Hypertension in pregnancy

Written by : Priyadarshini John DM, Anoushka Krishnan FRACP

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.

Introduction:

Hypertension in pregnancy is a predominant contributor to maternal-fetal morbidity and mortality globally. Identification of hypertension during pregnancy is of paramount importance. Leaving it unidentified can put women and infants at immediate risk of injury and potentially predispose affected mothers to an increased risk of cardiovascular complications later in life. Teng et al studied the association between maternal-fetal outcomes with hypertension and observed an increased risk of preterm delivery which resulted in early gestational age and low birth weight. Most concerning, hypertension during pregnancy may be a marker of undiagnosed glomerulonephritis or thrombotic microangiopathy.

Epidemiology of Hypertension in Pregnancy:

Hypertension in pregnancy can be new onset or preexisting. It is categorized into four presentations (Figure 1). The incidence of hypertension is 7.5% per each pregnancy, which likely underestimates the actual risk of hypertension per woman during reproductive years which is around 15.3%. A series by Fingar et al, who looked at four million hospital deliveries, reported that 11% had hypertension, out of which 4.7% had preeclampsia, 3.8% had gestational hypertension, 1.7 % had chronic hypertension, 0.6% had uncategorized HTN.

Figure 1: Different presentations of hypertension in pregnancy

Various criteria by different societies and obstetric bodies have been used to diagnose and manage hypertension in pregnancy. These include the NICE guidelines, ISSHP (International Society for the Study of Hypertension in Pregnancy), ACOG, SOGC ( Society of Obstetricians and Gynecologists of Canada ), and FIGO (International Federation of Gynecology and obstetrics). The definitions for various hypertensive disorders of pregnancy range from chronic hypertension, gestational hypertension, preeclampsia and preeclampsia/eclampsia on chronic hypertension are outlined in Figure 2.

Figure 2: Criteria for hypertensive disorders of pregnancy

Gestational Hypertension is the most common form of hypertension in pregnancy, not including preeclampsia. Ying et al in their review reported that the overall prevalence of gestational hypertension is 6-7%, and it is more prevalent in nulliparous women and multiparous women who had previous history of preeclampsia, obesity, and multifetal gestation. Gestational hypertension may ameliorate postpartum, but some women may have persistent hypertension postpartum or develop preeclampsia (Figure 3). Whether gestational hypertension is a precursor manifestation of preeclampsia is not clear from the available literature. Many studies have attempted to identify the predictors of progression to preeclampsia in gestational hypertension.

Barton et al reported that 10-50% of women with gestational hypertension may go on to develop preeclampsia in 1-5 weeks from the time of diagnosis.

Figure 3: Course of Gestational hypertension

Preeclampsia:In a systematic review by Abalos et al identified that preeclampsia was a manifestation in 4.6% of pregnancies worldwide. Risk factors for preeclampsia included nulliparity, multifetal gestation, elderly women, family and previous history of preeclampsia, use of artificial reproductive technology, and placental insufficiency. Another systematic review by Emily et al reported five times increased risk of preeclampsia in patients with chronic hypertension. As chronic hypertension is uncommon in the reproductive age group, it constitutes 5-10% of cases of preeclampsia. Maya et al found a proportional higher risk of preeclampsia with an increasing stage of hypertension. Worsening preexisting proteinuria, new onset proteinuria, sudden exacerbation of blood pressure, and other new organ dysfunction suggest preeclampsia superimposed on chronic hypertension.

Nir et al proposed that the following factors have a high likelihood of underlying preeclampsia.

(1) Gestational age of less than 34 weeks,

(2) Mean systolic blood pressure of >135 mm Hg on 24-hour ambulatory blood pressure monitoring,

(3) Increased serum uric acid level

(4) Abnormal uterine artery doppler velocimetry

(5) Increased serum levels of antiangiogenic markers like sFlt1 (soluble fms-related tyrosine kinase 1), sEng (soluble Endoglin), and decreased levels of proangiogenic markers like PIGF (Placental Growth factor).

