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Eclampsia


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assosciate Editor(s)-In-Chief: Navneet Kaur M.B.,B.S. , Prashanth Saddala M.B.B.S

Synonyms and keywords: Toxemia with seizures, preeclampsia, toxemia with seizures, hypertensive disorders of pregnancy, HDP, Hypertensive disorders of pregnancy, seizures during pregnancy

Overview

Overview

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assosciate Editor(s)-In-Chief: Navneet Kaur M.B.,B.S.

Overview

Eclampsia, an acute and life-threatening complication of pregnancy, is characterized by the appearance of tonic-clonic seizures in a patient who had developed preeclampsia; rarely does eclampsia occur without preceding preeclamptic symptoms. Hypertensive disorder of pregnancy and toxemia of pregnancy are terms used to encompass both preeclampsia and eclampsia. Seizures and coma that happen during pregnancy but are due to preexisting or organic brain disorders are not eclampsia.

Eclamptic convulsions may appear in the last trimester (rarely before), during labour, and in the first two days postpartum; it would be highly unusual to see eclampsia later than 48 hours after delivery.[1]

Historical Perspective

The importance of historical perspective lies in the fact that our current understanding of pathophysiology, classifications and management strategies is influenced by past hypotheses and scientific contributions, which have also shaped our current practice trends. The term is derived from Greek and refers to a flash, a term used by Hippocrates to designate a fever of sudden onset. Various theories have been proposed from time to time such as the theory of four humours, wet and dry theory, wandering womb theory during ancient times; dominant humour theory and Mauriceau’s suppressed lochia flow theory during the middle ages; During the 18th and the 19th century, physicians started noting the association of various symptoms such as headache, body edema, short term loss of vision, severe pain in the stomach, etc. during later months of pregnancy and the development of convulsions. Smith’s theory of toxic elements came during the same period. Extensive advancements in uncovering the pathophysiological changes were made in the 20th century, such as the trophoblastic shallow invasion theory and endothelial disorder theory. Various treatments were offered from time to time depending upon the theories proposed such as purging, bloodletting, altered diets, getting rid of toxic elements, placing the patient in a warm bath, opiates, etc. during the 20th century increased focus was placed on routine prenatal care and early recognition of warning signs and symptoms. In the early 20th century the use of magnesium sulphate was popularised and safety was established which still guides our treatment protocols.

Pathophysiology

Eclampsia is severe form of pre-eclampsia and all the changes that happen in pre-eclampsia are further intensified. It is associated with abnormal or defective spiral artery remodelling, that is, high-resistance, low-flow blood vessels are unable to convert to low-resistance, high-flow blood vessels, hypoperfusion of the fetoplacental unit, and chronic placental ischemia which result in oxidative stress and formation of reactive oxygen species. There is an imbalance between vasodilator agents such as prostaglandins and nitric oxide and vasoconstrictor agents such as thromboxane-II (TXA-2) amd angiotensin II. Also there is increased production of endothelin-1 which also acts as a vasoconstrictor. Enhanced expression of antiangiogenic factors like sFlt-1 and soluble endoglin (sEng) are also responsible for deranged cell signalling and inhibition of VEGF and TGF-beta. The oxidative stress results in various organ system damages and can ultimately lead to cerebral edema, cerebral anoxia, cerebral autoregulation failure and excess of excitatory neurotransmitters, which can result in convulsions.

Epidemiology and demographics

Hypertensive disorders of pregnancy (HDP), defined as a sex-specific cardiovascular disease, is one of the leading causes of maternal and fetal morbidity and mortality globally and a critical threat to maternal and infant health. Preeclampsia is a pregnancy-related hypertensive disorder occurring usually after 20 weeks of gestation and if left untreated, it progresses to eclampsia. Preeclampsia and eclampsia are not distinct disorders but the manifestation of the spectrum of clinical symptoms of the same condition. Although preeclampsia prevails to be a significant public health threat in both developed and developing nations bringing maternal and perinatal morbidity and mortality worldwide, the impact of the disease is witnessed to be harsher in the developing countries, where, unlike other more prevalent causes of maternal mortality (such as haemorrhage and sepsis), medical interventions may be ineffective due to late presentation of cases. The problem is confounded by the continued ambivalence of the aetiology and the unpredictable behavior of the disease. According to WHO, the incidence of preeclampsia is seven times higher in developing countries (2.8% of live births) than in developed countries (0.4%). In developing countries the prevalence of preeclampsia, the precursor of eclampsia, ranges from 1.8% to 16.7% and from 1990 to 2019, the incidence, prevalence, death and YLDs were highest in populations aged 25–29 years.

Risk Factors

The various risk factors associated with the development of eclampsia encompass a personal or family history of pre-eclampsia/eclampsia, nulliparity, primigravida, long interpregnancy intervals, conditions with a large placenta such as multiple gestations(twins or triplets) and H Mole, women with preexisting conditions such as chronic hypertension, history of gestational hypertension in the previous pregnancy, renal diseases, diabetes, gestational diabetes, obesity, certain thrombophilic diseases (such as the antiphospholipid antibody syndrome, protein C deficiency, protein S deficiency, anti-thrombin deficiency), connective tissue disorders, SLE and genetics.

Prevention

Detection and management of preeclampsia is critical to reduce the risk of eclampsia. Appropriate management of patients with preeclampsia generally involves the use of magnesium sulfate as an agent to prevent convulsions, and thus preventing eclampsia.

References

  1. ↑ Chesley LC. Hypertensive Disorders in Pregnancy, in Williams Obstetrics, 14th Edition. Appleton Century Crofts, New York (1971), page 700.

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Historical Perspective

Historical Perspective

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assosciate Editor(s)-In-Chief: Navneet Kaur M.B.,B.S.

Overview

The importance of historical perspective lies in the fact that our current understanding of pathophysiology, classifications and management strategies is influenced by past hypotheses and scientific contributions, which have also shaped our current practice trends. [1] The term is derived from Greek and refers to a flash, a term used by Hippocrates to designate a fever of sudden onset. Various theories have been proposed from time to time such as the theory of four humours, wet and dry theory, wandering womb theory during ancient times; dominant humour theory and Mauriceau’s suppressed lochia flow theory during the middle ages; During the 18th and the 19th century, physicians started noting the association of various symptoms such as headache, body edema, short term loss of vision, severe pain in the stomach, etc. during later months of pregnancy and the development of convulsions. Smith’s theory of toxic elements came during the same period. Extensive advancements in uncovering the pathophysiological changes were made in the 20th century, such as the trophoblastic shallow invasion theory and endothelial disorder theory. Various treatments were offered from time to time depending upon the theories proposed such as purging, bloodletting, altered diets, getting rid of toxic elements, placing the patient in a warm bath, opiates, etc. during the 20th century increased focus was placed on routine prenatal care and early recognition of warning signs and symptoms. In the early 20th century the use of magnesium sulphate was popularised and safety was established which still guides our treatment protocols.

Historical Perspective

Over time various theories and treatments based on those theories have been proposed.

Ancient Times

Theories

  • THEORY OF FOUR HUMORS
    • In late 5thand early 4th BCE
    • The balance between Four humors, blood, phlegm, yellow bile, and black bile, resulted in health and illness.[2]
  • WET AND DRY THEORY
    • Women’s skin was considered wet, porous, and soft and it was thought that she could accumulate lots of moisture which resulted in an overabundance of fluids and led to illness. [3]
  • WANDERING WOMB THEORY
    • Hippocrates believed that dried up uterus wandered the body in search of moisture, and as it wandered the body, it could wreak havoc upon the liver, spleen, lungs, and head, leading to disease.

Treatments Offered

Treatment directed towards the restoration of internal equilibrium by mechanisms that increased elimination of excess fluids and could consist of:

  • Altered diets
  • Purging
  • Blood-letting

Middle Ages

During the middle ages, between 400 CE and 700 CE, scientific progress, especially medical, came to a standstill as the Christians were opposed to human science and dissection. many medical schools were closed, such as at Athens and Alexandria. Hence, the main focus was on the compilation and rewriting. Later, the Christian influence began to decline and new theories emerged. In 1619, the word “eclampsia” first appeared in Varandaeus’ treatise on gynecology.[4]

Theories

  • DOMINANT HUMOR THEORY
    • One theory that emerged suggested that one humor dominated the other humors and controlled an individual’s physical and emotional characteristics, and was responsible for the signs and symptoms of eclampsia.
  • MAURICEAU’S THEORY
    • In 17th century, when medicine gained momentum again, Francois Mauriceau helped establish obstetrics as a specialty. He was the first to systematically describe eclampsia,[5] and to note that primigravidas were at a greater risk for convulsions compared to multigravidas. He attributed convulsions to either suppressed lochia flow which could lead to inflammation, pain in the head, convulsions, suffocation, and death, or intrauterine fetal death which could lead to foul-smelling humors and predispose a woman to convulsions.

Treatments Offered

Increasing Christian beliefs greatly influenced treatments which consisted of charms, amulets, prayers. However, as time passed treatments offered in ancients times were again practiced, such as phlebotomies.

