First‐trimester screening for pre‐eclampsia: moving from personalized risk prediction to prevention

Maternal gestational hypertensive disorders and their complications have ranked consistently as the primary cause of adverse maternal and neonatal outcome since the institution of prenatal care1. The recognition of predisposing circumstances, such as nulliparity, familial disposition, prior pre-eclampsia, renal disease, hypertension and diabetes, reaches back as far as four centuries. In 1984, Leon Chesley concluded that: ‘it does not seem likely that pre-eclampsia can be prevented on the basis of current knowledge. A major purpose of prenatal care is to detect incipient pre-eclampsia and to prevent its progression’1. Since then, research that has evolved around first-trimester screening algorithms for pre-eclampsia has offered a significant opportunity to rethink the potential for preventive strategies.

[1]  N. Rizzo,et al.  Prospective evaluation of ultrasound and biochemical‐based multivariable models for the prediction of late pre‐eclampsia , 2011, Prenatal diagnosis.

[2]  D. Luthy,et al.  Maternal plasma lipid concentrations in early pregnancy and risk of preeclampsia. , 2004, American journal of hypertension.

[3]  C. Redman,et al.  Hypertension in pregnancy: the NICE guidelines , 2011, Heart.

[4]  L. Shulman First-trimester placental protein 13 screening for preeclampsia and intrauterine growth restriction , 2008 .

[5]  L. Poston,et al.  World Health Organisation multicentre randomised trial of supplementation with vitamins C and E among pregnant women at high risk for pre‐eclampsia in populations of low nutritional status from developing countries , 2009, BJOG : an international journal of obstetrics and gynaecology.

[6]  L. Bublitschenko I. Zur Frage über gewisse konstitutionelle Eigentümlichkeiten bei Eklamptischen , 1925 .

[7]  B. Sibai,et al.  A comparison of no medication versus methyldopa or labetalol in chronic hypertension during pregnancy , 1991 .

[8]  P. Zimmet,et al.  Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO Consultation , 1998, Diabetic medicine : a journal of the British Diabetic Association.

[9]  K. Pulkki,et al.  Decreased PAPP-A is associated with preeclampsia, premature delivery and small for gestational age infants but not with placental abruption. , 2011, European journal of obstetrics, gynecology, and reproductive biology.

[10]  D. Wright,et al.  A Competing Risks Model in Early Screening for Preeclampsia , 2012, Fetal Diagnosis and Therapy.

[11]  A. Franx,et al.  Maternal Characteristics, Mean Arterial Pressure and Serum Markers in Early Prediction of Preeclampsia , 2013, PloS one.

[12]  D. Nelson,et al.  First-trimester placental protein 13, PAPP-A, uterine artery Doppler and maternal characteristics in the prediction of pre-eclampsia. , 2011, Placenta.

[13]  L. Hansson,et al.  Prediction of later hypertension following a hypertensive pregnancy. , 1983, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[14]  H. Cuckle Screening for pre-eclampsia--lessons from aneuploidy screening. , 2011, Placenta.

[15]  M. Schull,et al.  Heart failure and dysrhythmias after maternal placental syndromes: HAD MPS Study , 2012, Heart.

[16]  L. Vatten,et al.  Hypertension in Pregnancy and Later Cardiovascular Risk: Common Antecedents? , 2010, Circulation.

[17]  Etty Daniel-Spiegel,et al.  [TURNING THE PYRAMID IN PRENATAL CARE]. , 2015, Harefuah.

[18]  P. Elliott,et al.  Maternal blood pressure in pregnancy, birth weight, and perinatal mortality in first births: prospective study , 2004, BMJ : British Medical Journal.

[19]  Mike Kirby,et al.  Guidelines on the management of cardiovascular diseases during pregnancy The Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology ( ESC ) , 2011 .

[20]  S. Wen,et al.  A history of preeclampsia identifies women who have underlying cardiovascular risk factors. , 2009, American journal of obstetrics and gynecology.

[21]  Zhiwen Li,et al.  Folic Acid Supplementation During Early Pregnancy and the Risk of Gestational Hypertension and Preeclampsia , 2013, Hypertension.

[22]  G. Hankins,et al.  Transplacental transfer and distribution of pravastatin. , 2013, American journal of obstetrics and gynecology.

