Endocrine-Hypertension Division, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, Massachusetts 02115
Address correspondence and reprint requests to: Ellen W. Seely, M.D., Endocrine-Hypertension Division, Brigham and Womens Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail:
Hypertensive disorders of pregnancy affect approximately 68% of pregnancies and are the second leading cause of maternal mortality in the United States. They are also a leading cause of maternal and neonatal morbidity (1). Despite the frequency of these disorders, their cause is unknown and their treatment is inadequate. Hypertension in pregnancy is a gender specific condition by definition. As with many other disorders that affect women, hypertension in pregnancy involves the overlap of the fields of internal medicine and obstetrics. Whereas most essential hypertension is managed by internists, when a pregnant woman is hypertensive, the care of the hypertension is managed primarily by obstetricians. This leads to an interesting potential duality in the focus and approach of each specialty. In general, hypertension in pregnancy has been viewed as an obstetrical disorder and has not been an area of investigation for most internists. For the obstetrician, the disorder is one of pregnancy itself, and the focus is on the outcome of the individual pregnancy. On the other hand, for the internist an emerging focus is on the potential implications of hypertensive pregnancy for the future health of the individual woman.
Terminology
Hypertension in pregnancy is categorized according to the American College of Obstetrics and Gynecology as: 1) preexisting essential hypertension, 2) preeclampsia, 3) gestational hypertension, or 4) preeclampsia superimposed upon preexisting hypertension (1). These categories are important in that the various forms of hypertension that occur during pregnancy may imply different prognoses for the pregnancy itself as well as potentially for the long-term health of the mother. They may also represent different etiologies. Preeclampsia and gestational hypertension are defined as an increase in systolic blood pressure to 140 mm Hg or more, or diastolic to 90 mm Hg or more after 20 weeks of pregnancy and resolving postpartum. Preeclampsia differs from gestational hypertension due to its multisystem involvement, such as proteinuria as described below. When a women with preexisting hypertension develops an exacerbation of her hypertension during pregnancy accompanied by proteinuria or other systemic signs, this is termed hypertension with superimposed preeclampsia.
Diagnosis and clinical course
When a woman presents with hypertension in pregnancy, the first step is to establish whether it is of new onset or is preexisting. With more women delaying child bearing until later ages, pregnancies are occurring more frequently at an age when women have already developed essential hypertension. Essential hypertension carries with it an excellent prognosis in pregnancy unless superimposed preeclampsia develops. Two major areas of difference in management between hypertension during pregnancy vs. hypertension outside of pregnancy are in the choice of antihypertensive and the goal of treatment.
A major issue in antihypertensive use is the avoidance of certain classes of antihypertensives such as converting enzyme inhibitors, which can cause renal damage and fetal and neonatal demise (2), and angiotensin II receptor blockers, which may have similar effects. Therefore, practitioners caring for women with essential hypertension should discuss family planning with their patients and alter pharmacological treatment accordingly.
Alpha-methyl dopamine remains the most widely used antihypertensive in pregnancy and is recommended by the American College of Obstetrics and Gynecology (1) and by the National Working Group on High Blood Pressure in Pregnancy (3) as the first line antihypertensive. This recommendation is based on its long history of successful use in pregnancy without negative sequelae to the fetus or neonate. When alpha methyldopa is insufficient to control blood pressure, calcium channel blockers and beta-blockers are considered the second line agents. More studies are needed on comparative effectiveness and side effects of antihypertensive drugs in pregnancy to allow more informed clinical decision making.
In addition to differences in medication choice during pregnancy, goals for blood pressure control differ as well. Although there is controversy about the exact level of blood pressure at which pharmacological treatment should be initiated, there is consensus that the level is higher than is recommended in the nonpregnant state. The National Working Group on High Blood Pressure in Pregnancy (3) recommends initiating treatment when diastolic pressure exceeds 100 mm Hg. Because blood pressure usually falls during pregnancy, antihypertensive therapy can often be tapered.
