Hypertension in pregnancy

Introduction

Hypertension in pregnancy is prevalent since Hippocrates’s time. Hippocrates had coined the term ‘eclampsia’ which means ‘flash out’ in Greek since 4th century BC. In 1843, Lever from Guy’s hospital found that albuminuria and hypertension could precede the onset of fits which give rise to the term pre-eclampsia.

It is the commonest medical problem in pregnancy. The incidence of hypertension in pregnancy is 5-10% of all pregnancy and responsible for maternal mortality of 100,000 per year. It is the third commonest cause of maternal death in Myanmar and also a common cause of perinatal dealth.

Definition and Classification

Hypertension in pregnancy is defined as diastolic blood pressure (BP) of 90 mmhg or more and systolic pressure of 140 mmhg or more. Diastolic BP is the pressure at which the sound disappears (Korotkoff phase V). These BP must be recorded on at least two occasions 2 hours or more apart.

Proteinuria (albuminuria) is the presence of 300mg/l or more protein in a 24 hour urine specimen or proteinuria >/ 1+ with dipstick . Hypertension in pregnancy is classified into four category. Chronic hypertension is hypertension present at the booking visit, or before 20 weeks. It can be primary or secondary in etiology. If there is proteinuria only and the gestation is less than 20 weeks, it is known as chronic renal disease.

Hypertension arising for the first time after 20 weeks of gestation without significant proteinuria is called pregnancy induced hypertension or gestational hypertension and the BP returns to normal after 6 weeks postpartum. The development of hypertension with proteinuria after 20 weeks of pregnancy in woman with previously normal BP is defined as preeclampsia.

Any pregnant women with fits or new onset grand mal seizures also meets the criteria for pre-eclampsia, regardless of the level of blood pressure or proteinuria and without the history of epilepsy is said to have eclampsia.

Pre-eclampsia is further classified as mild and severe. Mild pre-eclampsia is when BP is >/ 140/ 90 mm hg with no criterion for severe pre-eclampsia. Severe pre- eclampsia is when the BP is > 160/ 110 mm hg with one or more of the clinical criteria for severe pre-eclampsia, proteinuria at least 5g in 24 hour collection or 3+ to 4+ on dip stick test collected at least 4hours apart.

Symptoms , biochemical and hematological impairments of severe PE includes oliguria (24 hour urine output of <500ml), cerebral or visual disturbances, scotomata or blurred vision, altered consciousness, pulmonary edema or cyanosis, epigastric or right upper quadrant pain caused by stretching of Glisson’s capsule, impaired liver function test, thrombocytopenia and HELLP syndrome.

Superimposed preeclampsia is new onset of proteinuria in a pregnant women with hypertension.

Etiology and Pathophysiology of preeclampsia

The etiology of preeclampsia is unknown. It is known as disease of theories. Much of the literature focused on the failure or incomplete trophoblastic invasion of endometrial spiral arterioles by the placenta leading to occlusion of the arterioles and decreased placental perfusion causing intrauterine growth restriction, intrauterine fetal death and perinatal death. It is also thought to be due to imbalance between the release of circulating factors, prostacyclin (PGI2), a vasodilator and thromboxane A2, a vasoconstricter. Another theory is capillary endotheliosis or generalized endothelial cell alteration causing endothelial cell damage leading to multi-organinvolvement.

Some believethat PE is an immune reaction as recurrence rate with same partner is 20% and usually appear at later gestation than the first pregnancy. A new partner increases the risk of recurrence. Prolonged exposure to paternal antigen prior to conception and cigarette smoking reduce the incidence.

Risk factors for preeclampsia

The moderate risk factors includes first pregnancy, age 40 years or older, pregnancy interval > 10 years, BMI 35kg/m2 at first visit, family history of pre-eclampsia and multiple pregnancy. High risks factors are history of hypertensive disease in previous pregnancy, chronic renal disease, autoimmune diseases such as systemic lupus erythematosus or antiphospholipid syndrome, Type 1 or type 2 diabetes and chronic hypertension.

Reducing the risk of hypertensive disorders in pregnancy

Pregnant women must be advised to see a healthcare professional immediately if they experience symptoms of severe PE. Symptoms include: severe headache, visual disturbances such as blurring or flashes before the eyes, severe pain just below the ribs, vomiting, sudden swelling of the face, hands or feet.

