Diagnosis of Hypertensive Disorders of Pregnancy in Sub‐Saharan Africa: A Poorly Assessed But Increasingly Important Issue

While maternal mortality has declined in many regions of the world, it has increased in most sub-Saharan African countries.1 According to a recent report of the World Health Organization (WHO), hypertensive disorders of pregnancy, which are associated with about 16% of maternal mortality, are the leading cause of maternal death (after hemorrhage) in sub-Saharan Africa (SSA).2 In some African settings, hypertensive disorders of pregnancy tend to overtake hemorrhage as the main cause of maternal mortality.3 Among the various conditions that form this group of diseases, affecting about 10% of all pregnancies worldwide,4 severe preeclampsia and eclampsia are the most deadly forms. Moreover, severe preeclampsia is an important cause of adverse maternal outcomes such as stroke, lung damage, and liver rupture, and severe perinatal morbidity including prematurity, intrauterine growth restriction, and fetal death.4 Long-term complications of this pregnancy-related syndrome include increased risk of cardiovascular events in both mother5 and child,6 which may contribute to the rising epidemic of cardiovascular disease in SSA countries. Although black race and low socioeconomic status have been proven to be important risks factors for preeclampsia,7, 8 there is dearth data on the determinants and particularities of this condition in SSA, which are critical for context-relevant lifesaving interventions. Thus, preeclampsia raises major concerns regarding both its epidemiological and diagnostic aspects in SSA. Anemia is the commonest complication in pregnancy in SSA, with more than half of pregnant women being affected according to WHO estimates.9 Recently, severe anemia was found to be a major risk factor for preeclampsia and eclampsia in limited-resource settings.10 The magnitude of anemia in SSA is exacerbated by HIV infection,11 another major public health issue whose incidence continues to increase in many African countries despite global efforts to limit the spread of this transmissible disease.12 Preeclampsia was an uncommon complication of pregnancy in HIV-infected women before the advent of highly active antiretroviral therapy (HAART).13 With the routine use of HAART in developed settings, the reported incidence of preeclampsia in HIV-infected pregnant women increased to such an extent that it was found to be the most frequent adverse event of pregnancy in women taking HAART in Europe.14 Although results from primary studies in SSA are lacking, HIV infection was identified as an independent risk for preeclampsia among women receiving HAART.15 Moreover, pregnant women taking HAART were recently found to have an increased risk of anemia.16 Since access to HAART is consistently extending in SSA, sustained reduction in morbidity and mortality from HIV infection is expected in the coming years. If HIV positive women properly take antiretroviral therapy, they may be healthy and have a normal life like HIV negative women. Since they are no longer at risk of dying quickly, they may also want to get pregnant and have children, increased incidence of anemia in pregnancy, and a subsequent increased incidence of preeclampsia in this region. While SSA is one of the poorest regions in the world with high rates of malnutrition, ongoing nutritional transition linked to the rapid process of urbanization is likely to pose a major public health challenge, with a significant proportion of women becoming hypertensive or overweight.17 Since obesity and chronic hypertension were found to be among the highest risk factors for preeclampsia in the developing world,10 a gradual increase in the incidence of this condition is expected over time in SSA. The most widely accepted definition of preeclampsia is the presence of hypertension (diastolic blood pressure [BP] ≥90 mm Hg) and significant proteinuria (≥300 mg in 24 hours) after 20 weeks of gestation.18 This definition is largely used in SSA, even though it does not take into account the specific characteristics of the African pregnant women. Studies have consistently found that compared with their white counterparts, black women had higher BP either during or in the absence of pregnancy.19, 20 In addition, black women were proven to be more likely to get pregnant with chronic hypertension or to develop hypertensive diseases during pregnancy than Caucasians.21 This suggests that BP values used to define hypertension should be reassessed and adjusted to the African context. Regarding proteinuria, recent reports query the relevance of including renal injury in the definition of preeclampsia since it is a multisystem disorder associated with uteroplacental and maternal endothelial dysfunction.22 Such a definition is restrictive as it does not account for the heterogeneous nature of this condition, which includes liver, kidney, lung, platelets, and neurological damages.23 This is of particular concern in SSA, where other common pregnancy-related diseases may mimic the clinical picture of preeclampsia. Malaria is an endemic infection representing a major public health problem in tropical Africa with substantial risks for the pregnant woman and her fetus.24 Women are increasingly susceptible to malaria during pregnancy because Plasmodium falciparum, the most common parasite responsible for malaria, avoids spleen clearance by binding to the placenta.25 Thus, P falciparum–infected erythrocytes accumulate in the placenta, whereas the peripheral blood can remain free of infected cells, which makes the diagnosis of malaria during pregnancy difficult. This is an important issue because there are many similarities between malaria and preeclampsia. In areas with high malaria transmission rates such as SSA countries, the adverse effects of pregnancy-related malaria are most pronounced among women of low socioeconomic status in their first pregnancy26—two characteristics that are known risk factors for preeclampsia.27 Clinical features of severe malaria include hemolytic anemia, hepatic cytolysis, acute lung injury, renal failure, cardiac involvement, thrombocytopenia, and neurological impairments,28 which are