INTRODUCTION

Hypertensive disorders of pregnancy remain an important cause of maternal mortality in both the developed and developing world.^1,2 An estimated 40,000 women die each year from this condition. Deaths due to hypertension were ranked fourth as a direct cause of maternal death in the United Kingdom during 2009–2012, with a maternal mortality ratio (MMR) of 0.25.³ A reduction in MMR was observed in the UK during 2012–2014 when a MMR of 0.08 was reported, when only two women died from pre-eclampsia and eclampsia, translating to approximately one death per 1,000,000 pregnancies.⁴ A sizeable proportion of hypertensive deaths may be avoided with good obstetric care. Approximately 70% of deaths in South Africa and France are considered avoidable, while a Dutch audit found that 90% of women who died from hypertensive disorders of pregnancy received substandard care.^1,5,6 Most hypertensive maternal deaths reported in South Africa are due to cerebral hemorrhage, therefore identification and treatment of severe hypertension is important.

The remarkable reduction in deaths reported in the UK indicates a considerable potential for reduction in other parts of the world. Interventions to prevent hypertensive disorders in pregnancy, including pre-eclampsia have been disappointing and an important factor associated with sub-standard care is poor detection. In a commentary on maternal deaths in the UK, Shennan et al. stated that hypertension and pre-eclampsia are only safe for the mother if identified and well managed.⁴

Assessment of urine for protein at booking, and thereafter as indicated by local guidelines, is a key step in ruling out or diagnosing severe conditions associated with high morbidity and mortality, particularly conditions such as pre-eclampsia and chronic renal disease. Pre-existing renal disease should be considered in women in whom proteinuria is documented before 20 weeks' gestation, while new-onset proteinuria after 20 weeks is a risk factor for pre-eclampsia, even in normotensive women.⁷ About one-third of women who present with proteinuria after 20 weeks will develop pre-eclampsia later in the pregnancy and adverse pregnancy and neonatal outcomes are more common as compared with women in whom hypertension was the first presenting sign of pre-eclampsia.⁸ It is important to distinguish between renal disease and pre-eclampsia because of different clinical management.

Physiological changes in pregnancy

Understanding the physiological changes in pregnancy is crucial when managing women with hypertensive disorders. Pregnancy is associated with significant hemodynamic and hormonal changes affecting the cardiovascular system. Maternal hemodynamic adaptation begins at 5–6 weeks’ gestation. Cardiac output increases gradually from 6 weeks’ gestation and reaches a plateau in the second and third trimester with levels increasing by 40% compared to pre-pregnancy. There is a simultaneous decrease in systemic vascular resistance (SVR) which is in turn responsible for the decrease in mean arterial blood pressure. Mean arterial blood pressure decreases significantly from the mid-follicular phase to 6 weeks’ gestation reaching a nadir between 16 and 20 weeks.⁹ After this period, blood pressure begins to rise slowly again, reaching pre-conception levels around term. The heart undergoes remodeling with an increase in left ventricular wall thickness and mass.¹⁰ Despite these changes, left ventricular contractile function is maintained and any changes in cardiac geometry are reversed within 3 months postpartum in normotensive women.

The fall in SVR also affects the renal vasculature. As a consequence of the renal vasodilatation, renal plasma flow and glomerular filtration rate (GFR) both increase compared to non-pregnant levels by 40–65% and 50–85%, respectively. Due to the increases in both GFR and glomerular capillary permeability to albumin, the fractional excretion of protein may increase up to 300 mg/day and the protein excretion also increases. In normal pregnancies the total protein concentration in urine does not increase above the upper normal limit. Uric acid excretion also increases due to increased GFR and/or decreased tubular reabsorption.¹¹

‘SCREENING’ IN PREGNANCY

General principles

‘Screening’ may be defined as the systematic application of a test or enquiry to identify individuals at sufficient risk of a specific disorder to warrant further investigation or direct preventive action, amongst persons who have not sought medical attention on account of symptoms of that disorder.¹² It has long been recognized that any screening program has both potential benefits and harms, and it was with a view to maximizing the former and minimizing the latter that Wilson and Jungner produced their 1968 WHO report titled Principles and practice of screening for disease.¹³ The principles enunciated in this classic report are presented in Box 1.

The explosion in genetic and genomic knowledge since then has prompted the WHO to revise these principles, to maintain their relevance in the face of these transformative technologies. The revised principles are presented in Box 2, and in many ways are more readily applicable to screening tests in pregnancy than the original criteria.

The requirement for screening programs to promote equity and access for the entire target population will necessitate varied approaches to screening in pregnancy depending on local resources and logistic considerations.

