Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 4 (2014) 249–252

Contents lists available at ScienceDirect

Pregnancy Hypertension: An InternationalJournal of Women’s Cardiovascular Health

journal homepage: www.elsevier .com/locate /preghy

Pre-eclampsia in 2014: Seven ways to make a difference

http://dx.doi.org/10.1016/j.preghy.2014.11.0012210-7789/� 2014 Published by Elsevier B.V. on behalf of International Society for the Study of Hypertension in Pregnancy.

Mark A. BrownPresident ISSHP, Dept. Renal Medicine, St George Hospital and University of NSW, Sydney, Australia

This commentary highlights the global burden of pre-eclampsia and the lifelong impact of this disorder on mothersand their babies. The International Society for the Study ofHypertension in Pregnancy (ISSHP) has developed a sevenpoint plan to improve our understanding and managementof the hypertensive disorders of pregnancy with an emphasison making a difference in low and middle income countries.

Setting the scene

A 25 year old previously well woman in her first preg-nancy develops new onset blood pressure 150/100 mmHgand 2+ proteinuria at 30 weeks gestation. What are yourinitial thoughts?

It is highly likely that most of us will consider this as acase of pre-eclampsia, at least until proved otherwise.Most of us will also have the capacity to make that diagno-sis in a short time frame, usually one or two hours at themost, by confirming the hypertension with further read-ings, estimating the proteinuria with a spot protein:creat-inine ratio and assessing renal function, liver functionand platelet count with appropriate blood tests [1]. Evenif there is no proteinuria we may still diagnose pre-eclampsia in many cases [2,3] and we can do that quickly.We will soon then assess the severity of the disorder byfurther examining the mother and ultrasounding the baby.Regardless of our findings, most of us will still envisagethat the pregnancy will end with a live mother and baby.

But that depends on where you live. The scenario aboveis standard for those of us fortunate to live in high incomecountries. It is vastly different for those living in low andmiddle income countries (LMIC). Firstly, the conditionmay not even be detected because of inadequate or non-existent antenatal care; secondly the capacity to makethe diagnosis with blood and urine tests is by no meansuniversal and then the ability to manage early onset pre-eclampsia may only be available in a centre many hoursor days away, which may be unattainable to many.

Pre-eclampsia in perspective

Let us for a moment consider HIV. This disorder wasunknown in 1981 when initial reports of pneumonia andcancers were appearing in young gay men. Within threeyears the virus had been identified and by 2011 experts wereable to make the following statement: ‘‘Thirty years later, weare gratified by the progress that has been made in under-standing, treating and preventing HIV/AIDS. We could nothave imagined these advances during the early days of AIDS,when all we could do was provide palliative care to waves ofdying patients. Whereas survival was once measured inweeks or months from the time of diagnosis, today, the crit-ical discovery of antiretroviral drugs and their use in combi-nation regimens has resulted in greatly improved lifeexpectancy—decades, rather than months—for many HIV-infected people who have access to these medicines andadhere to treatment ‘‘(http://www.nih.gov/news/health/jun2011/niaid-02.htm; accessed Nov 5th 2014). Note thelast statement; the importance of access to care.

Pre-eclampsia has been recognised since pre-Hippo-crates but we are unable to make similar statements aboutthis disorder today; we still do not know the precise cause,we do not have a definitive diagnostic test (or set of tests)and we do not have a cure apart from delivery of the pla-centa. Fortunately we have made good understanding aboutthe pathophysiology of the disease and pregnancy out-comes can be successful in Units that can monitor womencarefully and look after premature and small babies.

To put all this in perspective the WHO estimates thatHIV/AIDS killed 1.6 million people world-wide in 2012(http://www.who.int/gho/hiv/epidemic_status/deaths_text/en/; accessed Nov 5th 2014); pre-eclampsia and relatedhypertension in pregnancy is estimated to affect about10 million women per year and to kill almost 40% as manypeople as HIV, including 76,000 mothers and about half amillion babies (http://www.preeclampsia.org/health-information/149-advocacy-awareness/332-preeclampsia-and-maternal-mortality-a-global-burden; accessed

250 M.A. Brown / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 4 (2014) 249–252

Nov 5th 2014). Between March and October this year, sincethe outbreak of the Ebola virus, almost 5000 people havedied from this disease; in the same period about 30,000women will have died from Pre-eclampsia. It is unlikelythat anyone has not heard of HIV or Ebola yet many inthe community are unaware of pre-eclampsia, or if awaredo not appreciate the severity of this condition world-wide.