18th and 19th Century

Theories

  • In the 18th century, Bossier de Sauvages discerned eclampsia from epilepsy and believed that convulsions transpired due to nature trying to free the morbid elements from the organism. He also noted that eclampsia was acute in nature and epilepsy was chronic because convulsions due to eclampsia resolved once the precipitating cause was removed but epilepsy recurred over time. He also pointed out that eclampsia was not restricted to pregnancy and severe hemorrhage, various sources of pain, and vermicular infestations were several species of eclampsia.[6][1]
  • In 1797, Demanet noted a connection between edematous women and eclampsia.
  • In 1843, John Lever discovered albumin in the urine of eclamptic women.
  • In 1843, Dr Robert Johns pointed out an association between premonitory warnings, such as headache, short term loss of vision, severe pain in the stomach, edema of the hands, arms, neck and face, during the later months of pregnancy and the development of convulsions.
  • In the 19th century physicians continued to propose more theories. Dr Thomas Denman(1821) in his work entitled “Introduction to the Practice of Midwifery”, concentrated on labours affected by convulsions. He attributed convulsions to specific customs and behaviours analogous to living in big cities and towns but also noted that the largest risk came from the uterus. According to him, expansion of the uterus during pregnancy placed considerable pressure on the descending blood vessels, resulting in regurgitation of blood in the head and overload of cerebral blood vessels resulted in convulsions.[1]
  • Dr William Tyler Smith(1849) in his work, “Parturition and the Principles and Practice of Obstetrics” challenged Denman’s notion of cerebral congestion. He speculated that pregnancy was a state of increased fullness in Circulation. Dr Smith pointed out that if cerebral congestion was the rationale for seizures more cases would be anticipated during the second stage of labor as contractions during the second stage would interfere the most with the circulation of blood. He proposed other rationales such as:
    1. mechanical or emotional stimulus applied to the spinal cord
    2. variations in the wind, temperature, other atmospheric alterations
    3. bloodletting
    4. irritation of the uterus, uterine passages, intestinal canal, and the stomach
    5. the toxic elements
    • SMITH’S THEORY OF TOXIC ELEMENTS: Dr Smith speculated that the health of the pregnant woman depended on the exponential increase in the elimination of the waste elements, such as secretion of the bowels, and debris from the maternal and fetal system. Failure to eliminate such wastes could result in “toxemia”, in which morbid elements accumulate in the system and could irritate the nervous system.
  • In 1897, Vaquez and Nobecort were credited with the discovery of eclamptic hypertension and the concept of preeclamptic state was recognized. The presence of edema, headache, and proteinuria now raised concerns about the possibility of convulsions.

Treatments Offered

In the early 1800s:

  • Bloodletting: In the early 1800s, it continued as a staple in the treatment and prevention of eclampsia. The quantity and frequency of bloodletting were determined by the strength of the patient and the severity of symptoms. The initial site for bleeding was the arm and repeated if necessary, that is if the convulsions persisted. In some cases, the jugular vein or temporal artery were also opened.
  • Opiates: They were employed to curtail irritability of the female organs.
  • Splashing cold water on patients face
  • Placing the patient in a warm bath

If all other methods were ineffective, the Physician had to decide between expediting the childbirth or letting natural labor to start. According to Dr Denman, delivery was only hastened when the mother displayed the indications of being physiologically ready such as completion of dilation, rupturing of membranes, or descent of the fetus, because interventions in the early stage of labor could increase maternal mortality.

In the late 1800s:

  • Elimination of Toxins: When Smith’s theory of toxic elements emerged, treatments were targeted at the elimination of overabundant toxins. Some believed that meat toxins provoked eclampsia and advised against the consumption of meat products and prescribed diets consisting of vegetables, fruits and milk products.
  • Preventative therapies: Now women with preeclamptic states, those who had headaches and edema of the upper extremities, were increasingly recognised and admitted to lying-in hospitals where they underwent procedures such as bleeding and purging to prevent seizures.

20th Century

Extensive advancement occurred in uncovering the pathophysiological changes associated with eclampsia and several alterations were brought about in the classification of preeclampsia-eclampsia disease throughout the century.

Theories

  • Trophoblastic Shallow Invasion Theory: In the 1960s, numerous groups described differences in the physiology of the placentas from patients affected by pre-eclampsia versus the placentas from patients not affected by the same. Subsequently, after conducting the placental bed biopsies, it was discovered that Placental trophoblast cells failed to adequately invade the maternal spiral arteries and convert the arteries from small muscular vessels into large, low resistant vessels in pre-eclampsia. With the lack of spiral artery conversion in preeclampsia, arterial lumen diameter and distensibility was restricted which resulted in the restriction of blood flow to the placenta and growing fetus. These findings have been instrumental for the current understanding of eclampsia.[7][8][9][10]
  • The Hydatoxi lualba ( a parasitic worm) theory: This theory was published in the American Journal of obstetrics and gynaecology,1983. According to this theory, a worm-like organism was attributed to the development of preeclampsia-eclampsia. The basis of this theory was the finding of Hydatoxi lualba in the samples, which consisted of peripheral blood, bloody fluid on the maternal surface of the placenta, and umbilical cord blood gathered from women with preeclampsia-eclampsia.[11] But, this theory was soon refuted as other research groups illustrated that cellulose residue from laboratory paper products, starch powder from gloves, and altered staining techniques elicited identical worm-like organisms.[12]
  • Roberts and colleagues, 1989: Dr Robert and colleagues[13] posited preeclampsia to be an Endothelial disorder. Drawing from the past trophoblastic shallow invasion theory, they further hypothesized that the ischemic placenta released a damaging factor into the maternal circulation. This circulating factor could be responsible for the endothelial dysfunction and in turn result in the activation of the coagulation cascade, abnormalities in blood pressure, and loss of fluid from the intravascular fluid space.[14]
Progression of preeclampsia-eclampsia classification during the 20th Century
Year Citation Milestone
1903 Chesley, 1978 “pre-eclamptic state” included in textbooks
1961 Chesley, 1978 preeclampsia-eclampsia restricted to the obstetric definition
The table adapted from A Historical Overview of Preeclampsia-Eclampsia
Progression of preeclampsia-eclampsia classification during the 20th Century ( Adapted from A Historical Overview of Preeclampsia-Eclampsia )
Obstetrical Textbook Publication Year & Citation Terminology Classification Description
1966 Eastman & Hellman (1966) Toxemias of pregnancy A. acute toxemia of pregnancy (pre-eclampsia and eclampsia); chronic hypertensive disease with pregnancy; unclassified toxemia

B. preeclampsia diagnostic criteria: presence of hypertension, edema, or proteinuria after 24 weeks gestation

1976 Pritchard & McDonald (1976) hypertensive disorders of pregnancy A. “toxemias of pregnancy” replaced with “hypertensive disorders of pregnancy”

B. preeclampsia diagnostic criteria: development of hypertension with proteinuria, edema, or both commencing after 20 weeks gestation

1988 Hibbard (1988) pregnancy induced hypertension A. under the classification of hypertensive disorders of pregnancy, preeclampsia was further grouped under “pregnancy induced hypertension,” which also included hypertension that developed during pregnancy excluding the features of preeclampsia

B. preeclampsia diagnostic criteria: mild to moderate preeclampsia- presence of hypertension and edema; severe preeclampsia- presence of hypertension and proteinuria with or without edema or cerebral or visual disturbances after 20–24 weeks gestation

Treatments Offered

In the late 19th and early 20th a myriad of protocols was embarked towards the treatment of eclampsia. The physicians in Netherlands and Germany originally endorsed aggressive management consisting of prompt abdominal or vaginal cesarean section. But the aggressive management was associated with exceptionally high maternal mortality rates. Thereafter, a more conservative approach amassed popularity and was widely used. Tweedy of Dublin and Russia’s Stroganoff were the forerunner physicians behind the conservative management.

  • Tweedy’s Rationale for Conservative Management: According to Tweedy, accelerating labor and delivery could instigate convulsions via the induction of reflex stimulation. He proposed that physicians should avert from performing vaginal examinations, abdominal palpations, kidney massages, cold air blasts, dilation of the cervix to evade reflex stimulation. His management protocol included:
    • Patient’s sedation (included morphine).
    • If a patient went into labour, Tweedy believed that the application of forceps was acceptable if the os safely permitted their application.
  • Stroganoff’s Approach: Stroganoff’s primary objective was to terminate seizures because he believed that convulsions disrupted the functions of the heart, lungs, liver, and kidney. He ignored the pregnancy, treated the eclampsia, and waited for the natural onset of labour. Stroganoff allowed inspections and treatments under light anaesthesia, keeping the patient in a dark and quiet space to avoid any sensory stimuli. To further sedate the patient, if required, and to decrease the convulsions Morphine and chloral hydrate were also administered. In case of respiratory decompensation, oxygen was given. He examined the pulse as well as other cardiac functions regularly and if the pulse was feeble, digitalis was administered. Once the cervix was dilated to 6 cm, the membranes were artificially ruptured and labour was allowed to progress naturally.
  • The Introduction of Magnesium Sulfate: In 1906, Horn first employed ”magnesium sulphate”, which is the current mainstay of treatment, to manage preeclampsia-eclampsia. During the 1920s the parenteral use of magnesium sulphate was popularised by Dr Lazard and Dorsett. Dr Lazard in his work illustrated that treatment with intravenous magnesium sulphate was both efficacious as well as safe.
  • After the 1960s: Very few alterations have been made in the management of pre-eclampsia since the 1960s. This can be discerned from the texts used to educate pupils in healthcare fields. The management options recommended were:
    • Routine prenatal care:
      • Management commenced with routine prenatal care which entailed regular blood pressure measurements, maternal weight checkups, urine analysis, to recognize any early signs and symptoms.
    • Management of patients diagnosed with preeclampsia:
    • Management of patients with fulminating pre-eclampsia or the development of eclampsia:
      • Magnesium sulphate was given to manage convulsions
      • Antihypertensives were administered to tackle acute hypertension
      • Delivery: The decision to move forward with the vaginal delivery or the Cesarean section depended on various factors such as gestational age, condition of the cervix, maternal condition, and fetal condition.

