A 30-Year-Old Woman With Chronic Hypertension Trying to Conceive

DR BURNS: Mrs F is a 30-year-old woman with a history of chronic hypertension and possible preeclampsia with her first pregnancy. She wonders how her hypertension will affect a future intended pregnancy. She has commercial insurance.

Mrs F reports that she has had elevated blood pressure (150/100 mm Hg) at physician visits and at home since her early 20s. She has never been treated with antihypertensive medications. During her first pregnancy, 4 years ago, she was noted to have elevated blood pressure at 5 months' gestation but was not given medication. At 34 to 35 weeks, she was noted to have intrauterine growth restriction. She was monitored closely with regular nonstress tests and, at 38 weeks, she was delivered because of worsening hypertension. It is not clear if she developed superimposed preeclampsia. She required treatment with intravenous magnesium and antihypertensive agents at delivery, and delivered a healthy, 5-lb, 7-oz girl. Following delivery, her blood pressure remained elevated; however, she was not prescribed medication.

Mrs F desires a second pregnancy and is undergoing fertility treatment with clomiphene citrate and intrauterine insemination. The cause of her infertility remains unknown. She plans to have another cycle of intrauterine insemination.

Her medical history is otherwise unremarkable except for an episode of sepsis in January 2006 that was thought to be due to diverticulitis or appendicitis. She has been well since and has otherwise enjoyed good health.

Her only medication is fluoxetine, 20 mg, which she takes as needed for premenstrual syndrome. She is allergic to amoxicillin with development of a rash.

Her family history is remarkable for hypertension in her mother and father and coronary artery disease in her father. She has a sister who was recently diagnosed as having renal artery stenosis and another with severe intellectual disability related to spinal meningitis. She does not know the medical histories of her other sister or 2 brothers.

She is currently married and works as a special education teacher. She does not smoke cigarettes. She drinks 1 glass of wine per night. At the time of her initial visit, she was not exercising regularly.

On examination, her blood pressure was 139/90 mm Hg, with a body mass index of 23.7 (calculated as weight in kilograms divided by height in meters squared). She appeared well and had otherwise normal physical examination results. Her laboratory measurements revealed glucose, 78 mg/dL; creatinine, 0.8 mg/dL; potassium, 5.1 mEq/L (normal range, 3.5-5.0 mEq/L); calcium, 10.9 mEq/L (normal range, 8.8-10.6 mEq/L); thyrotropin, 1.2; white blood cells, 4.7 K/uL; hemoglobin, 15.2 g/dL; platelets, 297 K/uL; and a normal urinalysis result other than trace ketones. Her potassium and calcium levels were found to be normal on repeat examination.

She is concerned about how her hypertension will affect a future pregnancy and what, if anything, she should do now to prevent future problems.

My mother and my father both have high blood pressure. Right now my sister, who is 23, was just found to have high blood pressure. So, it's in the family.

During my last pregnancy, toward I’d say my 34th or 35th week, when they knew my blood pressure was an issue, they started monitoring me more closely, and they found that my daughter had stopped growing. My doctor at the time was pushing to get me to 38 weeks so that she could be delivered at term as opposed to a preemie. And we made it.

Now, I want to clear up any issues that I have, as far as the blood pressure goes, because it's elevated and it's a concern going into pregnancy. I need to know how involved it could get, especially because I have a daughter at home and a full-time job. I want her to have a sibling, so my husband and I are willing to take risks, to take the medications, and to go through the process. It comes as a struggle, as a family issue, because he's more worried about me. So that's where we kind of have to talk about it a lot, and just be aware of risks, and the stress that it will put on me if I do become pregnant.

Sitting in a doctor's office, I want answers, and I think I’m hesitant to show any emotion that it's hard. So I don't think it's always that the doctors don't acknowledge the emotional aspects of it. I think, I know myself—I can speak for myself and no one else. I go in there, I look for information, and the emotional stuff stays at home.