The next perspective is one of research. In the year 1981a cursory PubMed search shows about 290 research publi-cations on pre-eclampsia and none on HIV; in 2013 therewere about 1100 publications on pre-eclampsia and 6000on HIV. Granted pre-eclampsia is a difficult disorder toresearch but it is not surprising, given these publicationestimates, that our understanding and treatment of HIVsoon overtook that of pre-eclampsia.

What are the developments in pre-eclampsia research?

We have long considered this a disorder of the pla-centa that translates somehow, perhaps through therelease of a ‘toxin’ (hence the term toxaemia), to affectmaternal vasculature leading to endothelial dysfunction,capillary leak with plasma volume reduction and vaso-constriction, all of which causes hypoperfusion of thematernal kidneys, liver and brain and aggravates placen-tal dysfunction. Though this model has served us well weare in a new era of research with better understanding ofthe inflammatory, oxidative stress and anti-angiogenicnature of the disorder [4–6]. Others are proposing a mis-match between maternal supply and fetal oxygendemand as a unifying theme [7]. The recognition of manyand variable clinical presentations has made us think thatthere are likely to be many underlying pathophysiologypathways that differ amongst women [8,9], perhapsdependent upon genetic susceptibility. Importantly wenow recognise the life-long cardiovascular impacts ofpre-eclampsia with the potential for premature death inmany women. Recently there has been a greater focuson the immediate impact of pre-eclampsia on womenincluding increased likelihood of anxiety, depression andpost-traumatic stress disorder. Just a few of the impor-tant papers on these topics that have appeared in thisjournal since the last ISSHP World Congress are listedhere [10–17].

What can we do to improve the health of women withhypertension in pregnancy?

1. First we must increase our research into these disorders;to achieve this we need to make the public, politiciansand funding bodies much more aware of pre-eclampsiaand its impact on women and babies. It needs to be seenas having the same public health impact as HIV. We alsoneed to develop the capacity for greater collaborativeresearch by collecting similar clinical data and bio-bank-ing blood and urine samples across the world; in thisregard the proposals for standardised data collection

and bio-banking of the Co-Lab group are to be applaudedand are likely to enhance research world-wide withapplicability to LMIC as well [18].

2. Learn from improvements in care in high income coun-tries and apply these in LMIC. The Pre-Empt initiativeaims to do just that [19], citing the following key aimsin management in LMIC, all of which we take forgranted in high income countries:a. Effective routine antenatal care, with accelerated

visits near and at term (leading to pre-eclampsiadetection).

b. Increased awareness of, and responsiveness to,symptoms by women.

c. Diagnostic and surveillance capacity.d. Control of severe pregnancy hypertension.e. Prevention and treatment of eclampsia with

MgSO4.f. Timely delivery (given excellent neonatal support-

ive care).g. Maternal organ support (including intensive care

and blood transfusion, if necessary) during therecovery phase.

3. Change public (and clinician) thinking that pregnancy is‘‘9 months’’ to at least ‘‘15 months’’. This idea was putto me by a colleague (A/Prof Mangos, University ofNSW) recently and it is a great way of getting all of usto consider the importance of post-partum care partic-ularly for women with pre-eclampsia; in that way wecan detect ongoing hypertension or renal issues andaddress lifestyle factors that may accelerate their laterlife psychological and cardiovascular risk.

ISSHP has a seven point plan to improve the health ofwomen with hypertension in pregnancy

1. Speak the same language for clinical management andresearch� It is difficult to progress research or clinical manage-

ment if we are collecting different data on thesewomen, collaborating less than we could or usingdifferent criteria for diagnoses. For these reasonsISSHP supports the Co-Lab initiatives and urges cli-nicians to use the ISSHP guidelines for diagnosisand classification of the hypertensive disorders ofpregnancy [1]. We will also work with other guide-line groups such as NICE (UK), ACOG (USA), SOMANZ(Australia and New Zealand) and Canada, with theaim of developing a single endorsed system for clas-sification and diagnosis as well as agreed principlesof management (see Table 1).

