You are consulted on a 29-year-old gravida 1 at nine weeks gestation with a two-year history of Type 2 diabetes and hypertension. She is admitted to the obstetric inpatient service for glycemic control. Although prescribed metformin and lisinopril, she ran out of both four months ago. Her current hemoglobin A1C is 9%. Her blood pressure is 140/90 mmHg in both arms, with an appropriately sized manual cuff while seated. She does not have retinopathy, nephropathy, or neuropathy. The obstetric team will begin weight-based insulin to achieve glycemic targets, and they ask for your input regarding blood-pressure management. How should one approach a pregnant patient with hypertension?
The most common chronic medical issue in reproductive-age women, essential hypertension (termed chronic hypertension in obstetric literature) contributes significantly to maternal and perinatal morbidity and mortality, primarily via increased risk of preeclampsia.
Chronic hypertension complicates up to 5% of pregnancies in the U.S., or as many as 120,000 pregnant women per year.1 Rates of chronic hypertension are expected to increase with later childbearing and increased rate of obesity. Prior to and during pregnancy, hypertension is defined as blood pressure 140/90 mmHg or higher. Chronic hypertension can be either hypertension diagnosed prior to pregnancy or elevated blood pressures identified prior to 20 weeks gestation.2 Normal pregnancy physiology leads to decreased systemic vascular resistance by the end of the first trimester, dropping systolic and diastolic blood pressure between 10 and 15 mmHg, with maximal effect mid-pregnancy followed by a gradual return to baseline.3 Therefore, chronic hypertension might be masked in early pregnancy. Normal changes in pregnancy include renal vasodilatation and increased glomerular filtration rate, so the average serum creatinine (SCr) is 0.5 mg/dL.4
Newly identified hypertension or accelerating hypertension after 20 weeks warrants close evaluation for preeclampsia. Preeclampsia is a multisystem, life-threatening disorder characterized by hypertension and proteinuria (greater than 300 mg/day). Severe forms of preeclampsia include HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome and eclampsia (seizures with no other attributable cause). Superimposed preeclampsia occurs in 20% to 25% of women with chronic hypertension.5 Women with hypertensive target organ damage have an even greater likelihood of preeclampsia as well as maternal and fetal complications. Unfortunately, blood-pressure control during pregnancy has not been shown to minimize the likelihood of developing superimposed preeclampsia or associated maternal and fetal complications.6 The goal of antihypertensive management during pregnancy is to avoid acute maternal or fetal complications of severe hypertension.
Review of the Data
Q: How are hypertensive disorders of pregnancy classified?
The American College of Obstetrics and Gynecology and the National High Blood Pressure Education Program guideline committees have classified hypertensive disorders of pregnancy into four categories: chronic hypertension, preeclampsia, preeclampsia superimposed on chronic hypertension, and gestational hypertension.2,7
Chronic hypertension is defined as blood pressure 140/90 mmHg or greater on two occasions before pregnancy, prior to 20 weeks of gestation, or persisting 12 weeks postpartum. Severe hypertension is defined as diastolic blood pressure ≥110 mm Hg. Hypertensive women tend to have a greater decline in blood pressure during early pregnancy than normotensive women.8
Secondary hypertension is an important consideration in women of reproductive age. A brief screen for secondary causes includes bilateral arm pressures and femoral pulse assessment, renal bruit assessment, inquiry into snoring, gasping, and daytime somnolence, as well as measurement of serum thyrotropin, potassium, calcium, creatinine, and urinalysis. This kind of evaluation will assess for coarctation of the aorta, renal artery stenosis, obstructive sleep apnea, hyper- or hypothyroidism, hyperaldosteronism, hyperparathyroidism, and underlying renal disease.9,10 Patient reports of episodic headache, palpitations, and diaphoresis should prompt investigation for pheochromocytoma.
Hyperaldosteronism, pheochromocytoma, or hyperthyroidism might be quiescent during pregnancy but flare in the postpartum period.
