Hypertensive disorders in pre-term pregnancy: management and long-term consequences Langenveld, J.

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1 UvA-DARE (Digital Academic Repository) Hypertensive disorders in pre-term pregnancy: management and long-term consequences Langenveld, J. Link to publication Citation for published version (APA): Langenveld, J. (2011). Hypertensive disorders in pre-term pregnancy: management and long-term consequences General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 03 Dec 2018

2 Chapter 1 General introduction and outline of the thesis


4 General introduction and outline of the thesis General introduction Hypertensive disorders of pregnancy, including gestational hypertension (GH) and preeclampsia (PE) complicate 10% of all pregnancies and remain one of the leading causes of maternal mortality and morbidity, both internationally as well as in The Netherlands. 1-3 The clinical expression of the disease ranges from mild gestational hypertension or preeclampsia at term to severe conditions in the pre-term period. The maternal syndrome of PE is associated with severe complications (especially at early gestational ages) including eclampsia or other encephalopathies, placental abruption, stroke, pulmonary oedema, liver rupture and renal insufficiency. 4,5 The fetal or neonatal consequences include intra-uterine growth restriction, stillbirth and severe morbidity related to pre-term birth. Consequently, neonatal morbidity is strongly associated with the gestational age at onset of preeclampsia, as well as the severity of the maternal syndrome and related preterm delivery chapter Timing of delivery in hypertensive disorders in pregnancy The only causal treatment of hypertensive disorders in pregnancy is delivery of the placenta and inevitably delivery of the child. Signs and symptoms of GH or PE will subside within a few days after delivery. 5 In the pre-term period however this results in a premature born child with related severe morbidities. 6,9 The dilemma of maternal morbidity versus neonatal morbidity in the pre-term period has resulted in two management approaches: the interventionist approach of stabilizing and delivery, versus a more temporizing approach. 10 The interventionist approach is assumed to reduce the maternal risk of deterioration and the related maternal complications and the antenatal fetal risk of stillbirth. On the other hand temporizing management results in increased gestational age and therefore in reduction of neonatal morbidity and mortality. 11,12 Throughout gestational ages, different levels of evidence are available concerning the best management. Between 24 and 34 weeks gestational age there is a general consensus that temporizing management is justified if no severe maternal morbidity is present or anticipated and fetal condition is estimated to be satisfactory. Prolongation of pregnancy can be achieved without irreversible maternal morbidity and with improved neonatal outcome provided there is intensive monitoring of maternal and fetal well-being by experienced staff in a high-risk pregnancy care setting. This conclusion is based on several cohort studies and two randomized controlled trials. 11,13,14 The difficulty of the cohort studies is the variability of inclusion criteria used per study and the different diagnostic criteria used. The two trials were 9

5 underpowered to determine safety for temporizing care. Although temporizing management seems to be permitted at early gestational ages, the exact criteria for and moment of delivery is still an area of research. After 37 weeks perinatal outcome overall is known to be good and severe maternal morbidity is therefore not acceptable. 15,16 Timing of delivery of mild GH and PE has recently been investigated in the HYPITAT trial. 17 This randomized controlled trial comparing interventionist care versus temporizing care between and weeks gestational age, showed less severe hypertensive episodes in the interventionist approach (31% versus 44%, relative risk (RR) 0.71, 95% confidence interval (CI) 0.59 to 0.86). The number of patients randomised between 36 and 37 weeks was too low to draw definite conclusions. Importantly, induction of labour in the interventionist group showed a trend to a lower cesarean section rate (RR 0.75, 95% CI 0.55 to 1.0). Perinatal outcome was not different between groups and there was a reduction in costs and better maternal quality of life. 18,19 Between 34 and 37 weeks of gestational age there remains uncertainty on the best policy (temporizing versus interventionist management) as evidence for this specific group is missing. With lack of good clinical evidence on the subject and the resulting practice variation, we focus specifically on this group in this thesis. Long term consequences A pregnancy complicated by a hypertensive disorder is a window to assess future expected health for this mother and her child. The long term health problems are related to general health conditions and psychological consequences. General maternal health issues after a pregnancy complicated by a hypertensive disorder have been an intensively researched area in the past decade. There is abundant evidence for increased risk of cardiovascular and metabolic diseases and related death after a history of a hypertensive complication during pregnancy Pregnancy is seen as a stress-test for the vascular system of the mother and having preeclampsia is an expression of a failed stress-test. Not only the future health of the mother is at state, but also the fetus may experience long-term consequences, in line with the Barker hypothesis (fetal origin of adult disease). 23 Offspring from women who experienced a hypertensive disorder during their pregnancy, are at increased risk of stroke later in life. 24 Additionally preeclampsia is associated with being small for gestational age (SGA) as a result of a compromised utero-placental perfusion. Being small for gestational age is related to cardiovascular disease later in life. 25,26 We speculated that this SGA fetus might already have a compromised vascular system and in consequence it might have a higher risk for developing preeclampsia later in life in case of a 10

