A PROSPECTIVE STUDY OF FETOMATERNAL OUTCOME IN SEVERE PREECLAMPSIA

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A PROSPECTIVE STUDY OF FETOMATERNAL OUTCOME IN SEVERE PREECLAMPSIA

A Dissertation submitted to

THE TAMILNADU DR M.G.R MEDICAL UNIVERSITY CHENNAI

In partial fulfillment of the regulations for the award of the degree of M.S (OBSTETRICS AND GYNAECOLOGY) – BRANCH - II

REGISTER NUMBER:

221816203

THANJAVUR MEDICAL COLLEGE

THANJAVUR - 613004

THE TAMILNADU DR. M.G.R. MEDICAL UNIVERSITY CHENNAI, TAMILNADU

May 2021

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CERTIFICATE FROM INSTITUTION

This is to certify that the dissertation titled “A PROSPECTIVE STUDY

OF FETOMATERNAL OUTCOME IN SEVERE PREECLAMPSIA” is a bonafide work done by Dr.S.JAYAPRABHA, Post graduate student, Department of obstetrics and Gynaecology, Thanjavur Medical college,Thanjavur – 04, during the period JANUARY 2019 TO JUNE 2020 in partial fulfillment of rules and regulations of the Tamilnadu Dr. M.G.R Medical University,for the award of MS Degree Branch II (Obstetrics and Gynaecology) examination to be held in May 2021 .

Prof. Dr.S.MARUTHU THURAI MS.,MCh.(vascular)

THE DEAN ,

Thanjavur Medical College, Thanjavur -613 004

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CERTIFICATE

This is to certify that the dissertation titled “A PROSPECTIVE STUDY OF FETOMATERNAL OUTCOME IN SEVERE

PREECLAMPSIA” is a bonafide work done by Dr.S.JAYAPRABHA, Post graduate student, Department of Obstetrics and Gynaecology, Thanjavur Medical college,Thanjavur, under my guidance and supervision in partial fulfillment of rules and regulations of the Tamilnadu Dr. M.G.R Medical University, for the award of MS Degree Branch II (Obstetrics and Gynaecology) examination to be held in May 2021 . The period of study was from January 2019 to June 2020.

Prof . Dr.R.RAJARAJESWARI MD.,DGO.,DNB, Guide and Head of the Department ,

Department of Obstetrics and Gynaecology, Thanjavur Medical college ,

Thanjavur.

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CERTIFICATE FOR ANTI PLAGIARISM

This is to certify that this dissertation work titled “A PROSPECTIVE STUDY OF FETOMATERNAL OUTCOME IN SEVERE PREECLAMPSIA” of the candidate Dr.S.JAYAPRABHA with Registration Number 221816203 for the award of MS degree in the branch of Obstetrics & Gynaecology. I personally verified the urkund.com website for the purpose of plagiarism check. I found that uploaded thesis file contains from introduction to conclusion pages and result shows 6 percentage of plagiarism in the dissertation.

Prof . Dr.R.RAJARAJESWARI MD.,DGO.,DNB, Guide and Head of the Department ,

Department of Obstetrics and Gynaecology, Thanjavur Medical college ,

Thanjavur.

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DECLARATION

I solemnly declare that this dissertation titled “A PROSPECTIVE STUDY OF FETOMATERNAL OUTCOME IN SEVERE PREECLAMPSIA” was done by me at Department of Obstetrics and Gynaecology, Thanjavur Medical

College,Thanjavur, during year 2018-2021 under the guidance and supervision of Prof.Dr.R.RAJARAJESWARI, MD.,DGO.,DNB. This dissertation is submitted to The Tamil Nadu Dr. M.G.R. Medical University,Chennai in partial fulfillment of the University regulations for the award of M.S. BRANCH II (Obstetrics and Gynaecology).

Place: Thanjavur -04 Dr.S.JAYAPRABHA,

MS Post Graduate Student,

Date : Dept of Obstetrics and Gynaecology Thanjavur Medical College,

Thanjavur.

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ACKNOWLEDGEMENT

I gratefully acknowledge and sincerely thank Prof.Dr.S.MARUTHU THURAI MS.,MCH.,(vascular),The Dean,Thanjavur Medical College and hospital, Thanjavur for permitting me to conduct the study and use facilities of the institution for my Study.

I wish to express my respect and sincere gratitude to my beloved teacher and Head of the department Prof.Dr.R.RAJARAJESWARI,MD.,DGO.,DNB., Department of obstetrics and Gynaecology, Thanjavur Medical College, Thanjavur for her valuable guidance and encouragement during the study and also throughout my course period.

I Sincerely thank Associate Professors Dr.S.UDAYA ARUNA MD.,DGO and Dr. J. PRABHA.MD.,OG for their constant support and guidance throughout the study.