References

  1. ↑ 1.0 1.1 1.2 Bell MJ (2010). “A historical overview of preeclampsia-eclampsia”. J Obstet Gynecol Neonatal Nurs. 39 (5): 510–8. doi:10.1111/j.1552-6909.2010.01172.x. PMC 2951301. PMID 20919997.
  2. ↑ Demand N. Birth, death, and motherhood in classical Greece. Baltimore, MD: The John Hopkins University Press; 1994. [Google Scholar]
  3. ↑ Green MH. Unpublished doctoral dissertation. Princeton University; 1985. The transmission of ancient theories of female physiology and disease through the early Middle Ages.
  4. ↑ Ong,2004
  5. ↑ McMillen (2003)
  6. ↑ temkin,1917
  7. ↑ Brosens I, Robertson WB, Dixon HG (1967). “The physiological response of the vessels of the placental bed to normal pregnancy”. J Pathol Bacteriol. 93 (2): 569–79. doi:10.1002/path.1700930218. PMID 6054057.
  8. ↑ Brosens IA, Robertson WB, Dixon HG. The role of the spiral arteries in the pathogenesis of preeclampsia. Obstet Gynecol Annu. 1972;1:177–191. [PubMed] [Google Scholar]
  9. ↑ Gerretsen G, Huisjes HJ, Elema JD. Morphological changes of the spiral arteries in the placental bed in relation to pre-eclampsia and fetal growth retardation. Br J Obstet Gynaecol. 1981 Sep;88(9):876-81. doi: 10.1111/j.1471-0528.1981.tb02222.x. PMID: 7272259.
  10. ↑ Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol. 1986 Oct;93(10):1049-59. doi: 10.1111/j.1471-0528.1986.tb07830.x. PMID: 3790464.
  11. ↑ Lueck J, Brewer JI, Aladjem S, Novotny M. Observation of an organism found in patients with gestational trophoblastic disease and in patients with toxemia of pregnancy. Am J Obstet Gynecol. 1983 Jan 1;145(1):15-26. doi: 10.1016/0002-9378(83)90334-4. PMID: 6295163.
  12. ↑ Papoutsis DV, Irwin RL, Curry JJ, Zuspan FP. Parasitic etiology for preeclampsia: fact or artifact? Am J Obstet Gynecol. 1983 Dec 15;147(8):977-9. doi: 10.1016/0002-9378(83)90263-6. PMID: 6650642.
  13. ↑ Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol. 1989 Nov;161(5):1200-4. doi: 10.1016/0002-9378(89)90665-0. PMID: 2589440.
  14. ↑ Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol. 1989 Nov;161(5):1200-4. doi: 10.1016/0002-9378(89)90665-0. PMID: 2589440.

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Pathophysiology

Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Eclampsia is severe form of pre-eclampsia and all the changes that happen in pre-eclampsia are further intensified. It is associated with abnormal or defective spiral artery remodelling, that is, high-resistance, low-flow blood vessels are unable to convert to low-resistance, high-flow blood vessels, hypoperfusion of the fetoplacental unit, and chronic placental ischemia which result in oxidative stress and formation of reactive oxygen species. There is an imbalance between vasodilator agents such as prostaglandins and nitric oxide and vasoconstrictor agents such as thromboxane-II (TXA-2) amd angiotensin II. Also there is increased production of endothelin-1 which also acts as a vasoconstrictor. Enhanced expression of antiangiogenic factors like sFlt-1 and soluble endoglin (sEng) are also responsible for deranged cell signalling and inhibition of VEGF and TGF-beta. The oxidative stress results in various organ system damages and can ultimately lead to cerebral edema, cerebral anoxia, cerebral autoregulation failure and excess of excitatory neurotransmitters, which can result in convulsions.

Pathophysiology

Anatomy and Physiology of placenta

The formation of the placenta commences with the development of trophoblast. After the fertilization of the ovum in the fallopian tubes, it travels towards the uterus and by the time it reaches the uterus it has already become a morula. The morula is still surrounded by the zona pellucida which prevents it from sticking to the walls of the tube. The zona pellucida disappears soon after the blastocyst reaches the uterine cavity. Now the cells lining the blastocyst constitute the trophoblast whose function is to invade the surrounding uterine tissues to provide nutrition to the developing blastocyst. When the trophoblast attaches to the endometrium, it is known as implantation, which begins on the sixth day after fertilization in humans. This process is additionally enhanced by the proteolytic enzymes produced by the trophoblast and the interaction between the receptors present uterine epithelium and L-selectin and integrins produced by the trophoblast cells. Hence, implantation is a result of mutual exchange between the endometrium of the uterine cavity and the trophoblastic cells surrounding the blastocyst.

Decidua

After the implantation, the uterine endometrium is termed the Decidua. Once the implantation has occurred the stromal cells undergo a decidual reaction which consists of enlargement of the cells, vacuolisation and storage of glycogen and lipids.

Decidua basalis
  • The area of the endometrium or decidua that is deep to the blastocyst, where the placenta is to be formed is inferred as decidua basalis. It consists of the terminally differentiated large stromal cells which encompass largely lipids and glycogen that acts as a source of nutrition for the embryo. It also comprises of maternal vascular cells and maternal blood cells inside and outside those vessels.
  • This area is also known as the decidual plate and it is firmly united to the chorion.
  • The stromal cells also produce a variety of humoral proteins such as insulin-like growth factor binding proteins and prolactin and its family proteins.

Chorionic villi

These consist of the fetal portion of the placenta. They are offshoots or very small finger-like processes, hence called the villi, from the surface of the trophoblast cells. Within the substance of these villi are fetal blood capillaries and fetal blood cells which arise from the extra-embryonic mesoderm. Since the trophoblast and the extra-embryonic mesoderm constitutes the chorion, these villi are also known as chorionic villi.

Chorion fundosum

Originally the villi are formed all over the trophoblast and commence invading the surrounding decidua. Nevertheless gradually the villi related to the decidua capsularis degenerate and in contrast, those associated with the decidua basalis undergo further differentiation and substantial growth and helps form the placenta. This part is known as chorion fundosum. During the differentiation process, the trophoblast which is originally a single layer of cells multiplies into two distinct layers. The cells in the superficial layer, that is the layer which is in proximity with the decidua, lose their cell boundaries and mould into one consecutive layer of cytoplasm and several nuclei, known as the syncytiotrophoblast. The second layer cells, which rest on extra-embryonic mesoderm, however retain their cell walls and are known as the cytotrophoblast.

Placenta

  • The tissues of desidua basalis and chorion fundosum jointly form a disc-shaped structure called the placenta.
  • Various septa start growing into the intervillous space from the maternal side and subdivide the placenta into 15-20 lobes known as the maternal cotyledons.
  • Each lobe homes several anchoring villi and their branches. One such villus along with its branches constitute a fetal cotyledon.
  • The maternal vessels empty into the intervillous space and the maternal blood circulates through the intervillous space and the fetal blood travels through the fetal blood vessels in the villi. At any given time, the maternal and fetal blood do not mix and all exchanges take place via the placental membrane or the placental barrier.
  • The layers of the placental membrane(from the fetal side):
    1. The endothelium and the basement membrane of the fetal blood vessels
    2. Surrounding connective tissue(mesoderm)
    3. Cytotrophoblast
    4. Syncytiotrophoblast
  • The functions of the placenta include:
    • The transport of water, electrolytes, oxygen, and nutrition from mother to the baby
    • Excretion of waste products such as carbon dioxide, urea, etcetera produced by the fetus into the maternal blood
    • Passage for the maternal IgG to reach the fetus and give immunity against some infections
    • A barrier against many bacteria, certain viruses, and harmful substances
    • Synthesis of several hormones such as oestrogen(estriol), progesterone, human chorionic gonadotropin (hCG), somatomammotropin (hCS)

Spiral artery remodelling

  • Spiral artery remodelling of the maternal blood vessels, one of the physiological changes of pregnancy, is a process that begins in the first few weeks of pregnancy and modifies the low-flow, high-resistant arteries to high-flow, low-resistance blood vessels which are capable of meeting the demands of the growing fetus.
  • Spiral arteries develop from the radial arteries at the endometrial/myometrial border, and progressively remodel during the first 22 weeks of gestation. It correlates with extravillous trophoblast (EVT) invasion, which ultimately replaces the vascular endothelial cells and smooth muscle cells.
  • It is also accompanied by fibrinoid deposition and loss of responsiveness to vasoconstrictors.
  • The fetal trophoblast cells also synthesize a plethora of cytokines.
  • All these changes result in increased blood flow to the intervillous spaces which ensures a proper supply of nutrition and oxygen for the growth of the fetus.
  • Failure to properly remodel is a common feature seen in preeclampsia-eclampsia syndrome.
  • Mechanisms responsible for the loss of vascular cells:
    • Decidua-associated remodelling: Changes in the spiral artery structure before the arrival of the trophoblasts; may include, endothelial basophilia, vacuolation, and vessel dilation.
    • The vascular effects of oestrogen: Stimulate nitric oxide synthesis, increase vessel permeability and endothelial cell proliferation via increased vascular endothelial growth factor (VEGF) release.
    • Influence of progesterone: Enhanced recruitment of immune cells such as lymphocytes, macrophages and uterine natural killer cells to the endometrium, ability to up-regulate stromal cell chemokine expression.
    • Trophoblast-dependent transformation: Cytotrophoblast stem cells differentiate along two pathways, Villous trophoblasts and Extravillous trophoblasts. Extravillous trophoblasts are responsible for spiral artery remodelling via various processes which could include: adherence, migration, dedifferentiation, medial necrosis and fibrinoid deposition, phagocytosis/autophagy and apoptosis. Although, the research on human spiral artery remodelling is insufficient due to unavailability of material at all phases of pregnancy it is known that spiral artery remodelling plays a central role in establishing and maintaining a normal pregnancy and failure for this remodelling to occur normally may result in preeclampsia among other pregnancy disorders.[1]