6 General introduction and outline of the thesis female fetus. With vascular reactivity studies we aimed to unravel some of the pathophysiological mechanism of preeclampsia and its long-term consequences. Apart from the general health consequences, the psychosocial impact of a pre-term delivery due to a hypertensive disorder is often huge and associated with high incidences of symptoms of post traumatic stress disorder and depression. 27,28 The decision for future pregnancies largely depends on the information from the obstetrician on the estimated risk of recurrence of a pre-term delivery and the related severe maternal morbidity and serious neonatal morbidity. From a medical point of view, such counselling may influence management during the subsequent pregnancy. Information about recurrence is fragmentary and outdated, with recurrence rates ranging from as high as 65% to as low as 5%. 29,30 This variation is likely because of population selection differences and small numbers. Well numbered cohort studies that consecutively included their patients are missing, as well as individual risk prediction models. In the second part of this thesis we answered questions concerning recurrence rates and prediction of hypertensive disorders in the next pregnancy. 1chapter Outline of this thesis The aim of this thesis was to address specific questions concerning long term consequences, recurrence rates and management of hypertensive disorders during pregnancy in the pre-term period. Part I fundamental research describes vascular reactivity studies in offspring using mice models with a compromised vascular system in view of the fetal origin of adult disease hypothesis. Part II clinical research focuses on recurrence rates, prediction and management of hypertensive disorders in the pre-term period. Part III contains the summary and general discussion describing the general considerations and focuses on future research questions. Part I Fundamental research Chapter 2 explores the underlying pathophysiological mechanism of the impact of a compromised uterine environment on growth and vascular function of offspring and the adaptive mechanisms from successive pregnancies compared to first pregnancies. Chapter 3 explores the underlying pathophysiological mechanism of the long-term vascular consequences on offspring who developed in a compromised uterine environment. 11

7 Part II Clinical research Chapter 4 is an overview of existing literature on prediction and prevention of preeclampsia. Chapter 5 is a systematic review of published evidence on recurrence risk of a delivery before 34 weeks of pregnancy due to a severe hypertensive disorder. Chapter 6 is a report of a study on the recurrence risk of a delivery below 34 weeks due to a hypertensive disorder, after a history of an early onset hypertensive disorder and identifies parameters that predict adverse outcome. Chapter 7 is a report of a study on the recurrence risk of a hypertensive disorders after a history of a delivery between 34 and 37 weeks of gestation due to a hypertensive disorder and identifies parameters that predict adverse outcome. Chapter 8 explores the neonatal morbidity of children born between 34 and 37 weeks of gestation from pregnancies complicated by a hypertensive disorder. Chapter 9 describes the study protocol of a Dutch multicentre randomized controlled trial assessing the (cost-) effectiveness of induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia between 34 and 37 weeks gestation (HYPITAT-II trial). Part III Summary and general discussion Chapter 10 is a summary and general discussion of the previous chapters, and describes implications for future research. 12