Typically, new onset hypertension in pregnancy presents in the later half of gestation, usually in the third trimester, and is defined clinically as preeclampsia or gestational hypertension. There is much controversy as to whether these two conditions are pathogenically distinct, or whether they represent a single underlying process but are different points in a continuum. When proteinuria or other systemic signs such as generalized edema and elevated uric acid are present, it is termed preeclampsia.
Preeclampsia is the pregnancy-specific disorder that carries with it the greatest fetal and maternal mortality. When hemolysis, elevated liver function test, and low platelets occur, the syndrome is called by the acronym "HELLP". One of the most severe maternal risks is the development of eclampsia, which is characterized by generalized seizures occurring in a woman without any prior history of seizure disorder. The most severe fetal risk is intrauterine fetal demise, and intrauterine growth retardation is common. Preeclampsia most often occurs in first pregnancies, and thus far, no interventions have been proven to decrease the risk of development of preeclampsia. Once the condition is present, magnesium sulfate is superior to phenytoin as prophylaxis against seizures but does not treat other aspects of the disorder. The only effective treatment is delivery of the fetus, regardless of gestational age. For this reason, preeclampsia is a leading cause of prematurity. Antihypertensive treatment of the mother may lower maternal risks of hypertensive complications, but it has not been shown to benefit the fetus. In fact, some studies support greater intrauterine fetal growth retardation with antihypertensive therapy such as beta-blockers (1) rather than withholding such treatment.
Gestational hypertension is new onset hypertension arising in pregnancy, without proteinuria or other multisystem involvements that are seen in preeclampsia. Because preeclampsia may evolve over time, the diagnosis can only truly be made in retrospect. Gestational hypertension carries with it a good prognosis for the outcome of the pregnancy. In contrast to preeclampsia, which occurs typically in the first pregnancy, gestational hypertension commonly recurs in subsequent pregnancies. Whereas gestational hypertension may have a more benign course during pregnancy, it may carry with it the same increased cardiovascular risk in later life as preeclampsia.
Etiology
As is true of the etiology of essential hypertension, the etiology of pregnancy-induced hypertension remains unknown and is likely to be multifactorial. One of the hindrances to understanding the pathogenesis of new onset hypertension in pregnancy is the absence of an animal model. New onset hypertension in pregnancy is not seen naturally in any species. Various experimental animal models have been proposed but are not well extended to humans. Therefore, most of the meaningful research on this topic comes from clinical studies, which underscores the need for more clinical research support in this area.
Many of the popular theories for new onset hypertension in pregnancy
are depicted in Table 1. These will be
discussed in brief apart from insulin resistance, which will be
discussed in more detail as a possible mechanism for long-term
sequalae.
|
Insulin resistance in hypertensive pregnancy
Associated with insulin resistance is the finding of lipid abnormalities in women with new onset hypertension in pregnancy (15). These lipid abnormalities included higher triglycerides and free fatty acids and lower high density lipoprotein-2 and have also been shown to predate the onset of hypertension in pregnancy (16). The combination of insulin resistance, lipid abnormalities and hypertension has been viewed as Syndrome X of pregnancy.
One of the most intriguing ideas about new onset hypertension in pregnancy focuses not on the pregnancy itself but on the implications of a pregnancy complicated by new onset hypertension on the long-term cardiovascular risk factors in women. In this model, hypertension in pregnancy may be viewed as similar to gestational diabetes. It is clear that women with a history of gestational diabetes have an increased risk for future development of type 2 diabetes later in life. Estimates of this increased risk range as high as 60%. Pregnancy is seen as a metabolic stress on the woman that unmasks an underlying predisposition for glucose intolerance. Such a view of gestational diabetes is advantageous in several regards. It allows the study of the mechanism of disease when glucose intolerance is present and when it is not in the same individuals studied within short-term time intervals. Furthermore, it allows the potential for interventions to prevent the long-term sequelae. In this way, pregnancy offers a window into the future health of a womana window that does not exist in men.
Long-term sequelae of hypertensive pregnancy
The long-term sequelae of hypertension in pregnancy were evaluated as early as the 1960s, when Adams and MacGillivray noted an increase risk of hypertension many years after a hypertensive pregnancy (17). However, over the next 30 years, most investigation in this field focused on the health of the pregnancy itself and on improving its immediate outcome. Several investigators remained focused on the long-term prognosis of women with a history of hypertensive pregnancies. Results have been conflicting, with some authors finding no increased incidence of hypertension later in life (18).