[23]  E. Gratacós,et al.  Performance of a first-trimester screening of preeclampsia in a routine care low-risk setting. , 2013, American journal of obstetrics and gynecology.

[24]  Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. , 2000, American journal of obstetrics and gynecology.

[25]  M. Schull,et al.  Metabolic syndrome and the risk of placental dysfunction. , 2005, Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC.

[26]  B. Cha,et al.  Metabolic Syndrome and Cardiovascular Disease , 2003 .

[27]  N. Goldenberg,et al.  Height, weight, and motor-social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy. , 2004, Human reproduction.

[28]  E. Bennett,et al.  The first trimester. , 1984, JOGN nursing; journal of obstetric, gynecologic, and neonatal nursing.

[29]  M. Di Nisio,et al.  Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. , 2014, The Cochrane database of systematic reviews.

[30]  R. D'Agostino,et al.  Metabolic Syndrome as a Precursor of Cardiovascular Disease and Type 2 Diabetes Mellitus , 2005, Circulation.

[31]  A. Khalil,et al.  Association between first‐trimester maternal serum pregnancy‐associated plasma protein‐A and obstetric complications , 2013, Prenatal diagnosis.

[32]  R. Romero,et al.  A prospective cohort study of the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia , 2009, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[33]  S. Daly,et al.  Elevated plasma homocysteine in early pregnancy: a risk factor for the development of nonsevere preeclampsia. , 2003, American journal of obstetrics and gynecology.

[34]  M. Lucas,et al.  Diabetes complicating pregnancy. , 2001, Obstetrics and gynecology clinics of North America.

[35]  Ai-ming Wang,et al.  Effect of Metformin Intervention during Pregnancy on the Gestational Diabetes Mellitus in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis , 2014, Journal of diabetes research.

[36]  Michael A Black,et al.  Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohort , 2011, BMJ : British Medical Journal.

[37]  M. Pearce,et al.  Cardiovascular disease risk in women with pre-eclampsia: systematic review and meta-analysis , 2013, European Journal of Epidemiology.

[38]  M. Martinez-frias,et al.  Prenatal exposure to salicylates and gastroschisis: a case-control study. , 1997, Teratology.

[39]  M. Clowse,et al.  Aspirin for Prevention of Preeclampsia in Lupus Pregnancy , 2014, Autoimmune diseases.

[40]  M. Schull,et al.  Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study , 2005, The Lancet.

[41]  B. Carbonne,et al.  Nicardipine versus metoprolol in the treatment of hypertension during pregnancy: A randomized comparative trial , 1994, Obstetrics and gynecology.

[42]  M. LeFevre Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: U.S. Preventive Services Task Force recommendation statement. , 2014, Annals of internal medicine.

[43]  Jeffrey J. Myers,et al.  Angiogenic factors combined with clinical risk factors to predict preterm pre‐eclampsia in nulliparous women: a predictive test accuracy study , 2013, BJOG : an international journal of obstetrics and gynaecology.

[44]  J. Thornton Angiogenic factors combined with clinical risk factors to predict preterm pre‐eclampsia in nulliparous women: a predictive test accuracy study , 2014, BJOG : an international journal of obstetrics and gynaecology.

[45]  F. Audibert,et al.  Screening for preeclampsia using first-trimester serum markers and uterine artery Doppler in nulliparous women. , 2010, American journal of obstetrics and gynecology.

[46]  D. Henderson-smart,et al.  Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. , 2014, The Cochrane database of systematic reviews.

[47]  R. Hermida,et al.  Ambulatory Blood Pressure Monitoring for the Early Identification of Hypertension in Pregnancy , 2013, Chronobiology international.

[48]  L. Magder,et al.  Prediction of preeclampsia utilizing the first trimester screening examination. , 2014, American journal of obstetrics and gynecology.

[49]  W. Oyen,et al.  Co-occurrence of Cardiovascular and Prothrombotic Risk Factors in Women With a History of Preeclampsia , 2013, Obstetrics and gynecology.

[50]  J. Strauss,et al.  Effect of supplementation during pregnancy with L-arginine and antioxidant vitamins in medicalfood on pre-eclampsia in high risk population : Randomised controlled trial , 2019 .