How should chronic hypertension in a woman be managed before conception, what are the goals of therapy, and what are the preferred antihypertensive agents? What is a normal blood pressure during and after pregnancy and how does pregnancy affect blood pressure? How does hypertension affect the course of a pregnancy, does hypertension ever become a contraindication to pregnancy, and does antihypertensive therapy improve pregnancy outcome? How should hypertension be managed in pregnancy, what are the goals of therapy, and what are the preferred antihypertensive agents? What is preeclampsia, what are the risk factors for developing preeclampsia, and can preeclampsia be prevented? Is preeclampsia a risk factor for future cardiovascular events? What do you suggest for Mrs F? What does the future hold?

DR POWRIE: Mrs F is a 30-year-old woman with chronic hypertension who was taking no medications when I first saw her. Her previous pregnancy was complicated by intrauterine growth restriction and worsening hypertension. She is now undergoing treatment for infertility. She wants to know how her hypertension will affect a future pregnancy and how it can be safely managed now and during a pregnancy. Her comments and questions reflect how unsettling medical issues can be for women (and their families) who are either pregnant or considering a pregnancy.

Hypertension is defined both in and out of pregnancy as a blood pressure of 140/90 mm Hg or greater on at least 2 distinct occasions.¹ Blood pressure should be measured with the patient sitting in a chair, with her arm supported at the level of the heart and using a properly sized manual cuff that has been calibrated against a mercury sphygmomanometer.² Unfortunately, use of uncalibrated oscillometric automated machines^{3 - 5} and ill-fitting cuffs⁶ and improper positioning of the patient (particularly measurement of blood pressure in the left lateral decubitus position) are common occurrences in obstetric care.⁷

Whenever the diagnosis of hypertension is made, consideration of secondary causes, although rare, should be considered.¹ Unfortunately, obstetric visits are not the ideal setting for in-depth evaluations of medical problems. Table 1 reviews the secondary causes of hypertension and a simple, albeit imperfect, screen for each that in my opinion is appropriate for busy obstetric practices. These screens should also be performed in all pregnant women who are found to have an elevated blood pressure at earlier than 20 weeks' gestation. The screens probably should also be performed in all women with hypertension presenting after 20 weeks' gestation in whom there is any doubt about the diagnosis of preeclampsia.

Pregnancy (and contraception) may be one of the only reasons women in this age group seek medical care and provides a unique opportunity to address cardiovascular risk in women. Young women with hypertension should be examined for evidence of “target organ” damage due to chronic hypertension by obtaining an electrocardiogram, performing a fundoscopic examination of the retinal vessels, and assessing the carotid, femoral, and peripheral pulses. All patients should also have a complete evaluation for other cardiac risk factors (eg, hypercholesterolemia, smoking, diabetes, family history, sedentary lifestyle), which, in young women, are often far more potent predictors of cardiovascular disease than is isolated hypertension. If a woman presents with hypertension during pregnancy, cholesterol should not be measured until at least 6 weeks post partum, as cholesterol levels are frequently elevated in normal pregnancies and elevations in this time frame may still be attributable to the pregnancy.¹⁹

Mrs F underwent these evaluations and did not appear to have any secondary cause of her hypertension. Although her calcium and potassium levels were slightly elevated on initial testing, both were normal on subsequent evaluation. Her only additional cardiac risk factor was her failure to engage in a regular exercise program.

Despite the absence of sex-specific recommendations for treatment of hypertension, premenopausal women with isolated hypertension are at a relatively low absolute short-term risk of cardiovascular disease compared with men. While the relative risk (RR) of treatment of high blood pressure in both sexes is similar, in women aged 30 to 54 years, the absolute number who benefit from treatment is fewer compared with men. While hypertension treatment in women results in a 41% risk reduction in cerebrovascular events (95% confidence interval [CI], 8%-63%) and a 27% reduction in cardiovascular events (95% CI, 4%-44%), the number of women needed to treat for 5 years to prevent 1 stroke or myocardial infarction is 259.^{20 - 23} Most of this benefit is seen in black women. Among white women of this age, treatment of mild hypertension has not consistently produced statistically significant benefit (or harm).²⁴ Given the potential adverse fetal effects of antihypertensive therapy during pregnancy, less stringent treatment goals may be justifiable during pregnancy. Furthermore, other cardiovascular risk factors in premenopausal women with hypertension may be as important as their blood pressure.

