WHAT’S NEW IN PRE-ECLAMPSIA?

This is a summary of Prof Mark Brown’s opening address at ISSHP Euro in Budapest, September 2015. It encapsulates papers he has read this year, it is not meant to be a critical summary or analysis or each paper but rather to give a sense of emerging developments in this field.

Professor Mark Brown, President ISSHP

Department of Renal Medicine

St George Hospital and University of New South Wales, Sydney, Australia

 

 

Blood Pressure

 

  • Our diagnosis and much of our management of preeclampsia depends on detecting hypertension.  The question of what is normal blood pressure in pregnancy was revisited in a very large study of 7500 women in southwest England. The upper limits of normal in early pregnancy were 136/82 and by 37 weeks 140/88 mmHg.  Fortunately, the latter corresponds very closely to the traditional cut-off value of 140/90mmHg for diagnosing hypertension, usually later in the pregnancy(1).

 

  • Others have measured both brachial and central blood pressures preconception to postpartum, and shown a similar pattern, viz. a fall in blood pressure from preconception through early pregnancy to the second trimester, and then a small rise towards pre-pregnancy blood pressures by the third trimester.  These changes were a little more obvious with central blood pressure.  It is not clear what role measurement of central blood pressure will play in preeclampsia, if any(2).

 

  • With the removal of mercury sphygmomanometry, the majority of units have turned to automated blood pressure devices in pregnancy.  Whilst this is accurate in many cases, it is not clear whether automated devices can truly replace traditional mercury sphygmomanometry.  We tested a liquid crystal mercury-free sphygmomanometer compared with an automated device, and showed that whilst both devices would achieve a ‘grade A’ rating the liquid crystal sphygmomanometer performed more accurately.(3)

 

Pathogenesis

 

  • The cause of preeclampsia remains unknown, despite a myriad of new findings in the last decade.  There appears to be a definite genetic predisposition, but precisely how this influences the development of preeclampsia remains under study.  A recent paper defined new polymorphisms in the Activin receptor which may distort the usual influence of Activin A on trophoblastic cell migration and vascular smooth muscle invasion, leading to suboptimal spiral artery remodelling.  This is an interesting finding which no doubt will precipitate further studies as it links the genetics and one of the well-known placental abnormalities that appear to be primary to many (but not all) cases of preeclampsia.(4)

 

  • Preeclampsia is known to be an inflammatory state that is accompanied by disordered angiogenesis.  Linking these two abnormalities remains problematic but one recent study highlights the possibility that circulating foetal DNA might activate an interferon-inducible protein that then leads to increased production of soluble Flt-1 and endoglin, both of which are known abnormalities in preeclampsia(5).  On the other hand, in a case control study, although the cytokine IL-17 was increased in women with preeclampsia, the levels were not related to those of angiogenic factors(6).

 

  • A very interesting paper has shown in mice that the angiotensin-1 receptor autoantibody can induce hypoxia-inducible factor (HIF) followed by a downstream increase in soluble Flt-1 production.  This was also shown in human villous explants.  This raises a possible link between this autoantibody, which allegedly is common in preeclampsia, and a non-hypoxic stimulation of HIF and subsequent altered angiogenesis(7).  In a related study, it was shown that this antibody can be stimulated by IL-6, and both the antibody production and the hypertension response to IL-6 were attenuated by the addition of 17-hydroxyprogesterone(8).  This too is of interest as it may help determine the link between inflammation, immunity and progesterone in preeclampsia.

 

Clinical Management

 

  • The risk for foetal death with preeclampsia has been appreciated since the disorder was recognised.  However, the scale of this risk has been demonstrated in a study of more than 500,000 singleton pregnancies from Norway, with preeclampsia in about 4% of cases.  The relative risk for foetal death was increased by a factor of 70-80 if preeclampsia developed at 25-26 weeks gestation, with that risk still being threefold greater even when preeclampsia developed at 38 weeks.  It was not until 39 weeks gestation that the relative risk became statistically insignificant(9).

 

  • This risk was relevant to the HYPITAT 2 trial which compared immediate delivery with expectant monitoring in 700 women with non-severe hypertension in pregnancy between 34 and 37 weeks.  Just under half of each group had de novo preeclampsia, a further 15% had superimposed preeclampsia, and the remainder either gestational hypertension or deteriorating chronic hypertension.  Therefore, this was a fairly mixed group of patients entered into the trial.  The composite of adverse maternal outcomes was not statistically different between the group, but respiratory distress syndrome in the baby was threefold greater in those with early delivery. It would therefore appear reasonable in this group of patients to continue pregnancy until 37 weeks provided they are in a Unit where careful monitoring can be undertaken and delivery effected if there is evidence of maternal or foetal compromise(10).