Life style interventions like advice on rest, exercise during pregnancy as in healthy pregnant women and pharmacological interventions can reduce the risk of hypertensive disorders in pregnancy. However, nitric oxide donors, diuretics, progesterone and low molecular weight heparin should not be used to prevent hypertension in pregnancy. Nutritional supplements and diet such as magnesium, folic acid, antioxidants (vitamin C and E), fish or algal oils or garlic and restriction of salt intake are not recommended solely to prevent hypertensive disorders during pregnancy.

Pregnant women at high risk of PE should be advised to take 75- 150 mg of aspirin daily from 12 weeks until the birth of the baby. Aspirin is a cyclooxygenase enzyme inhibitor and it corrects the prostaglandin imbalance.

Life-threatening Complications in preeclampsia

Superimposed preeclamptic disorders on hypertension during pregnancy may lead to severe maternal complications, including eclamptic seizures, intracerebral hemorrhage, pulmonary edema, acute renal failure, proteinuria greater than 4-5 g/d, HELLP syndrome (microangiopathic hemolysis, elevated liver enzymes, and thrombocytopenia [platelets < 100/µL]), hepatic swelling with or without liver dysfunction, hepatic infarction/rupture and subcapsular hematoma (which may lead to massive internal hemorrhage and shock), DIC and/or consumptive coagulopathy (rare). Consumptive coagulopathy is usually associated with placental abruption.

Fetal complications include abruptio placentae, intrauterine growth restriction, premature delivery, and intrauterine fetal death.

Management of chronic hypertension in pregnancy

Pre-pregnancy advice

Women with chronic hypertension should be refered to a specialist in hypertensive disorders of pregnancy to discuss the risks and benefits of treatment. Women who take angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptorblocker (ARBs) must be told that there is an increased risk of congenital abnormalities if these drugs are taken during pregnancy.

Antihypertensive treatment is stopped in women taking ACE inhibitors or ARBs if they become pregnant (preferably within 2 working days of notification of pregnancy) and offer alternatives. Women who take thiazide or thiazide-like diuretics should be explained that there may be an increased risk of congenital abnormalities and neonatal complications. Alternative antihypertensive treatment must be discussed, if they are planning a pregnancy.

Women who take other antihypertensive treatments must be informed that the limited evidence available has not shown an increased risk of congenital malformation.

Treatment of chronic hypertension

Pregnant women with chronic hypertension should be offered advice on: weight management, exercise, healthy eating and lowering the amount of salt in their diet. Existing antihypertensive treatment is continued if safe in pregnancy, or switch to an alternative treatment, unless sustained systolic blood pressure is less than 110 mmHg or sustained diastolic blood pressure is less than 70 mmHg.

Antihypertensive treatment must be offered to pregnant women who have chronic hypertension and who are not already on treatment if they have sustained systolic blood pressure of 140 mmHg or higher or sustained diastolic blood pressure of 90 mmHg or higher. Treatment of hypertension in pregnancy should aim for a target blood pressure of 135/85 mmHg. Labetalol must be considered to treat chronic hypertension in pregnant women. Nifedipine is considered for women in whom labetalol is not suitable, or methyldopa if both labetalol and nifedipine are not suitable.

Base the choice on any pre-existing treatment, side-effect profiles, risks (including fetal effects). Pregnant women with chronic hypertension should be prescribed aspirin 75-150 mg once daily from 12 weeks.

Placental growth factor (PlGF)-based testing is offered to help rule out pre-eclampsia between 20 weeks and up to 35 weeks of pregnancy. In women with chronic hypertension, schedule additional antenatal appointments.

Management of gestational hypertension

In women with gestational hypertension, a full assessment should be carried out in a secondary care setting taking account of the risk factors mentioned above for additional assessment and follow up.Women with gestational hypertension should be offered the tests and treatment listed in table 1.

Table 1. Management of pregnancy with gestational hypertension

Labetalol is considered for treatment of gestational hypertension. Nifedipine is considered for women in whom labetalol is not suitable, and methyldopa if labetalol or nifedipineare is not suitable. Base the choice on side-effect profiles, risk (including fetal effects). Bed rest in hospital advised as treatment for gestational hypertension is not recommended.

Timing of birth for chronic hypertension and gestational hypertension

Planned early birth before 37 weeks is not offered if blood pressure is lower than 160/110 mmHg, with or without antihypertensive treatment, unless there are other medical indications. Women with blood pressure lower than 160/110 mmHg after 37 weeks, with or without antihypertensive treatment, timing of birth and maternal and fetal indications for birth should be agreed between the woman and the senior obstetrician. If planned early birth is necessary, a course of antenatal corticosteroids and magnesium sulfate is indicated.