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7)¹ recommends lifestyle modification as the initial treatment of mild or “stage 1” hypertension (140-159/90-99 mm Hg). Table 2 reviews the approximate decrease in systolic blood pressure that can be observed with different lifestyle modifications.

If these lifestyle modifications are unsuccessful in a woman who has hypertension, the next step is to try medication. The first-line treatments that are recommended by the JNC-7 are thiazide-type diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, β-blockers, and calcium channel blockers.²⁵ However, despite these agents having good evidence of efficacy in preventing the long-term outcomes associated with hypertension, concerns about fetal safety make many of these agents less ideal for women who are trying to conceive. Ideally, women with hypertension who desire a pregnancy should be treated with medications that they can safely take at the time of conception and continue to take into the pregnancy. Sometimes this is not possible because of issues with adherence, costs, or adverse effects or because there is a compelling indication in the short term, such as diabetic nephropathy, to use an agent that is not generally recommended for pregnancy. In these situations, the woman should be counseled to notify her physician in the days following her first missed period so that she can promptly switch to a preferred agent. Available data about the safety of different antihypertensive agents in pregnancy are reviewed in Table 3 but the current literature in this area remains too inadequate for any of the safety classifications listed to be considered definitive.^{43 - 44}

Labetalol and methyldopa are generally perceived to be the preferred antihypertensive agents for use in pregnancy. They both have the single major disadvantage of being twice-daily medications. Methyldopa is the better-studied antihypertensive agent of the 2. Although both atenolol³⁶ (110 children at 1 year) and nifedipine (190 children at 18 months)³² have data evaluating the health and neurodevelopment of exposed infants for up to 12 to 18 months, methyldopa is the only antihypertensive agent with follow-up of exposed children into their school years (242 children at 7.5 years), offering some reassurance that its use in pregnancy causes no significant physical, cognitive, or behavioral effects.⁴⁵ However, up to 20% of patients find the adverse effects of methyldopa (eg, lack of energy and dizziness) intolerable and need to switch to a different agent.⁴⁶ Although the combined α-/β-blocker labetalol is perhaps the next most studied antihypertensive agent in pregnancy and is generally very well tolerated, it lacks the long-term follow-up data that exist for methyldopa.

For patients in whom these agents are contraindicated, ineffective, or not tolerated, the extended-release form of the calcium channel blocker nifedipine or the β-blockers pindolol and the long-acting form of metoprolol are also acceptable options. Adverse pregnancy outcomes have not been associated with this class of agents, but the published experience with their use in early pregnancy is limited.^{27 ,47 - 48}

Hydrochlorothiazide is encouraged as a first-line agent for treatment of hypertension in nonpregnant patients because it is inexpensive, is well tolerated, and can be taken once a day. After many years of use, there is no evidence that this medication has adverse effects when used early in pregnancy.²⁷ Use of thiazide diuretics at a later stage in pregnancy has not been shown to adversely affect pregnancy outcomes but may affect maternal blood volume expansion⁴¹ and has been associated with an increased incidence of maternal adverse effects.⁴⁹ Therefore, I do not routinely use hydrochlorothiazide during pregnancy but believe it to be a reasonable option for blood pressure control in women who are trying to conceive.

The only antihypertensive agents that are contraindicated in pregnancy are the ACE inhibitors and the angiotensin receptor blockers because of their effects on fetal kidneys, lungs, and scalp. Until recently, it was generally believed that these medications should be discontinued during pregnancy but that their use at the time of conception was considered justifiable. However, more recent data suggest that use of these agents even around the time of conception may increase the risk of cardiac malformations.⁵⁰ Therefore, I no longer use these agents in women who are seeking a pregnancy unless they have a compelling short-term indication, such as a history of diabetic nephropathy or congestive heart failure. While no other commonly used antihypertensive agents have been shown to be teratogens, all have a critical lack of published data to guide treatment decisions.

