Functional Changes in Renal Function During Pregnancy Renal plasma flow Glomerular filtration rate Creatinine clearance Blood urea nitrogen/serum creatinine Glucosuria Protein excretion
1' 1' 50% 1' Common Increases slightly
Data from ref 1.
Effects on Renal Disease
Chronic renal disease per se is generally not affected by pregnancy and may actually appear to improve somewhat secondary to the increase in renal plasma flow and glomerular filtration rate associated with pregnancy. However, pregnant women with significant renal disease (ie, sert~.m creatinine --> 2.5 m g / d L ) and those with associated hypertension may be at significant risk for pregnancy complications, such as severe preeclampsia, fetal growth restriction, and premature delivery.x,a5 The treatment of chronic renal disease and associated hypertension is generally not altered by pregnancy, with the possible exception of medication dosage. However, the pregnant woman is especially susceptible to the development of acute pyelonephritis, especially in the presence of untreated bacteriuria (present in up to 6% to 12% of asymptomatic pregnant women). 1 Acute pyelonephritis is a serious complication during pregnancy and may be associated with sepsis, shock, and multiorgan system dysfunction, such as hematologic (anemia), pulmonary (adult respiratory distress syndrome), renal (decreased creatinine clearance), and hypothalamic (wide temperature ranges). 1,18 With the exception of the tetracyclines, most antibiotics (especially the beta-lactams) can be used safely during pregnancy. However, because of a marked reduction in the endogenous creatinine clearance in up to 20% of pregnant women with acute pyelonephritis, special attention must be given to medications excreted primarily by the kidneys. 1,19 Importantly, up to one third of pregnant women with acute pyelonephritis will develop another urinary tract infection if not given suppressive antibiotic therapy. Ureteral stones are relatively u n c o m m o n during pregnancy and are frequently asymptomatic
during pregnancy because of the ureteral dilatation.
Carbohydrate Metabolism
Pregnancy has been said to be "diabetogenic" secondary to the various changes in carbohydrate metabolism. In normal pregnancy there is usually a fasting hypoglycemia associated with a postprandial hyperglycemia. Hyperinsulinemia is also present (Table 6). 1 Although the exact physiology of these changes is not completely understood, they appear to be secondary to the interaction of estrogen, progesterone and especially, h u m a n placental lactogen. Effects on Disease
Pregnant women are at increased risk of "carbohydrate intolerance" and may develop overt diabetes. Women with insulin d e p e n d e n t diabetes may require more insulin during pregnancy. During the first trimester, such women may experience increasing episodes of hypoglycemia secondary to nausea and vomiting, while in the late trimester they may be more prone to hyperglycemia. Pregnant women with insulin depend e n t diabetes often require frequent hospitalization for diet and insulin adjustment. These women are also at increased risk for preeclampsia, fetal macrosomia, fetal growth restriction (if they have significant vascular disease), fetal congenital anomalies, and prematurity. Tight or rigid glucose control before becoming pregnant and during pregnancy may significantly reduce the risk of these complications. Special attention must also be given to the use of corticosteroids for fetal maturation during pregnancy as they may significantly affect glucose control and even lead to ketoacidosis.
Table 6. Changes in Carbohydrate Metabolism in Pregnancy Fasting hypoglycemia--a.m, ketosis Postprandial hyperglycemia Insulin resistance Hyperinsulinemia Lipolysis and I' circulating fatty acids Inhibition of maternal uptake of glucose and gluconeogenesis (sparing of glucose and protein) Data from ref 1.
Effects of Pregnancy on Specific Diseases
Table 7. Functional Changes in the Respiratory System During Pregnancy Tidal volume--- I' Minute volume---Minute 02 uptake-- 1' Residual volume-- $ Lung volume---unchanged Mild respiratory alkalosis from $ pCO 2 with compensatory 1" in plasma bicarbonate (22 mmol/L) Data from refs 1 and 8.
Respiratory Changes T h e m a j o r anatomical change in the respiratory system during p r e g n a n c y is a rise in the level o f the d i a p h r a g m of approximately 4 cm. T h e r e are several functional changes that may affect p u l m o n a r y illness during p r e g n a n c y (Table 7).
Effects on Disease T h e r e is controversy as to w h e t h e r p u l m o n a r y diseases such as p n e u m o n i a a n d asthma are worse during p r e g n a n c y c o m p a r e d to n o n p r e g n a n t state secondary to the decreased functional residual capacity a n d "relative i m m u n o s u p pression" during pregnancy. Most p u l m o n a r y diseases are the same in p r e g n a n t a n d nonp r e g n a n t women. Most antimicrobials a n d antiasthmatic medications can be used during pregnancy, although the dosage may have to be adjusted. It is i m p o r t a n t to note the usual lower p C O 2 and plasma bicarbonate level during pregnancy when m a n a g i n g w o m e n with an acute asthmatic attack.