2. Integrate basic science and clinical practice in all ourmeetings� Fundamental to improving our understanding of

pre-eclampsia is to integrate science with clinicalpractice; we aim to ensure that all our conferencesfrom now on adopt this principle. In this way clini-cians can develop a better understanding of the ori-gins of pre-eclampsia while scientists can appreciate

Table 1ISSHP plan to improve the health of women with hypertension inpregnancy.

1. Speak the same language for clinical management and research2. Integrate basic science and clinical practice in all our meetings3. Disseminate research widely4. Strengthening ties with other organisations5. Make a difference for pregnant women in LMIC6. World Pre-eclampsia day7. Support young investigators

M.A. Brown / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 4 (2014) 249–252 251

the complexity of clinical decision making and learnthe key relevant clinical questions that need to beanswered.

3. Disseminate research widely� Our main method for achieving this is through our

Journal, ‘‘Pregnancy Hypertension: an InternationalJournal of Women’s Cardiovascular Health’’. We areurging each researcher within ISSHP to submit at leastone paper to the journal between each Congress.

� Our 2nd yearly International Conferences provide usa wonderful opportunity to share research and clin-ical management developments whilst establishingprofessional contacts and friends across the globe.

� We plan a quarterly Newsletter next year not only tokeep abreast of developments within the Society butalso to share updates from key researchers aboutprogress in the field.

� Our website will be updated to enhance communi-cation amongst members of ISSHP and to promoteresearch collaboration.

4. Strengthening ties with other organisations� There are so many societies and conferences these

days that synergies can be lost and it becomes diffi-cult to attend meetings that are not co-located. Weplan to work with other societies, particularly theInternational Society of Obstetric Medicine (ISOM)to co-locate and integrate meetings where possible.In this way we hope to facilitate more cliniciansand scientists to attend both meetings.

5. Make a difference for pregnant women in LMIC� We have to move from acknowledging the problems

outlined above to doing something about it. ISSHPhas now established a sub-group of clinicians whowork in this field, to advise on the best ways to makea difference. We are working with the Pre-eclampsiafoundation (USA) to support research in India andlater in other LMIC and we will seek to have papercopies of our Journal distributed to these countrieson a regular basis. We are looking at ways to providemore travel grants to facilitate greater attendance atISSHP conferences from those living in LMIC.

6. World Pre-eclampsia day� As discussed above it will be difficult to make a dif-

ference for women without greater public, politicaland granting body awareness of the importance ofpre-eclampsia. ISSHP has decided to promote aware-ness by asking its members in all countries to pro-mote knowledge of pre-eclampsia on a day in Mayeach year.

7. Support young investigators� The future of research and clinical improvements in

managing the hypertensive disorders of pregnancydepends on having a system that supports genera-tion after generation of researchers. ISSHP now hassix awards at each conference for the best clinicaland scientific papers and supports about 50 younginvestigators to attend every second year.

Conclusions

Pre-eclampsia and the other hypertensive disorders ofpregnancy have a major impact on women’s health,responsible for far too many maternal and neonatal deathsworld-wide. The public health importance of hypertensionin pregnancy is up there with well-known disorders suchas HIV and Ebola virus. Yet to date we have failed as a med-ical community to make this known in as broad a fashionas possible; in turn this has hampered our capacity toresearch these disorders more fully and to implementchanges in clinical practice that will make a big differenceto outcomes. With plans such as those outlined above wecan change this and improve the way we care for about10 million women each year.

References

[1] Tranquilli AL, Dekker G, Magee L, Roberts J, Sibai BM, Steyn W, et al.The classification, diagnosis and management of the hypertensivedisorders of pregnancy: a revised statement from the ISSHP.Pregnancy Hypertens 2014;4:97–104.