I am bound my ties of gratitude to Assistant Professor Dr.T.DELPHINE ROSE.MD.,OG, for her valuable guidance in conducting this study.

I Wish to express my sincere thanks to all the Assistant Professors of

Obstetrics and Gynaecology Department for their support during the study.

I thank the Secretary and the Chairman of Institution Ethical Committee,Thanjavur Medical College, Thanjavur.

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I also thank Dr.L.MAHESHWARAN MD , Academic officer I/C ,Senior Assistant Professor ,Department of Pharmacology who helped a lot in doing statistics of my study.

I would be failing in my duty, if I don’t place my sincere thanks to those patients who were the subjects of my study. Above all I thank God Almighty for immense blessings.

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INTRODUCTION

Toxemia of pregnancy precedes an eclamptic convulsion , for a longer or shorter period by premonitory symptoms among the most common being edema, headache, epigastric pain and possibly disturbance of vision⁴

Preeclampsia is best described as pregnancy-specific syndrome that can affect virtually every organ system⁴. It occurs in approximately 4-5% of pregnancies (Martin 2012)⁴. It is an important cause of morbidity as well as mortality in both the mother and fetus.

Preeclampsia is a disorder of pregnancy associated with new onset hypertension , which occurs most often after 20 weeks of gestation and frequently near term¹⁰. It is described as severe preeclampsia if there is substantial increase of blood pressure and proteinuria or the occurrence of symptoms due to end organ damage. Hypertension and its complications is ranked as a third leading cause of maternal mortality, responsible for 16% of maternal deaths^1,2,3.

In India the incidence of preeclampsia is reported to be 8-10% of the pregnancies⁸¹.

In united states from 2011-2013 ,7.4% of pregnancy related ,maternal deaths are due to preeclampsia. A similar rate was 10% in France. Moreover ,in

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comparison women giving birth in 1980,those giving birth in 2003 were at 6-7 fold increased risk of severe preeclampsia.⁴

There is an increased risk of acute renal failure, cardiovascular and cerebrovascular complications, abruptio placenta, disseminated intravascular coagulation and even maternal death¹ . So, early diagnosis and close monitoring in preeclampsia plays a vital role in preventing its complications.

Delivery of the fetus is considered the only way to revert all these complications. So, termination of pregnancy is needed if there is fetal distress, in case of multi organ dysfunction or if the gestational age reaches 34 weeks.

But, prematurity due to early termination causes high perinatal morbidity and mortality^1,5,6. Accelerated fetal lung maturation does not occur in preeclampsia however expectant management to prolong pregnancy can be deleterious to the mother^7,9. Hence, potential benefits attained for the fetus should be weighed against the potential dangers that occur to the mother.

AIMS AND OBJECTIVES OF THE STUDY

1) To study the maternal and fetal outcome in severe preeclampsia.

2) To note the variable factors associated with maternal and fetal morbidity and mortality

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REVIEW OF LITERATURE

HISTORICAL ASPECTS:

 Pre- eclampsia is a complex disease labeled as “disease of theories” due to numerous schools of thought.

 Eclamptic convulsions have been recognized in ancient Chinese, Indian, and Greek literature 4000 years back.

 Hippocrates around 400 BC stated headache accompanied by convulsions during Pregnancy was considered bad.

 Bossier de saurages (1739) introduced the word Eclampsia and also

differentiated eclampsia from epilepsy.( Eclampsia is defined by new-onset tonic-clonic , focal, or multifocal seizures in the absence of other causative conditions such as epilepsy, cerebral arterial ischemia and infarction, intracranial hemorrhage, or drug use.)¹⁰

 Demanet (1797) recognized swelling in eclamptic women. Pierre Rayer (1840) discovered protein in urine while John Lever (1843) reported proteinuria was specific to Pre-eclampsia.

 Vasquez and Nobcourt (1897) discovered eclamptic hypertension.

 Chesley (1984) said Sensory stimuli were reduced by keeping the patients in dark quite room. Horn (1906) first used Mgso4 to manage pre-eclampsia – Eclampsia.

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 Lazard and Dorsett (1920) popularized the parenteral use of magnesium sulphate only in 1990. Major studies demonstrated the superiority of magnesium sulphate over other anticonvulsants.

 In 1967, Robertson and Brosens described structural changes of the utero placental unit in pre-eclampsia.

MAGNITUDE OF THE PROBLEM:

Pre-eclampsia has a prevalence rate of 2-8%¹⁰. 50% of the women with severe pre-eclampsia present at less than 34 weeks of gestation. Delivery is mandatory either for maternal or fetal reasons within 24 hours of admission.