Pathophysiology

  • In pre-eclampsia there is an abnormal or defective invasion of the spiral arteries by trophoblast cells resulting in abnormal modelling of the fetal-maternal interface and hypoperfusion of the fetoplacental unit which in turn leads to chronic placental ischemia and oxidative stress.
  • In normal pregnancy, following the remodelling and displacement of endothelial cells, the vascular system becomes refractory to the pressor agents such as Angiotensin-ΙΙ and there is increased production of vasodilator agents such as prostaglandin-12(PG12), nitric oxide(NO) but in preeclampsia, there is an imbalance of the components of prostaglandins. There is a deficiency of PG12 and increased synthesis of thromboxane-A2 (TXA2), a potent vasoconstrictor from the platelets.
  • In normal pregnancy, Angiotensin-ΙΙ is destroyed by angiotensinase produced by the placenta, but in preeclampsia, the angiotensinase activity is decreased following its excretion in urine via proteinuria.
  • There is a deficiency of nitric oxide, a significant vasodilator, which is normally synthesised from L-arginine in the vascular endothelium and syncytiotrophoblast. It normally relaxes smooth muscles, inhibits platelet aggregation, and prevents inter-villous thrombi formation; but its deficiency leads to the development of hypertension.
  • Increased synthesis of Endothelin-Ι, a potent vasoconstrictor, from endothelial cells also contribute to hypertension.
  • Increased production of inflammatory mediators such as tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), among others, from activated WBCs further cause endothelial injury.
  • Placental hypoventilation and decreased oxygen leads to abnormal lipid metabolism, which further results in oxidative stress. It leads to the production of superoxide radicals such as reactive oxygen species (ROS), lipid peroxides, superoxide anion radicals, which further enhance endothelial dysfunction.
  • Oxidative stress induces the release of substances such as free radicals, oxidized lipids, cytokines, and serum soluble vascular endothelial growth factor-1 (VEGF1) into the maternal circulation.
  • These abnormalities are responsible for endothelial dysfunction with vascular hyperpermeability, thrombophilia, and hypertension, to compensate for the decreased flow in the uterine arteries due to peripheral vasoconstriction.
  • Role of Angiogenic and antiangiogenic factors: Several studies have suggested the role of increased expression of Anti-angiogenic factors, such as sFlt1 and soluble Endoglin in the pathogenesis of preeclampsia and eclampsia. [2] [3]
    • sFlt1(Soluble fms-like tyrosine kinase-1): sFlt1 is produced as a result of deranged splicing of Flt1(fms-like tyrosine kinase-1) protein. SFlt1 differs from Flt1 protein in way that it retains the extracellular ligand binding domain but looses of transmembrane as well as intracellular signalling domain. Flt1 is an endothelial receptor for VEGF (Vascular Endothelial Growth Factor) and PlGF (Placental Growth Factor), and is essential for intracellular angiogenic signals. With the increased production of sFlt1 it binds to and antagonizes VEGF and PlGF [4].
    • Soluble Endoglin (sEng): Endoglin (CD150), a transmembrane glycoprotein in vascular endothelium, is a cell surface receptor for transforming growth factor-beta (TGF-β) and plays a key role in angiogenesis. Soluble Endoglin is a deranged and truncated form of endoglin and when it binds to TGF-β, it antagonising its action and alters the cell signalling pathway.
    • Hence, the secretion of Sflt1 and sEng antagonises VEGF and TGF-β1 signalling. Under normal circumstances, VEGF/PlGF and TFG-β1 are accountable for protecting endothelial health via their interaction with various receptors. But their inhibition ultimately results in endothelial cell dysfunction, declined NO production, reduced prostacyclin generation, and heightened procoagulant elements. [5] All these elements contribute to the various symptoms of preeclampsia and eclampsia.

Various mechanisms behind the convulsions in eclampsia

Several factors that cause cerebral irritation can provoke cerebral convulsion, and include:

  • Cerebral edema: [6] [7] [8] [9] [10] [11] [12] Cerebral edema is a key characteristic of eclampsia, as numerous clinical measures such as CT findings, MRI findings, post-mortem etc have exhibited varying extents of edema and vasculopathy. Although both cytotoxic and vasogenic causes have been suggested, the reversibility of neurological symptoms and radiological lesions within few days to weeks postpartum points towards vasogenic edema. The increase in the extracellular space as a consequence of oedema takes up room within the closed cavity of the skull and results in progressive brain compression and the symptoms of eclampsia such as nausea, vomiting, headache, cortical blindness, and seizures. [13] [14]
  • Cerebrovascular autoregulation failure: [15] [16][17] In a normotensive adult, if cerebral perfusion pressure is in the range of 60 to 150 mmHg, the Cerebral Blood Flow (CBF) is maintained at nearly 50 mL per 100 g of brain tissue per minute. Above 150 mmHg and below 60 mmHg, the autoregulation of blood flow is lost and a linear relationship between Cerebral Blood Flow (CBF) and Mean Arterial Pressure (MAP) begins. Above the autoregulation limit, the myogenic vasoconstriction of the blood vessels is overpowered by the increased intravascular pressure, resulting in forceful cerebral vessel dilation. This results in excessive cerebral blood flow, significant Blood-Brain Barrier destruction and vasogenic edema formation which contributes to eclampsia. [18] [19] [20]
  • Cerebral anoxia
  • Cerebral dysrhythmia: The numerous inflammatory cytokines and vasoconstrictor elements released as a result of uteroplacental ischemia can cause the stimulation of excitatory neuronal receptors and result in neuronal excitability and convulsions. [21]
  • Excitatory neurotransmitters: [22] Preeclampsia is associated with the upregulation of a large number of proinflammatory cytokines in the blood, most notably tumor necrosis factor-alpha (TNF-α). Dissimilar to most cytokines, which do not easily traverse into the brain, circulating TNF-α can cross the Blood-Brain Barrier via receptor-mediated endocytosis. TNF-α then upregulates the expression of endothelial cell adhesion molecules such as E-selectin, VCAM-1, and ICAM-1 which facilitate the passage of White Blood cells into the brain. Leukocyte infiltration can trigger the microglia, which can then produce more TNF-α. TNF-α production in the brain can both decreases the seizure threshold and induce seizure itself via impacts on AMPA and GABA receptors.