[2] ACOG Taskforce. Hypertension in pregnancy. ACOG Practiceguideline WQ 24; 2013.

[3] Homer CS, Brown MA, Mangos G, Davis GK. Non-proteinuric pre-eclampsia: a novel risk indicator in women with gestationalhypertension. J Hypertens 2008;26:295–302.

[4] Craici IM, Wagner SJ, Weissgerber TL, Grande JP, Garovic VD.Advances in the pathophysiology of pre-eclampsia and relatedpodocyte injury. Kidney Int 2014;86:275–85.

[5] Chaiworapongsa T, Chaemsaithong P, Yeo L, Romero R. Pre-eclampsia part 1: current understanding of its pathophysiology.Nat Rev Nephrol 2014;10:466–80.

[6] Staff AC, Benton SJ, von Dadelszen P, Roberts JM, Taylor RN, PowersRW, et al. Redefining preeclampsia using placenta-derivedbiomarkers. Hypertension 2013;61:932–42.

[7] Dennis AT, Castro JM. Hypertension and haemodynamics in pregnantwomen – is a unified theory for pre-eclampsia possible? Anaesthesia2014;69:1183–9.

[8] Roberts JM, Bell MJ. If we know so much about preeclampsia, whyhaven’t we cured the disease? J. Reprod. Immunol. 2013;99:1–9.

[9] Nelson DB, Ziadie MS, McIntire DD, Rogers BB, Leveno KJ. Placentalpathology suggesting that preeclampsia is more than one disease.Am J Obstet Gynecol 2014;210:66.e1–7.

[10] Zhang Y, Wang T, Shen Y, Wang X, Baker PN, Zhao A. 2-Methoxyestradiol deficiency is strongly related to hypertension inearly onset severe pre-eclampsia. Pregnancy Hypertens2014;4:215–9.

[11] Petrella E, Pignatti L, Neri I, Facchinetti F. The l-arginine/nitric oxidepathway is impaired in overweight/obese pregnant women.Pregnancy Hypertens 2014;4:150–5.

[12] Mukherjee R, Ray CD, Ray S, Dasgupta S, Chaudhury K. Alteredmetabolic profile in early and late onset preeclampsia: an FTIRspectroscopic study. Pregnancy Hypertens 2014;4:70–80.

[13] Gurusinghe S, Wallace EM, Lim R. The relationship between ActivinA and anti-angiogenic factors in the development of pre-eclampsia.Pregnancy Hypertens 2014;4:3–6.

[14] Løset M, Johnson MP, Melton PE, Ang W, Huang R-C, Mori TA, et al.Preeclampsia and cardiovascular disease share genetic risk factorson chromosome 2q22. Pregnancy Hypertens 2014;4:178–85.

[15] Postma IR, Groen H, Easterling TR, Tsigas EZ, Wilson ML, Porcel J,et al. The brain study: cognition, quality of life and social functioning

252 M.A. Brown / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 4 (2014) 249–252

following preeclampsia; An observational study. PregnancyHypertens 2013;3:227–34.

[16] Porcel J, Feigal C, Poye L, Postma IR, Zeeman GG, Olowoyeye A, et al.Hypertensive disorders of pregnancy and risk of screening positivefor Posttraumatic Stress Disorder: a cross-sectional study. PregnancyHypertens 2013;3:254–60.

[17] Downing JW, Baysinger CL, Johnson RF, Paschall RL. Review:potential druggable targets for the treatment of early onsetpreeclampsia. Pregnancy Hypertens 2013;3:203–10.

[18] Myatt L, Redman CW, Staff AC, Hansson S, Wilson ML, Laivuori H,et al. Strategy for standardization of preeclampsia research studydesign. Hypertension 2014;63:1293–301.

[19] von Dadelszen P, Sawchuck D, JustusHofmeyr G, Magee LA, BrackenH, Mathai M, et al. PRE-EMPT (PRE-eclampsia-Eclampsia Monitoring,Prevention and Treatment): a low and middle income countryinitiative to reduce the global burden of maternal, fetal and infantdeath and disease related to pre-eclampsia. Pregnancy Hypertens2013;3:199–202.