8 General introduction and outline of the thesis References 1. Sibai BM. Diagnosis and management of gestational hypertension and preeclampsia. Obstet Gynecol. 2003; 102: Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PF. WHO analysis of causes of maternal death: a systematic review. Lancet Apr 1; 367: Schutte JM, Steegers EA, Schuitemaker NW, Santema JG, de Boer K, Pel M, Vermeulen G, Visser W, van Roosmalen J; Netherlands Maternal Mortality Committee. Rise in maternal mortality in the Netherlands. BJOG Mar; 117(4): Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. 2005; 365: Ganzevoort W, Rep A, Bonsel GJ, De Vries JI, Wolf H; PETRA investigators. BJOG Jun;114(6): Wood NS, Marlow N, Costeloe K et al. Neurologic and developmental disability after extremely preterm birth. EPICure Study Group. N Engl J Med 2000; 343: van Baar AL, van Wassenaer AG, Briet JM et al. Very preterm birth is associated with disabilities in multiple developmental domains. J Pediatr Psychol 2005; 30: Ganzevoort W, Rep A, de Vries JI, Bonsel GJ, Wolf H: PETRA-investigators. Prediction of maternal complications and adverse infant outcome at admission for temporizing management of early-onset severe hypertensive disorders of pregnancy. Am J Obstet Gynecol 2006 Aug; 195(2): Hall DR, Odendaal HJ, Kirsten GF, Smith J, Grové D. Expectant management of early onset, severe pre-eclampsia: perinatal outcome. BJOG Oct; 107(10): Ganzevoort W, Sibai BM. Temporising versus interventionist management (preterm and at term). Best Pract Res Clin Obstet Gynaecol Mar Sibai BM, Mercer BM, Schiff E, Friedman SA. Aggressive versus expectant management of severe preeclampsia at 28 to 32 weeks gestation: a randomized controlled trial. Am J Obstet Gynecol Sep;171(3): Bombrys AE, Barton JR, Habli M, Sibai BM. Expectant management of severe preeclampsia at 27(0/7) to 33(6/7) weeks gestation: maternal and perinatal outcomes according to gestational age by weeks at onset of expectant management. Am J Perinatol 2009; 26: Odendaal HJ, Pattinson RC, Bam R, Grove D, Kotze TJ. Aggressive or expectant management for patients with severe preeclampsia between weeks gestation: a randomized controlled trial. Obstet Gynecol Dec; 76(6): Magee LA, Yong PJ, Espinosa V, Côté AM, Chen I, von Dadelszen P. Expectant management of severe preeclampsia remote from term: a structured systematic review. Hypertens Pregnancy. 2009;28(3): Lubow JM, How HY, Habli M, Maxwell R, Sibai BM. Indications for delivery and short-term neonatal outcomes in late preterm as compared with term births. Am J Obstet Gynecol May; 200(5):e Hutcheon JA, Lisonkova S, Magee LA, Liu S et al. Optimal timing of delivery in pregnancies with pre-existing hypertension. BJOG 2011; 118: Koopmans CM, Bijlenga D, Groen H et al; HYPITAT study group. Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks gestation (HYPITAT): a multicentre, open-label randomised controlled trial. Lancet Sep 19; 374(9694): chapter 13

9 18. Vijgen SM, Koopmans CM, Opmeer BC, Groen H, Bijlenga D, Aarnoudse JG, Bekedam DJ, van den Berg PP, de Boer K, Burggraaff JM, Bloemenkamp KW, Drogtrop AP, Franx A, de Groot CJ, Huisjes AJ, Kwee A, van Loon AJ, Lub A, Papatsonis DN, van der Post JA, Roumen FJ, Scheepers HC, Stigter RH, Willekes C, Mol BW, Van Pampus MG; HYPITAT study group. An economic analysis of induction of labour and expectant monitoring in women with gestational hypertension or pre-eclampsia at term (HYPITAT trial).. BJOG Dec;117(13): D Bijlenga, CM Koopmans, E Birnie, BWJ Mol, JA Van der Post, KW Bloemenkamp, HC Scheepers, C Willekes, A Kwee, MH Heres, E van Beek, CA van Meir, ME van Huizen, MG van Pampus, GJ Bonsel. Health-related quality of life after induction of labour versus expectant monitoring in gestational hypertension or pre-eclampsia at term. Hypertens Pregnancy Smith GC, Pell JP, Walsh D. Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet Jun 23;357(9273): Mongraw-Chaffin ML, Cirillo PM, Cohn BA. Preeclampsia and cardiovascular disease death: prospective evidence from the child health and development studies cohort. Hypertension Jul;56(1): Rich-Edwards JW, McElrath TF, Karumanchi SA, Seely EW. Breathing life into the lifecourse approach: pregnancy history and cardiovascular disease in women. Hypertension Sep;56(3): Barker DJ, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet May 10;1(8489): Kajantie E, Eriksson JG, Osmond C, Thornburg K, Barker DJ. Pre-eclampsia is associated with increased risk of stroke in the adult offspring: the Helsinki birth cohort study. Stroke Apr; 40(4): Painter RC, Osmond C, Gluckman P, Hanson M, Phillips DI, Roseboom TJ.Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life. BJOG Sep; 115(10): Barker DJ, Osmond C, Kajantie E, Eriksson JG. Growth and chronic disease: findings in the Helsinki Birth Cohort. Ann Hum Biol Sep-Oct;36(5): Van Pampus MG, Wolf H, Weijmar Shultz WC, Neeleman J, Aarnoudse JG. Posttraumatic stress disorder following preeclampsia and HELLP syndorme. J Psychosom Obstet Gynaecol Sep-Dec; 25(3-4): Rep A, Ganzevoort W, Bonsel GJ, Wolf H, de Vries JI. Psychosocial impact of early-onset hypertensive disorders and related complications in pregnancy. Am J Obstet Gynecol Aug; 197(2): 158e Sibai BM, Mercer B, Sarinoglu C. Severe preeclampsia in the second trimester: recurrence risk and long-term prognosis. Am J Obstet gynecol. 1991; 165: Van Rijn BB, Hoeks LB, Bots ML, Franx A, Bruinse HW. Outcomes of subsequent pregnancy after first pregnancy with early-onset preeclampsia. Am J Obstet Gynecol Sep; 195(3):