A FIGO initiative in 2019 categorized preeclampsia into 4 subtypes depending upon maternal perinatal morbidity and mortality:

(1) Early onset preeclampsia (delivery before 34 weeks gestational age)- also referred to as placental preeclampsia

(2) Preterm preeclampsia (delivery before 37 weeks gestational age)

(3) Late onset preeclampsia (delivery after 34 weeks gestational age) - maternal preeclampsia.

(4) Term preeclampsia (delivery after 37 weeks gestational age)

These subtypes are not mutually exclusive. If diagnosed in a timely manner, the native course of early onset and preterm preeclampsia may be mitigated by appropriate measures suggested by FIGO screen and prevention strategy.

Pathophysiology of Hypertension during pregnancy

Fetomaternal factors play a major role in the pathogenesis of preeclampsia. Correa at al studied placenta morphology in preeclampsia and found that preeclamptic placentas have many syncytial knots and fibrin deposits. Hence, the placenta is a central factor in the pathophysiology of preeclampsia, where there appears to be an imbalance between angiogenic and antiangiogenic factors. In normal pregnancy, the cytotrophoblast cells of fetal origin penetrate the uterine decidua via anchoring villi, and a few extra villous cytotrophoblast cells pierce uterine arteries. This is facilitated by remodeling terminal spiral arteries, providing a high capacity/low resistance system to enable adequate uteroplacental perfusion.

In preeclampsia, there is failure of the endovascular invasion of cytotrophoblast and defective remodeling of uterine spiral arteries, creating a high resistance system and making the placenta hypoxic. In placental preeclampsia, a hypoxic placenta causes oxidative stress within the placenta, impairing villous angiogenesis. The pathologic placenta secretes antiangiogenic factors, like soluble fms-like tyrosine kinase-1 [sFlt-1] and endoglin, which bind with vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). This cascade causes widespread maternal vascular inflammation, endothelial dysfunction, and vascular injury, leading to hypertension, glomerulopathy, and systemic manifestations of preeclampsia.

In maternal preeclampsia, pregnancy poses physiological stress which can aggravate pre-existing maternal vascular and endothelial dysfunction secondary to long-standing diabetes, obesity, chronic hypertension, or autoimmune diseases. Figure 4 lists the features of preeclampsia.

Figure 4: Features of preeclampsia

There are four commercial assays available for the diagnosis of preeclampsia.Triage Placental growth factor (PLGF) assay, Elecsys sFLT1/PLGF ratio, Delfia Xpress PLGF 1-2-3 test, Brahms sFLT1/PLGF ratio.NICE(National Institute for Health and Care Excellence) and German Society of Gynaecology and Obstetrics recommends sFLT1/PLGF ratio and serum PLGF levels for the diagnosis of preeclampsia. PLGF levels<100pg/ml before 35 weeks gestational age lessens the likelihood of diagnosis of preeclampsia in the next two weeks.Ratio of sFLT1/PLGF <38 has 99% negative predictive value for preeclampsia within one week and 95% in the next four weeks, hence used for ruling out preeclampsia. Presently,these assays are in vogue in European countries.

Effect of preeclampsia on Kidney

In Preeclampsia, GFR and renal plasma flow decrease by 30-40% compared to normal pregnancy and peer gestational age. Hypoperfusion can cause acute tubular necrosis. Preeclampsia causes glomerular capillary endotheliosis. On light microscopy, glomeruli are enlarged with endothelial and mesangial cell hypertrophy, causing the appearance of a bloodless glomerular capillary lumen. Podocytes are usually swollen with PAS-positive hyaline droplets. Immunofluorescence is positive for fibrin. Electron microscopy shows endotheliosis and loss of endothelial fenestrae with subendothelial and mesangial electron-dense deposits with preserved foot process of the podocytes. Glomerular swelling and endotheliosis disappears by eight weeks postpartum, which correlates with the resolution of proteinuria. FSGS is seen in 50% of cases of glomerular endotheliosis during pregnancy.