Gastrointestinal Changes D u r i n g Pregnancy T h e r e are also several changes in the gastrointestinal, hepatic, and biliary system during pregnancy that can affect various diseases. 1 Anatomically, the stomach and intestines are displaced-resulting in altered physical findings for certain diseases (ie, appendicitis). Gastric emptying and intestinal transit time are also altered during pregnancy. T h e r e is also altered gallbladder function during p r e g n a n c y with decreased e m p tying a n d increase in biliary sludge. Hepatic changes include a decrease in s e r u m a l b u m i n (which in turn may affect s e r u m levels o f medications a n d decrease the colloid oncotic pres-
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sure), increase in alkaline phosphatase, increase in transferring a n d b i n d i n g proteins (which may alter various laboratory tests a n d serum levels of various substances a n d medications), a n d an increase in hepatic microsomal activity (which as previously m e n t i o n e d , may affect drug clearance).
Effects of Gastrointestinal Changes on Disease Because o f the changes in gastric emptying, there may be an increase in pyrosis, as well as an increased risk o f regurgitation a n d aspiration. Biliary sludge may lead to an increase in cholelithiasis and cholecystitis. Certain diseases, such as ulcerative colitis may worsen in up to o n e third o f p r e g n a n t women.
Summary In summary, there are n u m e r o u s physiological changes associated with p r e g n a n c y that can have an effect on various diseases. O f p a r a m o u n t importance is the m a r k e d increase in blood volume, which may affect the s e r u m levels of m a n y medications. Equally i m p o r t a n t is the change in renal function d u r i n g pregnancy, as well as the increase in hepatic microsomal activity, which in turn may result in an increase in clearance or metabolism of certain drugs a n d medications. Finally, the increase in workload associated with pregnancy may result in a significant increase in stress to the cardiovascular system.
References 1. Cunningham FG, MacDonald PC, Gant NF,et al: Williams Obstetrics (ed 20). Appleton & Lange, Stamford, CT, 1997 2. DuffP, JorgensenJH, Gibbs RS, et al: Serum gentamicin levels in patients with post-cesarean endomyometritis. Obstet Gynecol 61:723-727, 1983 3. Zaske DE, Cipolle RJ, Strate RG, et al: Rapid gentamicin elimination in obstetric patients. Obstet Gynecol 56:559564, 1980 4. Gilstrap LC III, Little BB: Antimicrobial agents during pregnancy, in Gilstrap LC III, Little BB (eds): Drugs and Pregnancy (ed 2). Chapman & Hall, NewYork, NY, 1998, pp 45-75 5. LevyRH, Yerby MS: Effects of pregnancy on antiepileptic drug utilization. Epilepsia 26 (Suppl):S52-57, 1985 6. Cantrell DTC, Gilstrap LC III, Little BB: Anticonvulsant drugs during pregnancy. Drugs and Pregnancy, 2nd Edi-
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7.
8.
9.
10.
11.
12.
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don. Eds Gilstrap LC III and Little BB.Chapman & Hall. New York. 1997, pp137-147 Clark SL, Cotton DB, Lee W, Bishop C, et al: Central hemodynamic assessment of normal term pregnancy. A m J Obstet Gynecol 161:1439-1442, 1989 Clark SL, Cotton DB, Hankins GDV, Phelan JP: Pregnancy-induced physiologic alterations. Critical Care Obstetrics. 3rd Edition. Eds Clarke SL, Cotton DV, Hankins GDV, PhelanJP. Blackwell Science. Malden, Mass, 1997, pp 1- 32 BaIT M, Cohen MM: ACE inhibitor fetopathy and hypocalvaria: the kidney-skull connection. Teratology 44: 485-495, 1991 Brent RL, Beckman DA: Angiotensin-converting enzyme inhibitors, an embryopathic class of drugs with unique properties: information for clinical teratology counselors. Teratology 43:543-546, 1991 PiperJM, Ray WA, Rosa FW: Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors. Obstet Gynecol 80:429-432, 1992 Pryde PG, Sedman AB, Nugent CE, et al: Angiotensinconverting enzyme inhibitor fetopathy. J Am Soc Nephrol 3:1575-1582, 1993
13. American College of Obstetricians and Gynecologists. Cardiac Disease in Pregnancy. Technical bulletin no. 168, June 1992 14. Hall JG, Pauli RM, Wilson KM: Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 68:122-140, 1980 15. Anonymous. Nadonal High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 183:81-$22, 2OOO 16. Sibai BM, Grossman RA, Grossman HG: Effects of diuretics on plasma volume in pregnancies with longterm hypertension. Am J Obstet Gynecol 150:831-835, 1984 17. Collins R, Yusuf S, Peto R: Overview of randomized trials of diuretics in pregnancy. BMJ 290:1%23, 1985 18. Gilstrap LC III, Cunningham FG, Whalley PJ: Acute pyelonephritis in pregnancy: An anterospective study. Obstet Gynecol 57:409-413, 1981 19. Whalley PJ, Cunningham FG, Martin FG: Transient renal dysfunction associated with acute pyelonephritis of pregnancy. Obstet Gynecol 46:174-177, 1975