When I first met Mrs F, she was not pregnant and her blood pressure had been greater than 140/90 mm Hg for some time. She believed that she had delayed taking a medication long enough and wanted to start something while she modified her lifestyle. Her other cardiac risk factors were such that I would have been comfortable with either approach.

Because of Mrs F's difficulty with infertility, we were not sure how long it would take for her to conceive, so we opted to use an inexpensive once-a-day regimen that would be reasonable for her to take when attempting to become pregnant, even if she did not continue that medication while pregnant. I treated her with hydrochlorothiazide, 12.5 mg/d, with the goal of bringing her blood pressure down to less than 140/90 mm Hg. She began exercising more and lost some weight, and with the medication, her blood pressure came under good control. If the hydrochlorothiazide had not been effective for her, I would have then switched her to methyldopa or labetalol if she thought she could take a twice-daily regimen. If not, I would have suggested pindolol, oxprenolol, or a long-acting form of nifedipine.

Blood pressure decreases by 10 to 15 mm Hg in the first 16 to 18 weeks of pregnancy so that the average blood pressure for a woman in her 20th week of pregnancy is about 100/60 mm Hg.⁵¹ It then increases gradually toward its previous prepregnancy values, reaching a plateau at 36 weeks' gestation. Importantly, this pattern of blood pressure change may be exaggerated in women with chronic hypertension² such that hypertension may be masked in the first half of pregnancy and manifest only in the final trimester, leading the clinician to incorrectly attribute the increasing blood pressure to preeclampsia.

Most women with chronic hypertension can expect a good pregnancy outcome and should be reassured of this fact. The greatest risk associated with chronic hypertension in pregnancy is that of developing superimposed preeclampsia, characterized by worsening maternal hypertension and proteinuria and an increased risk of adverse perinatal outcomes. Preeclampsia occurs in at least 25% of women with chronic hypertension—a 2- to 4-fold increase from that seen in the general population.^{52 - 54} The incidence may be higher than 40% in patients with severe or “stage 2” hypertension (>160/100 mm Hg) or in patients with chronic hypertension who had preeclampsia in a prior pregnancy.⁵⁵ Fortunately, serious irreversible maternal complications from preeclampsia are rare in the developed world because of the ability of clinicians to identify most cases early and deliver them safely. The greatest fetal risk is that of prematurity, which occurs in 12% to 34%⁵⁴ of pregnancies in women with chronic hypertension and in up to 70% of women who have severe hypertension at the beginning of their pregnancy.⁵⁶ With current neonatal management, however, most of these infants do well, especially if born after 28 weeks' gestation.⁵⁷ Women with chronic hypertension have the following increased risks compared with women without hypertension: abruption (in 0.7%-1.5% of patients [summary odds ratio, 2.0; 95% CI, 1.1-3.7]), birth weight of less than 2500 g (RR, 5.5; 95% CI, 2.6-11.9), and perinatal mortality (random-effects summary odds ratio, 3.4; 95% CI, 3.0-3.7).⁵⁴ Eight to fifteen percent of pregnancies in women with chronic hypertension result in small-for-gestational-age fetuses.⁵⁶ However, with careful obstetric and neonatal care, most of these complications can be managed with good long-term outcomes for both mother and infant. For this reason, I never advise a woman against pregnancy because of chronic hypertension.

Does antihypertensive therapy improve any of these pregnancy outcomes for women with chronic hypertension? As of 2000, 13 randomized controlled trials had examined the benefits of antihypertensive therapy during pregnancy,⁵⁴ evaluating 11 different regimens in 1055 participants in 6 countries. Only 6 of these studies were placebo-controlled and most studied either labetalol or methyldopa. Despite these limitations, the working group reviewing the studies concluded that antihypertensive therapy does not appear to decrease the incidence of the common complications of hypertension in pregnancy (eg, intrauterine growth restriction [IUGR] and perinatal mortality) and, in particular, that it does not decrease a woman's chances of developing preeclampsia. The authors of this review did caution that the data lacked sufficient power to detect a 20% to 30% beneficial or adverse treatment effect. Subsequent data have suggested the possibility that treatment of mild hypertension in pregnancy (particularly with β-blockers) may actually increase the risk of a small-for-gestational-age fetus,^{34 ,58} one of the outcomes that treatment would be hoped to prevent.