Postnatal investigation, monitoring and treatment of chronic and gestational hypertension

In women with who have given birth, measure blood pressure daily for the first 5 days after birth and as clinically indicated if antihypertensive treatment is changed after birth. For women with gestational hypertension who have given birth, continue antihypertensive treatment if requiredand reduce antihypertensive treatment if their blood pressure falls below 130/80 mmHg.

If a woman has taken methyldopa to treat gestational hypertension, stop within 2 days after the birth and change to an alternative treatment if necessary . For women with gestational hypertension who did not take antihypertensive treatment and have given birth, start antihypertensive treatment if their blood pressure is 150/100 mmHg or higher.

A care plan should be written for women with gestational hypertension who have given birth and are being transferred to community care. Women who have had gestational hypertension and who remain on antihypertensive treatment, a medical review with their GP or physician 2 weeks after transfer to community care and 6-8 weeks after birth.

Management of pre-eclampsia

Assessment of women with pre-eclampsia should be performed by a healthcare professional trained in the management of hypertensive disorders of pregnancy and offer admission to hospital for surveillance and any interventions needed. Concerns could include any of the following: sustained systolic blood pressure of 160 mmHg or higher; any maternal biochemical or hematological investigations that cause concern, for example, a new and persistent rise in creatinine (90 micromol/litre or more, 1 mg/100 ml or more); rise in alanine transaminase (over 70 IU/litre, or twice upper limit of normal range); a fall in platelet count (under 150,000/microlitre); signs of impending eclampsia; and signs of impending pulmonary edema and suspected fetal compromise.

Treatment of pre-eclampsia

Women with pre-eclampsia should be offered the tests and treatments listed in table 2.

Table 2. Management of pregnancy with pre-eclampsia

Use labetalol to treat hypertension in pregnant women with pre-eclampsia. Offer nifedipine for women in whom labetalol is not suitable, and methyldopa if labetalol or nifedipine are not suitable. Base the choice on any pre-existing treatment, side-effect profiles, risks (including fetal effects).

Timing of birth for preecalmpsia

Record maternal and fetal thresholds for planned early birth before 37 weeks in women with pre-eclampsia. Thresholds for considering planned early birth could include the following: known features of severe pre-eclampsia; inability to control maternal blood pressure despite using 3 or more classes of antihypertensives in appropriate doses; maternal pulse oximetry less than 90%; progressive deterioration in liver function, renal function, haemolysis, or platelet count; ongoing neurological features, such as severe intractable headache, repeated visual scotomata; eclampsia; placental abruption, reversed end-diastolic flow in the umbilical artery doppler velocimetry, a non-reassuring cardiotocograph or stillbirth.

A Senior obstetrician must be involved in any decisions on timing of birth for women with pre-eclampsia and the anaesthetic team and neonatal team should discuss if birth is planned in a woman with pre-eclampsia and if neonatal complications are anticipated.

Intravenous magnesium sulfate and a course of antenatal corticosteroids is indicated, if early birth is planned for women with preterm pre-eclampsia.

Postnatal investigation, monitoring and treatment (including after discharge from critical care)

In women with pre-eclampsia who did not take antihypertensive treatment and have given birth, measure blood pressure till day 5 after birth. Women with pre-eclampsia who did not take antihypertensive treatment and have given birth, start antihypertensive treatment if blood pressure is 150/100 mmHg or higher. Thewomen with pre-eclampsia who have given birth must be asked about symptoms of severe PE each time and blood pressure is measured. For women with pre-eclampsia who have taken antihypertensive treatment and have given birth, continue antihypertensive treatment consider reducing antihypertensive treatment if their blood pressure falls below 140/90 mmHg and reduce antihypertensive treatment if their blood pressure falls below 130/80 mmHg.

If a woman has taken methyldopa to treat pre-eclampsia, stop within 2 days after the birth and change to an alternative treatment. For women with pre-eclampsia who have given birth, transfer to community care if all of the criteria have been met: no symptoms of pre-eclampsia, blood pressure, with or without treatment is 150/100 mmHg or less; and blood test results are stable or improving. For thosewomen who have had pre-eclampsia and who remain on antihypertensive treatment, a medical reviews with their specialist 2 weeks after transfer to community care . All women who have had pre-eclampsia need a medical review with the physician 6–8 weeks after the birth.

Hematological and biochemical monitoring of all women who have pre-eclampsia with mild hypertension, or after step-down from critical care is necessary 48–72 hours after birth and repeat test are clinically indicated until results return to normal. Urinary reagent-strip test should be carried out 6–8 weeks after the birth.

If women who had pre-eclampsia and still have proteinuria (1+ or more) at 6-8 weeks after the birth, a further review with their specialist at 3 months after the birth to assess kidney function. If there is abnormal kidney function assessment, consider a specialist kidney assessment.