 

  • A study from our unit of almost 700 preeclamptic women addressed the clinical outcomes of women with early onset, late preterm and term preeclampsia.  About 13% of this cohort had early onset preeclampsia.  The women with late preterm presentation of preeclampsia had similar rates of small-for-gestational-age babies and low perinatal mortality rates.  Those with early onset preeclampsia (before 34 weeks) had higher small-for-gestational-age and perinatal mortality rates, but there were no significant differences in severity of maternal disease.  The message from this study is that although early onset preeclampsia is a more severe condition for the baby, late preterm and term preeclampsia are just as bad for the mother and occur far more frequently (11).

  

 

Hypertension Management

 

  • The major study of hypertension management published this year is the CHIPS trial of non-proteinuric, non-severe hypertension in women between 14 and almost 34 weeks gestation.  About 75% of the cohort had chronic hypertension at study entry. They were randomised to less tight blood pressure control with a target diastolic pressure of 100, or tight blood pressure control with a target diastolic blood pressure of 85 mmHg.  The primary outcome of pregnancy loss or high level neonatal care did not differ between groups but there was a clear benefit of tight control in reducing the likelihood of maternal severe hypertension.  Given that this factor is the most consistent association with maternal stroke, this seems logically a good outcome of this treatment approach.  Importantly, there was no statistical difference for small-for-gestational-age babies in this study (12).  Somewhat surprisingly, The Society for Maternal Foetal Medicine (USA) produced a statement soon after recommending that pharmacological  antihypertensive therapy should not be commenced unless the blood pressure was above 160 systolic or 105 mmHg diastolic.  They acknowledged the reduction in severe hypertension with ‘tight’ blood pressure control in the CHIPS study, but restated their former view that there is a lack of data confirming maternal or perinatal benefit of anti-hypertensive treatment(13).  No doubt this question will continue to be debated worldwide, but the CHIPS study in my view contributes significantly to the data for a lack of adverse effects on mother or baby with such antihypertensive treatment, and a clear benefit in reducing episodes of severe hypertension which logically seems a good outcome.

 

  • How to treat severe hypertension was addressed in a trial of intravenous hydralazine compared with labetalol, and there were no significant differences in final blood pressure, persistent hypertension or side effects, meaning that Units can decide which of these drugs they prefer to use and can be reassured there will be a similar effect (14).

 

  • There have long been concerns about potential teratogenic effects of antihypertensives in pregnancy.  A case control study of over 5500 cases with birth defects and 7200 without malformation has shown an increased risk for oesophageal atresia and VSD in women with hypertensive pregnancies not managed pharmacologically.  In those managed pharmacologically, the increased risk was for hypospadias.  The authors have proposed that the changes in early pregnancy that manifest in later hypertension may also play a role in the aetiology of these birth defects (15).

 

Post-Partum

 

  • Women want to know what is going to happen to them after their pre-eclamptic pregnancy.  A study of almost 100,000 women (with individual patient data) showed that overall 1 in 5 women who have had preeclampsia will have some form of hypertension in a future pregnancy, about 16% having recurrent preeclampsia.  An interesting finding in this study was that almost 30% of women for whom the data were available felt they had refrained from a next pregnancy because of a much higher perceived risk of recurrent preeclampsia.  These data should help us inform women of their true risks(16).

 

  • The long-term postpartum cardiovascular risks of preeclampsia are now well recognised.  A small study from the Netherlands has confirmed that amongst women with preeclampsia, more of them were overweight five years later and as a group had higher HOMA scores suggesting insulin resistance, and higher blood pressure.  Within this group, more had developed chronic hypertension (or perhaps had had this in any case) and it was within this subgroup that the 10-year cardiovascular predicted risk was higher, but not in the remainder of the preeclamptics(17).
  • Importantly, a further study has shown that physicians are less likely than gynaecologists to include a pregnancy history when assessing cardiovascular risk, though once the risk is identified they are more likely to obtain appropriate risk testing(18). This study reminds us just how important it is to ask women what happened in their pregnancies, and then to consider the potential impact on their long-term cardiovascular outcome.