Mrs F was well aware of most of these risks, having had her previous pregnancy complicated by both IUGR and worsening hypertension. I reviewed the potential complications and prepared her for the possibility of the need for another induced or even preterm delivery. However, I also reassured her that she was still most likely to have an uncomplicated pregnancy and that even if complications did occur, she should anticipate a good final outcome for her and her baby.

If antihypertensive therapy does not appear to have a profound effect on pregnancy outcome, what should the goals be for treatment in pregnancy? Experts disagree, with some suggesting a goal of less than 160/100 mm Hg and others suggesting less than 140/90 mm Hg.⁵⁹ Many experts accept a higher blood pressure goal in pregnancy because of the lack of evidence that antihypertensive therapy for patients with mild hypertension has any short-term benefits for most pregnant patients and their fetuses and the evidence from some studies that overly aggressive control of blood pressure in pregnancy is associated with an increased rate of IUGR and small-for-gestational-age infants.⁶⁰ Because of the absence of compelling data to treat mild hypertension in pregnancy, I follow the adage “above all, do no harm,” and aim for a blood pressure of less than 160/100 mm Hg in patients who have no established renal or cardiac disease or evidence of target organ damage from previous hypertension.

The main clinical goals of the first 20 weeks of pregnancy are to firmly establish the patient's pregnancy dates with an early ultrasound and to adjust her medications to keep her blood pressure below the stated goal with a minimum of adverse effects. If the decision is made to tolerate a higher blood pressure in pregnancy, many patients with chronic hypertension in pregnancy may be able to taper and discontinue their medication during this period. This strategy is aided by the physiologic drop in blood pressure in the first half of pregnancy. Even if medications are continued, dose adjustments may be necessary in response to the changes in blood pressure associated with pregnancy.

After 20 weeks' gestation, the possibility of superimposed preeclampsia becomes increasingly real and patients should be screened at every medical and obstetric visit for its signs and symptoms, including asking about headaches, visual phenomena, epigastric pain, and excessive weight gain. While edema is a common manifestation of preeclampsia, it is too commonly seen in healthy pregnancies to be useful as a diagnostic criterion for this condition.⁵⁹ Patients should be educated to report any of these symptoms to their clinician. I tell my trainees to consider every woman with chronic hypertension in the second half of pregnancy “guilty (of having preeclampsia) until proven innocent” at each and every encounter (preeclampsia is extremely rare prior to 20 weeks' gestation). On each visit after 20 weeks, patients with chronic hypertension should be examined for increasing blood pressure, epigastric tenderness, clonus, and facial edema. Patients should also have a urine dipstick test for proteinuria at every visit.

Recommendations for monitoring of the fetus in the context of chronic hypertension vary. Many experts recommend monthly ultrasounds for growth after 24 to 28 weeks' gestation and once- or twice-weekly nonstress tests after 32 to 34 weeks.^{59 ,61} Some centers use umbilical artery Doppler flow velocimetry as an additional assessment of fetal well-being and some, but not all, studies suggest that its use may have a role in the monitoring of high-risk pregnancies.^{62 - 65} When signs or symptoms of preeclampsia are identified, the physician caring for the patient should perform “preeclampsia laboratory tests” (eg, complete blood count, uric acid,^{66 - 67} creatinine, aspartate aminotransferase, and 24-hour urine protein measurement), assess fetal well-being to guide short-term management, and consider whether the patient's status warrants hospitalization for monitoring.