Identifying evolving concerns specific to pregnancy versus identifying hitherto unrecognized but pre-existing problems

All ‘routine’ examinations and investigations performed in pregnancy can be considered as screening tests, and should therefore adhere to the principles outlined above. Many such assessments aim to identify pre-existing maternal conditions, such as iron deficiency anemia or chronic hypertension, that could increase the chance of an adverse pregnancy outcome if left untreated. Such assessments may, of course, have benefits that extend beyond the end of the pregnancy, and highlight the opportunistic potential for pregnancy care to improve the health of mothers in the long term, especially those whose prior interactions with the healthcare system may have been limited.¹⁵

Other antenatal screening assessments aim to identify conditions unique to pregnancy when they are present, such as pre-eclampsia or fetal growth restriction, or predict the risk of such conditions at a sufficiently early gestation to permit initiation of prophylactic therapies and/or triaging of ongoing care to an appropriate facility or provider. Hypertension and proteinuria may, of course, be either pre-existing or of new onset in pregnancy, whereas the specific syndrome of pre-eclampsia is unique to the gestational state.

DEFINITIONS OF HYPERTENSION AND PROTEINURIA

Hypertension in pregnancy is diagnosed at blood pressure levels of >140/90 mmHg on two occasions 4 hours apart. A single reading indicative of severe hypertension (blood pressure >160/110 mmHg) is sufficient to establish a diagnosis. The concept of pre-hypertension has been proposed by the South African National Department of Health in their guideline on managing hypertension in pregnancy.¹ The guideline recommends that women with borderline blood pressure levels of 135/85–139/89 mmHg have their blood pressure repeated within 30 minutes to 2 hours and, if still borderline, are asked to return to have their blood pressure checked within 3–7 days. The International Society for the Study of Hypertension in Pregnancy (ISSHP) has classified hypertension in pregnancy as follows:¹⁶

• Chronic hypertension – hypertension diagnosed before 20 weeks’ gestation
• Gestational hypertension – hypertension arising de novo after 20 weeks’ gestation in the absence of proteinuria and without biochemical or hematological abnormalities. It is usually not associated with fetal growth restriction.
• White-coat hypertension refers to elevated blood pressure levels recorded at a clinic (140/90 mmHg), but normal levels measured at home or work (< 135/85 mmHg). May be diagnosed before 20 weeks.
• Transient gestational hypertension – hypertension diagnosed during the second or third trimester but normalizes with repeated readings.
• Pre-eclampsia is diagnosed by hypertension after 20 weeks' gestation accompanied by proteinuria and/or evidence of acute kidney injury, liver dysfunction, neurological features, hemolysis or thrombocytopenia in the mother or fetal growth restriction.

Screening for proteinuria is best assessed using dipstix urinalysis and, if positive, quantified by a spot urine protein/creatinine ratio or 24-hour urine protein collection. A 24-hour urinary protein >300 mg/day or spot urine protein/creatinine ratio of >30 mg per mmol is abnormal.

SCREENING FOR HYPERTENSION

Pre-pregnancy counseling

Pre-pregnancy counseling may be of significant benefit in women who are known to have chronic hypertension or who have had previous episodes of gestational hypertension. It is vital to identify these patients prior to attempting pregnancy, in order to optimize their blood pressure control before the start of pregnancy and to ensure correct treatment and lifestyle modifications. All women planning a pregnancy should be encouraged to attend their primary health care provider to identify hitherto unrecognized hypertension and start on the correct management. This also represents an opportunity for counseling regarding lifestyle modification, especially weight optimization, and to recommend early booking for women with risk factors for pre-eclampsia (including chronic hypertension, obesity, diabetes, systemic lupus erythematosus, antiphospholipid syndrome, etc.), so that aspirin prophylaxis can be commenced in a timely fashion (see below).

Women taking angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) should be informed of an increased risk of adverse fetal outcomes if these drugs are taken during pregnancy.¹⁷ Both these drugs form part of the first-line management of blood pressure control outside pregnancy and also optimize proteinuria. Pre-pregnancy counseling will identify women who are using these and other potentially unsuitable drugs such as diuretics and high dose beta blockers. In patients with reliable access to care, these drugs only need to be changed once a pregnancy is confirmed. Clinicians may choose to avoid these drugs in women who are at risk of unplanned pregnancies that may be detected late.

Screening for hypertension during pregnancy

WHO released new basic antenatal care (BANC plus) guidelines in 2016.¹⁸ In these guidelines, they recommend eight antenatal care contacts during all pregnancies. They increased the number of contacts from four visits to eight contacts. The term ‘contact’ is used as this does not have to be a hospital or clinic visit, but may occur in the community by a trained community health worker. These recommendations are based on evidence that more frequent contacts lead to an increased detection of hypertension in pregnancy, thereby potentially reducing the stillbirth rate. A 1-year prospective trial conducted in 2017 in Pretoria, South Africa proved an increase in detection of hypertension in pregnancy, however, there was an unchanged rate in stillbirths.¹⁹ An increased detection of hypertension in pregnancy may, however, have other maternal and fetal benefits. This was a small study and will need to be repeated in multiple centers.

