Hypertension in pregnancy: Challenges and solutions
Rahul Mehrotra*, Manish Bansal*Ravinder s. Sambi, Krishna C. K
Deptt of * Consultant Cardiology, Medanta- The Medicity, Gurgaon, haryana.
Deptt of Cardiology,Moolchand Medcity, New Delhi

Introduction
Hypertension is the most common medical problem encountered during pregnancy worldwide. An estimated 8-10% pregnancy is complicated by hypertensive disorders and about 25% of all antenatal admissions are due to hypertension related complications (1). In the majority of cases hypertension develops during pregnancy but in up to one third, hypertension is preexisting before pregnancy. With more and more women delaying pregnancy, the impact of pre-existing hypertension is likely to increase. 
Hypertensive disorders in pregnancy remain a major cause of morbidity and mortality in the mother, the fetus and the neonate in the developed as well as in the developing countries. Pregnant women with hypertension suffer from complications such as abruptio placentae, cerebrovascular accident, disseminated intravascular coagulation, preeclampsia syndrome and multiorgan failure. The fetus is at risk of intrauterine growth retardation, prematurity, stillbirth and intrauterine death (2).
A thorough understanding of the various aspects of hypertensive disorders in pregnancy is essential as optimum management can result in favorable outcome of pregnancy with healthy mother and a healthy child.
We discuss here the physiology, the technique for detection, management and outcome of hypertension in pregnancy.

Physiology of blood pressure (BP) during pregnancy
During the first trimester of pregnancy, the BP continues to fall and reaches a nadir at about 20-24 weeks. The fall in diastolic BP is more ((8-15mmHg) as compared to systolic BP (4-6 mmHg). As a result, the pulse pressure widens and the mean BP falls by about 6-10 mmHg. The exact etiology of these changes is not known but it is believed to occur due to a combination of factors- increased circulation of vasodilator hormones like prostaglandins and nitric oxide; increased heat production by the fetus and generation of a low resistance vascular bed in the uterus.
The blood pressure reaches the pregestational values by full term. Immediately after delivery, the BP usually falls again, but rises over the first week or so, sometimes causing transient hypertension even in women who had a normal BP throughout pregnancy (perhaps owing to vasomotor instability seen during this period).   

These changes in blood pressure are seen in normotensive as well as in hypertensive women who become pregnant (3). The fall in BP in the first trimester is more pronounced in the latter and has several important implications as discussed later.

BP measurement technique during pregnancy
Blood pressure in a pregnant woman should be measured in sitting position with the arm resting at the level of heart. It has been shown that the BP recorded in the left arm in the left lateral recumbent position does not differ significantly from the values recorded in the sitting position. Therefore, the left lateral recumbent position is a reasonable alternative, especially during labor.
Elevated BP readings should be confirmed on two separate occasions using mercury sphygmomanometer as the gold standard (4). In general, automatic devices for BP measurement have not been shown to be reliable in pregnancy and differences as high as 15 mmHg have been reported when compared to mercury sphygmomanometry. Besides, automatic devices consistently underestimate BP in conditions like pre-eclampsia.
There has been considerable controversy and confusion regarding the use of Korotkoff phase IV and V for measuring DBP during pregnancy. Phase V (disappearance of sounds) is now recommended for measurement of DBP during pregnancy. This is because several studies have confirmed that phase V is more close to true intra-arterial BP, is easier to detect, reproducible and is rarely very low or close to zero. Phase IV (muffling of sounds) is taken as the DBP value only in the rare situation where Korotkoff sounds persist even as the level approaches 0 (5).
Recently, the role of ambulatory BP measurement (ABPM) has been studied in pregnancy and it has been shown that ABPM is very useful in detection of white coat hypertension, a condition quite common in pregnant women. Also, hypertension in pregnancy as diagnosed by ABPM is a better  predictor of unfavourable outcomes of pregnancy like low birth weight, proteinuria and  pre-term delivery as compared to office based BP measurements (6). As of now, ABPM is not routinely recommended but it may be a useful technique for close supervision in high risk pregnant women with hypertension and in pregnant women with nephropathy (7).   