For Mrs F, we planned that when she did conceive we would stop hydrochlorothiazide and that if her blood pressure increased to higher than 160/100 mm Hg we would treat it with either labetalol or methyldopa. Her obstetrician would perform an early ultrasound to ensure good dating and we would both educate her recurrently about the signs and symptoms of preeclampsia and screen for evidence of it in her and her fetus after 20 weeks' gestation. Her obstetrician would make a decision in the third trimester about the need for additional fetal surveillance.

Pathophysiology. The current understanding of preeclampsia suggests that the condition begins early in pregnancy and that 3 distinct, sequential phases are necessary for its evolution.^{68 - 70} The first phase is incomplete invasion of the trophoblast into the endometrium, perhaps due to a maladaptive immune response in the mother, which leads to inadequate formation of the placenta (“placentation”). This inadequate placentation leads to the second phase, in which decreases in the levels of angiogenic growth factor⁷¹ and increased placental debris are found in the maternal circulation and believed to be either causes or manifestations of evolving placental ischemia. The third phase, which leads to the maternal preeclamptic syndrome as it is detected clinically, is the response of the maternal endothelium and cardiovascular system to these stressors, which is modulated by the woman's own level of metabolic and cardiovascular health. All 3 phases are believed to be necessary for preeclampsia to become manifest.

Risk Factors for Preeclampsia. The risk factors for preeclampsia can be categorized as maternal and fetal. Maternal risk factors include first pregnancy, new matings, age younger than 18 years or older than 35 years, chronic hypertension, personal or family history of preeclampsia, systemic lupus erythematosus, thrombophilia, pregestational diabetes, obesity, and renal disease.^{72 - 73} Fetal risk factors include multiple gestations, molar pregnancies, hydrops, and triploidy.⁶⁹

Preventive Strategies. Much work has been done to try to identify strategies for preventing preeclampsia in patients who are at risk. These strategies have included diet and exercise; protein and salt restriction; magnesium, zinc, fish oil and calcium supplementation⁷⁴ ; and antihypertensive treatment.⁷⁵ None of these interventions have proven to be effective. Recently, 2 large randomized controlled trials suggested that antioxidant therapy (vitamins C and E) also does not prevent preeclampsia and may even be harmful to some patients.^{39 ,76}

The only intervention that may help prevent preeclampsia and its associated adverse outcomes is low-dose (<100 mg/d) aspirin. Aspirin for preeclampsia has had a long and checkered history, with many small trials initially suggesting that low-dose aspirin provided substantial benefit in decreasing the incidence of preeclampsia, but then 2 well-designed randomized controlled trials contradicted these findings and showed no benefit.^{77 - 78} However, a subsequent Cochrane database meta-analysis of 41 randomized controlled trials in more than 36 500 women found that aspirin use was associated with a 19% decrease in the risk of preeclampsia (RR, 0.81; 95% CI, 0.75-0.88; number needed to treat [NNT], 69; 95% CI, 51-109), a 7% decrease in the risk of preterm delivery (RR, 0.93; 95% CI, 0.89-0.98; NNT, 83; 95% CI, 50-238), and a 16% decrease in the risk of fetal and neonatal death (RR, 0.84; 95% CI, 0.74-0.96; NNT, 227; 95% CI, 128-909).⁷⁹ There was also an 8% reduction in small-for-gestational-age infants (RR, 0.92; 95% CI, 0.85-1.00). Aspirin had no significant effects on the need for cesarean delivery or induction of labor. A more rigorous recent meta-analysis found a 10% reduction in the RR of both preeclampsia and preterm birth before 34 weeks (P = .01) and a 9% reduction in the RR of stillbirth or baby death before discharge.⁸⁰ There are many varying opinions as to the interpretation of these findings, but what does seem clear is that low-dose aspirin is inexpensive, it does not appear to be unsafe, and it has at least some possibility of preventing fetal and neonatal death. For these reasons, I did recommend to Mrs F (and do to all women with chronic hypertension) that when she is pregnant, she should take 81 mg/d of aspirin after the first trimester.