WHO proposes a booking visit as early in pregnancy as possible (before 14 weeks) with follow-up contacts at: 20, 26, 30, 34, 36, 38, 40 weeks (Table 1). Blood pressure and urine should be tested at every contact.

Screening for hypertension during labor

Blood pressure should be routinely monitored four hourly during the first stage of labor and hourly during the second stage of labor. Blood pressure should be checked after delivery is complete.¹⁷

Screening for hypertension by healthcare staff outside maternity services

Hypertension is mostly asymptomatic or may present with atypical features. Concerning signs include headache, blurred vision, epigastric pain, nausea and vomiting and difficulty breathing.²⁰ Blood pressure checks are advised in all women who are pregnant presenting to health care facilities outside of their antenatal care facility, even with unrelated or loosely related complaints.

Postpartum screening for chronic hypertension

Women who were managed for chronic hypertension, gestational hypertension or pre-eclampsia during their pregnancy should have daily blood pressure monitoring for the first 2 days post-delivery. They should have another blood pressure assessment at least once between days 3 and 5, aiming for blood pressures below 140/90 mmHg.¹⁷ These women should be offered a postnatal follow-up appointment at 6 weeks to monitor their blood pressure and proteinuria. If these are not controlled, further investigation is required, including a possible kidney biopsy for systemic causes of proteinuria.

Numerous studies have tried to predict recurrence of hypertensive disorders in a following pregnancy. Women with gestational hypertension have a 13–53% chance of recurrence.^17,20,21 Recurrence of pre-eclampsia is discussed in the section of this chapter on pre-eclampsia.

Accurate blood pressure measurement

Technique

The most recommended method of measuring blood pressure during and outside of pregnancy, is described in the European Society of Cardiology guidelines for the management of cardiovascular disease during pregnancy.²¹ The patient should be in the seated position (or left lateral recumbent position during labor), with an appropriately sized cuff (the bladder length of which should be 80% of the patient's arm circumference, and the width at least 40%)²² placed around the upper arm at the level of the heart. Most health services have two different sizes of blood pressure cuff, at most, with the larger cuff used when the mid-upper arm circumference is >33 cm. Korotkoff V (disappearance of sounds) should be used to determine diastolic blood pressure.

Equipment

Mercury manometers are still seen as the gold standard of measuring blood pressure, although such devices are no longer available. Unfortunately, the best alternative – liquid-crystal sphygmomanometry – is not yet widely available.¹⁶ Aneroid devices are commonly employed in their place, but these require regular calibration given their tendency to be inaccurate.

Untrained health care workers may find it easier to use automated cuffs, which are preferable to aneroid devices if they have been shown to be reliable in pregnancy in the presence or absence of pre-eclampsia. A group of British researchers have developed and tested a vital signs device that is reliable in pregnancy and has been validated in low- to middle-income countries.²³ The Microlife® CRADLE (Community blood pressure monitoring in Rural Africa & Asia. Detection of underLying pre-Eclampsia and shock) Vital Signs Alert (VSA) is a hand-held, upper-arm, semi-automated device measuring blood pressure and pulse. The device uses a traffic light early warning system to aid untrained health care workers in referrals to health care facilities.

Self-monitoring

Women may elect to monitor their blood pressure at home on a calibrated blood pressure manometer. There is only moderate evidence for this practice,²⁴ although the ISSHP guidelines recommend its use for women with chronic high blood pressure and ‘white coat’ hypertension.¹⁶ The woman’s blood pressure device should be brought in and compared to a calibrated device in the health center to ensure accuracy of measurements. A list of validated home blood pressure assessment devices (not specific to pregnancy) is available at http://bhosc.ord/bp-monitors/bp-monitors/.

Ambulatory blood pressure monitoring

There is a limited evidence for the use of ambulatory blood pressure monitoring (ABPM) in women with suspected white coat hypertension.²⁴ A hyperbaric index (HBI) is calculated as the amount of blood pressure excess during a given time period above a 90% tolerance limit, with units of mmHg multiplied by hours. A single study has shown a 93% sensitivity and 100% specificity for an HBI calculated from an ABPM over 48 hours.²⁵ Other studies have not been able to reproduce these results.^26,27

Initial management of new-onset hypertension in pregnancy

Most young adults diagnosed with hypertension are asymptomatic. A thorough history and clinical examination is warranted before special investigations are requested.²⁸

History

A detailed history should include enquiry into a previous diagnosis of chronic medical conditions (hypertension, diabetes mellitus, premature cardiovascular disease, stroke); use of medication (including antiretroviral therapy, immune-modulatory drugs, glucocorticoids); a history of stimulants (caffeine, alcohol, tobacco products, or illicit drugs such as cocaine and amphetamines); and risk factors for pre-eclampsia (multiple pregnancy, prior pre-eclampsia, family history of pre-eclampsia).

