Pre-eclampsia in less developed countries: how to make a difference – Peter Von Dadelszen

As many members of the Society know, I have the singular honour to be the principal investigator of the Bill & Melinda Gates Foundation-funded PRE-eclampsia-Eclampsia Monitoring, Prevention & Treatment (PRE-EMPT) initiative (pre-empt.cfri.ca) ^1-3. This opportunity has allowed me to think about, travel to, and begin intervening in those countries where women are most likely to die as a result of pregnancy hypertension. Globally, the hypertensive disorders of pregnancy, and pre-eclampsia in particular, claim the lives of some 50-80,000 women annually and some 500,000 fetuses and newborns – over 99% of those lives are lost in less developed countries. In thirty years since medical school I have witnessed three women experience eclampsia – this does not reflect any particular skill on my part, but rather that I have had the privilege of having been trained and practicing in effective, socialised health systems in societies where women generally have full autonomy of decision-making.

We cannot be certain that the biological pathways to disease, patterns of complications and therapeutic responses can be generalised to settings where the social and nutritional status of women, the rates of intercurrent illnesses, and access to effective health care are remarkably, and clearly dangerously, different from those settings in which the evidence has been largely derived ⁴. Notable exceptions to this less developed country-relevant knowledge deficit have been the identification of calcium to prevent pre-eclampsia in women with low dietary intake and the primacy of magnesium sulphate as the agent to prevent and treat the seizures of eclampsia. Within PRE-EMPT, the Global Pregnancy Collaboration (PI: Jim Roberts) is investigating the pathways to disease particular to women in less and more developed countries ^3;5-7. In addition, in the Calcium And Pregnancy trial (PI: Justus Hofmeyr), we are testing whether or not pre- and early-pregnancy low-dose (500mg) calcium replacement, rather than supplementation (1.5-2.0g) will reduce the risk of recurrent pre-eclampsia in South African, Zimbabwean, and Argentinian women ^3;8.

In my opinion, there are some (relatively) easy wins to make rapid progress in reducing the maternal and perinatal burden related to the HDP. First is the provision of effective and free at the point-of-care antenatal surveillance. Over 90% of the observed fall in HDP-related maternal deaths in the UK over the past six decades of the Confidential Enquiries occurred prior to the introduction of either effective antihypertensives (in the 1970s) or magnesium sulphate (in the 1990s) – what occurred in the 1952-to-mid-1970s interval was the provision of midwifery-led antenatal surveillance using the Scottish paradigm of accelerating visits, the diagnosis of pre-eclampsia and timed delivery to initiate the process of recovery. However, in many less developed countries women do not access antenatal care, and, if they do, no more frequently than the WHO-mandated four visits during a pregnancy – the last being at around 36 weeks. Pre-eclampsia is largely a term disease and its detection was the primary motivation for the Scots to introduce weekly visits from 36 weeks a century ago.

Through PRE-EMPT we are examining the sociological, geographical, and health service reasons why women attend (or not) for antenatal care, and have introduced a model of mobile health (mHealth)-supported, community health worker-led antenatal care in women’s homes in the context of the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised controlled trials ³. The CLIP trials are currently recruiting an estimated total of 80,000 pregnant women in Nigeria, Mozambique, Pakistan, and India. In CLIP, we are using the Microlife CRADLE semi-automated sphygmomanometer to screen for hypertension ^9;10.