Fetal monitoring

In women with chronic hypertension, carry out an ultrasound for fetal growth and amniotic fluid volume assessment, and umbilical artery doppler velocimetry at 28 weeks, 32 weeks and 36 weeks andcardiotocography only if clinically indicated. In women with gestational hypertension, carry out an ultrasound for fetal growth and amniotic fluid volume assessment and umbilical artery doppler velocimetry at diagnosis and if normal repeat every 2 to 4 weeks, if clinically indicated.

In women with gestational hypertension, carry out cardiotocography only if clinically indicated.

Intrapartum care

Duringlabour, measure blood pressure hourly, in women with mild hypertension and every 15–30 minutes until blood pressure is less than 160/110 mmHg in women with severe hypertension. Antihypertensive treatment is continued during labour. Determine the need for hematological and biochemical tests during labour in women with hypertension using the same criteria as in the antenatal period even if regional analgesia is being considered.

Preload to women who have severe pre-eclampsia with intravenous fluids should be avoided before establishing low-dose epidural analgesia or combined spinal epidural analgesia.

Management of second stage of labour

The duration of the second stage of labour should not be limited in women with controlled hypertension. Operative or assisted birth is considered in the second stage of labour for women with severe hypertension whose hypertension has not responded to initial treatment.

Medical management of severe hypertension, severe pre-eclampsia or eclampsia in a critical care setting

Anticonvulsants

If a woman in a critical care setting has severe hypertension , severe pre-eclampsia ,an eclamptic fit or if birth is planned within 24 hours, intravenous magnesium sulfate must be given. Prophylactic magnesium sulfate treatment is considered if features of severe pre-eclampsia is present or if there is progressive deterioration in laboratory blood tests (such as rising creatinine or liver transaminases, or falling platelet count).

The Collaborative Eclampsia Trial regimen for administration of magnesium sulfate

A loading dose of 4 g should be given intravenously over 5 to 15 minutes, followed by an infusion of 1 g/hour maintained for 24 hours. If the woman has had an eclamptic fit, the infusion should be continued for 24 hours after the last fit. Recurrent fits should be treated with a further dose of 2–4 g given intravenously over 5 to 15 minutes. Diazepam, phenytoin or other anticonvulsants must not be used as an alternative to magnesium sulfate in women with eclampsia.

Antihypertensives

Treat women with severe hypertension who are in critical care during pregnancy or after birth immediately with labetalol (oral or intravenous) or oral nifedipine, or intravenous hydralazine and modify treatment according to response. Consider using up to 500 ml crystalloid fluid before or at the same time as the first dose of intravenous hydralazine in the antenatal period.

Corticosteroids for fetal lung maturation

If early birth is considered likely within 7 days in women with pre-eclampsia, offer a course of antenatal corticosteroids for fetal lung maturation. Do not use dexamethasone or betamethasone for the treatment of HELLP syndrome.

Volume expansion in women with severe pre-eclampsia is not used unless hydralazine is the antenatal antihypertensive. In women with severe pre-eclampsia, limit maintenance fluids to 80 ml/hour unless there are other ongoing fluid losses (for example, haemorrhage).

Caesarean section versus induction of labour

Choose mode of birth for women with severe hypertension, severe pre-eclampsia or eclampsia according to the clinical circumstances.

Antihypertensive treatment during the postnatal period, including during breastfeeding

For women with hypertension who wish to breastfeed, their treatment can be adapted to accommodate breastfeeding, and the need to take antihypertensive medication does not prevent them from breastfeeding. Explain that antihypertensive medicines can pass into breast milk in very low levels, so the amounts taken in by babies are very small and would be unlikely to have any clinical effect.

Blood pressure of babies, especially those born preterm, have symptoms of low blood pressure for the first few weeks and advise women to monitor their babies for drowsiness, lethargy pallor, cold peripheries or poor feeding when discharged home. Enalaprilcan be used during the postnatal period, with appropriate monitoring of maternal renal function and maternal serum potassium.

For women with hypertension in the postnatal period, if blood pressure is not controlled with a single medicine, consider a combination of nifedipine (or amlodipine) and enalapril.. If this combination is not tolerated or is ineffective, consider either adding atenolol or labetalol to the combination treatment or swapping one of the medicines already being used for atenolol or labetalol. Use medicines that are taken once daily when possible.