Most women with chronic hypertension will not develop preeclampsia, IUGR, or abruption and will have a healthy delivery. For women who do develop these complications, early delivery may be necessary. Delivery is generally the best plan for the mother with preeclampsia and should only be deferred when its manifestations are mild and there is a potential benefit to the fetus of prolonging the pregnancy.⁶¹ A large, international randomized controlled trial involving 9992 participants has shown that magnesium lowers the risk of eclampsia by 58% (95% CI, 40%-71%) in women with preeclampsia, although adverse effects (predominantly flushing, nausea, or weakness) were experienced by 24% of the women in the treatment group.⁸¹ These data are clear for women with severe preeclampsia, but expert opinion varies as to how to apply these data to women with milder forms of the disease. Care must be taken to avoid excessive fluid administration in preeclamptic patients because excessive fluid can precipitate pulmonary edema.⁸² Severe hypertension is typically treated in this setting with intravenous labetalol, hydralazine, or oral nifedipine when diastolic blood pressure increases to higher than 105 to 110 mm Hg.^{31 ,59} Although there is no evidence to definitively support one agent over another,⁴³ at least 1 meta-analysis suggests that hydralazine may be the least preferable of these 3.⁸³

Postpartum Management of Hypertension. In the first 96 hours after an infant is delivered, blood pressure typically rises in all women by about 6 mm Hg of systolic blood pressure and 4 mm Hg of diastolic blood pressure.⁸⁴ If a woman with hypertension has developed superimposed preeclampsia, it may affect her blood pressure for up to 12 weeks, although studies suggest that the effect of preeclampsia on most women's blood pressure will resolve in 1 to 4 weeks.⁸⁵ This is important clinically because during this time, women with preeclampsia may need frequent blood pressure checks and adjustments in their medication. Mrs F's blood pressure was relatively stable after her delivery, but this is not always the case.

In the weeks following delivery, I aim to reduce the patient's blood pressure to the usual goal for this age group: less than 140/90 mm Hg for most and less than 130/80 mm Hg for those with diabetes or cardiac or renal disease.¹

I generally discharge patients once their blood pressure is consistently less than 160/100 mm Hg. However, the amount that the blood pressure has changed from its baseline is also important and should be taken into consideration when deciding about treatment, discharge, and frequency of outpatient visits.⁸⁶

Ensuring that patients with chronic hypertension and superimposed preeclampsia have timely, clear, and reliable follow-up arranged at the time of discharge is critical. New mothers have many responsibilities on their minds and they need their clinician's help to make sure they get the care they deserve.

There are few limitations on the choices of antihypertensive agents in postpartum women but there is also very little guidance from the literature.²⁶ In patients with superimposed preeclampsia, I often use nifedipine to bring the blood pressure down into a range that will allow that patient to be discharged from the hospital. Evidence to guide these therapeutic decisions, however, is sorely lacking.⁸⁷

Breastfeeding. Women with hypertension should be encouraged to breastfeed because of breast milk's significant benefits for the infant compared with formula feeding. While very few antihypertensive agents have been definitively shown to cause harm to breastfed infants, specific agents are preferred for use in breastfeeding mothers because milk drug levels are low and reports of infant adverse effects are rare. Safety recommendations for most commonly used antihypertensive agents while breastfeeding are reviewed in Table 3.^{26 - 28}

Long-term Risks of Preeclampsia. The development of preeclampsia is associated with an increased risk of cardiovascular death (RR, 3.07; 95% CI, 2.18-4.34) in subsequent years, particularly in the years after menopause.^{88 - 89} Current thinking is that pregnancy represents a physiologic stress test and that women who are unable to tolerate the endothelial stressors associated with inadequate placentation are more likely to also develop cardiovascular disease in response to other stressors. This appears to be particularly true for women with preeclampsia that occurs in consecutive pregnancies and in women who have preeclampsia before 37 weeks, necessitating preterm delivery of their fetus.^{90 - 93} Increased insulin resistance, hypertension, and hyperlipidemia are seen both in women with preeclampsia and in women who develop cardiac disease.⁹⁴ In this regard, preeclampsia could be considered to be a first manifestation of metabolic syndrome in women. Women who have had preeclampsia, regardless of whether they have underlying chronic hypertension, should therefore receive targeted and repeated counseling to decrease cardiovascular risk.