Histopathology

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References

  1. ↑ Whitley GS, Cartwright JE. Trophoblast-mediated spiral artery remodelling: a role for apoptosis. J Anat. 2009 Jul;215(1):21-6. doi: 10.1111/j.1469-7580.2008.01039.x. Epub 2009 Feb 9. PMID: 19215319; PMCID: PMC2714635.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714635/
  2. ↑ Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S; et al. (2003). “Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia”. J Clin Invest. 111 (5): 649–58. doi:10.1172/JCI17189. PMC 151901. PMID 12618519.
  3. ↑ Ahmad S, Ahmed A (2004). “Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia”. Circ Res. 95 (9): 884–91. doi:10.1161/01.RES.0000147365.86159.f5. PMID 15472115.
  4. ↑ Kendall RL, Thomas KA (1993). “Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor”. Proc Natl Acad Sci U S A. 90 (22): 10705–9. doi:10.1073/pnas.90.22.10705. PMC 47846. PMID 8248162.
  5. ↑ Maynard SE, Karumanchi SA (2011). “Angiogenic factors and preeclampsia”. Semin Nephrol. 31 (1): 33–46. doi:10.1016/j.semnephrol.2010.10.004. PMC 3063446. PMID 21266263.
  6. ↑ Zunker P, Happe S, Georgiadis AL, Louwen F, Georgiadis D, Ringelstein EB; et al. (2000). “Maternal cerebral hemodynamics in pregnancy-related hypertension. A prospective transcranial Doppler study”. Ultrasound Obstet Gynecol. 16 (2): 179–87. doi:10.1046/j.1469-0705.2000.00194.x. PMID 11117090.
  7. ↑ Thomas SV (1998). “Neurological aspects of eclampsia”. J Neurol Sci. 155 (1): 37–43. doi:10.1016/s0022-510x(97)00274-8. PMID 9562320.
  8. ↑ Fletcher JJ, Kramer AH, Bleck TP, Solenski NJ (2009). “Overlapping features of eclampsia and postpartum angiopathy”. Neurocrit Care. 11 (2): 199–209. doi:10.1007/s12028-009-9221-0. PMID 19404782.
  9. ↑ Koch S, Rabinstein A, Falcone S, Forteza A (2001). “Diffusion-weighted imaging shows cytotoxic and vasogenic edema in eclampsia”. AJNR Am J Neuroradiol. 22 (6): 1068–70. PMC 7974798 Check |pmc= value (help). PMID 11415899.
  10. ↑ Kanki T, Tsukimori K, Mihara F, Nakano H (1999). “Diffusion-weighted images and vasogenic edema in eclampsia”. Obstet Gynecol. 93 (5 Pt 2): 821–3. doi:10.1016/s0029-7844(98)00575-4. PMID 10912407.
  11. ↑ Williams KP, Wilson S (1999). “Persistence of cerebral hemodynamic changes in patients with eclampsia: A report of three cases”. Am J Obstet Gynecol. 181 (5 Pt 1): 1162–5. doi:10.1016/s0002-9378(99)70101-8. PMID 10561638.
  12. ↑ Manfredi M, Beltramello A, Bongiovanni LG, Polo A, Pistoia L, Rizzuto N (1997). “Eclamptic encephalopathy: imaging and pathogenetic considerations”. Acta Neurol Scand. 96 (5): 277–82. doi:10.1111/j.1600-0404.1997.tb00284.x. PMID 9404996.
  13. ↑ Dinsdale HB, Mohr JP. Hypertensive Encephalopathy. In: Barnett Henry JM, Mohr JP, Stein Bennet M, Yatsu Frank M., editors. Stroke Pathophysiology, Diagnosis and Management. 3. Vol. 34 Churchill Livingston; New York, NY
  14. ↑ Cipolla MJ. Stroke and the Blood-Brain Interface. In: Spray D, Dermietzel R, editors. Blood-brain Barrier Interfaces. Wiley Press; 2006
  15. ↑ Euser AG, Cipolla MJ (2007). “Cerebral blood flow autoregulation and edema formation during pregnancy in anesthetized rats”. Hypertension. 49 (2): 334–40. doi:10.1161/01.HYP.0000255791.54655.29. PMID 17200432.
  16. ↑ Phillips SJ, Whisnant JP (1992). “Hypertension and the brain. The National High Blood Pressure Education Program”. Arch Intern Med. 152 (5): 938–45. PMID 1580719.
  17. ↑ Heistad DD, Kontos HA. The Cardiovascular System III. In: Berne RM, Sperelakis N, editors. Handbook of Physiology. Vol. 5. American Physiological Society; Bethesda, MD: 1979. pp. 137–182.
  18. ↑ Busija DW, Heistad DD (1984). “Factors involved in the physiological regulation of the cerebral circulation”. Rev Physiol Biochem Pharmacol. 101: 161–211. doi:10.1007/BFb0027696. PMID 6441228.
  19. ↑ Kontos HA, Wei EP, Navari RM, Levasseur JE, Rosenblum WI, Patterson JL (1978). “Responses of cerebral arteries and arterioles to acute hypotension and hypertension”. Am J Physiol. 234 (4): H371–83. doi:10.1152/ajpheart.1978.234.4.H371. PMID 645875.
  20. ↑ Kontos HA, Wei EP, Dietrich WD, Navari RM, Povlishock JT, Ghatak NR; et al. (1981). “Mechanism of cerebral arteriolar abnormalities after acute hypertension”. Am J Physiol. 240 (4): H511–27. doi:10.1152/ajpheart.1981.240.4.H511. PMID 7223903.
  21. ↑ Wasseff S (2009). “Mechanisms of convulsions in eclampsia”. Med Hypotheses. 72 (1): 49–51. doi:10.1016/j.mehy.2008.08.017. PMID 18840393.
  22. ↑ Cipolla MJ, Kraig RP (2011). “Seizures in Women with Preeclampsia: Mechanisms and Management”. Fetal Matern Med Rev. 22 (2): 91–108. doi:10.1017/S0965539511000040. PMC 3119563. PMID 21709815.

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Differentiating Eclampsia from other Diseases

Differentiating Eclampsia from other Diseases

To go back to the main page, click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Navneet Kaur M.B.,B.S.

Overview

Seizures during pregnancy that are unrelated to Preeclampsia need to be distinguished from Eclampsia. This is essential to recognize the correct cause and provide the targeted treatment necessary in a timely manner.

Differentiating Eclampsia from other Diseases

Eclampsia must be differentiated from other diseases that can cause seizures during pregnancy. The differentiation can be done by obtaining a proper history, physical examination, diagnostic tests, or imaging. Such disorders include:

Usually, the presence of the signs of severe preeclampsia that precede and accompany eclampsia facilitates the diagnosis.

Differential Diagnosis Similar Features Differentiating Features
Acute exacerbation of SLE
  • Lupus flares can present with proteinuria, hypertension, deterioration in kidney function, thrombocytopenia and seizure also observed in eclampsia.
  • On urine examination, cellular casts and proteinuria can be found in SLE while only proteinuria is seen in Eclampsia. SLE is associated with decreasing levels of complement and incresing titre of anti-dsDNA. Also, a history of previous SLE and onset of symptoms before 20 weeks points towards lupus and a renal biopsy can help confirm the diagnosis although it is genereally not recommended during pregnancy.
Acute adrenal insufficiency
  • Adrenal insufficiency can present with fatigue, nausea, vomiting, increased heart rate, increased respiratory rate, loss of appetite, headache, abdominal pain, confusion, loss of consciousness, abnormal body movements, or coma, also seen in eclampsia.
  • Adrenal insufficiency will present with hypotension, whereas eclampsia is associated with high blood pressure. Also, AI patients may have a history of chronic use of steroids for diseases such as asthma, rheumatoid arthritis, etc.[1] Patients may present with symptoms only in the postpartum period as during pregnancy they may acquire cortisol transplacentally from the fetus.[2] Diagnostic tests show decreased morning basal serum cortisol, decreased salivary free cortisol, not seen in eclampsia. Further cosyntropin test and basal ACTH levels can be done. Imaging (MRI without gadolinium administration should be done in pregnant women) may show a pituitary tumor or a cranial SOL.
Brain tumor(s)
  • Brain tumor often presents with signs of raised Intracranial pressure, such as headache, nausea, vomiting and seizures, also seen in eclampsia. Commom tumors that can be found are meningiomas[3], pituitary tumors, gliomas, etc.
  • Presence of past history of convulsions and absence of hypertension and proteinuria points towards cerebral pathology. Brain tumour may present with partial or localized seizures rather than GTCS and can have localized symptoms, such as visual disturbances in pituitary adenomas, localized sensory or motor changes, etc which could differentiate it from eclampsia. Also, brain imaging such as MRI can help establish the diagnosis.
Intracranial Haemorrhage/ Ruptured Brain Aneurysm
  • On physical exam, history and diagnostic test, ICH demonstrates headache, nausea and vomiting, vision abnormalities(such as blurring, scotomas, diminished vision), seizures, loss of consciousness also observed in Eclampsia.
  • The headache in ICH is often described as the worst headache of life. Presence of symptoms such as stiffness of neck, sensitivity to light, unilateral drooping of eyelid, unilateral symptoms of stroke(sensory or motor weakness), and absence of proteinuria, oliguria, edema, gestational hypertension differentiates its from Eclampsia. Neuroimaging (CT or MRI brain) will show AV malformation, ruptured blood vessel, blood in the subarachnoid space that distinguish it from Eclampsia.
Disseminated herpes simplex/ Herpes Simplex Encephalitis(HSE)
  • On physical exam and history Herpes Simplex Encephalitis(HSE) may present with Headache, Seizures( seen in 50% of cases [4]), vision abnormalities, confusion, hyperactivity also observed in eclampsia.
Drug overdose/Drug Intoxication
  • Careful history and past records will indicate if the patient is taking any recreational or prescriptional medication respectively that could lead to overdose. Other symptoms of preeclampsia like proteinuria, edema are generally absent. Urine drug screening and Blood screening will confirm the diagnosis.
Drug Withdral Syndromes
Encephalitis
  • Encephalitis, inflammation of the brain, is most often caused by viral infection [6] , presents with seizures in 2-67% of cases [4], and headache also seen in eclampsia.
Acute Fatty Liver of Pregnancy (AFLP)
  • On history and physical exam AFLP demonstrates nausea and vomiting (seen in 50-60%), abdominal pain (50-60%), edema, mental status changes (altered sensorium, confusion, disorientation, psychosis, restlessness, seizures or coma) (60–80%), tachycardia (50%) also seen in eclampsia. [7]

References

  1. ↑ A. Chrisoulidou, C. Williamson, M. De Swiet, Assessment of adrenocortical function in women taking exogenous glucocorticoids during pregnancy. J. Obstet. Gynaecol. 23(6), 643–644 (2003)
  2. ↑ Drucker D, Shumak S, Angel A. Schmidt’s syndrome presenting with intrauterine growth retardation and postpartum addisonian crisis. Am J Obstet Gynecol. 1984 May 15;149(2):229-30. doi: 10.1016/0002-9378(84)90206-0. PMID: 6720805.
  3. ↑ Hala M. Goma (April 10th 2013). Management of Brain Tumor in Pregnancy — An Anesthesia Window, Clinical Management and Evolving Novel Therapeutic Strategies for Patients with Brain Tumors, Terry Lichtor, IntechOpen, DOI: 10.5772/54250. Available from: https://www.intechopen.com/chapters/43971
  4. ↑ 4.0 4.1 Misra UK, Tan CT, Kalita J (2008). “Viral encephalitis and epilepsy”. Epilepsia. 49 Suppl 6: 13–8. doi:10.1111/j.1528-1167.2008.01751.x. PMID 18754956.
  5. ↑ Chen HY, Albertson TE, Olson KR (2016). “Treatment of drug-induced seizures”. Br J Clin Pharmacol. 81 (3): 412–9. doi:10.1111/bcp.12720. PMC 4767205. PMID 26174744.
  6. ↑ Michael BD, Solomon T (2012). “Seizures and encephalitis: clinical features, management, and potential pathophysiologic mechanisms”. Epilepsia. 53 Suppl 4: 63–71. doi:10.1111/j.1528-1167.2012.03615.x. PMID 22946723.
  7. ↑ 7.0 7.1 7.2 7.3 Ko H, Yoshida EM (2006). “Acute fatty liver of pregnancy”. Can J Gastroenterol. 20 (1): 25–30. doi:10.1155/2006/638131. PMC 2538964. PMID 16432556.