Once pregnancy hypertension has been identified there must be a response. Hypertensive pregnant women need to be referred into the formal health care system in a manner that reflects and respects cultural norms but responds to the acuity of risk. This leads me to the second opportunity for rapid improvements in outcomes – the ability to use mobile devices to provide distributed personalised health surveillance and interventions wherever they live. To achieve this within the CLIP trials we are engaging communities (women’s, men’s and decision makers’ groups) around issues related to maternal health in general and pregnancy hypertension specifically. In addition, we are assessing individualised risk in pregnant women through the miniPIERS (Pre-eclampsia Integrated Estimate of RiSk) outcome prediction model developed and validated in less developed countries within the wider PRE-EMPT initiative ¹¹. miniPIERS has the ability to discriminate between those women with pregnancy hypertension who are likely to develop life-threatening complications from those who are not. In Mozambique and Pakistan the miniPIERS model is being strengthened by phone oximetry ¹². To enable the diagnosis and risk stratification of hypertensive pregnant women by community health workers with limited clinical training, we have included the miniPIERS model in the PIERS on the Move mHealth application ¹³. The app directs the community health worker to administer the first dose of magnesium sulphate and, with severe hypertension, methyldopa, to hypertensive pregnant women with a high miniPIERS score, severe hypertension, seizure(s) or vaginal bleeding, and to arrange urgent transfer for effective and definitive facility-based care. Women with less severe pregnancy hypertension are advised to enter a system of formal assessment and follow-up within 24 hours. We anticipate that the CLIP trials will report in late 2017-early 2018.

In my opinion, a third opportunity to effect rapid change is to move from parenteral to oral therapy for the management of severe hypertension in pregnancy. A survey of essential medicines lists (EMLs) in less developed countries has advised us that methyldopa and nifedipine are the most widely available antihypertensives; labetalol is neither on EMLs nor national pharmacopoeiae in many less developed countries ^14;15. Nifedipine has the particular advantages of (i) being more effective than hydralazine in lowering severely elevated blood pressure in pregnancy, without overshooting to relative hypotension with resulting fetal compromise ¹⁶, (ii) requiring neither intramuscular nor intravenous administration, and (iii) being able to be administered by cadres of health workers less qualified than doctors. Within PRE-EMPT, Gynuity Health Projects is leading a RCT with a head-to-head comparison of the effectiveness of oral labetalol, nifedipine, and methyldopa to bring blood pressure to within a target range over six hours in women with severe pregnancy hypertension (PI: Hillary Bracken). For CLIP, we chose methyldopa as we anticipate that it will lower blood pressure most gently during the time that women are moving from their homes to facilities without any recourse to fetal monitoring.

Finally, we need to continue to advocate for these women, whose lives and deaths often go uncounted. I believe that our advocacy has helped international agencies to recognise that both systolic and diastolic blood pressures matter – systolic hypertension being more predictive of stroke than diastolic. Similarly, there is increased recognition that magnesium sulphate is both not an antihypertensive and unlikely to be more important than effective blood pressure control in the management of pregnancy hypertension, despite the lack of RCT evidence to support the latter. As with parachutes (thanks, Gordon ¹⁷), there has not been, nor should there be, a placebo-controlled trial of antihypertensives for women with severe pregnancy hypertension. I would resist either the president-elect of ISSHP or her (and my) daughter/future daughters-in-law being randomised into such a trial.

As I travel through heat, dust, and humidity, I see and meet young women whose futures will be endangered, and even foreshortened, by pregnancy complications – an important one of which is pre-eclampsia. They have a right to the same reproductive safety that we provide in the settings where most of us practice and/or conduct our research. PRE-EMPT is an amazing opportunity – and fearsome responsibility – to effect change.

Reference List

(1) von Dadelszen P, Firoz T, Donnay F, Gordon R, Hofmeyr GJ, Lalani S et al. Preeclampsia in low and middle income countries-health services lessons learned from the PRE-EMPT (PRE-Eclampsia-Eclampsia Monitoring, Prevention and Treatment) project. J Obstet Gynaecol Can 2012; 34(10):917-926.

(2) von Dadelszen P, Ansermino JM, Dumont G, Hofmeyr GJ, Magee LA, Mathai M et al. Improving maternal and perinatal outcomes in the hypertensive disorders of pregnancy: a vision of a community-focused approach. Int J Gynaecol Obstet 2012; 119 Suppl 1:S30-S34.

(3) von Dadelszen P, Sawchuck D, Hofmeyr GJ, Magee LA, Bracken H, Mathai M et al. PRE-EMPT (PRE-eclampsia-Eclampsia Monitoring, Prevention and Treatment): a low and middle income country initiative to reduce the global burden of maternal, fetal and infant death and disease related to pre-eclampsia. Pregnancy Hypertens 2013; 3(3):199-202.

