A 32-year-old woman, who has never been pregnant and who has a 5-year history of hypertension, wants to become pregnant. She has stopped using contraception. Her only medication is lisinopril at a dose of 10 mg per day. Her blood pressure is 124/68 mm Hg, and her body-mass index (the weight in kilograms divided by the square of the height in meters) is 27. She has a strong family history of hypertension with both parents suffering from hypertension and one older sibling also hypertensive. Her kidneys are normal in size and structure. She has no evidence of SLE, chronic kidney disease such as proteinuria or casts in her urine and her creatinine clearance is 80 ml/min. She has no cardiomegaly or signs of heart failure and is in sinus rhythm. She is not diabetic. She has researched hypertension in pregnancy on the internet and has some questions for you. What would you advise?
Some of her questions are:
- Is my pregnancy likely to be normal or complicated by preeclampsia or eclampsia or other complications of pregnancy?
- Am I likely to carry the baby to term?
- Babies are small in size at birth and are more likely to need an incubator and other assistance for breathing. Is that likely to happen?
- Is the baby likely to suffer from congenital defects of the heart?
- Is the baby likely to be born with defective kidneys?
- Are my blood pressure medications likely to affect the baby?
This woman is suffering from chronic hypertension, which is defined as a blood pressure of at least 140 mm Hg systolic or 90 mm Hg diastolic pressure before pregnancy or, for women who first present for care during pregnancy, before 20 weeks of gestation.
The chances are good that this woman is likely to carry the pregnancy to term with a good outcome. Her blood pressure is well controlled and her renal function is in Stage 2 (creatinine clearance of 80 ml/min) so she has no end organ damage. The risk of an adverse outcome increases with the severity of hypertension and end-organ damage.
Her chance of getting a complication like eclampsia, preeclampsia, abruptio placenta, fetal growth restriction, preterm birth, and cesarean section are higher than in women who are normotensive. The risk of superimposed preeclampsia increases with an increasing duration of hypertension. Preeclampsia is a leading cause of preterm birth and cesarean delivery in this population.
In a study involving 861 women with chronic hypertension, preeclampsia developed in 22%, and the condition occurred in nearly half these women at less than 34 weeks of gestation, earlier than is typical in women without antecedent hypertension.
Definitions of hypertensive syndromes in pregnancy.
Preeclampsia refers to the new onset of hypertension and proteinuria or the new onset of hypertension and significant end-organ dysfunction with or without proteinuria after 20 weeks of gestation in a previously normotensive woman
Eclampsia refers to the occurrence of a grand mal seizure in a woman with preeclampsia in the absence of other neurologic conditions that could account for the seizure.
HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) probably represents a subtype of preeclampsia with severe features in which hemolysis, elevated liver enzymes, and thrombocytopenia are the predominant features rather than hypertension or central nervous system or renal dysfunction, although the latter do occur. The majority of patients, but not all, have hypertension (82 to 88 percent) and/or proteinuria (86 to 100 percent).
●Chronic hypertension – Chronic hypertension is defined as hypertension that precedes pregnancy or is present on at least two occasions before the 20th week of gestation or persists longer than 12 weeks postpartum. It can be primary or secondary to a variety of medical disorders.
●Preeclampsia superimposed upon chronic hypertension – Preeclampsia is considered superimposed when it occurs in a woman with preexisting chronic hypertension. It is characterized by worsening or resistant hypertension (especially acutely), the new onset of proteinuria or a sudden increase in proteinuria, and/or significant new end-organ dysfunction after 20 weeks of gestation in a woman with chronic hypertension
Gestational hypertension – Gestational hypertension refers to hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) without proteinuria or other signs/symptoms of preeclampsia-related end-organ dysfunction that develops after 20 weeks of gestation. Development of proteinuria upgrades the diagnosis to preeclampsia.
The diagnosis of preeclampsia with severe features (formerly severe preeclampsia) is made in the subset of women with preeclampsia who have severe hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥110 mmHg) and/or specific signs or symptoms of significant end-organ dysfunction that signify the severe end of the preeclampsia spectrum.