 

References

 

  1. Macdonald-Wallis C, Silverwood RJ, Fraser A, Nelson SM, Tilling K, Lawlor DA, et al. Gestational-age-specific reference ranges for blood pressure in pregnancy: findings from a prospective cohort. Journal of hypertension. 2015;33(1):96-105.
  2. Mahendru AA, Everett TR, Wilkinson IB, Lees CC, McEniery CM. A longitudinal study of maternal cardiovascular function from preconception to the postpartum period. Journal of hypertension. 2014;32(4):849-56.
  3. Davis GK, Roberts LM, Mangos GJ, Brown MA. Comparisons of auscultatory hybrid and automated sphygmomanometers with mercury sphygmomanometry in hypertensive and normotensive pregnant women: parallel validation studies. Journal of hypertension. 2015;33(3):499-506.
  4. Williamson RD, O’Keeffe GW, Kenny LC. Activin signalling and pre-eclampsia: From genetic risk to pre-symptomatic biomarker. Cytokine. 2015;71(2):360-5.
  5. Li N, Fu Y, Chen W, Hu G-Q, Zhou M, Yu S-X, et al. IFI16 mediates soluble Flt-1 and endoglin production by trophoblast cells. Journal of hypertension. 2015;33(8):1658-65.
  6. Molvarec A, Czegle I, Szijártó J, Rigó Jr J. Increased circulating interleukin-17 levels in preeclampsia. Journal of Reproductive Immunology. 2015;112:53-7.
  7. Iriyama T, Wang W, Parchim NF, Song A, Blackwell SC, Sibai BM, et al. Hypoxia-Independent Upregulation of Placental Hypoxia Inducible Factor-1α Gene Expression Contributes to the Pathogenesis of Preeclampsia. Hypertension. 2015;65(6):1307-15.
  8. Amaral LM, Cornelius DC, Harmon A, Moseley J, Martin JN, LaMarca B. 17-Hydroxyprogesterone Caproate Significantly Improves Clinical Characteristics of Preeclampsia in the Reduced Uterine Perfusion Pressure Rat Model. Hypertension. 2015;65(1):225-31.
  9. Harmon QE, Huang L, Umbach DM, Klungsøyr K, Engel SM, Magnus P, et al. Risk of Fetal Death With Preeclampsia. Obstetrics & Gynecology. 2015;125(3):628-35.
  10. Broekhuijsen K, van Baaren G-J, van Pampus MG, Ganzevoort W, Sikkema JM, Woiski MD, et al. Immediate delivery versus expectant monitoring for hypertensive disorders of pregnancy between 34 and 37 weeks of gestation (HYPITAT-II): an open-label, randomised controlled trial. The Lancet. 2015;385(9986):2492-501.
  11. Pettit F, Mangos G, Davis G, Henry A, Brown MA. Pre-eclampsia causes adverse maternal outcomes across the gestational spectrum. Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health. 2015;5(2):198-204.
  12. Magee LA, von Dadelszen P, Rey E, Ross S, Asztalos E, Murphy KE, et al. Less-Tight versus Tight Control of Hypertension in Pregnancy. New England Journal of Medicine. 2015;372(5):407-17.
  13. SMFM Statement: benefit of antihypertensive therapy for mild-to-moderate chronic hypertension during pregnancy remains uncertain. American Journal of Obstetrics & Gynecology.213(1):3-4.
  14. Delgado De Pasquale S, Velarde R, Reyes O, De La Ossa K. Hydralazine vs labetalol for the treatment of severe hypertensive disorders of pregnancy. A randomized, controlled trial. Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health.4(1):19-22.
  15. van Gelder M, Van Bennekom CM, Louik C, Werler MM, Roeleveld N, Mitchell AA. Maternal hypertensive disorders, antihypertensive medication use, and the risk of birth defects: a case–control study. BJOG: An International Journal of Obstetrics & Gynaecology. 2015;122(7):1002-9.
  16. van Oostwaard MF, Langenveld J, Schuit E, Papatsonis DNM, Brown MA, Byaruhanga RN, et al. Recurrence of hypertensive disorders of pregnancy: an individual patient data metaanalysis. American journal of obstetrics and gynecology. 2015;212(5):624.e1-.e17.
  17. Breetveld NM, Ghossein-Doha C, van Kuijk SMJ, van Dijk AP, van der Vlugt MJ, Heidema WM, et al. Cardiovascular disease risk is only elevated in hypertensive, formerly preeclamptic women. BJOG: An International Journal of Obstetrics & Gynaecology. 2015;122(8):1092-100.
  18. Wilkins-Haug L, Celi A, Thomas A, Frolkis J, Seely EW. Recognition by Women’s Health Care Providers of Long-Term Cardiovascular Disease Risk After Preeclampsia. Obstetrics & Gynecology. 2015;125(6):1287-92.