CLASSIFICATION

To update and codify the terminology and classification of hypertensive disorders of pregnancy ,a Task force of the ACOG (2013) provided the following⁴,

• preeclampsia and eclampsia syndrome

• chronic hypertension of any etiology

• preeclampsia superimposed on chronic hypertension

• gestational hypertension

DEFINITIONS

PRE-ECLAMPSIA

Pre-eclampsia is defined as rise in systolic pressure of 140 mmHg or greater or diastolic pressure of 90 mmHg or greater that develops for the first time in pregnancy after 20 weeks of gestation in atleast two occasions accompanied by

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proteinuria. Proteinuria defined as 0.3g or more of urinary protein per 24 hours or persistent 30 mg/dL (1+ dipstick) in a random urine sample.

SEVERE PRE-ECLAMPSIA:

Severe pre-eclampsia is defined as hypertension (diastolic blood pressure ≥ 110 mm Hg) with proteinuria (≥5gm in 24 hours urine specimen or ≥ 3+ on a

dipstick).

ACOG CRITERIA FOR SEVERE PREECLAMPSIA

: Severe Pre eclampsia is considered in the presence of one or more of the following¹⁰

1) Systolic blood pressure of 160 mm Hg or more, or diastolic blood pressure of 110 mm Hg or more on two occasions at least 4 hours apart (unless

antihypertensive therapy is initiated before this time)

2) Thrombocytopenia (platelet count less than 100,000 * 10⁹/L) 3) Impaired liver function as indicated by abnormally elevated blood

concentrations of liver enzymes (to twice the upper limit normal concentration), and

4) severe persistent right upper quadrant or epigastric pain unresponsive to medication and not accounted for by alternative diagnoses

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5) Renal insufficiency (serum creatinine concentration more than 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease)

6) Pulmonary edema

7) New-onset headache unresponsive to medication and not accounted for by alternative diagnoses

8) Visual disturbances RISK FACTORS:

The most predictive risk factors of pre-eclampsia were mean arterial pressure and parity.The risk with mean arterial pressure was 8% when < 75mm Hg and 27% if > 85 mm Hg. Risk was 26% in nulliparous where as 17% in parous patients¹⁵

There is increased risk of preeclampsia in women with periodontal disease and systemic inflammation in early pregnancy with (CRP ≥ 75th percentile)¹⁷ . Recent study demonstrated a significant association between maternal thrombophilia and severe preeclampsia¹⁸ .

Maternal and paternal genetic factors increase the risk of pre eclampsia.

Pregnancy associated: - -Chromosomal abnormalities - Hydatidiform mole

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- Hydrops fetalis - Multiple gestations.

Maternal specific: -

-Primi parity

- Age < 20 &> 35 Yrs.

- Previous pre-eclamptic - BMI > 35

- Family history of pre-eclampsia.

- Gestational diabetes or pre-existing diabetes.

- Chronic hypertension.

- Nephropathy and thrombophilia Paternal Specific: -

-First time father

- Previously fathered a pre-eclampsia pregnancy in another woman.

ETIOPATHOGENESIS:

Any satisfactory theory concerning the origins of preeclampsia must account for the observation that gestational hypertensive disorders are more likely to develop in women with the following characteristics⁴:

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 Are exposed to chorionic villi for the first time

 Are exposed to a superabundance of chorionic villi, as with twins or hydatiform mole

 Have preexisting conditions associated with endothelial cell activation or inflammation,such as diabetes,obesity,cardiovascular or renal

disorders,immunological disorders or hereditary influences

 Are genetically predisposed to hypertension developing during pregnancy

A fetus is not a prerequisite for preeclampsia to develop, and although chorionic villi are essential,they need not be intrauterine. For example,preeclampsia can develop with an abdominal pregnancy regardless of precipitating etiology,the cascade of events leading to preeclampsia syndrome is characterized by

abnormalities that result in systemic vascular endothelial damage with resultant vasospasm, transudation of plasma and ischemic and thrombotic sequelae⁴.

ETIOLOGY

1) Abnormal trophoblastic invasion:

Normally the uterine spiral arteries are invaded by endovascular trophoblasts. In pre-eclampsia there is incomplete trophoblastic invasion²².With this ,decidual vessels,but not myometrial vessels ,become lined with

endovascular trophoblasts⁴.The deeper myometrial arterioles thus do not lose their endothelial lining and musculoelastic tissue,and their mean external diameter is only half of that of corresponding vessels in normal placenta.

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In a recent study of placental morphology, placentas from early onset (34 weeks) were studied. An abnormal placental morphology was found in early onset, whereas placentas from late onset disease were morphologically similar to those from same gestational age controls.

The abnormally narrow lumen of spiral arterioles likely impairs placental blood flow. Diminished perfusion and a hypoxic environment eventually lead to release of placental debris or microparticles.