Women with chronic hypertension with superimposed preeclampsia are at increased risk for giving birth to an infant who is small for gestational age and for placental abruption, as compared with women with chronic hypertension without superimposed preeclampsia. Even in the absence of superimposed preeclampsia, women with chronic hypertension have an increased risk of adverse outcomes. Fetal growth restriction (estimated or actual fetal weight, <10th percentile for population norms) complicates 10 to 20% of such pregnancies. In an analysis of the Danish National Birth Cohort, after adjustment for age, body-mass index, smoking status, parity, and diabetes, chronic hypertension was associated with approximately five times the risk of preterm birth and a 50% increase in the risk of giving birth to an infant who is small for gestational age.8 Women with hypertension have an increased risk for abruptio placentae and stillbirth.
Hypertension along with diabetes, obesity, SLE, thyroid disease and phenylketonuria is a risk factor for congenital heart disease in the fetus.
What happens to the blood pressure during pregnancy in women with chronic hypertension?
Most women with chronic hypertension have a decrease in blood pressure during pregnancy, similar to that observed in normotensive women; blood pressure falls toward the end of the first trimester and rises toward prepregnancy values during the third trimester. As a result, antihypertensive medications can often be tapered during pregnancy. However, in addition to the subset of women with chronic hypertension in whom preeclampsia develops, another 7 to 20% of women have worsening of hypertension during pregnancy without the development of preeclampsia.
How should you evaluate a woman with chronic hypertension in pregnancy. Follow the JNC 7 guidelines. ( 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;289:2560–2572[Erratum, JAMA 2003;290:197.) Such recommendations include the use of electrocardiography and assessment of blood glucose, hematocrit, serum potassium, creatinine, calcium, and lipoprotein profile, as well as urinalysis. Given the increased risk of preeclampsia in women with chronic hypertension, evaluation before pregnancy should also include a 24-hour quantification of urine protein to facilitate the identification of subsequent superimposed preeclampsia. The presence of end-organ manifestations of hypertension may worsen the prognosis during pregnancy and should be taken into account in counseling. For example, the presence of proteinuria at baseline increases the risks of superimposed preeclampsia and growth restriction. Do not do any tests requiring radiation if the patient is already pregnant.
How to monitor preeclampsia?
Superimposed preeclampsia should always be considered when the blood pressure increases in pregnancy or when there is a new onset of or an increase in baseline proteinuria. An elevated uric acid level may help to distinguish the two conditions, although there is substantial overlap in levels. The presence of thrombocytopenia or elevated values on liver-function testing may also support a diagnosis of preeclampsia. Recently, serum and urinary angiogenic markers have been studied as possible aids in the diagnosis of superimposed preeclampsia, but data are currently insufficient to support their use in this population.
How to treat the hypertension?
Which antihypertensive drug to use in pregnancy?
Methyl dopa is the the drug with the best safety profile. Methyldopa is both an alpha-2-agonist and an amino acid decarboxylase enzyme inhibitor that blocks the transformation of DOPA to DA and NE, causing a net decrease in central monoamine neurotransmitter levels. α2 agonist: inhibits adenylyl cyclase activity, reduces brainstem vasomotor center-mediated CNS activation; used as antihypertensive, sedative & treatment of opiate dependence and alcohol withdrawal symptoms). Effect of alpha 2 receptor blockade: Common effects include: Suppression of release of norepinephrine (noradrenaline) by negative feedback. Transient hypertension (increase in blood pressure), followed by a sustained hypotension (decrease in blood pressure). This effect may be enhanced by the simultaneous use of labetolol as the alpha-2 blockade may kick in later so methyldopa will then stimulate the alpha-2 receptors. Either avoid or monitor carefully.
Methyldopa and beta-blockers may have additive hypotensive effects. In addition, potentiation of hypertensive rebound associated with withdrawal of methyldopa or beta-blockers may occur if both drugs are withdrawn at the same time. The proposed mechanism may involve increased catecholamine release after methyldopa and/or a beta-blocker are withdrawn, which may lead to unopposed alpha-adrenergic effects and vasoconstriction.