[51]  R. Rodrigo,et al.  Prediction of early and late pre‐eclampsia from maternal characteristics, uterine artery Doppler and markers of vasculogenesis during first trimester of pregnancy , 2013, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[52]  H. Meiri,et al.  Placental protein 13 as an early marker for pre‐eclampsia: a prospective longitudinal study * , 2008, BJOG : an international journal of obstetrics and gynaecology.

[53]  H. Laivuori,et al.  Evidence of a state of increased insulin resistance in preeclampsia. , 1999, Metabolism: clinical and experimental.

[54]  R. Romero,et al.  Supplementation with vitamins C and E during pregnancy for the prevention of preeclampsia and other adverse maternal and perinatal outcomes: a systematic review and metaanalysis. , 2011, American journal of obstetrics and gynecology.

[55]  S. Millard,et al.  Prevention of preeclampsia: a randomized trial of atenolol in hyperdynamic patients before onset of hypertension. , 1999, Obstetrics and gynecology.

[56]  B. Sibai,et al.  A comparison of no medication versus methyldopa or labetalol in chronic hypertension during pregnancy. , 1990, American journal of obstetrics and gynecology.

[57]  A. Baschat,et al.  First-Trimester Risk Factors for Preeclampsia Development in Women Initiating Aspirin by 16 Weeks of Gestation , 2014, Obstetrics and gynecology.

[58]  S. Haeri,et al.  Maternal serum dyslipidemia occurs early in pregnancy in women with mild but not severe preeclampsia. , 2008, American journal of obstetrics and gynecology.

[59]  Trevor Hastie,et al.  Regularization Paths for Generalized Linear Models via Coordinate Descent. , 2010, Journal of statistical software.

[60]  A. Hofman,et al.  Blood pressure tracking during pregnancy and the risk of gestational hypertensive disorders: the Generation R Study. , 2011, European heart journal.

[61]  A. Papageorghiou,et al.  Early prediction and prevention of pre-eclampsia. , 2011, Best practice & research. Clinical obstetrics & gynaecology.

[62]  L. Smits,et al.  Early-Pregnancy Changes in Maternal Lipid Profile in Women With Recurrent Preeclampsia and Previously Preeclamptic Women With Normal Next Pregnancy , 2011, Reproductive Sciences.

[63]  D. S. Buchanan,et al.  Uteroplacental vascular development and placental function: an update. , 2010, The International journal of developmental biology.

[64]  K. Rye,et al.  Cardiovascular risk, lipids and pregnancy: preeclampsia and the risk of later life cardiovascular disease. , 2014, Heart, lung & circulation.

[65]  H. Figueroa-Diesel,et al.  First trimester prediction of early onset preeclampsia using demographic, clinical, and sonographic data: a cohort study , 2013, Prenatal diagnosis.

[66]  J. Pell,et al.  Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129 290 births , 2001, The Lancet.

[67]  I. Herraiz,et al.  Application of a first‐trimester prediction model for pre‐eclampsia based on uterine arteries and maternal history in high‐risk pregnancies , 2009, Prenatal diagnosis.

[68]  A. Baschat,et al.  OC08.05: Impact of 1st trimester aspirin on population prevalence of pre‐eclampsia , 2009 .

[69]  J. Kingdom,et al.  Antithrombotic therapy for improving maternal or infant health outcomes in women considered at risk of placental dysfunction. , 2013, The Cochrane database of systematic reviews.

[70]  Z. Akkuş,et al.  Potential atherogenic roles of lipids, lipoprotein(a) and lipid peroxidation in preeclampsia. , 2005, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[71]  I. Young,et al.  Vitamins C and E for prevention of pre-eclampsia in women with type 1 diabetes (DAPIT): a randomised placebo-controlled trial , 2010, The Lancet.

[72]  J. Kastelein,et al.  Statin use during pregnancy: a systematic review and meta-analysis , 2012, Expert review of cardiovascular therapy.

[73]  T. Benedetti,et al.  Maternal Hemodynamics in Normal and Preeclamptic Pregnancies: A Longitudinal Study , 1990, Obstetrics and gynecology.

[74]  S. Kane,et al.  New directions in the prediction of pre‐eclampsia , 2014, The Australian & New Zealand journal of obstetrics & gynaecology.