Dewolf et al examined the arteries from utero-placental implantation site. They observed early preeclamptic changes which include endothelial damage, proliferation of myointimal cells, insudation of plasma constituents into vessel walls and medial necrosis. These changes result in diminished placental perfusion, leading to pre-eclampsia syndrome.

Figure 1

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2) Genetic Predisposition:

Preeclampsia appears to be a multifactorial ,polygenic disorder⁴.

An association between HLA DR4 and protienuric hypertension has been reported.Ward and taylor (2015) cite an incident risk for preeclampsia of 20-40%

for daughters of preeclamptic mother: and 11-37% for sisters of preeclamptic women; and 22-47% for twins.

Table 1 -Genes with possible association with preeclampsia syndrome

GENE

(Polymorphism)

Function affected

MTHFR Methylene tetrahydrofolate

reductase

F5(Leiden) Factor V

AGT(M235T) Angiotensinogen

HLA(various) Human leukocyte antigen NOS3(Glu 298 Asp) Endothelial nitric oxide F2(G20210A) Prothrombin (factor II)

ACE(I/D ^atIntron 16) Angiotensin converting enzyme

CTLA4 Cytotoxic T lymphocyte associated

protein

LPL Lipoprotein lipase

SERPINE1 Serine peptidase inhibitor

GNA promoter Decreased methylation

Data from Buurma ,2013; Staines –Urias, 2012; Triche , 2014; Ward ,2014;

3)Immunological theories:

Loss of maternal tolerance to paternally derived placental and fetal antigens is a cited theory for preeclampsia⁴.

Inferential data also suggest that preeclampsia is an immunomediated disorder⁴.

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These theories are based on incompatibility at the feto-maternal interface.

There is disruption of equilibrium between fetal genotype and maternal immune responses required for normal placentation.²³

Absence of blocking antibodies - There is an imbalance between the ratio of fetal antigenic load and maternal blocking antibodies. This might be due to excess fetal antigen load¹² (hydatidiform mole, multiple gestations) or absence of blocking antibodies (as in first pregnancy).

Figure 2

4)Endothelial Cell Activation

Inflammatory changes are believed to be a continuation of stage 1 alterations. In response to ischemia or other inciting causes, placental factors are released and begin a cascade of events (Davidge, 2015). Thus, antiangiogenic

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and metabolic factors and other inflammatory leukocyte mediators are thought to provoke systemic endothelial cell injury, which is used synonymously here with endothelial cell activation or dysfunction.

Endothelial cell dysfunction may result from an extreme activated state of leukocytes in the maternal circulation . Briefly, cytokines such as tumor necrosis factor-α (TNF-α) and the interleukins may contribute to the systemic oxidative stress associated with preeclampsia.

This is characterized by reactive oxygen species and free radicals that lead to formation of self-propagating lipid peroxides . These peroxides in turn generate highly toxic radicals that injure systemic vascular endothelial cells, modify nitric oxide production by these cells, and interfere with prostaglandin balance.

Other consequences of oxidative stress include production of the lipid- laden macrophage foam cells seen in placental atherosis, activation of systemic microvascular coagulation manifested by thrombocytopenia, and greater

systemic capillary permeability reflected by edema and proteinuria⁴.

PATHOGENESIS:

1)Vasospasm

The concept of vasospasm with preeclampsia has been advanced for a century . Systemic endothelial activation causes vasospasm that elevates resistance to produce subsequent hypertension. Concurrently, systemic

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endothelial cell injury promotes interstitial leakage, and blood constituents, including platelets and fibrinogen, are deposited subendothelially⁴.

Endothelial junctional proteins are also disrupted, and the

subendothelial region of resistance arteries undergoes ultrastructural change . The much larger venous circuit is similarly involved. With diminished blood flow because of maldistribution from vasospasm and interstitial leakage,

ischemia of the surrounding tissues can lead to necrosis, hemorrhage, and other end-organ disturbances characteristic of the syndrome. One important clinical correlate to this is the markedly attenuated blood volume seen in women with severe preeclampsia .

2)Endothelial Cell Injury

Injury to systemic endothelial cells is now a centerpiece of preeclampsia pathogenesis (Davidge, 2015). In this scheme, protein factor(s)—likely

placental—are secreted into the maternal circulation and provoke activation and dysfunction of the systemic vascular endothelium. Many facets of the clinical syndrome of preeclampsia are thought to result from these widespread

endothelial cell changes.

Intact endothelium has anticoagulant properties. Also, systemic

endothelial cells, by releasing nitric oxide, blunt the response of vascular smooth muscle to agonists. Injured or activated endothelial cells may produce less nitric oxide and may secrete substances that promote coagulation and greater

sensitivity to vasopressors⁴.