(4) Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet 2010; 376(9741):631-644.

(5) Burton GJ, Sebire NJ, Myatt L, Tannetta D, Wang YL, Sadovsky Y et al. Optimising sample collection for placental research. Placenta 2014; 35(1):9-22.

(6) Myatt L, Redman CW, Staff AC, Hansson S, Wilson ML, Laivuori H et al. Strategy for standardization of preeclampsia research study design. Hypertension 2014; 63(6):1293-1301.

(7) Staff AC, Benton SJ, von Dadelszen P, Roberts JM, Taylor RN, Powers RW et al. Redefining preeclampsia using placenta-derived biomarkers. Hypertension 2013; 61(5):932-942.

(8) Hofmeyr GJ, Belizan JM, von Dadelszen P. Low-dose calcium supplementation for preventing pre-eclampsia: a systematic review and commentary. BJOG 2014; 121(8):951-957.

(9) de Greeff A, Nathan H, Stafford N, Liu B, Shennan AH. Development of an accurate oscillometric blood pressure device for low resource settings. Blood Press Monit 2008; 13(6):342-348.

(10) Nathan HL, de Greeff A, Hezelgrave NL, Chappell LC, Shennan AH. An accurate semiautomated oscillometric blood pressure device for use in pregnancy (including pre-eclampsia) in a low-income and middle-income country population: the Microlife 3AS1-2. Blood Press Monit 2015; 20(1):52-55.

(11) Payne BA, Hutcheon JA, Ansermino JM, Hall DR, Bhutta ZA, Bhutta SZ et al. A risk prediction model for the assessment and triage of women with hypertensive disorders of pregnancy in low-resourced settings: the miniPIERS (Pre-eclampsia Integrated Estimate of RiSk) multi-country prospective cohort study. PLoS Med 2014; 11(1):e1001589.

(12) Payne BA, Hutcheon JA, Dunsmuir D, Cloete G, Dumont G, Hall D et al. Assessing the incremental value of blood oxygen saturation (SpO2) in the miniPIERS (Pre-eclampsia Integrated Estimate of RiSk) risk prediction model. J Obstet Gynaecol Can 2015; 37(1):16-24.

(13) Dunsmuir DT, Payne BA, Cloete G, Petersen CL, Gorges M, Lim J et al. Development of mHealth applications for pre-eclampsia triage. IEEE J Biomed Health Inform 2014; 18(6):1857-1864.

(14) Firoz T, Magee LA, MacDonell K, Payne BA, Gordon R, Vidler M et al. Oral antihypertensive therapy for severe hypertension in pregnancy and postpartum: a systematic review. BJOG 2014; 121(10):1210-1218.

(15) Lalani S, Firoz T, Magee LA, Sawchuck D, Payne B, Gordon R et al. Pharmacotherapy for preeclampsia in low and middle income countries: an analysis of essential medicines lists. J Obstet Gynaecol Can 2013; 35(3):215-223.

(16) Magee LA, Cham C, Waterman EJ, Ohlsson A, von Dadelszen P. Hydralazine for treatment of severe hypertension in pregnancy: meta-analysis. BMJ 2003; 327(7421):955-960.

(17) Smith GC, Pell JP. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ 2003; 327(7429):1459-1461.

Peter von Dadelszen is a professor of obstetrics and gynaecology and consultant in maternal-fetal medicine in Vancouver, Canada. Trained in New Zealand, the UK, and Canada, he shares the leadership of a pregnancy hypertension-focussed research group with his wife, Laura Magee (with whom he shared the 2014 Chesley Award). His research covers discovery biology as well as clinical, health services, and global health topics. Increasingly, Peter’s focus has been on global maternal health through his leadership of the Gates Foundation-funded PRE-EMPT project. Most importantly, Peter is a lifelong All Blacks supporter and is backing his team to win RWC 2015!