Examination

The examination should focus on determining the presence of target organ damage and features of secondary hypertension. Features suggestive of target organ damage include:

• A pressure loaded apex suggested of left ventricular hypertrophy;
• Retinal changes suggestive hypertensive retinopathy;
• The presence of blood or protein on a urine dipstick.

Features suggestive of secondary causes include:

• A difference in pulse volumes (vasculopathy, e.g. Takayasu’s arteritis);
• Radio-femoral delay, low or abnormal arm to leg blood pressures (coarctation of the aorta);²⁹
• Abdominal bruits (renal artery stenosis);²⁹
• Flushing, sweating, tachycardia (phaeochromocytoma);
• Thin skinfold, central obesity, moon facies, ecchymoses (Cushings disease);²⁹
• Elevated body mass index (obesity and insulin resistance).

The absence of these clinical signs does not exclude the possibility of secondary causes.

Routine investigations

Hypertension diagnosed before 20 weeks’ gestation warrants a set of basic laboratory tests for initial assessment. These include serum urea and electrolytes, calcium, thyroid-stimulating hormone (TSH), fasting blood glucose, hematocrit, urine microscopy and protein excretion, and an electrocardiogram.

Fetal assessment

New-onset hypertension in the second half of pregnancy is an indication for sonographic assessment of fetal size in the third trimester, given that fetal growth restriction is a common corollary of gestational hypertension, and is one of the criteria that permits the diagnosis of pre-eclampsia.

Further assessment of secondary causes of chronic hypertension

Pregnancy-related hypertension is usually diagnosed in the second half of pregnancy and typically resolves within 3 months of delivery. If hypertension is diagnosed for the first time in the first half of pregnancy, or does not resolve after delivery, it is likely that the woman has undiagnosed chronic hypertension. Hypertension before the age of 35 should not be seen as essential hypertension until secondary causes have been investigated.¹⁸ In the developing world antiretroviral therapy³⁰ and obesity are among the most common causes of early onset hypertension. Rare causes of hypertension should not be missed.

More than 90% of young patients with hypertension have primary (essential) hypertension. Secondary causes should only be pursued if clinically suspected or in cases of true refractory hypertension.³¹ The following are causes of secondary hypertension, and should be considered when suggested by the patient’s history and examination:³²

• Renal disease of any form
  • Polycystic kidney disease, chronic kidney disease, nephritic syndrome, etc.
• Renovascular disease
  • Fibromuscular dysplasia in the young woman
  • Arterosclerosis in advanced age
• Primary aldosteronism
  • Presenting with refractory hypertension, hypokalemia and hypernatremia
• Cushings disease
  • Excess cortisol production
• Pheochromocytoma
  • Catecholamine secreting tumor
• Miscellaneous causes
  • Obstructive sleep apnea
  • Coarctation of the aorta
• Other endocrine disorders
  • Thyroid disease
  • Acromegaly
  • Hypercalcemia of any cause.

Evidence for the benefit of identifying secondary causes of hypertension during pregnancy is lacking.²⁴ None of the international guidelines has a suggested approach to the work-up of chronic hypertension. In centers where special investigations are possible and a clinical suspicion of secondary causes warrant further investigation, an appropriate work-up would include:^28,33

• Electrolytes particularly potassium (Conn’s Syndrome), sodium (Cushing’s disease), calcium (hypercalcemia). Follow with specialized testing if abnormal;
• Urea, creatinine, urinalysis for blood and protein, urine microscopy for casts (intrinsic renal disease);
• Renal ultrasound (intrinsic renal disease, obstruction);
• An echocardiogram:
  • ECG changes suggestive of left ventricular hypertrophy;
  • Suspicion of coarctation of the aorta;
• Polysomnograph (obstructive sleep apnea);
• Fasting plasma or 24-hour fractionated urinary metanephrines (low index of suspicion of phaeochromocytoma).³⁴

Only tests appropriate to the specific patient should be performed: clinicians should refrain from sending patients for a batch of tests to look for secondary causes. True refractory hypertension is defined as a blood pressure that remains above goal in spite of concurrent use of three antihypertensive agents of different classes.³³

Hypertension detected after 20 weeks should be seen as pregnancy-related hypertension until proven otherwise, i.e. by persistence after delivery. Only patients with a clinical suspicion of secondary hypertension or refractory hypertension warrant specialized investigation. The initial work-up would be the same as for patients with hypertension before 20 weeks’ gestation.