Women with severe chronic hypertension or target organ damage have higher rates of superimposed preeclampsia. In these individuals, preeclampsia is more likely to present early (before 34 weeks gestation) or with severe disease.1
Preeclampsia is defined as hypertension and proteinuria (greater than 300 mg/day) at or beyond 20 weeks gestation in a previously normotensive woman. Preeclampsia rates vary from 5% to 10% of nulliparous women, to much higher rates in women with medical comorbidities or fetal factors (e.g., multiple gestations, molar pregnancies, hydrops, or triploidy). Preeclampsia’s pathogenesis is attributed to abnormal placental implantation with abnormal maternal immune adaptation, altered angiogenic factors with increased systemic vascular resistance and endothelial dysfunction leading to the clinically apparent maternal syndrome.11
Severe preeclampsia criteria include any of the following: eclampsia, HELLP syndrome (platelets less than 100,000/mm³, transaminases more than twice the upper limit of normal, and/or epigastric pain), SBP ≥160 mmHg, DBP ≥110 mmHg, proteinuria ≥5 grams per day, oliguria, pulmonary edema, placental abruption, or fetal manifestations such as intrauterine growth restriction (≤10th percentile of expected fetal weight based on gestational age), decreased amniotic fluid index, or fetal demise.2,5,12
Maternal symptoms might include headache, visual disturbances, epigastric or right upper quadrant (RUQ) pain, rapid weight gain, and severe edema. Some women remain asymptomatic. Preeclampsia can rapidly progress from “less severe” to severe. Maternal symptoms and abnormal lab findings are more predictive of adverse pregnancy outcomes than the degree of hypertension and/or proteinuria.1
It is always in the mother’s interest to deliver when preeclampsia is diagnosed, because preeclampsia will not resolve until after delivery, with hypertension and lab abnormalities sometimes persisting for months postpartum. Preeclampsia might be diagnosed before fetal viability (approximately 24 weeks gestation), although the vast majority of cases occur near term.
Risks of premature delivery must be balanced with the risks of progressively severe manifestations for the mother and fetus. Guidelines for expectant management of early (<34 weeks) preeclampsia are based on available evidence and expert opinion.13 Magnesium sulfate has been shown to be the most effective agent to minimize the likelihood of seizure in preeclamptic women.14 With an initial bolus of 4 g to 6 g IV followed by infusion of 1-2 g/hour, magnesium sulfate is usually continued for 24 to 48 hours after delivery.
Preeclampsia can first appear postpartum, most likely in the first days to weeks. A growing body of literature links preeclampsia, particularly early and/or recurrent, to subsequent increased risk for cardiovascular disease and end-stage renal disease.15
Preeclampsia superimposed on chronic hypertension is defined as the new onset or markedly increasing proteinuria or accelerating hypertension in the latter half of pregnancy. Maternal symptoms, transaminase elevation, thrombocytopenia, or fetal manifestations further support this diagnosis.
Gestational hypertension, previously known as pregnancy-induced hypertension, is defined as hypertension in the absence of proteinuria in the latter half of pregnancy. Symptoms and lab abnormalities of preeclampsia will be absent. At least half of women with hypertension in the latter half of pregnancy progress to preeclampsia, so gestational hypertension should be considered a provisional diagnosis. Severe gestational hypertension, even without proteinuria or other lab abnormalities, carries increased perinatal risk.
Q: What factors contribute to increased preeclampsia risk?
Maternal factors include: first pregnancy, first pregnancy with a new father, maternal age >35, particularly >40, personal or family history of preeclampsia, chronic hypertension, diabetes mellitus (Type 1, 2 or gestational), systemic lupus erythematosus, antiphospholipid antibody syndrome, renal disease, and obesity. Fetal factors include: multiple gestations, molar pregnancies, hydrops, and triploidy.5,12
Q: When should antihypertensive medications be used in pregnancy?
Most women are hesitant to expose their fetus to medication, and thus must be in therapeutic alliance with their obstetrician and consultants. The overriding principle of medication use in pregnancy is that a healthy fetus requires a healthy mother, and medication use is justified when there is definite benefit to the mother. Due to increased metabolism during pregnancy, medications otherwise dosed once per day often require two doses per day, and those dosed twice daily often require every-eight-hour dosing to maintain efficacy. Additionally, titration up every few days may be required.
Therapy goals include avoiding maternal and fetal complications from severely elevated blood pressure, as well as avoiding fetal growth restriction due to impaired uteroplacental flow. The ideal blood pressure for a hypertensive pregnant woman has not been established, but recommendations are based upon available data and expert opinion.2,5,10,12 Maternal risk of intracerebral hemorrhage increases with SBP ≥160 mmHg.16 Diastolic BP ≥110 mmHg has been associated with greater risk of placental abruption and intrauterine growth restriction.
Pharmacologic treatment generally is initiated or adjusted to achieve SBP <160 mm Hg and DBP <100 to <105 mmHg, although some societies advocate treatment initiation at 140/90 mmHg.2,5,12,17,18 If a woman has target organ damage or concomitant medical issues warranting tighter control (e.g., diabetes or pre-existing renal disease), 130/80 mmHg is preferable.19 Activity limitation and/or bed rest, although commonly recommended, have not been shown to reduce maternal or fetal morbidity or mortality, or prolong time to delivery.