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Further evidence of endothelial activation includes the characteristic changes in glomerular capillary endothelial morphology, greater capillary permeability, and elevated blood concentrations of substances associated with endothelial activation. Likely, multiple factors in the plasma of preeclamptic women combine to exert these vasoactive effects (Myers, 2007; Walsh, 2009).

3)Increased Pressor Responses

 Pregnant women normally develop refractoriness to infused vasopressors . Women with early preeclampsia, however, have enhanced vascular reactivity to infused norepinephrine and angiotensin II

 Moreover, increased sensitivity to angiotensin II clearly precedes the onset of gestational hypertension . Paradoxically, women who develop preterm

preeclampsia have lower circulating levels of angiotensin II (Chase, 2017).

 Several prostaglandins are thought to be central to preeclampsia syndrome pathophysiology. Specifically, the blunted pressor response seen in normal pregnancy is at least partially due to diminished vascular responsiveness mediated by endothelial prostaglandin synthesis.

 For example, compared with normal pregnancy, endothelial prostacyclin (PGI2 ) production is lower in preeclampsia. This action appears to be mediated by phospholipase A2 (Davidge, 2015). At the same time, thromboxane A2 secretion by platelets is increased, and the prostacyclin:thromboxane A2 ratio declines²⁴. The net result favors greater sensitivity to infused angiotensin II and, ultimately, vasoconstriction .

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 These changes are apparent as early as 22 weeks’ gestation in gravidas who later develop preeclampsia .

 Nitric oxide is a potent vasodilator synthesized from l-arginine by endothelial cells²⁷. Inhibition of nitric oxide synthesis raises mean arterial pressure, lowers heart rate, and reverses the pregnancy-induced refractoriness to vasopressors.

The effects of nitric oxide production in preeclampsia are unclear. It appears that the syndrome is associated with decreased endothelial nitric oxide synthase expression, thus resulting in lower nitric oxide activity (Davidge, 2015).

 Endothelins are 21-amino-acid peptides and potent vasoconstrictors. Endothelin- 1 (ET-1) is the primary isoform produced by human endothelium (Karumanchi, 2016b)²⁵. Plasma ET-1 levels are elevated in normotensive pregnant women, but women with preeclampsia have even higher levels . Interestingly, treatment of preeclamptic women with magnesium sulfate lowers ET-1 concentrations . And, in animal studies, sildenafil reduces ET-1 concentrations (Gillis, 2016).

4)Angiogenic and Antiangiogenic Proteins

Placental vasculogenesis is evident by 21 days after conception. The list of pro- and antiangiogenic substances involved in placental vascular

development is extensive, and the families of vascular endothelial growth factor (VEGF) and angiopoietin are the most studied⁴. Angiogenic imbalance describes excessive amounts of antiangiogenic factors, which are thought to be stimulated by worsening hypoxia at the uteroplacental interface.

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Trophoblast of women destined to develop preeclampsia overproduces at least two antiangiogenic peptides that enter the maternal circulation (Karumanchi, 2016a).

First, soluble fms-like tyrosine kinase 1 (sFlt-1) is a receptor for VEGF, elevated maternal sFlt-1 levels inactivate and reduce circulating free placental growth factor (PlGF) and VEGF concentrations, leading to endothelial dysfunction . Importantly, sFlt-1 levels begin to rise in maternal serum months before

preeclampsia is evident . These high levels in the second trimester are associated with a doubling of the risk for preeclampsia (Haggerty, 2012).

PATHO PHYSIOLOGICAL CHANGES:

1 )HEMODYNAMIC AND CARDIAC CHANGES⁴:In Pre-eclampsia,

a) Cardiac preload decreases due to generalized vasospasm (pathologically diminished volume expansion)²²

b) Cardiac after load increases due to increase in vascular resistance.

c) MAP is reduced as there is increase is peripheral vascular resistance.

d) endothelial activation leading to interendothelial extravasation of intravascular fluid into the extracellular space, mainly into lungs.

Of women with preeclampsia serial ECHO studies document diastolic dysfunction in 40-45%.diastolic dysfunction stems from ventricular remodeling, which is judged to be an adaptive response to maintain normal contractility despite the increased afterload of preeclampsia.

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2) HEMATOLOGICAL CHANGES²²:

a) Thrombocytopenia – occurs in 10 to 25 % of women having pre-eclampsia. It is probably immunologically mediated or because of increase in platelet

deposition at the endothelial damage site. It then usually rises progressively to reach a normal level within 3-5days.Levels of platelet bound and platelet – bindable immunoglobulins are elevated which suggests platelet surface alterations.

b) Hyper coagulation in pre-eclampsia is due to

• Increased activity of intrinsic factors.

• Increased platelet aggregation.