Correspondence:  Dr. Manish Bansal,Consultant Cardiology,Medanta- The Medicity,Sector 38, Gurgaon, Haryana-122001, INDIA
E-mail: manishaiims@hotmail.com

Definition and classification of hypertension during pregnancy
Systolic BP ≥ 140 mmHg or a DBP ≥ 90 mmHg is considered to be the cutoff value for diagnosis of hypertension during pregnancy using appropriate technique as mentioned above (8).
Hypertension in pregnancy is classified as-
•Pre existing hypertension
•Gestational hypertension
•Pre existing hypertension with superimposed gestational hypertension and proteinuria
•Antenatally unclassifiable hypertension

Pre existing hypertension - is present when BP ≥140/90 mmHg is known to be present before pregnancy or detected before 20 weeks of gestation. This type of hypertension complicates up to 5% of pregnancies but the incidence is rising due to the increasing trend of delaying pregnancy into later ages and increased prevalence of hypertension in younger individuals. An interesting caveat associated with this type of hypertension is that it may commonly be missed during the first trimester since the BP values normally dip during this time, as discussed earlier. This type of hypertension usually persists for more than 42 days after delivery and may or may not be associated with proteinuria.

Gestational hypertension - Also called as pregnancy induced hypertension, it develops after 20 weeks of gestation and is the commonest variety complicating 6-7% of pregnancies. It results in impaired organ perfusion and usually resolves within 42 days post partum.
 The syndrome of gestational hypertension in association with significant proteinuria (>300mg/L or > 500 mg/24 hr or 2+ or more on dipstick), is called pre-eclampsia. Pre-eclampsia remains one of the most common causes of maternal death worldwide. It is a pregnancy specific syndrome complicating about 5% of pregnancies and is five times more common in women with preexisting hypertension. Women with obesity, diabetes, renal disease, collagen vascular disease and those belonging to low socioeconomic strata are also more prone to develop pre-eclampsia. Edema was earlier a part of the diagnostic criteria but is no longer included since it is extremely common, non-specific finding in pregnancy. Pre-eclampsia is associated with generalized hypo perfusion as a result of endothelial dysfunction, vasospasm, and hypercoagulable state, forming microthrombi in the vasculature. The fetus suffers from placental hypo perfusion, intrauterine growth retardation and pre-mature delivery (9). In view of its detrimental effects on the pregnant mother and the fetus, pre-eclampsia should be suspected and looked for in vulnerable populations and managed appropriately. It is useful to remember that proteinuria is often a late manifestation and pregnant women with new onset hypertension who complain of headache, flank pain, visual disturbance or have thrombocytopenia and altered liver enzymes, pre-eclampsia should be suspected (10).

Pre-existing hypertension plus superimposed gestational hypertension with proteinuria    
In this condition, pregnant women who are hypertensive even before pregnancy develop further elevation of BP and proteinuria > 3gm/day after 20 weeks of gestation.

Antenatally unclassifiable hypertension  
In the patients in whom BP is recorded for the first time after 20 weeks of gestation, it is not possible to classify them in any of the above category. If on repeat BP measurement performed after 42 days post partum, hypertension has resolved, it is reclassified as gestational hypertension. If the BP remains elevated even after this stage, a diagnosis of pre-existing hypertension should be made. Proteinuria can complicate either of the above condition and should be looked for.

Evaluation and management of hypertension during Pregnancy 
A detailed history regarding presence of hypertension and use of antihypertensive medications during pregnancy should be sought from the patient and BP recorded meticulously at every antenatal visit.  In pregnant women detected to have hypertension, the type of hypertension, severity and target organ damage should be assessed. Laboratory tests like-complete hemogram including hematocrit, platelet counts, liver function tests, kidney function tests, urine examination including detection of proteinuria with dipstick method should be done in all patients. If dipstick test is positive for proteinuria, 24 hour urine collection with estimation of proteinuria should be done. Even if dipstick test is negative in presence of risk factors of preeclampsia, 24 hour urine collection and protein estimation is useful since dipstick test has high false negativity.
Routine ultrasound abdomen and estimation of catecholamine in urine to screen for phaeochromocytoma has been recommended by few (11) but considering the rarity of the tumor and the cost of investigations is not feasible in a country like ours.

Management of hypertension
There is a paucity of data regarding treatment of hypertension in pregnancy since the pharmaceutical industry and investigators have been reluctant to try out drugs in this subset. There has been no good quality clinical trial with adequate numbers involving this population group for the last more than 25 years. The trial involving alpha methyl dopa and having an infant follow up of 7.5 years was published way back in 1976 (12).Most of the other trials have been small, with inadequate follow-up and with flawed design. As such, most of the antihypertensive drugs have insufficient database to back their use pregnancy.