Admission

The care pathway for patients in whom new-onset hypertension has been identified will vary according to the location and model of care in question. In many centers, such patients are admitted to ‘day assessment units’,³⁵ in which serial blood pressure measurements may be performed, in addition to routine investigations for pre-eclampsia and fetal well-being. Such day units allow for a diagnosis to be made (transient hypertension, gestational hypertension or pre-eclampsia) without an inpatient admission. Further detail on the inpatient versus outpatient management of women with confirmed gestational hypertension or pre-eclampsia may be found in the respective chapters.

Admission for work-up of hypertension should always be considered for patients who:

• Have refractory hypertension and require urgent improvement of their blood pressure;
• Live far away from the hospital and require numerous special investigations; or
• Have other signs of maternal or fetal compromise.

Summary screening pathways for hypertension in pregnancy

Hypertension identified for the first time prior to 20 weeks’ gestation

Hypertension identified for the first time after 20 weeks’ gestation

SCREENING FOR PROTEINURIA IN PREGNANCY

Proteinuria is an essential part of the diagnosis of pre-eclampsia. It is also a complication of intrinsic renal disease such as nephropathy related to diabetes, HIV or autoimmune disease. All these conditions are associated with a higher risk for pre-eclampsia in pregnancy. It can be very difficult to distinguish between primary renal disease and pre-eclampsia.

Proteinuria of more than 300 mg/24 hours in a pregnant woman is considered as abnormal and requires further investigation.³⁶ Women with multiple pregnancies typically have a higher excretion of proteins; however, 300 mg/24 hours remains the upper acceptable limit of normal.³⁷

The initial diagnosis of proteinuria in pregnancy should be quantified. If the onset is before 20 weeks’ gestation, this could point towards intrinsic kidney disease. Women with known chronic kidney disease who have more than 1 g/24 hours are at risk of adverse maternal and neonatal outcomes including preterm delivery, small for gestational age infants and admissions to neonatal ICU.³⁸

Screening at antenatal visits

An assessment for proteinuria should be performed at the booking visit for all women. This can be done by sending a midstream urine sample for microbiological culture and sensitivity, or by dipsticking a clean catch of urine at the point of care. If proteinuria is present, urinary infection must be excluded as a cause. In the absence of infection, the presence of proteinuria necessitates further investigation, the nature of which would be determined by the patient’s history, examination findings, and gestation.

Guidelines differ in their recommendations regarding the role of screening for proteinuria at every antenatal contact or visit after the booking visit. An increased incidence of intrinsic renal disease has been reported in low- to middle-income countries such as South Africa.^39,40 Routine screening for proteinuria is performed at every antenatal visit in these centers, by means of bedside urine dipstick testing. Similarly, in the UK, the NICE (National Institute for Health and Care Excellence) guidelines recommend screening for proteinuria at every antenatal visit, as a part of routine care for all patients⁴¹ (including those with mild to moderate hypertension).¹⁷ Women with severe hypertension (160/110 mmHg or greater) should be admitted and have daily assessment for proteinuria performed as part of their workup.

In contrast, guidelines for antenatal care in Australia⁴² and the USA⁴³ do not recommend screening for proteinuria at every visit for healthy patients, only in those with pre-existing renal or systemic conditions (such as systemic lupus erythematosus or type 1 diabetes mellitus), or those with new-onset hypertension (to assess for pre-eclampsia). Women who enter pregnancy with established proteinuria are clearly not candidates for screening, but should have quantification of proteinuria performed periodically during pregnancy, especially if a flare of disease activity is suspected.

Advantages and disadvantages of urine dipstick testing

Bedside urine dipstick tests have been shown to have a high rate of false positive as well as false negative results when compared to a 24-hour urine protein excretion.⁴⁴ A systematic review of 14 studies evaluating the accuracy of urine dipsticks in pregnancy found a wide range of accuracy (sensitivity 22–100%; specificity 36–100%).⁴⁵ A comparison of manual and automated urine dipstick tests a found poor interobserver as well as observer to machine relationship.⁴⁶ In many settings, manual urine dipsticks are still the only available measure of proteinuria.

A positive reaction on the dipstick (1+) develops when there is approximately 30 mg/dL of protein in the urine; this is the equivalent of 300 mg per day. Table 2 demonstrates the correlation between urinary dipstick readings and proteinuria values.

False positive tests may result from:

• Macroscopic hematuria
• Semen
• Very alkaline urine (pH >7)
• Quaternary ammonium compounds
• Detergents, disinfectants
• Drugs
• Radio-contrast agents
• Concentrated urine (SG >1.030).