Where possible, avoid using diuretics or angiotensin receptor blocker to treat hypertension in women in the postnatal period who are breastfeeding or expressing milk. The overall risk of recurrence of hypertentionin future pregnancies is approximately 1 in5. There is also increased risk of hypertension and cardiovascular disease in later life.

Discuss how to reduce their risk of cardiovascular disease, including hypertensive disorders, with their GP or specialist, regarding avoiding smoking, maintaining a healthy lifestyle and weight gain. In women who have had pre-eclampsia or hypertension with early birth before 34 weeks, consider pre-pregnancy counselling .

Administration of magnesium sulfate for longer than 5–7 days in pregnancy has been associated with skeletal adverse effects and hypocalcaemia and hypermagnesemia in neonates. Consider monitoring of neonates for abnormal calcium and magnesium levels and skeletal adverse effects.

Recommendations by American College of Obstetricians and Gynaecologists

Acute-onset, severe hypertension that is accurately measured using standard techniques and is persistent for 15 minutes or longer is considered a hypertensive emergency. Intravenous (IV) labetalol and hydralazine are considered first-line medications for the management of acute-onset, severe hypertension in pregnant women and women in the postpartum period. Oral nifedipine also may be considered as a first-line therapy. Parenteral labetalol should be avoided in women with asthma, heart disease or congestive heart failure.

When urgent treatment is needed before the establishment of IV access, the oral nifedipine algorithm can be initiated as IV access is being obtained or a 200-mg dose of labetalol can be administered orally. The latter can be repeated in 30 minutes if appropriate improvement is not observed.

Magnesium sulfate is not recommended as an antihypertensive agent, but magnesium sulfate remains the drug of choice for seizure prophylaxis in severe preeclampsia and for controlling seizures in eclampsia.

Sodium nitroprusside is reserved for extreme emergencies and used for the shortest amount of time possible because of concerns about cyanide and thiocyanate toxicity in the mother and fetus or newborn, and increased intracranial pressure with potential worsening of cerebral oedema in the mother.

Recommendations by Society of Obstetricians and Gynaecologists of Canada

Women should have their BP measured using a standardized protocol after a period of rest in a quiet environment and be in a sitting position with their arm at the level of the heart using an appropriately sized cuff (ie, length 1.5 times the circumference of the arm). The arm with higher BP values should be used for hypertension diagnosis and BP monitoring. Non severe elevated BP should be remeasured at the same visit, with at least an interval of 15 minutes. Antihypertensive therapy is recommended for SBP measurements of ≥140 mm Hg or DBP measurements of ≥90 mm Hg in pregnant women with chronic hypertension, gestational hypertension or preeclampsia.

Initial antihypertensive therapy should be monotherapy from the following first-line drugs: oral labetalol, oral methyldopa, long-acting oral nifedipine, or other oral β-blockers (acebutolol, metoprolol, pindolol, and propranolol). Other antihypertensive drugs can be considered as second-line drugs, including clonidine, hydralazine, and thiazide diuretics.

ACE inhibitors and angiotensin receptor blockers should not be used in pregnant women. Additional antihypertensive drugs should be used if target BP levels are not achieved with standard-dose monotherapy. Add-on drugs should be from a different drug class chosen from first-line or second-line options.

Women with severe hypertension with SBP ≥160 or DBP ≥110 mm Hg in pregnancy require urgent antihypertensive therapy because it is considered an obstetric emergency due to risk of stroke.

References

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2. American College of ObstetriciansandGynaecologists. Practice bulletin no. 125: chronic hypertension in pregnancy. Obstet Gynecol. 2012 Feb. 119(2 Pt 1):396.
3. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of hypertension. National Guideline ClearinghouseHenderson JT, Whitlock EP, O’Conner E, et al. Low-Dose Aspirin for the Prevention of Morbidity and Mortality From Preeclampsia: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Evidence Syntheses, No. 112. 2014
4. Butalia S, Audibert F, Côté AM, Firoz T, Logan AG, Magee LA, et al. Hypertension Canada’s 2018 Guidelines for the Management of Hypertension in Pregnancy. Can J Cardiol. 2018 May. 34 (5):526-531.
5. Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 2006 . 354(23):2443-51.
6. Henderson JT, Whitlock EP, O’Conner E, et al. Low-Dose Aspirin for the Prevention of Morbidity and Mortality From Preeclampsia: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Evidence Syntheses, No. 112. 2014 Apr.
7. National Institute for Clinical Excellence: Hypertension in Pregnancy : diagnosis and management [NG133] June 2019

Yin YinSoe Professor (Retired), Department of Obstetrics and Gynaecology, University of Medicine 1, Yangon, Senior Consultant Obstetrician and Gynaecologist