 Non drug management and prevention- All pregnant women with hypertension are candidates for  close supervision, limitation of activities and some bed rest in left lateral position. A nutritious diet rich in calcium should be encouraged. Calcium supplementation-up to 2g/day may be added since it has shown to reduce the incidence of gestational hypertension and preeclampsia (13,14).Salt restriction and weight reduction in obese, a routine practice in nonpregnant women and male hypertensive, is not recommended during pregnancy since it interferes with uteroplacental circulation and fetal growth.   
Drug therapy -    As discussed previously, there is no clear evidence about most drugs regarding their safety, especially to the fetus or efficacy during pregnancy. All drugs should be presumed to cross placenta and affect the fetus. Centrally acting Methyldopa, calcium antagonist Nifedipine and combined alfa and beta blocker-Labetalol are the most studied and recommended drugs in this situation, the goal being reduction of maternal risk (table 1). Methyldopa is generally considered the drug of first choice by most clinicians worldwide. It has a long history of safety, proven efficacy and relatively few side effects. It does not interfere with maternal cardiac output and uteroplacental circulation and has been used for long durations throughout pregnancy. Labetalol is generally considered the second choice although its efficacy was shown to be similar to methyldopa in a trial comparing these two drugs with with each other and to placebo (15).  Similarly, long acting formulation of nifedipine has been used safely in later half of pregnancy but can cause serious hypotension when used concomitantly with magnesium sulphate (used to prevent pre-eclampsia and treat seizures). Direct vasodilator hydralazine was used initially but found to be insufficient alone to control hypertension.Due to reflex tachycardia and sympathetic stimulation, a beta blocker or methyldopa has to be added to hydralazine. There also have been reports about thrombocytopenia associated with it use (16) and due to all these issues, hydralazine is being avoided in pregnancy.
Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers are known to be fetotoxic and contraindicated in pregnancy. Similarly, diuretics should not be used since they can compromise on intravascular fluid volume and uteroplacental circulation. Atenolol should also be avoided since it interferes with fetal growth.
The generally accepted indications for drug therapy include a BP >140 and/or 90 mmHg in -

• Gestational hypertension with or without proteinuria
• Preexisting hypertension with target organ damage and
• Preexisting hypertension with superimposed gestational hypertension.

Table 1: Antihypertensive agents considered safe during pregnancy

that the threshold for initiating treatment should be SBP of 150 mmHg and DBP of 95 mmHg.Milder hypertension need not be treated and patients with more severe forms definitely benefit from therapy (17).
In hypertensive emergency during pregnancy (defined as SBP≥170 or DBP≥110 mmHg), immediate hospitalization with intravenous labetalol, oral nifedipine or oral methyldopa should be initiated.
In Preeclampsia associated with pulmonary edema, intravenous nitroglycerine is the drug of choice (5µg/min -100µg/min titrated every 3-5 minutes). Close hemodynamic monitoring is recommended with the use of nitroglycerine to tailor the therapy.
Intravenous hydralazine and sodium nitroprusside are no longer considered safe for use in pregnancy due to the risk of adverse perinatal events (hydralazine) and fetal cyanide poisoning (nitroprusside) (18). Magnesium sulphate is the drug of choice for the treatment of seizures with eclampsia (19).
In severe preeclampsia, with multi organ involvement and fetal distress, delivery induction is the only appropriate treatment option.

BP management Post partum- As discussed earlier, BP usually rises in the first few days after delivery before normalizing. Close monitoring and follow up is required during this period in hypertensive mothers. All the drugs are excreted in the breast milk and caution should be exercised in choosing the drugs. The same drugs used in pregnancy may be continued postpartum also since there is no long term data for the effect on the lactating child. It should be remembered that bromocriptine, sometimes used for suppression of lactation, causes elevation of BP and methyldopa, considered safe during pregnancy has shown to increase post partum depression.

Long term implications
Women who develop hypertension during pregnancy are at risk of developing hypertension in future pregnancies. The earlier the onset of hypertension in the first gestation, the higher is the risk. Similarly women developing hypertension and preeclampsia are at increased risk of cerebrovascular events and coronary artery disease later in the life (20, 21).

CONCLUSION
Hypertension during pregnancy is a unique clinical condition which has major short-term and long-term implications. If not treated adequately, it can result in serious maternal and fetal complications including fetal loss. At the same time, it serves as a window of opportunity to predict future cardiovascular risk- something not possible in nulliparous women. However, unlike other forms of hypertension, pregnancy related hypertension requires thorough understanding of the physiology and deep insights into the various aspects of its diagnosis and management by the obstetrician/gynecologist and cardiologists. Besides, availability of only a limited number of antihypertensive drugs that have documented safety and efficacy in pregnancy makes the task even more challenging.

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