To know more about preeclampsia and its effects on glomerulus, read here the amazing blog and tweetorial.

Complications of Preeclampsia

HELLP (Hypertension, Elevated Liver function, Low Platelets) is seen in 1-2% of preeclamptic women, and 15-20% of patients with HELLP may not have preeclampsia. It is characterized by hemolysis as evidenced by severe anemia, schistocytes on peripheral smear, elevated LDH, and serum bilirubin. Liver enzymes ALT and AST increased to two times the normal limit, and platelets were less than 100,000 cells/microL. Preeclampsia is occasionally complicated by eclampsia which is secondary to vasogenic cerebral edema in the posterior portion of white matter and cerebral vasoconstriction.

The following infographic summarizes the differential diagnosis of hypertension in pregnancy (Figure 5).

Figure 5: Differential Diagnosis of hypertension in pregnancy

Broad principles of management

The goals of ongoing antenatal care in the setting of hypertension include optimization of blood pressure, early recognition, and management of pre-eclampsia with the aim of delaying progression to more severe complications and optimizing birth for both the mother and the baby.

1. Management of mild to moderate hypertension (SBP 140-169 mmHg and/or DBP 90-109 mmHg): The use of anti-hypertensive therapy halves the risk of developing severe hypertension (risk ratio {RR}: 0.49, 95% CI: 0.40-0.60). While there is limited evidence about the optimal blood pressure targets for mild to moderate hypertension, drug therapy should be considered when SBP is persistently above 140 mmHg, DBP is persistently over 90 mmHg, or if there is a concern for pre-eclampsia. More recently, the CHAP trial evaluated treating mild chronic hypertension in pregnancy (BP <160/100 mmHg) and randomized 2408 women to anti-hypertensive treatment (aiming for BP < 140/90 mmHg) versus no treatment (control). The primary outcome was a composite of severe preeclampsia, preterm birth at < 35 weeks, placental abruption and fetal or neonatal death. The incidence of primary outcome events was lower in the active treatment group (hazard ratio HR: 0.82, 95% CI: 0.72-0.94), thus providing some impetus to tighter BP control. Following this, the American College of Obstetrics and Gynaecology (ACOG) revised their previous threshold of 160/110 mmHg to using a target of 140/90 mmHg to initiate or titrate anti-hypertensive therapy. Targeting the lower end of this spectrum may be appropriate if there are other comorbidities. ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are contraindicated in pregnancy. However, methyldopa, labetalol, and nifedipine are typically safe to use in pregnancy. Alternate agents include hydralazine and clonidine. Additionally low dose aspirin is recommended as prophylaxis in women at high risk of preeclampsia and should be initiated between 12 weeks and 28 weeks of gestation and continued daily until delivery. Calcium supplementation may also reduce the risk of pre-eclampsia.

2. Management of severe hypertension (BP > 160/110 mmHg): Recognition and prompt management of severe hypertension are important as this is considered to be a medical emergency, with potentially deleterious outcomes on both the mother and the fetus. Therapy should be promptly administered if SBP is equal to or above 160 mmHg and/or DBP is equal to or above 110 mmHg with the aim to gradually lower the BP to a target of 130-150 mmHg systolic and 80-90 mmHg diastolic. This is to ensure that blood flow to the fetus is not compromised. A range of anti-hypertensive agents can be used to manage BP as an ideal agent of choice has not been established, which includes immediate release oral nifedipine, intravenous (IV) administration of hydralazine or labetalol. Refractory hypertension will require the administration of multiple doses and the concomitant administration of oral therapy with IV therapy will result in a more sustained BP lowering effect. Treatment should be provided in a high acuity unit with frequent (15-20 minute) BP monitoring until stable followed by a minimum of 4 hourly monitoring with frequent maternal and fetal assessments, including continuous fetal heart rate (FHR) monitoring.