[75]  A. Youssef,et al.  Uterine artery Doppler and biochemical markers (PAPP‐A, PlGF, sFlt‐1, P‐selectin, NGAL) at 11 + 0 to 13 + 6 weeks in the prediction of late (>34 weeks) pre‐eclampsia , 2011, Prenatal diagnosis.

[76]  B. Sibai,et al.  Elevated plasma homocysteine in early pregnancy: a risk factor for the development of severe preeclampsia. , 2002, American journal of obstetrics and gynecology.

[77]  Jackson T. Wright,et al.  2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). , 2014, JAMA.

[78]  A. Odibo,et al.  Predicting the risk of pre‐eclampsia between 11 and 13 weeks' gestation by combining maternal characteristics and serum analytes, PAPP‐A and free β‐hCG , 2010, Prenatal diagnosis.

[79]  G. Saade,et al.  First-Trimester Prediction of Preeclampsia in Nulliparous Women at Low Risk , 2012, Obstetrics and gynecology.

[80]  M. Reilly,et al.  Evaluating the association between all components of the metabolic syndrome and pre-eclampsia , 2009, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[81]  L. Chesley History and Epidemiology of Preeclampsia - Eclampsia , 1984, Clinical obstetrics and gynecology.

[82]  G. Pedrazzi,et al.  Calcium supplementation and prevention of preeclampsia: a meta-analysis , 2012, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[83]  K. Nicolaides,et al.  Low‐dose aspirin for prevention of adverse outcomes related to abnormal placentation , 2014, Prenatal diagnosis.

[84]  K. Salvesen,et al.  Metformin treatment in pregnant women with polycystic ovary syndrome—is reduced complication rate mediated by changes in the uteroplacental circulation? , 2007, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[85]  Lippincott Williams Wilkins,et al.  National High Blood Pressure Education Program Working Group Report on Hypertension in Diabetes , 1994, Hypertension.

[86]  G. D'ottavio,et al.  First trimester maternal serum PIGF, free β-hCG, PAPP-A, PP-13, uterine artery Doppler and maternal history for the prediction of preeclampsia. , 2012, Placenta.

[87]  C. Lenfant Working group report on high blood pressure in pregnancy. , 2001, Journal of clinical hypertension.

[88]  S. Leodolter,et al.  Maternal hypotension: fetal outcome in treated and untreated cases. , 1979, Gynecologic and obstetric investigation.

[89]  Kypros H Nicolaides,et al.  First-Trimester Prediction of Hypertensive Disorders in Pregnancy , 2009, Hypertension.

[90]  M. Wolf,et al.  First-trimester placental protein 13 screening for preeclampsia and intrauterine growth restriction. , 2007, American journal of obstetrics and gynecology.

[91]  P. Taipale,et al.  Aspirin in the prevention of pre‐eclampsia in high‐risk women: a randomised placebo‐controlled PREDO Trial and a meta‐analysis of randomised trials , 2013, BJOG : an international journal of obstetrics and gynaecology.

[92]  T. Leivestad,et al.  Preeclampsia and the risk of end-stage renal disease. , 2008, The New England journal of medicine.

[93]  J. Bland,et al.  Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy. , 1983, Placenta.

[94]  V. Novack,et al.  Association of lipid levels during gestation with preeclampsia and gestational diabetes mellitus: a population-based study. , 2009, American journal of obstetrics and gynecology.

[95]  Argyro Syngelaki,et al.  Prediction of early, intermediate and late pre‐eclampsia from maternal factors, biophysical and biochemical markers at 11–13 weeks , 2011, Prenatal diagnosis.

[96]  M. Ikawa,et al.  Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model , 2010, Proceedings of the National Academy of Sciences.

[97]  Jeffrey R. Wilson,et al.  CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women , 1994, The Lancet.

[98]  Dowell Rt,et al.  Maternal hemodynamics and uteroplacental blood flow throughout gestation in conscious rats. , 1997 .

[99]  A. Hofman,et al.  Hemodynamic adaptations in different trimesters among nulliparous and multiparous pregnant women; the Generation R study. , 2012, American journal of hypertension.

[100]  Daniel W. Jones,et al.  The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. , 2003, JAMA.