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Epidemiology and Demographics

Epidemiology and Demographics

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [10]

Overview

Hypertensive disorders of pregnancy (HDP), defined as a sex-specific cardiovascular disease, is one of the leading causes of maternal and fetal morbidity and mortality globally and a critical threat to maternal and infant health. [1][11] Preeclampsia is a pregnancy-related hypertensive disorder occurring usually after 20 weeks of gestation and if left untreated, it progresses to eclampsia.[2] Preeclampsia and eclampsia are not distinct disorders but the manifestation of the spectrum of clinical symptoms of the same condition.Closing </ref> missing for <ref> tag Although preeclampsia prevails to be a significant public health threat in both developed and developing nations bringing maternal and perinatal morbidity and mortality worldwide, [3][4]the impact of the disease is witnessed to be harsher in the developing countries [5] [6],where, unlike other more prevalent causes of maternal mortality (such as haemorrhage and sepsis), medical interventions may be ineffective due to late presentation of cases[7][8]. The problem is confounded by the continued ambivalence of the aetiology and the unpredictable behavior of the disease [9]. According to WHO, the incidence of preeclampsia is seven times higher in developing countries (2.8% of live births) than in developed countries (0.4%).[10] In developing countries the prevalence of preeclampsia, the precursor of eclampsia, ranges from 1.8% to 16.7% and from 1990 to 2019, the incidence, prevalence, death and YLDs were highest in populations aged 25–29 years.

Epidemiology and Demographics of Eclampsia

Incidence

  • Since preeclampsia and eclampsia are one of the main causes of maternal deaths, the data on incidence is required at both national and local levels to inform policies to further target the affected population and for the focused distribution of resources.
  • According to WHO, the incidence of preeclampsia is seven times higher in developing countries (2.8% of live births) than in developed countries (0.4%).[11]
  • The incidence of eclampsia in the developed countries of North America and Europe is similar and estimated to be about 5–7 cases per 10,000 deliveries. On the other hand, incidence of eclampsia in developing nations varies widely, ranging from 1 case per 100 pregnancies to 1 case per 1700 pregnancies [2, 14]. Rates from African countries such as South Africa, Egypt, Tanzania, and Ethiopia range from 1.8% to 7.1% [12][13]. The prevalence in Nigeria spans between 2% to 16.7%.[14][15]
  • A systematic review conducted for the incidence of hypertensive disorders of pregnancy (HDP) with the objective of evaluating its magnitude globally, representing 39 million women from 40 countries, estimates the incidence to be 4.6% (95% uncertainty range 2.7-8.2), and 1.4% (95% uncertainty range 1.0-2.0) of all deliveries for preeclampsia and eclampsia respectively, with a wide variation across regions.[16]
  • The incidence of hypertensive disorders of pregnancy increased from 16.30 million to 18.08 million worldwide, with a total increase of 10.92% from 1990 to 2019.[17]
  • The age-standardized incidence rate decreased, with an estimated annual percentage change of -0.68 (95% CI -0.49 to -0.86). Worldwide, the age-standardized incidence rate (ASIR) decreased from 579 (95% UI 482 to 689) per 100,000 population in 1990 to 463 (95% UI 392 to 541) per 100,000 population in 2019. Age-standardized incidence rates were higher in countries/regions with lower sociodemographic indices and human development indices.[18]
  • The estimated incidence rate was lowest in the group aged 25-29 years and higher in the youngest and oldest groups.[19]
  • The Estimated Annual Percentage Change fot the age-standardized deaths rate (ASDR) was − 2.38 (95% CI 1.67 to -6.27).
  • Positive associations between incidence and sociodemographic index and human development index were found for all countries and regions in 2019.[20]

Prevalance

Overview of HDP by country and region for both sexes combined. (A) The prevalence of HDP in 2019 (B) The ASIR of HDP per 100,000 population in 2019. (C) The EAPC in the ASDR of HDP from 1990 to 2019. ASIR, age-standardized incidence rate; ASDR, age-standardized death rate; EAPC, estimated annual percentage change; HDP, hypertensive disorders of pregnancy.
  • In developing countries the prevalence of preeclampsia, the precursor of eclampsia, ranges from 1.8% to 16.7%.
  • From 1990 to 2019, prevalence, death and YLDs were highest in populations aged 25–29 years, followed by populations aged 30–34 and 20–24 years and lowest in those 10–14 and 55–59 years old.[21]
  • The prevalence rate of HDP based on pregnant women was the lowest in the group aged 25–29 years but higher in the youngest and oldest age groups.[22]
  • The prevalence of eclampsia was reported to be 0.56 per 1,000 births (from US data from 1979-86) and 26 per 1,000 births for pre-eclampsia.[23]
  • While mortality can be kept low when antenatal care and maternal-fetal services are provided, mortality rates are substantial in challenging settings. In a setting in India, maternal mortality and perinatal mortality were reported to be 32% and 39%, respectively, in the year 1993.[24]

Age

  • From 1990 to 2019, incidence, prevalence, death and YLDs were highest in populations aged 25–29 years, followed by populations aged 30–34 and 20–24 years and lowest in those 10–14 and 55–59 years old.[25]
  • The incidence and prevalence rate of HDP based on pregnant women was the lowest in the group aged 25–29 years but higher in the youngest and oldest age groups.[26]

Gender

Eclampsia, one of the four hypertensive disorders of the pregnancy, has been defined as a female sex-specific cardiovascular disorder, usually during or after the 20th week of gestation or in the postpartum period.

Race

Eclampsia patterns varies by race and ethnicity. Non-Hispanic black women are more probable to have a pregnancy with chronic hypertension and to develop mild, severe or superimposed preeclampsia/eclampsia syndrome.

Impact

  • Total deaths attributable to pregnancy-related causes are over half a million and 99% of these deaths come from low- to middle-income nations.
  • High blood pressure during pregnancy is seen in ten percent of women and preeclampsia complicates 2% to 8% of pregnancies which can include problems in the liver, kidneys, brain and the clotting system and risks for the baby include poor growth and prematurity.[27]
  • Although preeclampsia can be devastating and life-threatening the outcome is often good and manageable.
  • Overall, 10% to 15% of direct maternal deaths are associated with preeclampsia and eclampsia and most of these deaths are attributable to eclampsia, rather than preeclampsia.[27]
  • Perinatal mortality is high following preeclampsia, and even higher following eclampsia.
  • The Millennium Development Goals have placed maternal health at the core of the struggle against poverty and inequality, as a matter of human rights.
  • The number of deaths attributed to hypertensive disorders of pregnancy was approximately 27.83 thousand in 2019 which was a 30.05% decrease from the year 1990. [28]

Challenges in prevention of eclampsia

  • Primary prevention of any disease process requires:
    • recognising the risk factors and preventing exposure to them by altering unhealthy or unsafe behaviours via the availability of methods for prediction of those at high risk for the disorder
  • Secondary prevention of any disease process requires:
    • early detection, and
    • early treatment
  • Even though a myriad of clinical and biochemical examinations and investigations have been suggested for prediction or timely detection of preeclampsia, most remain unrealistic for extensive use in most developing nations. Currently, not a single reliable and cost-effective screening test exists for preeclampsia which can be recommended for use in most developing countries[29].
  • Although some studies on uterine artery Doppler studies and first-trimester maternal serum markers for early detection of preeclampsia have shown promise[30][31][32]. There is not enough evidence to suggest their routine use in clinical practice, more so in resource poor settings[33].
  • In terms of prophylaxis, aspirin therapy has been shown to be beneficial in decreasing the occurrence of preeclampsia in specific populations, for example, those with abnormal second trimester uterine Doppler flow[34][35][36]. However, to recommend its widespread use in all patients is not judicious or evidence-based.
  • Similarly, even though the Cochrane review has stated some usefulness of calcium supplementation, especially for those at greatest risk and those with low baseline calcium consumption[37][38], the dilemma of choosing appropriate patients to be started on the therapy can be demanding from a public health perspective.
  • Also, findings of earlier studies that previously indicated the benefits of vitamin supplementation[39] [40][41][42]have been refuted by a recent study by the WHO particularly for vitamins C and E [43].