3. Preeclampsia of pregnancy (hypertension and involvement of one or more organs and/or the fetus): The severity and onset of clinical features of preeclampsia are often unpredictable. Delivery is the definitive management resulting in resolution for all components of pre-eclampsia, which can take anywhere from a few days up to three months postpartum. Any combination of oral and IV agents may be used to manage blood pressure (as mentioned above) and the agent of choice would be the one that the treatment team is most familiar with. Preeclampsia is a risk factor for venous thromboembolism (VTE), and nephrotic-range proteinuria further increases this risk. All women should undergo a risk assessment for VTE and should be offered prophylaxis, typically using low molecular weight heparin in high risk individuals. Infusion of large volumes of IV fluid should be avoided due to peripheral or pulmonary edema risk. While diuretics are not usually recommended unless there is evidence of peripheral or pulmonary edema, strict monitoring of fluid balance should be maintained (with an indwelling catheter if required). Magnesium sulfate is the drug of choice for the prevention and treatment of eclampsia. Magnesium sulfate halves the risk of eclampsia and probably reduces maternal mortality. The need for this drug should be carefully discussed with obstetricians and obstetric physicians. Recommended indications include eclampsia, pre-eclampsia with signs of central nervous system irritability and severe pre-eclampsia (SBP more than or equal to 170 mmHg/ DBP more than or equal to 110 mmHg and 3+ proteinuria or SBP more than or equal to 150 mmHg/ DBP more than or equal to 100 mmHg on two occasions and 2+ proteinuria with at least two signs of symptoms of imminent eclampsia- defined below). Risks of the drug include circulatory collapse and neuromuscular dysfunction. Therefore, local protocols should be developed for magnesium administration.

4. HELLP syndrome (hemolysis, elevated liver enzymes, low platelets): Indicators of severe disease include maternal platelet count of <100, liver transaminases at over twice the normal range, and microangiopathic hemolytic anemia (MAHA). It is important to liaise with the obstetrician, anesthetist, and hematologist early. Delivery should be considered if the gestation age is > 34 weeks and/or maternal or fetal condition is deteriorating. The administration of antenatal corticosteroids may be considered (for fetal lung maturation), and platelet transfusions may be required if the platelet count poses a hazard to operative birth or there is associated postpartum bleeding. Magnesium sulfate may also be considered for the indications described above.

5. Eclampsia: Eclampsia is uncommon, however, it is associated with high morbidity and mortality. The main goals of treatment include seizure termination, prevention of seizure recurrence, control of blood pressure, and prevention of maternal and fetal hypoxia. Seizures may occur ante, peri or post (usually within 24 hours)-partum and unfortunately, there are no reliable markers that predict pre-eclampsia. Imminent eclampsia is defined as at least two of the following: recurrent or severe headaches, visual disturbances, clonus/ hyperreflexia, and altered level of consciousness. Principles of management include resuscitation, magnesium sulfate infusion and consideration of benzodiazepines (such as diazepam, clonazepam or midazolam) if seizures are prolonged or recur. Delivery should be considered in conjunction with the obstetrics team.

6. Anti-hypertensive therapy in the postpartum period: Women should be counseled that anti-hypertensive therapy can be adapted to allow for breast-feeding. Although small amounts may pass into the breastmilk, this is likely to be low enough to preclude any clinical effects in the baby. The choice of agent should be determined in conjunction with the patient based on their underlying clinical condition. ACEi (with close monitoring of kidney function and serum potassium) or calcium channel blockers such as nifedipine or amlodipine may be offered as agents of choice.

Management strategies of hypertension in pregnancy are summarized in the following infographic (Figure 6).