False negative tests may result from:

• Dilute urine (SG <1.010)
• High salt concentration
• Highly acidic urine
• Non-albumin proteinuria.

Quantifying proteinuria

If a urine dipstick is used to detect proteinuria, any reading of 1+ or more should be formally quantified for proteinuria via a spot urinary protein : creatinine ratio or 24-hour urine protein excretion.¹⁷ Significant proteinuria is diagnosed if the urinary protein : creatinine ratio is greater than 30 mg/mmol or a 24-hour urinary protein collection is greater than 300 mg.

The NICE guidelines¹⁷ and ACOG guidelines²⁴ suggest quantifying proteinuria with either a spot protein : creatinine ratio or a 24-hour urine protein excretion. The ISSHP and Australian guidelines advocate quantifying of proteinuria with a spot protein : creatinine ratio.^16,48 A ratio of ≥30 mg/mmol (0.3 mg/mg) is abnormal.

There is disagreement in the literature about the accuracy of the urinary spot protein : creatinine ratio for the detection of proteinuria in pregnant women with hypertension. A systemic review of 13 studies concluded that the protein : creatinine ratio is a reasonable “rule-out” test for screening for proteinuria of more than 0.3 g/day.⁴⁹ Lane et al. argued that the predicted protein excretion compared poorly with a 24-hour excretion of protein when more than 1 g/24 hours was present.⁵⁰ The protein : creatinine ratio did, however, provide good threshold values for above or below protein excretion rates of 300 mg/day. There are numerous benefits for the use of a spot urine collection including time, convenience, and reduced workload on nursing staff. Therefore, while a protein : creatinine ratio is not as accurate for quantifying proteinuria, it may be used to rule out the presence of abnormal levels of proteinuria.⁵¹

Follow-up of proteinuria

Unlike blood pressure, where the risk of adverse events correlates with higher values, there is no clear relationship between the severity of pre-eclampsia and the degree of proteinuria. Serial quantifying measures will rarely influence management.⁵² Formal quantifying of proteinuria should not be repeated once the diagnosis of pre-eclampsia has been established. In patients with intrinsic renal disease, repeat collections of protein excretion should be reserved for when progression of disease is suspected.

Summary screening pathway for proteinuria in pregnancy

SCREENING FOR PRE-ECLAMPSIA

Screening for the diagnosis of pre-eclampsia is largely achieved through the identification of hypertension in generally asymptomatic patients, followed by an assessment for the presence of other systemic features of the disease (including but not exclusively proteinuria), the absence of which would confer a diagnosis of gestational hypertension assuming it is of new-onset and no other cause is evident.

The principles of screening for hypertension and proteinuria have been covered above. This section focuses on antenatal assessments that can aid in the prediction of those women destined to develop pre-eclampsia. The purpose of such predictive assessments is threefold:⁵³

• To allow initiation of prophylactic therapies in those at high risk, specifically aspirin⁵⁴ and calcium;⁵⁵
• To ensure the model of ongoing antenatal care is commensurate with a patient’s level of risk; and
• To permit the efficient recruitment of truly high-risk patients to trials of novel prophylactic therapies.

A range of approaches to the prediction of pre-eclampsia has evolved, the composition and performance of which are outlined below. This section is limited to reviewing approaches to the prediction of pre-eclampsia in women yet to develop the condition; strategies to predict the clinical outcome of women with established disease – such as the fullPIERS⁵⁶ and miniPIERS⁵⁷ models – are covered in another chapter.

Risk-factor based screening

History-based risk factor assessment remains the basis for all approaches to screening for pre-eclampsia.⁵⁸ Indeed, the isolated use of other biochemical or ultrasonographic predictors of pre-eclampsia, without applying them to an a priori risk generated by risk factor assessment, is generally of limited clinical utility.

Clinical guidelines commonly recommend that an assessment of a patient’s risk of pre-eclampsia be determined at the booking visit.^16,59 The relative risk associated with more common risk factors is outlined in Table 3 (adapted from Duckitt and Harrington).⁶⁰

Use of these risk factors in one of a range of algorithms will permit prediction of a substantial proportion of pre-eclampsia – up to 89% of early-onset (that requiring delivery by 34 weeks) and 93% of later onset disease – but at a ‘false positive’ rate of 64%,⁶¹ i.e. almost two-thirds of women would be deemed at high risk of pre-eclampsia but would not go on to develop the condition. The potential burden of this approach is not congruent with the principles of screening (see above), and has prompted the development of screening approaches that have lower false-positive rates.