References

  1. ↑ Garovic V, White W, Vaughan L, Saiki M, Parashuram S, Garcia-Valencia O,et al. Incidence and long-term outcomes of hypertensive disorders of pregnancy. J Am Coll Cardiol. 2020;75(18):2323–34
  2. ↑ Medicine for Africa – Medical Information Service. preeclampsia/ eclampsia. 2008, http://www.medicinemd.com/
  3. ↑ World Health Organization. Global Program to Conquer Preeclampsia/Eclampsia. 2002.
  4. ↑ McClure EM, Saleem S, Pasha O, Goldenberg RL. Stillbirth in developing countries: a review of causes, risk factors and prevention strategies. Journal of Maternal-Fetal and Neonatal Medicine. 2009;22(3):183–190.
  5. ↑ Igberase G, Ebeigbe P. Eclampsia: ten-years of experience in a rural tertiary hospital in the Niger delta, Nigeria. Journal of Obstetrics and Gynaecology. 2006;26(5):414–417.
  6. ↑ Adamu YM, Salihu HM, Sathiakumar N, Alexander GR. Maternal mortality in Northern Nigeria: a population-based study. European Journal of Obstetrics Gynecology and Reproductive Biology. 2003;109(2):153–159.
  7. ↑ Ikechebelu JI, Okoli CC. Review of eclampsia at the Nnamdi Azikiwe University teaching hospital, Nnewi (January 1996-December 2000) Journal of Obstetrics and Gynaecology. 2002;22(3):287–290
  8. ↑ Onakewhor JUE, Gharoro EP. Changing trends in maternal mortality in a developing country. Nigerian Journal of Clinical Practice. 2008;11(2):111–120
  9. ↑ Duley L. Pre-eclampsia and the hypertensive disorders of pregnancy. British Medical Bulletin. 2003;67:161–176
  10. ↑ WHO. Make every mother and child count, in The world health report 2005. Geneva, Switzerland: World Health Organization; 2005.
  11. ↑ WHO. Make every mother and child count, in The world health report 2005. Geneva, Switzerland: World Health Organization; 2005.
  12. ↑ Kimbally KG, Barassoumbi H, Buambo SF, et al. Arterial hypertension: epidemiological aspects and risk factors on pregnant and delivered woman. Dakar Médical. 2007;52(2):148–152
  13. ↑ Teklu S, Gaym A. Prevalence and clinical correlates of the hypertensive disorders of pregnancy at Tikur Anbessa Hospital, Addis Ababa, Ethiopia. Ethiopian Medical Journal. 2006;44(1):17–26.
  14. ↑ Omole-Ohonsi A, Ashimi AO. Pre-eclampsia: a study of risk factors. Nigerian Medical Practitioner. 2008;53(6):99–102.
  15. ↑ Population Council Nigeria. Administering Magnesium Sulfate to Treat Severe Pre-eclampsia and Eclampsia. 2009,http://www.popcouncil.org/projects/134_AdminMagSulfPreeclampsia.asp.
  16. ↑ Abalos E, Cuesta C, Grosso AL, Chou D, Say L (2013). “Global and regional estimates of preeclampsia and eclampsia: a systematic review”. Eur J Obstet Gynecol Reprod Biol. 170 (1): 1–7. doi:10.1016/j.ejogrb.2013.05.005. PMID 23746796.
  17. ↑ Wei Wang, Xin Xie, Ting Yuan et al. Epidemiological Trends of Maternal Hypertensive Disorders of Pregnancy at the Global, Regional, and National Levels: A Population-Based Study, 18 January 2021, PREPRINT (Version 1) available at Research Square [1]
  18. ↑ Wei Wang, Xin Xie, Ting Yuan et al. Epidemiological Trends of Maternal Hypertensive Disorders of Pregnancy at the Global, Regional, and National Levels: A Population-Based Study, 18 January 2021, PREPRINT (Version 1) available at Research Square [2]
  19. ↑ Wei Wang, Xin Xie, Ting Yuan et al. Epidemiological Trends of Maternal Hypertensive Disorders of Pregnancy at the Global, Regional, and National Levels: A Population-Based Study, 18 January 2021, PREPRINT (Version 1) available at Research Square [3]
  20. ↑ Wei Wang, Xin Xie, Ting Yuan et al. Epidemiological Trends of Maternal Hypertensive Disorders of Pregnancy at the Global, Regional, and National Levels: A Population-Based Study, 18 January 2021, PREPRINT (Version 1) available at Research Square [4]
  21. ↑ Wei Wang, Xin Xie, Ting Yuan et al. Epidemiological Trends of Maternal Hypertensive Disorders of Pregnancy at the Global, Regional, and National Levels: A Population-Based Study, 18 January 2021, PREPRINT (Version 1) available at Research Square [5]
  22. ↑ Wei Wang, Xin Xie, Ting Yuan et al. Epidemiological Trends of Maternal Hypertensive Disorders of Pregnancy at the Global, Regional, and National Levels: A Population-Based Study, 18 January 2021, PREPRINT (Version 1) available at Research Square [6]
  23. ↑ Saftlas AF, Olson DR, Franks AL, Atrash HK, Pokras R. “Epidemiology of preeclampsia and eclampsia in the United States, 1979-1986”. Am J Obstet Gynecol. 1990 Aug;163(2): 460-5. PMID 2396132.
  24. ↑ Swain S, Ojha KN, Prakash A, Bhatia BD. “Maternal and perinatal mortality due to eclampsia”. Indian Pediatr. 1993 Jun;30(6):771-3.
  25. ↑ Wei Wang, Xin Xie, Ting Yuan et al. Epidemiological Trends of Maternal Hypertensive Disorders of Pregnancy at the Global, Regional, and National Levels: A Population-Based Study, 18 January 2021, PREPRINT (Version 1) available at Research Square [7]
  26. ↑ Wei Wang, Xin Xie, Ting Yuan et al. Epidemiological Trends of Maternal Hypertensive Disorders of Pregnancy at the Global, Regional, and National Levels: A Population-Based Study, 18 January 2021, PREPRINT (Version 1) available at Research Square [8]
  27. ↑ 27.0 27.1 Duley L (2009). “The global impact of pre-eclampsia and eclampsia”. Semin Perinatol. 33 (3): 130–7. doi:10.1053/j.semperi.2009.02.010. PMID 19464502.
  28. ↑ Wei Wang, Xin Xie, Ting Yuan et al. Epidemiological Trends of Maternal Hypertensive Disorders of Pregnancy at the Global, Regional, and National Levels: A Population-Based Study, 18 January 2021, PREPRINT (Version 1) available at Research Square [9]
  29. ↑ Wagner LK. Diagnosis and management of preeclampsia. American Family Physician. 2004;70(12):2317–2324.
  30. ↑ Kharb S. Serum markers in pre-eclampsia. Biomarkers. 2009;14(6):395–400.
  31. ↑ Audibert F, Boucoiran I, An N, et al. Screening for preeclampsia using first-trimester serum markers and uterine artery Doppler in nulliparous women. American Journal of Obstetrics and Gynecology. 2010;203(4):383.e1–383.e8.
  32. ↑ Yale University. Simple test can help predict and diagnose preeclampsia. ScienceDaily. February 5, 2010
  33. ↑ Papageorghiou AT, Campbell S. First trimester screening for preeclampsia. Current Opinion in Obstetrics and Gynecology. 2006;18(6):594–600.
  34. ↑ Louden K, Kilby M. Low-dose aspirin: the rationale for preventing pre-eclampsia and intra-uterine growth retardation: a role after CLASP? In: Bonnar J, editor. Recent Advances in Obstetrics and Gynaecology, No 19. Edinburgh, UK: Churchill Livingstone; 1995.
  35. ↑ Bujold E, Roberge S, Lacasse Y, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstetrics and Gynecology. 2010;116(2):402–414.
  36. ↑ Duley L, Henderson-Smart D, Knight M, King J. Antiplatelet drugs for prevention of pre-eclampsia and its consequences: systematic review. British Medical Journal. 2001;322(7282):329–333.
  37. ↑ Atallah AN, Hofmeyr GJ, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database of Systematic Reviews. 2002;(1) Article ID CD001059. [PubMed] [Google Scholar]
  38. ↑ Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database of Systematic Reviews. 2010;8 Article ID CD001059.
  39. ↑ Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM. Maternal vitamin D deficiency increases the risk of preeclampsia. Journal of Clinical Endocrinology and Metabolism. 2007;92(9)
  40. ↑ Marya RK, Rathee S, Manrow M. Effect of calcium and vitamin D supplementation on toxaemia of pregnancy. Gynecologic and Obstetric Investigation. 1987;24(1):38–42.
  41. ↑ Olsen SF, Secher NJ. A possible preventive effect of low-dose fish oil on early delivery and pre-eclampsia: Indications from a 50-year-old controlled trial. British Journal of Nutrition.
  42. ↑ Bodnar LM, Tang G, Ness RB, Harger G, Roberts JM. Periconceptional multivitamin use reduces the risk of preeclampsia. American Journal of Epidemiology. 2006;164(5):470–477.
  43. ↑ Villar J, Purwar M, Merialdi M, 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. BJOG. 2009;116(6):780–788.

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Risk Factors

Risk Factors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

The various risk factors associated with the development of eclampsia encompass a personal or family history of pre-eclampsia/eclampsia, nulliparity, primigravida, long interpregnancy intervals, conditions with a large placenta such as multiple gestations(twins or triplets) and H Mole, women with preexisting conditions such as chronic hypertension, history of gestational hypertension in the previous pregnancy, renal diseases, diabetes, gestational diabetes, obesity, certain thrombophilic diseases (such as the antiphospholipid antibody syndrome, protein C deficiency, protein S deficiency, anti-thrombin deficiency), connective tissue disorders, SLE and genetics.