• Increased thrombin – Anti thrombin ratio.

• Decreased anti thrombin III and fibrinogens 3)HEMOLYSIS:

Severe preeclampsia is frequently accompanied by hemolysis , which manifests as elevated serum lactate dehydrogenase levels and reduced

haptoglobin levels⁴. Other evidence comes from schizocytosis, spherocytosis, and reticulocytosis in peripheral blood, These derangements result in part from microangiopathic hemolysis caused by endothelial disruption with platelet adherence and fibrin deposition.

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4)ENDOCRINE CHANGES:

In Pre-eclampsia there is suppression of renin- angiotensin - aldosterone axis and sodium retention is increased²² .

5)FLUID CHANGES AND ELECTROLYTE ALTERATIONS:

In women with severe preeclampsia, the volume of extracellular fluid, manifest as edema, is usually much greater than that in normal pregnant women.

the mechanism responsible for pathological fluid retention is endothelial injury²² (Davidge, 2015).

In addition to generalized edema and proteinuria, these women have reduced plasma oncotic pressure. This reduction creates a filtration imbalance and further displaces intravascular fluid into the surrounding interstitium.

Electrolyte concentrations do not differ appreciably in women with preeclampsia compared with those of normal pregnant women.

6)KIDNEY

During normal pregnancy, renal blood flow and glomerular filtration rate rise appreciably . With preeclampsia, several reversible anatomical and

pathophysiological changes ensue⁴.

1) renal perfusion and glomerular filtration are reduced. Morphological changes are characterized by glomerular endotheliosis, which blocks the barrier that allows filtration. Diminished filtration causes serum creatinine levels to rise to values

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seen in nonpregnant individuals, that is, 1 mg/mL, and sometimes higher . Abnormal values usually begin to normalize 10 days or later delivery . 2) In most preeclamptic women, the urine sodium concentration is elevated.

3) Urine osmolality rises,

4) urine: plasma creatinine ratio is elevated, and

5) fractional excretion of sodium is low, which all indicated that a prerenal mechanism is involved.

Sodium-containing crystalloid infusion raises the ventricular filling pressure, and although oliguria temporarily improves, rapid infusions may cause clinically apparent pulmonary edema. Intensive intravenous fluid therapy is not indicated as “treatment” for preeclamptic women with oliguria unless urine output is diminished from hemorrhage or fluid loss from vomiting or fever.

6) Plasma uric acid concentration is typically elevated in preeclampsia.

7 ) LIVER

Liver involvement with preeclampsia may clinically display at least three manifestations.

First, pain is considered a sign of severe disease. It typically manifests by moderate-to-severe right upper quadrant or mid epigastric pain and tenderness.

Second, elevations of serum AST and ALT levels are markers for severe preeclampsia. Values seldom exceed 500 U/L, but levels reaching more than 2000 U/L have been reported.

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In general, serum concentrations inversely follow platelet levels, and they both usually normalize within 3 days following delivery.

As a third presentation, hemorrhagic infarction may extend to form a hepatic hematoma. This in turn can extend to form a subcapsular hematoma that may rupture. CT scanning or MRI imaging greatly aids diagnosis . Unruptured hematomas are probably more common than clinically suspected and are more likely to be found with HELLP syndrome.

8)HELLP SYNDROME:

There is no universally accepted strict definition of HELLP syndrome, and thus its incidence varies by investigator. In the previously noted study of 183 women with HELLP syndrome, 40 % had adverse outcomes, . Complications included eclampsia in 6%, placental abruption—10 %, acute kidney injury—5

%, and pulmonary edema—10 %. Stroke, hepatic hematoma, coagulopathy, acute respiratory distress syndrome, and sepsis were other serious complication 9)BRAIN

The first theory suggests that in response to acute and severe hypertension, cerebrovascular overregulation leads to vasospasm . In this scheme, diminished cerebral blood flow is hypothesized to result in ischemia, cytotoxic edema, and eventually tissue infarction,

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The second theory is that sudden elevations in systemic blood pressure exceed the normal cerebrovascular autoregulatory capacity . Regions of forced vasodilation and vasoconstriction develop, especially in arterial boundary zones.

At the capillary level, disruption of end-capillary pressure causes

increased hydrostatic pressure, hyperperfusion, and extravasation of plasma and red cells through endothelial tight-junction openings. This leads to vasogenic edema. The most likely mechanism is combination of the two.

With imaging studies, these manifest as the posterior reversible

encephalopathy syndrome . The lesions of this syndrome principally involve the posterior brain—the occipital and parietal cortices.

The classic microscopic vascular lesions consist of fibrinoid necrosis of the arterial wall and perivascular microinfarcts and hemorrhages.