If Mrs F does get pregnant and has a successful delivery, in her postpartum period I would likely change her treatment back to a once-a-day regimen such as hydrochlorothiazide, with a goal of keeping her blood pressure lower than 140/90 mm Hg. During her pregnancy, if she develops preeclampsia, I would monitor her blood pressure closely in the first 1 to 3 months after delivery as she would likely need her medication adjusted. During these interactions, I would continue to encourage her to adapt and maintain a heart-healthy lifestyle. In the years ahead, I would regularly screen her for additional cardiac risk factors and aggressively address any that are identified.

Hypertension in pregnancy continues to have a remarkable lack of data available. Too few data exist about any antihypertensive agents to make definitive and meaningful statements about their safety or risk in pregnancy. Similarly, large, well-designed trials examining the risks and benefits of treating mild hypertension in pregnancy are still needed. Progress in understanding preeclampsia also remains frustratingly slow. There is hope that serologic markers, such as soluble fms-like tyrosine kinase 1, placental growth factor, and endoglin, may be used to identify patients who are destined to develop preeclampsia 8 to 12 weeks before they actually do.⁷¹ Detection before overt manifestation of disease would greatly help to effectively triage resources and also allow more expeditious evaluation of preventive strategies. Finally, researchers in preeclampsia may need to further explore the theoretical construct that preeclampsia is a heterogeneous disease and that there may not be just 1 “type” of preeclampsia any more than there is 1 type of cancer or 1 type of acute respiratory distress syndrome.⁹⁵ Preeclampsia may be the final common pathway for a variety of pathophysiologic processes. If preeclampsia is simply what happens when inadequate placentas stress susceptible mothers, perhaps prevention and understanding of the disease should focus more on particular subtypes of the syndrome rather than studying patients with the disease as if they were a homogenous population.⁹⁵

QUESTION: You recommend starting aspirin after 12 weeks' gestation. Can it be started earlier?

DR POWRIE: I recommended 12 weeks to a general audience because most of the trials on low-dose aspirin in pregnancy were started after the first trimester. We therefore lack extensive data about its safety during organogenesis. What data exist, however, are reassuring. Many experts therefore advocate the use of low-dose aspirin starting even at the time of conception^{96 - 97} (or more practically, before conception) in the hopes that aspirin may have its greatest impact when started early in the evolution of preeclampsia. However, the Cochrane database meta-analysis did not find a difference in effect when aspirin was started earlier.⁸⁷ Therefore, in the absence of clear data to discern a risk/benefit, I tend to believe the most prudent approach is to start aspirin after the period of organogenesis.

QUESTION: Do you change your approach when patients have a high body mass index and are hypertensive? What about for African American patients?

DR POWRIE: My treatment approach for these 2 groups is largely unchanged. I do encourage obese patients to try to lose weight before becoming pregnant, as obesity is associated with an increase in adverse pregnancy outcomes.^{98 - 99} I also make sure that I am measuring blood pressure with a properly sized cuff—a surprisingly common error in obstetric settings. Despite the fact that we know that β-blockers and ACE inhibitors are less likely to be effective at controlling blood pressure in African American patients,¹⁰⁰ I still tend to start with methyldopa or labetalol for these patients during pregnancy because of the safety profile of these medications. If these agents are not successful, nifedipine can be an excellent alternative.

QUESTION: I’m interested in the fact that you are an internist speaking on a topic that would usually be considered the domain of obstetricians. Can you comment a bit about this?

DR POWRIE: I am one of a growing number of medical specialists who are interested in bridging the gap between medicine and obstetrics care and helping to train internists and medical subspecialists to be more involved and helpful in the care of obstetric patients before, during, and after a pregnancy. Obstetricians, maternal-fetal medicine specialists, internists, and medical subspecialists all have a distinct and valuable perspective, with different but complementary knowledge sets. When they are willing to work together it can really enhance the care of women throughout their reproductive years.