Risk factors

  • History of pre-eclampsia/eclampsia: Personal history of a similar event in the past or family history is a significant risk factor for recurrence in the next pregnancy. Having pre-eclampsia in one pregnancy is a strong predictor for recurrence of pre-eclampsia in future gestations. The risk for women to develop pre-eclampsia during the second pregnancy is approximately 15% if the first pregnancy was affected by pre-eclampsia and 1.1% for those without a history of pre-eclampsia. The risk during the third pregnancy is approximately 30% for women who have had two previous affected pregnancies and remains 1.1% for those without any history. For women with the first occurrence of pre-eclampsia in their second pregnancy, the risk was 15.9% during the third pregnancy and 29.0% during the fourth when they had developed pre-eclampsia in the previous two pregnancies.[1]
  • Nulliparity: The risk for multiparous women without a history of pre-eclampsia was around 1%.[1]
  • Primigravida: The risk of pre-eclampsia is 4.1% in the first pregnancy and 1.7% in later pregnancies overall if none of the previous pregnancies have been affected by pre-eclampsia.[1] This association is the core of theory that says that pre-eclampsia is the consequence of a maternal immune reaction against paternal antigens expressed in the placenta which might result in defective trophoblast invasion and subsequent placental dysfunction. The lower risk of pre-eclampsia among multiparous women has been attributed to desensitisation after exposure to paternal antigens in the placenta during previous pregnancies.[2][3] and to smoother trophoblastic invasion after modification of maternal spiral arteries during the first pregnancy.[4] For this reason pre-eclampsia is also known as a disease of primiparity.
  • Interpregnancy interval: A long interpregnancy interval is associated with increased risk of preeclampsia, supporting the hypothesis that some factors delaying clinically recognized conception may also be in a causal pathway for preeclampsia.[5]
  • Conditions with a large placenta:
    • Multiple gestations: The relative risk of preterm preeclampsia in di-chorionic and mono-chorionic twin pregnancies is similar and substantially higher than in singleton pregnancies. In a study, it was found that the incidence of pre-eclampsia in singleton pregnancies was 2.3% compared to 8% in dichorionic(DC) twin pregnancies and 6% in monochorionic(MC) twin pregnancies. Compared to singletons, the relative risk of total pre-eclampsia was 3.5 for DC twins and 2.6 for MC twins.[6]
    • Hydatiform mole: Hydatiform moles pose a high risk of early-onset preeclampsia if the pregnancy continues with the moles left untreated[7]. Preeclampsia can develop as early as the 2nd trimester in 30–40% of pregnancies with untreated hydatiform moles.[8] [9]
  • Women with preexisting vascular diseases:
    • Chronic hypertension: Chronic hypertension is defined as high blood pressure present before pregnancy or before 20 weeks of pregnancy. If left untreated, it can progress to gestational hypertension, pre-eclampsia, or eclampsia. Development of preeclampsia is the most prevalent complication in pregnancy in women with chronic hypertension[10]. 17% to 25% of women with chronic hypertension develop preeclampsia compared to the general population where the risk is 3-5%.[11] [12] [13]
    • Gestational hypertension: Untreated gestational hypertension can eventually progress to preeclampsia/eclampsia. Approximately 15-25% of patients with gestational hypertension will progress to preeclampsia or severe gestational hypertension[14]. The rate of the progression depends on gestational age at the time of diagnosis and the pregnancy outcome is usually good when the diagnosis is made at ≥ 37 weeks of gestation.[15]
    • Renal diseases
    • Diabetes/ Gestational diabetes/ History of Gestational diabetes: Preexisting diabetes is a risk factor for preeclampsia. In comparison to the relatively low incidence of preeclampsia in non-diabetic women (2-7%)[16] [17] , preeclampsia is diagnosed in 15-20% of pregnancies in women with type 1 diabetes [18][19] [20] and 10-14% of pregnancies in women with type 2 diabetes [21] .
    • Obesity: The risk of preeclampsia and hence eclampsia increases by about 3-fold with obesity, and in developed countries is the leading attributable risk for the disorder. [22]
    • Preexisting thrombophilias: A strong association between maternal thrombophilic disorders and severe preeclampsia has been established in various studies. Examples include:
    • Connective tissue disorders
    • Systemic lupus erythematous
  • Genetics: Patients whose mother or sister had the condition are at a higher risk.[23]

References

  1. ↑ 1.0 1.1 1.2 Hernández-Díaz S, Toh S, Cnattingius S (2009). “Risk of pre-eclampsia in first and subsequent pregnancies: prospective cohort study”. BMJ. 338: b2255. doi:10.1136/bmj.b2255. PMC 3269902. PMID 19541696.
  2. ↑ Luo ZC, An N, Xu HR, Larante A, Audibert F, Fraser WD (2007). “The effects and mechanisms of primiparity on the risk of pre-eclampsia: a systematic review”. Paediatr Perinat Epidemiol. 21 Suppl 1: 36–45. doi:10.1111/j.1365-3016.2007.00836.x. PMID 17593196.
  3. ↑ Saftlas AF, Levine RJ, Klebanoff MA, Martz KL, Ewell MG, Morris CD; et al. (2003). “Abortion, changed paternity, and risk of preeclampsia in nulliparous women”. Am J Epidemiol. 157 (12): 1108–14. doi:10.1093/aje/kwg101. PMID 12796047.
  4. ↑ Moore MP, Redman CW (1983). “Case-control study of severe pre-eclampsia of early onset”. Br Med J (Clin Res Ed). 287 (6392): 580–3. doi:10.1136/bmj.287.6392.580. PMC 1548969. PMID 6411232.
  5. ↑ Basso O, Weinberg CR, Baird DD, Wilcox AJ, Olsen J, Danish National Birth Cohort (2003). “Subfecundity as a correlate of preeclampsia: a study within the Danish National Birth Cohort”. Am J Epidemiol. 157 (3): 195–202. doi:10.1093/aje/kwf194. PMID 12543618.
  6. ↑ Francisco, C., Wright, D., Benkő, Z., Syngelaki, A. and Nicolaides, K.H. (2017), Hidden high rate of pre-eclampsia in twin compared with a singleton pregnancy. Ultrasound Obstet Gynecol, 50: 88-92. https://doi.org/10.1002/uog.17470
  7. ↑ Iriyama, T., Wang, G., Yoshikawa, M. et al. Increased LIGHT leading to sFlt-1 elevation underlies the pathogenic link between hydatidiform mole and preeclampsia. Sci Rep 9, 10107 (2019). https://doi.org/10.1038/s41598-019-46660-4https://doi.org/10.1038/s41598-019-46660-4
  8. ↑ Kohorn, E. I. Molar pregnancy: presentation and diagnosis. Clinical obstetrics and gynecology 27, 181–191 (1984).
  9. ↑ Soto-Wright, V., Bernstein, M., Goldstein, D. P. & Berkowitz, R. S. The changing clinical presentation of complete molar pregnancy. Obstetrics and gynecology 86, 775–779, https://doi.org/10.1016/0029-7844(95)00268-V (1995)
  10. ↑ Chronic Hypertension in Pregnancy Ellen W. Seely and MD Jeffrey EckerMD Originally published18 Mar 2014https://doi.org/10.1161/CIRCULATIONAHA.113.003904Circulation. 2014;129:1254–1261 https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.113.003904
  11. ↑ Sibai BM. Chronic hypertension in pregnancy.Obstet Gynecol. 2002; 100:369–377.
  12. ↑ Rey E, Couturier A. The prognosis of pregnancy in women with chronic hypertension.Am J Obstet Gynecol. 1994; 171:410–416.
  13. ↑ McCowan LM, Buist RG, North RA, Gamble G. Perinatal morbidity in chronic hypertension.Br J Obstet Gynaecol. 1996; 103:123–129.
  14. ↑ Saudan P, Brown MA, Buddle ML, Jones M. Does gestational hypertension become pre-eclampsia? Br J Obstet Gynaecol. 1998 Nov;105(11):1177-84. doi: 10.1111/j.1471-0528.1998.tb09971.x. PMID: 9853766.
  15. ↑ Obstetrics and Gynecology Gestational Hypertension – Preeclampsia Baha M. Sibai Fadi G. Mirza https://www.cancertherapyadvisor.com/home/decision-support-in-medicine/obstetrics-and-gynecology/gestational-hypertension-preeclampsia/
  16. ↑ Knuist M, Bonsel GJ, Zondervan HA, Treffers PE. Intensification of fetal and maternal surveillance in pregnant women with hypertensive disorders. Int J Gynaecol Obstet. 1998;61(2):127–33. doi:S0020729298000241 [pii]
  17. ↑ Hauth JC, Ewell MG, Levine RJ, Esterlitz JR, Sibai B, Curet LB, et al. Pregnancy outcomes in healthy nulliparas who developed hypertension. Calcium for Preeclampsia Prevention Study Group. Obstet Gynecol. 2000;95(1):24–8. doi:S0029784499004627
  18. ↑ Jensen DM, Damm P, Moelsted-Pedersen L, Ovesen P, Westergaard JG, Moeller M, et al. Outcomes in type 1 diabetic pregnancies: a nationwide, population-based study. Diabetes Care. 2004;27(12):2819–23. doi:27/12/2819
  19. ↑ Persson M, Norman M, Hanson U. Obstetric and perinatal outcomes in type 1 diabetic pregnancies: A large, population-based study. Diabetes Care. 2009;32(11):2005–9. doi:dc09-0656 [pii] 10.2337/dc09-0656.
  20. ↑ Knight KM, Thornburg LL, Pressman EK. Pregnancy outcomes in type 2 diabetic patients as compared with type 1 diabetic patients and nondiabetic controls. J Reprod Med. 2012;57(9-10):397–404.
  21. ↑ Groen B, Links TP, van den Berg PP, Hellinga M, Moerman S, Visser GH, et al. Similar adverse pregnancy outcome in native and nonnative dutch women with pregestational type 2 diabetes: a multicentre retrospective study. ISRN obstetrics and gynecology. 2013;2013:361435. doi: 10.1155/2013/361435.
  22. ↑ Roberts JM, Bodnar LM, Patrick TE, Powers RW (2011). “The Role of Obesity in Preeclampsia”. Pregnancy Hypertens. 1 (1): 6–16. doi:10.1016/j.preghy.2010.10.013. PMC 3082136. PMID 21532964.
  23. ↑ Chesley LC, Annitto JE, Cosgrove RA. “The familial factor in toxemia of pregnancy”. Obstet Gynecol 1968;32:303.

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Natural History, Complications and Prognosis

Natural History, Complications and Prognosis

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Diagnosis

Diagnosis

History and Symptoms | Physical Examination | Laboratory Findings

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Preeclampsia

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