also known as severity criteria or complications of preeclampsia.4 In the absence of alerting BP, health workers in SSA may initially treat women presenting with other symptoms (eg, headaches, jaundice, abdominal pains, and blurred vision) as severe malaria, which may result in inappropriate use of financial resources and delay in diagnosis and referral of patients. Although prevention strategies for pregnancy-related malaria have been implemented in SSA, most women in malaria-endemic areas do not receive the intermittent presumptive therapy.29 Moreover, current recommendations state that the first dose should not be given before quickening, at about 20 weeks, which is the gestational age at which preeclampsia is considered to occur.30 Therefore, determining whether systemic manifestations in pregnant women or fetal complications are associated with preeclampsia or with malaria is not easy in SSA Even if we assume proteinuria is associated with preeclampsia, the crucial issue of adequate measurement arises. Estimation of proteinuria from 24-hour urine, which is the most appropriate method in pregnant women,31 is cumbersome and hardly feasible in most heathcare facilities in SSA. The only test for proteinuria detection that is readily available and can be performed in a point-of-care manner in developing countries is dipstick. However, the poor reproducibility and limited accuracy of dipstick testing for proteinuria32 question its clinical utility for the diagnosis of preeclampsia. Although the spot protein-to-creatinine ratio seems to be a promising alternative to 24-hour urine collection for proteinuria screening during pregnancy in high-income settings,33 its interpretation and suitability to the African context remain to be explored. Considering the high rate of false-negatives when dipstick is used for proteinuria detection in developed countries—up to 18% in a Neo Zealand study34—it is likely that this rate is even higher in SSA since routes for strips supply, conditions of transport, and storage in most primary health centers are less than optimal. Thus, a significant proportion of pregnant women with false-negative proteinuria may have been mistakenly classified as having gestational hypertension, causing a decline in vigilance that may partly explain the high morbidity and mortality rates observed in SSA. In addition, some reports have proposed the introduction of a new category of preeclampsia called “nonproteinuric preeclampsia”—different from gestational hypertension that does not cause multiorgan involvement—which was found to be associated with a higher risk of liver disease and platelet disorders than “proteinuric preeclampsia.”35 Moreover, perinatal adverse outcomes were found to be less frequent in women with proteinuric preeclampsia compared with women with nonproteinuric preeclampsia.36 Recently, a study found that even though proteinuria in women with preeclampsia is associated with adverse outcomes in pregnancy, it is not a sufficient predictor of unfavorable consequences of preeclampsia.37 These findings suggest that the presence of proteinuria may not necessarily be an indicator of maternal or perinatal mortality and morbidity. As far as we know, no study aiming to assess the relevance of these novel concepts in SSA have been performed to date. Yet, ignoring nonproteinuric preeclampsia may have led to an underestimation of the seriousness of pregnancy-related hypertension in SSA and resulted in inadequate monitoring of some cases and subsequent unfavorable outcomes. Not only is the definition of this pregnancy-specific condition unclear, but how to separate mild from severe preeclampsia is also controversial. Since the classification of hypertensive disorders of pregnancy was proposed by the International Society for the Study of Hypertension in Pregnancy in the early 2000s, several developments have occurred in high-income settings, with significant variations across professional societies and organizations providing guidelines.4 The most glaring differences include the integration of early onset (before 34 weeks in Canada and 35 weeks in the United States) among severity criteria of preeclampsia, the need to exclude white-coat hypertension, and the choice of BP thresholds to define severe preeclampsia.4 Women who present with early-onset preeclampsia are usually younger than those who present with late-onset preeclampsia.22 This is a key element in Africa, where most women tend to get pregnant at a younger age.38 While a diastolic BP of 110 mm Hg is commonly accepted as the threshold for the definition of severe hypertension, the consensus on systolic BP at either 160 mm Hg or 170 mm Hg is still to be achieved since concerns about maternal cerebrovascular event risks at the lower cutoff for BP are growing.39 The lack of consensus at the international level is reflected in a high variation in the definition and management of preeclampsia within and between African countries. Since black women experience more severe pregnancy-related hypertensive disease than those of other origins,21 the threshold for severe hypertension during pregnancy should be lower in Africans, to capture the maximum of those who need special care or intervention to avoid complications. A risk prediction model based on simple clinical tools allowing identification of women with pregnancy-related hypertension who are at higher risk for complications, the Pre-Eclampsia Integrated Estimate of Risk (miniPIERS), was recently designed for limited-resource settings.40 Although primary results are promising, utility in clinical practice and suitability to SSA remain to be demonstrated. SSA countries should come together to contextualize and harmonize protocols and guidelines for definition and classification of hypertensive disorders of pregnancy, so that the implementation of effective interventions targeting risk factors, provision of quality health services, and averting adverse maternal and perinatal outcomes can be possible. This requires performing well-designed studies in SSA that will provide evidences to support local recommendations. The authors report no specific funding in relation to this research and no conflicts of interest to disclose.