Figure 6: Principles of management of HTN in pregnancy

Figure 7: Antihypertensive drugs in pregnancy

Long-term outcomes of gestational hypertension or preeclampsia

Women who have been diagnosed with preeclampsia or gestational hypertension are at risk of developing chronic hypertension (RR 3.7, 95% CI: 2.70-5.05), cardiovascular disease (RR 2.16, 95% CI: 1.86-2.52) and kidney failure (RR: 4.3, 95% CI: 3.3-5.6) in the future. The risk of kidney failure is exacerbated in the presence of underlying kidney disease, although the absolute risk is probably low in the absence of proteinuria or underlying kidney disease. Other risks include deep vein thrombosis, type 2 diabetes, and hypothyroidism. Additionally, there is an approximately 20% risk of developing preeclampsia in future pregnancies.

Women with a history of preeclampsia should be counseled with regard to maintaining a healthy diet and regular physical activity, and smoking cessation should be advised. Annual blood pressure check should be recommended along with a 5-yearly (or more frequently if indicated) assessment of cardiovascular risk factors such as lipid profile and blood glucose monitoring.

Other types of hypertension in pregnancy

Apart from the four major types of presentations in pregnancy, hypertension in pregnant women can be masked or manifest as white coat hypertension.

Masked hypertension is said to be present when blood pressure is normal in the office and more than 140/90 mmHg at home. Salazar et al observed the prevalence of masked hypertension in pregnant women to be 33.3%. They suggested careful observation for masked hypertension, especially during high-risk pregnancies, including those with multifetal gestation, gestational diabetes, and previous pregnancy with preeclampsia. In the absence of high risk pregnancies, masked hypertension should be suspected in women who have consistent systolic pressure over 120mmHg and diastolic pressure over 80mmHg for 3 consecutive clinic readings, women with family history of HTN, obesity, elderly pregnancy and women who smoke. In another study, Naiha et al concluded that women with masked hypertension were at risk for developing preeclampsia and eclampsia (at term or near term), adding to maternal and fetal mortality and morbidity. Masked hypertension can be diagnosed by 24-hour automated home or ambulatory blood pressure monitoring.

White coat hypertension (WCH) is diagnosed when home blood pressure is less than 135/85 mmHg but more than 140/90 mmHg when measured in a clinic. White coat hypertension in pregnancy is not a benign condition and can be an important risk factor for preeclampsia. There is sparse literature regarding the outcome of white-coat hypertension pregnancies. Interventions, including BP recording done by a nurse rather than a doctor and taking repeated measurements, may help ease patient anxiety. Brown et al found the prevalence of white coat hypertension to be around 32%. Of those, 40% developed (benign) gestational hypertension with good pregnancy outcomes, while 8% developed proteinuric preeclampsia. It was estimated that there is approximately double the risk of preeclampsia in women with WCH. Therefore, the need for home blood pressure monitoring in women with WCH and continuous surveillance for preeclampsia is recommended. There is no strong superiority evidence between automated and ambulatory blood pressure monitoring(ABPM). ABPM has greater sensitivity whereas automated blood pressure monitoring is more feasible and reproducible.

The International Society for the Study of Hypertension(ISSHP) has proposed the following evaluation process for white coat hypertension (Figure 8).

Figure 8: Evaluation process for white coat hypertension

Conclusions:

Hypertension in pregnancy is not an uncommon clinical scenario. Pre-eclampsia, in particular, is an important and multi-faceted problem with a significant impact on maternal and fetal health. The lack of prevention and screening tools for severe disease makes the management of this condition challenging. The cornerstones of current management include accurate diagnosis, monitoring, anti-hypertensive therapy, magnesium, and early birth, particularly in more severe cases. Improved diagnostic tools and treatment approaches remain the ultimate goal to improve maternal and fetal health worldwide.

Reviewed by : Amy Yau MD, Shina Menon MD, Brian Rifkin MD, Sophia Ambruso MD, Silvi Shah MD.

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.