10)EYE

Scotoma, blurred vision or diplopia are common with severe

preeclampsia and eclampsia , .these usually improve with Mgso4 therapy and /or lowered blood pressure. Blindness is less common , usually reversible, and may arise from three potential areas. These are the visual cortex of the occipital lobe, the lateral geniculate nuclei and the retina.

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PREDICTORS OF PRE ECLAMPSIA:

1. Testing related to placental perfusion /vascular resistance:

Roll over test,isometric hand grip or cold pressor test,pressor response to aerobic exercise,angiotensin II infusion,mid trimester mean arterial

pressure,24 hour ambulatory blood pressure monitoring,uterine artery or fetal transcranial Doppler velocimetry.

2. Testing related to endothelial dysfunction/oxidant stress

Angiogenic and antiangiogenic factors placental growth factor (PIGF), fms-like tyrosine kinase (SFlt – 1), vascular endothelial growth factor,endoglin.

3. Testing related to Fetal-Placental unit endocrine dysfunction:

Human chorionic gonodotrophin,alpha-fetprotein,estriol,pregnancy associated protein A(PAPP A),procalcitonin,kisspeptin,activin A,inhibin A.

4. Testing related to renal dysfunction:

Serum uric acid,microalbuminuria,urinary calcium or kallikrein,microtransferrinuria,cystatin C.

5.OTHER- antithrombin III, ANP ,haptoglobulin,transferrin,hepatic transferase

6.Total 25 – hydroxy vitamin D (25 – 0H – D) level is decreased in women developing early onset severe pre-eclampsia. To understand the impact of vitamin D on pregnancy outcomes, further studies are needed.

Prediction of complications in pre-eclampsia

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Table 2-Description of the prediction models(NICE guidelines)

Prediction model

Description Factors included in the model

FullPIERS fullPIERS is a free online tool

developed to identify the probability of adverse outcomes in women with preeclampsia at 48 hours or 7 days from baseline.

fullPIERS has been validated in women up to 37 weeks gestation.

 Gestational age

 Presence/absence of chest pain or dyspnoea

 Oxygen saturation

 Platelets (x109 /L)

 Creatinine (µmol/L)

 AST/ALT (U/L)

MiniPIERSa miniPIERS is a free online tool aimed to be used in low and middle income countries.

It was developed to identify the probability of adverse outcomes in women with preeclampsia up to 7 days before complications arise

 Gestational age at admission

 Previous deliveries before 20 weeks gestation

 Presence/absence of chest pain/dyspnoea

 Presence/absence of headache and/or visual changes

 Presence/absence of vaginal bleeding with abdominal pain

 Systolic blood pressure (mmHg)

 Oxygen saturation (optional)

PREP-L PREP-L aims to

predict the overall risk of maternal complications by

 Maternal age

 Gestational age at diagnosis

 Presence/absence of preexisting conditions (hypertension, renal

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PREP-L can be used in women up to 34+6 weeks gestation.

disease, diabetes mellitus, autoimmune disease, previous occurrence of preeclampsia)

 Urea (mmol/l)

 Protein creatinine ratio (mg/mmol)

 Whether woman received any antihypertensive or magnesium sulfate at diagnosis or within 24 hours

PREP-S PREP-S aims to

predict the risk time of adverse outcomes at a number of time periods (from 2 days to 42 days) from baseline.

PREP-S can be used in women up to 34+6 weeks gestation.

 Maternal age

 Gestational age at diagnosis

 Presence/absence of tendon reflexes

 Presence/absence of preexisting conditions (hypertension, renal disease, diabetes mellitus, autoimmune disease, previous occurrence of preeclampsia)

 Oxygen saturation

 Urea (mmol/l)

 Protein creatinine ratio (mg/mmol)

 Whether woman received any antihypertensive or magnesium sulfate at diagnosis or within 24 hours

AST: aspartate transaminase; mmHg: millimetres of mercury; mmol: millimole; mg:

milligramme; PIERS: Preeclampsia Integrated Estimate of RiSk; PREP-L: Prediction model for

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Risks of complications in Early-onset Preeclampsia (logistic regression model); PREP-S:

Prediction model for Risks of complications in Early-onset Preeclampsia (survival analysis model); SGOT: serum glutamic-oxaloacetic transaminase; µmol: micromole; U/L: units per litre aThis tool was developed to be used in low and middle income countries, however it was included it in the report as it may be useful for triage in a primary care setting, or when results of blood tests are not immediately available.

ASSESSMENT OF PROTEINURIA (NICE Guidelines)

 Use an automated reagent-strip reading device for dipstick screening for proteinuria in pregnant women in secondary care settings. [2019]

 If dipstick screening is positive (1+ or more), use albumin:creatinine ratio or protein:creatinine ratio to quantify proteinuria in pregnant women. [2019]

 Do not use first morning urine void to quantify proteinuria in pregnant women.