An ongoing, randomized, prospective trial will compare maternal and fetal outcomes in women with mild chronic hypertension with deliberate blood-pressure stratification (goal DBP 85 mmHg vs. goal DBP 100 mmHg).20
Q: What are reasonable treatment options for a woman with chronic hypertension during pregnancy?
Due to vasodilatation of pregnancy, antihypertensive agents often can be discontinued early in pregnancy with close, ongoing monitoring. The majority of women with mild chronic hypertension will have blood pressures <160/100 mmHg without medication during the first half of pregnancy.
If a woman has been using a pharmacologic agent not advisable during pregnancy, she could be switched to a preferred agent. If a woman has been using a pharmacologic agent preferred during pregnancy, she could continue this agent.
Q: What antihypertensives are favored during pregnancy?
Methyldopa and labetalol have been used extensively. Methyldopa has not been found to adversely affect cognitive development in children exposed in utero. On the maternal side, somnolence, dizziness, and dry mouth are common side effects.
Labetalol is widely used as a first- or second-line agent. It can be used intravenously or orally. Intravenous labetalol in escalating doses (10 mg, 20 mg, 40 mg, 80 mg) is the first line of acute treatment for severe hypertension/preeclampsia.
Atenolol and propranolol have been associated with fetal growth restriction, metoprolol to a lesser degree.
Metoprolol is useful in women with coronary artery disease, tachyarrhythmias, and/or requiring migraine prophylaxis during pregnancy.
Nifedipine is often used as a second-line agent, with extended-release preparation preferred. Short-acting nifedipine should be used with caution during pregnancy due to the potential for acute impairment of uteroplacental flow. However, short-acting nifedipine is used for tocolysis in pre-term labor.
Intravenous hydralazine is another option for acute treatment in the setting of severe hypertension/preeclampsia.
Angiotensin-converting enzyme (ACE) inhibitors are contraindicated during pregnancy due to association with increased rates of cardiovascular and central nervous system malformations when used in the first trimester, as well as fetal anuric renal failure when used later in pregnancy.21 Due to similar mechanisms of action, angiotensin receptor blockers (ARBs) are contraindicated.
In general, antihypertensive agents are considered compatible with lactation, with most minimally excreted into breast milk. Women requiring antihypertensive agents or almost any medication during lactation seek particular reassurance from caregivers.
It is essential to emphasize the benefit of breastfeeding for both mother and newborn, which far outweighs the risk of medication exposure to the newborn—with rare exceptions. Enalapril and captopril are considered compatible with breastfeeding by the American Academy of Pediatrics.22
Q: Can we identify and possibly prevent preeclampsia?
Escalating hypertension or maternal symptoms, especially in women with increased risk factors, warrant careful examination and laboratory assessment for preeclampsia. Physical findings may include retinal vasospasm, rales on pulmonary exam, cardiac gallop, RUQ or midepigastric tenderness from hepatic capsule stretching, nondependent edema (e.g., face, hands), or clonus on deep tendon reflex evaluation. Useful laboratory values include complete blood count, serum creatinine, hepatic transaminases, uric acid, and urinalysis.
Marked anemia or hemoconcentration, thrombocytopenia, SCr ≥0.8 mg/dL, transaminases above normal, uric acid ≥5.0 mg/dL, urine protein 1+ or greater on dipstick, are all suggestive of preeclampsia, particularly if worsened compared to prior values. Urine protein-to-creatinine ratios have not reliably correlated with 24-hour urine protein collections in preeclamptic patients, although very high or low values could be helpful.23
Women are typically admitted for fetal monitoring, 24-hour urine protein collection, and blood-pressure management during a preeclampsia evaluation.
Thus far, the only intervention shown to reduce the likelihood of preeclampsia in women at increased risk is low-dose aspirin. A recent meta-analysis noted 10% reduction of relative risk of preeclampsia and pre-term birth prior to 34 weeks in women with history of preeclampsia treated with aspirin from the second trimester onward.24 Other interventions in trials that have not displayed reduced risk include vitamin C, vitamin E, calcium, fish oil, zinc, magnesium, and antihypertensive therapy.
Back to the Case
Our patient has chronic hypertension and diabetes, so she should have a blood-pressure goal of <130/80 mmHg. She could be initiated on methyldopa or labetalol. She should have a screen for secondary hypertension via exam and serum thyrotropin, potassium, and calcium, as well as baseline “preeclampsia labs”: complete blood count, serum creatinine, transaminases, uric acid, and 24-hour urine protein assessment. Aspirin at 81 mg daily should be considered from 12 weeks gestation to delivery.