Predictive tests in ‘asymptomatic’ women

Considerable research effort has been expended in attempting to identify a biochemical or biophysical parameter that could be assessed in early pregnancy to improve the predictive performance of maternal risk factors alone. No single such parameter – neither uterine artery Doppler analysis,^62,63 nor any one of a wide range of serum biomarkers^64,65 – has demonstrated adequate utility in this population. The search for a single predictive test continues, and has recently expanded to the ‘-omics’⁶⁶ and cell-free DNA in maternal blood,⁶⁷ but an optimal candidate remains elusive,⁴⁷ likely as a consequence of the many antecedent pathways that lead to a final common maternal manifestation of the syndrome of pre-eclampsia.⁶⁸

The experience of combined first-trimester screening for aneuploidy, in which multivariate analysis has permitted the development of multiparametric algorithms that combine a range of parameters to achieve high sensitivity and low false-positive rates, has informed the development of similar multiparametric predictive tests for pre-eclampsia.⁶⁹ Such approaches generally combine maternal risk factors, maternal mean arterial pressure, uterine artery Doppler analysis, and one or more serum biomarkers such as placental growth factor (PlGF) and pregnancy-associated plasma protein A (PAPP-A).⁷⁰ These models have been developed at a range of gestations, including the second⁷¹ and third trimesters,⁷² but are likely to be of greatest utility in the first trimester, when the capacity to prevent disease (a key principle of screening) is greatest. A summary of some of these multiparametric models and their performance in the cohort in which they were developed is contained in Table 4.⁶²

The performance of these tests is such that some,^16,83 but not all,⁸⁴ professional guidelines recommend early pregnancy screening for pre-eclampsia using these multiparametric approaches, if they can be integrated into the local health system. The shift in guidance toward recommending such tests has largely arisen from the publication of the ASPRE study, which demonstrated a significant reduction in preterm pre-eclampsia in women screened to be high risk by a multiparametric model and administered aspirin when compared to an unscreened population (1.6% vs. 4.3%).⁸⁵ The Fetal Medicine Foundation has made its predictive algorithm – incorporating maternal risk factors + mean arterial pressure ± mean uterine artery pulsatility index ± serum levels of PlGF or PAPP-A – available for use without charge on its website: https://fetalmedicine.org/research/assess/preeclampsia/first-trimester (accessed April 2019). FIGO recommends the universal application of this algorithm in the first trimester, and advises that maternal risk factors and mean arterial pressure should be used to assess the risk of pre-eclampsia in the first trimester where facilities for serum biomarker and uterine artery Doppler assessment are not available, rather than maternal risk factors alone.⁸³

Nevertheless, these multiparametric predictive tests have a range of limitations that merit consideration.⁸⁶ Their predictive utility is maximal for early-onset pre-eclampsia, whereas their performance in predicting later disease – which accounts for a majority of cases – is much poorer. The tests are complicated and expensive, requiring specialist laboratory and ultrasound equipment and expertise, and will thus be of no benefit in most low-income settings, where the incidence of pre-eclampsia is higher.⁸⁷ Even in high-income settings, the economic justification for these tests may be challenging, given that the primary prophylactic agent employed in women at high risk is aspirin – a safe, cheap and well-tolerated drug that has potential benefits beyond the prevention of hypertensive disease, including lower rates of preterm birth, fetal growth restriction and perinatal death.⁸⁸ Such observations have prompted repeated calls for universal aspirin prophylaxis to be considered by health authorities,^89,90 in place of these screening tests.

Finally, it is important to note that test performance in one population cannot be assumed to be the same in others. Although similar results can be obtained when the validation population is similar to that in which the multiparametric algorithm was derived,⁹¹ quite varied results can occur in other populations, as outlined in Table 5.

In light of the above, it is imperative that individual institutions and health jurisdictions develop locally applicable approaches to the identification in early pregnancy of women at high risk of pre-eclampsia that reflect local resources and models of care.⁸³

Predictive tests in women with suspected pre-eclampsia

It is not uncommon for maternity clinicians to suspect a diagnosis of pre-eclampsia in the course of routine antenatal care, often on account of borderline hypertension or symptoms such as headache. Most such patients will not go on to develop pre-eclampsia, although the process of excluding the evolution of this disease commonly involves repeated visits to an antenatal ‘day assessment’ unit or similar, wherein serial measurements of blood pressure are taken, along with blood and urine tests. This process is time and resource intensive for health services and patients alike, and has prompted the development of ‘rule-in/rule-out’ tests that can potentially result in an efficient and cost-effective means of determining those at low versus high risk.

In contrast to the multiparametric approaches described above, the focus in this population has been on the utility of a single blood test for angiogenic factors, most commonly for placental growth factor (PlGF) alone, or the ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to PlGF. The results of the largest cohort and randomized trial studies of these tests are presented in Table 6.