[101]  S. Bond Is Preeclampsia a Marker for End‐Stage Renal Disease?; Vikse BE, Irgens LM, Leivestad T, Skjærven R, Iversen BM. Preeclampsia and the risk of end‐stage renal disease. N Engl J Med 2008;359:800–9 , 2009 .

[102]  E. Kajantie,et al.  Free fatty acid profiles in preeclampsia. , 2009, Prostaglandins, leukotrienes, and essential fatty acids.

[103]  C. D. Kauer,et al.  Maternal hemodynamics and uteroplacental blood flow throughout gestation in conscious rats. , 1997, Methods and findings in experimental and clinical pharmacology.

[104]  A. Baschat,et al.  First‐trimester prediction of pre‐eclampsia: external validity of algorithms in a prospectively enrolled cohort , 2014, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[105]  A. Hofman,et al.  Blood pressure in different gestational trimesters, fetal growth, and the risk of adverse birth outcomes: the generation R study. , 2011, American journal of epidemiology.

[106]  N. Sattar,et al.  Classic and Novel Risk Factor Parameters in Women With a History of Preeclampsia , 2003, Hypertension.

[107]  K. Nicolaides,et al.  Hypertensive disorders in pregnancy: combined screening by uterine artery Doppler, blood pressure and serum PAPP‐A at 11–13 weeks , 2010, Prenatal diagnosis.

[108]  J. Twisk,et al.  First trimester screening for intra‐uterine growth restriction and early‐onset pre‐eclampsia , 2011, Prenatal diagnosis.

[109]  Daniel W. Jones,et al.  Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. , 2003, Hypertension.

[110]  J. Deanfield,et al.  The Task Force on the Management of Grown-up Congenital Heart Disease of the European Society of Cardiology (ESC) Endorsed by the Association for European Paediatric Cardiology (AEPC) , 2010 .

[111]  M. Moser,et al.  The Treatment of Hypertension During Pregnancy: When Should Blood Pressure Medications Be Started? , 2013, Current Cardiology Reports.

[112]  D. Chestnut Prevention of Preeclampsia and Intrauterine Growth Restriction With Aspirin Started in Early Pregnancy: A Meta-Analysis , 2011 .

[113]  H. Salehi-pourmehr,et al.  Association of the folic acid consumption and its serum levels with preeclampsia in pregnant women , 2012, Iranian journal of nursing and midwifery research.

[114]  G. Yoshino,et al.  Low-density lipoprotein particle diameter in normal pregnancy and preeclampsia. , 2002, Journal of atherosclerosis and thrombosis.

[115]  A. W. Woods,et al.  Rheological and Physiological Consequences of Conversion of the Maternal Spiral Arteries for Uteroplacental Blood Flow during Human Pregnancy , 2009, Placenta.

[116]  A. Baschat,et al.  First trimester maternal characteristics, Doppler parameters and serum analytes after preeclampsia , 2014, Hypertension in pregnancy.

[117]  A. Hofman,et al.  Ethnic Differences in Blood Pressure and Hypertensive Complications During Pregnancy: The Generation R Study , 2012, Hypertension.

[118]  M. Torloni,et al.  Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. , 2014, The Cochrane database of systematic reviews.

[119]  G Koren,et al.  Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis , 2000, The Lancet.

[120]  W. Gu,et al.  The efficacy of metformin in pregnant women with polycystic ovary syndrome: A meta-analysis of clinical trials , 2013, Journal of Endocrinological Investigation.

[121]  Ja Wilson,et al.  Principles and practice of screening for disease , 1968 .

[122]  J. Biggio,et al.  Risk of Adverse Pregnancy Outcomes in Women With Mild Chronic Hypertension Before 20 Weeks of Gestation , 2014, Obstetrics and gynecology.

[123]  J. Dungan Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data , 2008 .

[124]  P. Kaufmann,et al.  Pressure dependence of so‐called transtrophoblastic channels during fetal perfusion of human placental villi , 1997, Microscopy research and technique.

[125]  E. Stekkinger,et al.  Metabolic syndrome and the risk for recurrent pre‐eclampsia: a retrospective cohort study , 2013, BJOG : an international journal of obstetrics and gynaecology.

[126]  A. Baschat,et al.  External validity of first‐trimester algorithms in the prediction of pre‐eclampsia disease severity , 2014, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.