Preeclampsia and eclampsia: the conceptual evolution of a syndrome

Abstract

Preeclampsia, one of the most enigmatic complications of pregnancy, is considered a pregnancy-specific disorder caused by the placenta and cured only by delivery. This article traces the condition from its origins-once thought to be a disease of the central nervous system, recognized by the occurrence of seizures (ie, eclampsia)-to the present time when preeclampsia is conceptualized primarily as a vascular disorder. We review the epidemiologic data that led to the recommendation to use diastolic hypertension and proteinuria as diagnostic criteria, as their combined presence was associated with an increased risk of fetal death and the birth of small-for-gestational-age neonates. However, preeclampsia is a multisystemic disorder with protean manifestations, and the condition can be present even in the absence of hypertension and proteinuria. Toxins gaining access to the maternal circulation have been proposed to mediate the clinical manifestations-hence, the term "toxemia of pregnancy," which was used for several decades. The search for putative toxins has challenged investigators for more than a century, and a growing body of evidence suggests that products of an ischemic or a stressed placenta are responsible for the vascular changes that characterize this syndrome. The discovery that the placenta can produce antiangiogenic factors, which regulate endothelial cell function and induce intravascular inflammation, has been a major step forward in the understanding of preeclampsia. We view the release of antiangiogenic factors by the placenta as an adaptive response to improve uterine perfusion by modulating endothelial function and maternal cardiovascular performance. However, this homeostatic response can become maladaptive and lead to damage of target organs during pregnancy or the postpartum period. Early-onset preeclampsia has many features in common with atherosclerosis, whereas late-onset preeclampsia seems to result from a mismatch of fetal demands and maternal supply, that is, a metabolic crisis. Preeclampsia, as it is understood today, is essentially vascular dysfunction unmasked or caused by pregnancy. A subset of patients diagnosed with preeclampsia are at greater risk of the subsequent development of hypertension, ischemic heart disease, heart failure, vascular dementia, and end-stage renal disease. However, these adverse events may be the result of a preexisting vascular pathologic process; it is not known if the occurrence of preeclampsia increases the baseline risk. Therefore, the understanding, prediction, prevention, and treatment of preeclampsia are healthcare priorities.

Keywords: Elevated Liver enzymes and Low Platelets (HELLP) syndrome; Hemolysis; acute fatty liver; albuminuria; angiogenic factor; biomarker; blood pressure; cardiovascular disease; chronic hypertension; convulsion; eclampsia; edema; fetal death; genetic predisposition; gestational hypertension; great obstetrical syndromes; history; hypertension; hysterotonin; imitator; ischemia; placental growth factor (PlGF); postpartum preeclampsia; pregnancy-induced hypertension; proteinuria; severe preeclampsia; small for gestational age (SGA); soluble fms-like tyrosine kinase-1 (sFlt-1); stillbirth; toxemia; toxin; uteroplacental ischemia; vascular endothelial growth factor (VEGF).

Figure 1.

(A) The Kahun Gynaecological Papyrus. A medical text from the late Middle Kingdom (1850–1700 BC) addressing women’s health. The Papyrus was found near the modern-day Egyptian town of Lehun in 1889 by Flinders Petrie. The Kahun Gynaecological Papyrus (UC 32057) is housed at University College London, London, UK. 21367707). In this Figure, pages 1, 2, and 3 of Plate VI are shown. Modified from https://en.wikipedia.org/wiki/Kahun_Gynaecological_Papyrus (B) The Kahun Gynaecological Papyrus was translated in 1893 by F. Griffiths and published as The Petrie Papyri: Hieratic Papyri from Kahun and Gurob (Principally of the Middle Kingdom). This figure shows the translation of Prescription No XXXIII from page 3 of the Plate VI (Medical Papyrus). It describes a cure to prevent a woman from biting her tongue the day of birth. Modified from Griffith FL. Hieratic Papyri from Kahun and Gurob:(principally of the Middle Kingdom). B. Quaritch; 1898.

Figure 2.

The title page of Cases of Puerperal Convulsions, with Remarks, in which Dr. John C. W. Lever, a British obstetric physician, reported the association between puerperal convulsions and albuminuria. Modified from Lever JC. Cases of puerperal convulsions, with remarks. Guys Hosp Rep 1843;2:495–517.

Figure 3.

Sphygmographic Tracings in Puerperal Eclampsia. The sphygmographic tracings record blood pressure from women with preeclampsia (A) during pregnancy and (B) in the postpartum period. Modified from Ballantyne JW. Sphygmographic Tracings in Puerperal Eclampsia. Trans Edinb Obstet Soc. 1885;10:56–70.