With the emerging focus on the importance of cardiovascular disease as the leading cause of death in women, the lessons that may be learned from hypertension in pregnancy for long-term cardiovascular health in women will be the focus of the remainder of this commentary. Most recent studies that have examined women at least 1020 yr postpartum support the earlier observations of increased blood pressure later in life for women who have a history of hypertensive pregnancy (19, 20). Of note, these same women have higher insulin levels, which correlates with both systolic and diastolic blood pressure (19).
The increase in blood pressure as well as carbohydrate and lipid abnormalities may explain the suggested increase in cardiovascular risk in these women. Mann et al.(21), in a retrospective case-control study of 77 women, reported a greater incidence of myocardial infarction in women with a history of preeclampsia. In this series, a history of preeclamptic pregnancy requiring hospitalization or medication carried with it a 3-fold increased risk of myocardial infarction. In another study, a review of 7543 obstetrical records demonstrated that women with a history of hypertension in pregnancy had an increased relative risk of death from ischemic heart disease compared to the general population (22). Of interest, the risk increased, moving from categories of any hypertension in pregnancy, to preeclampsia (defined as hypertension and proteinuria), to eclampsia.
A recent analysis of women who were recruited for the Royal College of General Practitioners oral contraception study showed that women with a history of hypertension in pregnancy had a significantly increased risk of hypertension, myocardial infarction, and ischemic heart disease later in life (23). The relative risk of hypertension was 2.35, of acute myocardial infarction 2.24, of chronic ischemic heart disease 1.65, and of angina 1.53. Of particular interest was the finding that women who had had normotensive pregnancies had a lower risk of subsequent essential hypertension than women who were nulliparous. This study supports the concept that pregnancy can be a predictor of not only increased but also decreased long-term cardiovascular risk for women.
These studies, however, are all limited in that they rely on a medical diagnosis that was not well standardized nor made using current terminology. In addition, many of these did not adjust for many of the possible confounders, such as obesity. Furthermore, there is no way to determine which criteria were used for the diagnosis of hypertension in pregnancy and whether these criteria were consistent within and between studies. Despite the limitations of these studies, they support the importance of looking at cardiovascular sequelae in women with a history of hypertensive pregnancy. Because hypertension complicates approximately 68% of all pregnancies, the information that could be gained concerning future cardiovascular disease risk would affect a large proportion of the female population. Therefore, studies investigating the long-term prognosis of women with a history of hypertensive pregnancy are of significant importance. Furthermore, defining whether women with any type of new onset hypertension in pregnancy have increased cardiovascular risk or whether the increase is specific to those with preeclampsia is another area for investigation.
Genetics
Support for the theory that pregnancy-induced hypertension unmasks a genetic predisposition for essential hypertension comes from similarities in angiotensinogen gene allele distribution in these two conditions. Ward et al.(24) have reported a higher incidence of a variant allele of the angiotensinogen gene in women with a history of preeclamptic pregnancy compared with normotensive pregnancy. This same variant allele has also been found more frequently in essential hypertensives. Another group of investigators found another abnormality in the angiotensinogen gene in women with hypertension in pregnancy (25). However, other investigators have not confirmed these results (26, 27). Conflicting results may arise because of the different populations studied and because of the potential heterogeneity in etiology of hypertension in pregnancy.
The future
In summary, pregnancy is associated, in certain women, with hypertension and other manifestations of insulin resistance. The blood pressure and metabolic responses that occur during pregnancy may be important and generally unrecognized predictors of future cardiovascular risk in these women. Because women with a history of hypertension in pregnancy make up 68% of the female population, more investigation is warranted into the implications of hypertension in pregnancy beyond the pregnancy itself. The nature of this condition will require a multidisciplinary approach.
Footnotes
1 Dr. Seely is a Harvard Medical School Scholar in Medicine.
Received January 20, 1999.
Revised March 15, 1999.
Accepted March 16, 1999.
References