Methyldopa manufacturers recommend adjusting the beta blocker dose if methyldopa is added to therapy, and not exceeding a methyldopa dose of 500 mg/day when it is first added to therapy. Patients should be instructed to notify their doctor if they have a reduced heart rate, dizziness, fainting or headaches, chest pain or vision problems.
Long-acting calcium-channel blockers also appear to be safe in pregnancy, although experience is more limited than with labetalol.21 Nifedipine is listed as the preferred drug for the treatment of hypertension in pregnancy only the extended action form may be used. However the rapid release form may be used to control severe hypertension in eclampsia as a last resort.
Use of nifedipine in preterm labour.
Nifedipine can be used in preterm labour to delay pregnancy by 48 hours to 7 days. It acts a tocolytic agent.
Diuretics were long considered contraindicated in pregnancy because of concern about volume depletion. However, a review of nine randomized trials showed no significant difference in pregnancy outcomes among women with hypertension who took diuretics and those who took no antihypertensive medication. Accordingly, some guidelines support the continuation of diuretic therapy during pregnancy in women with chronic hypertension who were previously treated with these agents.
Which anti-hypertensive drugs to avoid in pregnancy?
Angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) are contraindicated in pregnancy. All the angiotensin-converting-enzyme inhibitors like captopril, enalapril, lisinopril etc are to be withheld before the start of pregnancy and not used in pregnancy because they cause neonatal renal failure.Their use in the second half of pregnancy has been associated with oligohydramnios (probably resulting from impaired fetal renal function) and neonatal anuria, growth abnormalities, skull hypoplasia, and fetal death.
Mineralocorticoid receptor antagonists (MRAs; eg, spironolactone, eplerenone) are another class of drugs that block the renin angiotensin aldosterone system. Spironolactone crosses the placenta and has never been proven to be safe in pregnancy. The anti-androgenic activity of spironolactone has always been a concern, particularly in male fetuses. Feminization of male rat fetuses has been reported after treatment of pregnant female rats with high doses of spironolactone. Whether eplerenone, an MRA without anti-androgenic properties introduced approximately 10 years ago, will be safe for human pregnancy is unknown. The epithelial sodium channel (ENaC) inhibitor amiloride has been used rarely to treat pregnant women with hyperaldosteronism or Liddle’s syndrome, and there are sporadic case reports with favorable outcomes. Its use cannot be recommend at this time because of limited experience.
Nitroprusside — Limited clinical experience (22 pregnancies) and the possibility of fetal cyanide poisoning have restricted the use of nitroprusside in pregnancy. Nitroprusside (0.5 to 10 mcg/kg/min) is the agent of last resort for urgent control of refractory severe hypertension; its use should be limited to a short period of time in an emergency situation
Can we use any therapy to prevent eclampsia other than good control of blood pressure?
Since superimposed preeclampsia is the major adverse pregnancy outcome associated with chronic hypertension, many women ask whether any therapies can decrease this risk. Large, randomized, placebo-controlled trials have shown no significant reduction in the risk of preeclampsia associated with the use of low-dose aspirin, calcium supplementation, or antioxidant supplementation with vitamins C and E.
Efforts to monitor women and their fetuses for complications may include more frequent prenatal visits for women with chronic hypertension than for women without this condition. Such visits are intended to monitor women closely for complications of chronic hypertension by measuring blood pressure and urine protein.
Many obstetricians supplement regular evaluation of fundal height with ultrasonographic estimation of fetal weight, beginning in the early third trimester and continuing at intervals of 2 to 4 weeks, depending on maternal blood pressure, medications, complications, and findings on previous imaging. Although data from low-risk populations suggest that ultrasonography and evaluation of fundal height have shown similar results for the detection of growth restriction, ultrasonography also assesses amniotic-fluid volume and fetal movements and tone (biophysical profile), evaluations that may be useful with respect to the risks associated with chronic hypertension in pregnancy.
Testing may also include the evaluation of the pattern and variability of the fetal heart rate (nonstress testing). Maternal complications (e.g., preeclampsia or worsening hypertension), nonreassuring fetal-testing results, or concern about fetal growth restriction are often indications for early delivery.