Figure 4.

Changes in diastolic blood pressure in patients with preeclampsia and controls (A) on postpartum day 6 and (B) at 6 weeks postpartum after plasma autotransfusion. Modified from Pirani BB, MacGillivray I. The effect of plasma retransfusion on the blood pressure in the puerperium. Am J Obstet Gynecol. 1975 Jan 15;121(2):221–6.

Figure 5.

Risk of stillbirth in patients with normotensive, gestational hypertension, chronic hypertension, and proteinuria by ethnic group. Modified from Page EW, Christianson R. Influence of blood pressure changes with and without proteinuria upon outcome of pregnancy. Am J Obstet Gynecol. 1976 Dec 1;126(7):821–33.

Figure 6.

The book cover of Pregnancy Hypertension: A Systematic Evaluation of Clinical Diagnostic Criteria authored by Emanuel A. Friedman and Raymond K. Neff and published in 1977. In this book, the authors reported on the Collaborative Perinatal Project, in which the relationship between blood pressure, proteinuria, and adverse pregnancy outcomes was analyzed. Modified from Friedman EA, Neff RK. Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria. PSG Publishing Company, Inc.: Littleton, MA, 1977.

Figure 7.

Rate ratios for fetal mortality by diastolic pressure and proteinuria combinations. The synergistic effect of diastolic blood pressure and proteinuria is evident, and it determines a considerable increase in the risk of fetal mortality. Modified from Friedman EA, Neff RK. Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria. PSG Publishing Company, Inc.: Littleton, MA, 1977, page 170.

Figure 8.

“Severe pre-eclampsia: another great imitator.” Modified from Goodlin RC. Severe pre-eclampsia: another great imitator. Am J Obstet Gynecol. 1976 Jul 15;125(6):747–53.

Figure 9.

The original paper in which the term HELLP was coined. “Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy” Am J Obstet Gynecol. 1982 Jan 15;142(2):159–67.

Figure 10.

Preeclampsia as a multi-systemic disease that involves virtually every organ system in humans.

Figure 11.

(A) Remodeling of the spiral arteries increases blood supply to the fetus. (B) In preeclampsia, sFlt-1 is overexpressed in the placenta, leading to hypertension and proteinuria. Modified from Luttun A, Carmeliet P. Soluble VEGF receptor Flt1: the elusive preeclampsia factor discovered? J Clin Invest. 2003 Mar;111(5):600–2.

Figure 12.

Effect of uterine curettage on blood pressure in a woman with postpartum eclampsia. In one patient with postpartum eclampsia and three episodes of convulsions, curettage was performed, maternal hypertension improved, and convulsions did not recur. Modified from Hunter CA Jr, Howard WF, McCormick CO Jr. Amelioration of the hypertension of toxemia by postpartum curettage. Am J Obstet Gynecol. 1961 May;81:884–9.

Figure 13.

(A) Postpartum uterine curettage not only has an effect on blood pressure (B) but also on platelet count in patients with preeclampsia. Modified from Magann EF, Martin JN Jr, Isaacs JD, Perry KG Jr, Martin RW, Meydrech EF. Immediate postpartum curettage: accelerated recovery from severe preeclampsia. Obstet Gynecol. 1993 Apr;81(4):502–6.

Figure 14.

Plasma concentration of sFlt-1 in women with normal pregnancy, preeclampsia, HELLP syndrome, and acute fatty liver of pregnancy. Women with acute fatty liver of pregnancy have a higher plasma concentration of sFlt-1 compared to the other conditions. Data are presented as individual values (dot) and median (bar). Modified from Neuman RI, Saleh L, Verdonk K, et al. Accurate Prediction of Total PlGF (Placental Growth Factor) From Free PlGF and sFlt-1 (Soluble Fms-Like Tyrosine Kinase-1): Evidence for Markedly Elevated PlGF Levels in Women With Acute Fatty Liver of Pregnancy. Hypertension. 2021 Aug;78(2):489–498. HELLP: Hemolysis, Elevated Liver enzymes and Low Platelets; sFlt-1: Soluble Fms-Like Tyrosine Kinese-1.

Figure 15.

Vascular dysfunction during pregnancy may result in one of several obstetrical syndromes. The timing and magnitude of the insult may determine the clinical syndromes.

Figure 16.

Relative risk of cardiometabolic disease in women with a history of preeclampsia. Modified from Ramlakhan KP, Johnson MR, Roos-Hesselink JW. Pregnancy and cardiovascular disease. Nat Rev Cardiol. 2020 Nov;17(11):718–731.