The primary utility of these tests is in ‘ruling out’ the development of pre-eclampsia in the ensuing week or month, as the positive predictive values of these tests are not sufficiently high to permit clinical utility in ‘ruling in’ the development of the disease. Health technology assessments⁹⁸ have informed the 2019 UK National Institute for Health and Care Excellence (NICE) guidance that recommends the use of these tests to ‘rule out’ pre-eclampsia, along with standard clinical assessment and follow-up.⁹⁹ In contrast, international guidelines still recommend that such testing only be performed in the research context,¹⁶ although the PARROT⁹⁷ study provides randomized controlled trial-level evidence of neonatal safety that was previously a source of concern.

Again, it is essential that individual health jurisdictions assess the performance and economic implications of these tests in their own populations prior to their introduction.

Management of the ‘screen positive’ patient – frequency of visits, prophylaxis

A key principle of screening is having a defined care pathway for those deemed to be at ‘high risk’, regardless of the process by which such risk is ascertained. This pathway will vary depending on local resources and models of care, and may also depend on the magnitude of the risk estimate. In the context of screening for pre-eclampsia, a ‘screen positive’ result should optimally prompt two actions:

• Initiation of prophylactic therapies (see below); and
• Triage to a ‘higher risk’, more intensive model of antenatal care, within which frequent assessment of blood pressure and other clinical features of pre-eclampsia can be performed, with ready access to facilities for additional testing and evaluation. This would generally occur at least fortnightly after 24 weeks’ gestation, with more frequent assessments or inpatient admission indicated by the clinical course.

Aspirin has been shown to have a modest but consistent beneficial effect in reducing the incidence of pre-eclampsia by about 10%.¹⁰⁰ There is ongoing debate as to the optimal dose, gestation of initiation and time of administration of ‘low dose’ aspirin for this purpose,¹⁰¹ which is reflected in the disparate recommendations made in various guidelines.^16,17 Although subgroup analyses in recent systematic reviews have suggested that aspirin is only effective when commenced ≤16 weeks’ gestation and at doses of ≥100 mg,¹⁰² such analyses have significant limitations,^101,103 and do not align with the findings of recent individual patient data (IPD) meta-analyses, in which beneficial effect is still observed whether treatment is started before or after 16 weeks,¹⁰⁴ and with doses of <100 mg.¹⁰⁵ It has been proposed that aspirin is more effective in preventing pre-eclampsia when taken in the evening,¹⁰⁶ although further studies are required to confirm this finding.

The placebo-controlled ASPRE study⁸⁵ used 150 mg of aspirin nocte in the treatment arm, in which the incidence of preterm pre-eclampsia was reduced to 1.6% from 4.3% in the control group. The latest guidelines from the International Society for the Study of Hypertension in Pregnancy recommend that 100–150 mg of aspirin be taken by at-risk women preferably from before 16 weeks’ gestation,¹⁶ although they acknowledge the uncertainty surrounding these parameters. The NICE guidelines recommend 75 mg of aspirin daily for this population,¹⁷ while ACOG – reflecting the position of the United States Preventive Services Task Force – recommends 81 mg daily.¹⁰⁷ Further research will hopefully address these uncertainties and allow an alignment of recommendations.

The other prophylactic therapies that have shown benefit and should be recommended include:

• Calcium 1.2–2.5 g daily, in women with low calcium intake (< 600 mg/day);⁵⁵ and
• Aerobic and strength/flexibility training exercise for 50 minutes per day, 3 times per week.¹⁰⁸

Patients with previous early-onset pre-eclampsia that necessitated an extremely preterm delivery, and those with a history of pregnancy complications arising from antiphospholipid antibody syndrome (which has the added complexity of requiring low molecular weight heparin therapy in addition to aspirin), are at especially high risk for pre-eclampsia and require care in a multidisciplinary environment where available. Similarly, patients with pre-existing endocrine, cardiovascular or other autoimmune diseases (such as type 1 diabetes, essential hypertension and systemic lupus erythematosus) are at risk of a range of adverse pregnancy outcomes, and also require multidisciplinary care in pregnancy, ideally including input from an internist specializing in pregnancy (an obstetric physician).¹⁰⁹

Centers in which ‘rule out’ testing has been introduced also need clear care pathways both for those deemed to be at higher risk, and those whose risk is assessed to be low. Figure 1 reproduces the algorithm used in the PARROT⁹⁷ trial, the components of which would require modification for the resources of individual care settings.

PRACTICE RECOMMENDATIONS FOR HIGH-RESOURCE SETTINGS

PRACTICE RECOMMENDATIONS FOR LOW-RESOURCE SETTINGS