Glycemic control is critical in early gestation to avoid increased risk for congenital malformations and spontaneous abortion, and later on to minimize macrosomia. Close monitoring for maternal symptoms of preeclampsia and blood-pressure assessment is advisable. With medical comorbidities of hypertension and diabetes mellitus, the woman’s risk of preeclampsia is at least 25%. Her pregnancy dating should be confirmed by a first-trimester ultrasound.
A pregnant woman with chronic hypertension should have evaluation for secondary causes of hypertension, adjustment or initiation of preferred antihypertensive agents to achieve blood pressures that minimize the risk for acute hypertensive complications and fetal growth impairment, and close monitoring for superimposed preeclampsia. TH
Dr. Hayes is an obstetric internist at Women & Infants’ Hospital and assistant professor of medicine (clinical) at the Warren Alpert Medical School of Brown University, Providence, R.I.
- Sibai BM. Caring for women with hypertension in pregnancy. JAMA. 2007;298(13):1566-1568.
- Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol. 2000;183:S1-S22.
- Christianson RE. Studies on blood pressure during pregnancy. I. Influence of parity and age. Am J Obstet Gynecol. 1976;125(4):509-513.
- Gibson P, Rosene-Montella K. Normal renal and vascular changes in pregnancy. In: Rosene-Montella K, Keely E, Barbour LA, Lee RV, eds. Medical Care of the Pregnant Patient. 2nd ed. Philadelphia: American College of Physicians; 2008:149-152.
- ACOG practice bulletin, No. 33, January 2002. Diagnosis and management of preeclampsia and eclampsia. Obstet Gynecol. 2002;99(1):159-167.
- Sibai BM. Chronic hypertension in pregnancy. Obstet Gynecol. 2002;100(2):369-377.
- Mulrow CD, Chiquette E, Ferrer RL, et al. Management of Chronic Hypertension During Pregnancy. Rockville: Agency for Healthcare Research and Quality; 2000.
- Pickering TG, Hall JE, Appel LJ, et al. Recommendations for blood pressure measurement in humans and experimental animals: part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Prof-essional and Public Education of the American Heart Association Council on high blood pressure Research. Circulation. 2005;111(5):697-716.
- Powrie RO. A 30-year-old woman with chronic hypertension trying to conceive. JAMA. 2007; 298(13):1548-1558.
- Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003:289(19):2560-2571.
- Widmer M, Villar J, Benigni A, Conde-Agudelo A, Karumanchi SA, Lindheimer M. Mapping the theories of preeclampsia and the role of angiogenic factors: a systematic review. Obstet Gynecol. 2007; 109(1):168-180.
- Magee LA, Helewa M, Moutquin JM, van Dadelszen P. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. SOGC Clinical Practice Guideline. J Obstet Gynaecol Can. 2008; 30:S1-S48.
- Sibai BM, Barton JR. Expectant management of severe preeclampsia remote from term: patient selection, treatment, and delivery indications. Am J Obstet Gynecol. 2007;196(6):514.e1-514.e1-9.
- Duley L, Gülmezoglu AM, Henderson-Smart DJ. Magnesium sulphate and other anticonvulsants for women with preeclampsia. Cochrane Database Syst Rev. 2003;(2):CD000025.
- McDonald SD, Malinowski A, Zhou Q, Yusuf S, Devereaux PJ. Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses. Am Heart J. 2008;156(5):918-930.
- Martin JN Jr., Thigpen BD, Moore RC, Rose CH, Cushman J, May W. Stroke and severe preeclampsia and eclampsia: a paradigm shift focusing on systolic blood pressure. Obstet Gynecol. 2005;105(2): 246-254.
- Lindheimer MD, Taler SJ, Cunningham FG. Hyper-tension in pregnancy. J Am Soc Hypertens. 2008; 2(6):484-494.
- Podymow T, August P. Update on the use of antihypertensive drugs in pregnancy. Hypertension. 2008; 51(4):960-969.
- Kitzmiller JL, Block JM, Brown FM, et al. Managing preexisting diabetes for pregnancy: summary of evidence and consensus recommendations for care. Diabetes Care. 2008;31(5):1060-1079.
- Magee LA, von Dadelszen P, Chan S, et al. The Control of Hypertension In Pregnancy Study pilot trial. BJOG. 2007;114(6):770,e13-e20.
- Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 2006; 354(23):2442-2451.
- American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics. 2001;108(3):776-789.
- Papanna R, Mann LK, Kouides RW, Glantz JC. Protein/creatinine ratio in preeclampsia: a systematic review. Obstet Gynecol. 2008;112(1):135-144.
- Askie LM, Duley L, Henderson-Smart DJ, Stewart LA, PARIS Collaborative group. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007;369(9575): 1791-1798.