Do not routinely use 24-hour urine collection to quantify proteinuria in pregnant women. [2019]

 If using protein:creatinine ratio to quantify proteinuria in pregnant women:

 use 30 mg/mmol as a threshold for significant proteinuria

 if the result is 30 mg/mmol or above and there is still uncertainty about the diagnosis of pre-eclampsia, consider re-testing on a new sample, alongside clinical review. [2019]

 If using albumin:creatinine ratio as an alternative to protein:creatinine ratio to diagnose pre-eclampsia in pregnant women with hypertension:

 use 8 mg/mmol as a diagnostic threshold

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 if the result is 8 mg/mmol or above and there is still uncertainty about the diagnosis of pre-eclampsia, consider re-testing on a new sample, alongside clinical review. [2019]

FETOMATERNAL OUTCOME:

Maternal Outcome

: Women with Severe Pre-eclampsia are at increased risk for abruptio placenta, acute renal failure, disseminated intravascular coagulation, cerebral hemorrhage, pulmonary edema, circulatory collapse²⁸. Murphy and stirrat²⁹ studied 71 preeclamptic women with gestational age less than 30 weeks and reported 21% had developed HELLP syndrome, 15% had abruptio placenta, 13% had renal failure and 1.4% eclampsia but no maternal mortality was observed.

Al –Mulhim et al reported that the commonest complication to be abruptio placenta.

Perinatal Outcome:

Perinatal outcome is usually dependent on one or more of the following:

1.Gestational age at the onset of pre eclampsia.

2. Gestational age at the time of delivery.

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3. Severity of the disease.

4.Presence of multiple gestation.

5. Presence of other medical disorders.

Pre-eclampsia accounts for more than 40% of pre-mature deliveries and there is a substantial increase in the risk of low birth weight and SGA babies32,33,34,35 .

In a study performed by odegard et al³⁶ compared 307 live singleton born to pre eclamptic women to 619 controls, pre-eclampsia and severe preeclampsia were associated with a 5% and 12% reduction in birth weight respectively, and birth weight was 23% lower than expected.

Magee et al³⁷ in a multi centric retrospective study found out that 16% of pre-eclampsia pregnancies being complicated by birth weight less than third percentile.

Very low birth weight (VLBW less than 1500 grms) and extremely low birth weight (ELBW, less than 1000 grms) babies often require re-admission to hospital in the first two years for respiratory infections³⁸ .

TERMINATION OF PREGNANCY:

Termination is the only cure for preeclampsia.

Termination is needed in the following conditions¹³ FETAL:-

 Abnormal fetal testing

 Fetal death

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 Fetus without expectation for survival at the time of maternal diagnosis

 Persistent reversed end-diastolic flow in the umbilical artery

MATERNAL:

 Uncontrolled severe-range blood pressures (persistent systolic blood pressure 160 mm Hg or more or diastolic blood pressure 110 mm Hg or more not responsive to antihypertensive medication

 Persistent headaches, refractory to treatment

 Epigastric pain or right upper pain unresponsive to repeat analgesics

 Visual disturbances, motor deficit or altered sensorium

 Stroke

 Myocardial infarction

 HELLP syndrome

 New or worsening renal dysfunction (serum creatinine greater than 1.1 mg/dL or twice baseline)

 Pulmonary edema

 Eclampsia

 Suspected acute placental abruption or vaginal bleeding in the absence of placenta previa

 Fundus grade II and IV

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Management of pre-eclampsia (NICE guidelines- 2019)

Assessing pre-eclampsia

1) Assessment of women with pre-eclampsia should be performed by a

healthcare professional trained in the management of hypertensive disorders of pregnancy. [2010, amended 2019]

2) Carry out a full clinical assessment at each antenatal appointment for women with pre-eclampsia, and offer admission to hospital for surveillance and any interventions needed if there are concerns for the wellbeing of the woman or baby. Concerns could include any of the following:

• sustained systolic blood pressure of 160 mmHg or higher Hypertension in pregnancy: diagnosis and management (NG133) © NICE 2020.

• any maternal biochemical or haematological investigations that cause concern, for example,

a new and persistent:

－ rise in creatinine (90 micromol/litre or more, 1 mg/100 ml or more) or

－ rise in alanine transaminase (over 70 IU/litre, or twice upper limit of normal range) or

－ fall in platelet count (under 150,000/microlitre)

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• signs of impending eclampsia

• signs of impending pulmonary oedema • other signs of severe pre-eclampsia • suspected fetal compromise

• any other clinical signs that cause concern. [2019]

3) Consider using either the fullPIERS or PREP-S validated risk prediction models to help guide decisions about the most appropriate place of care (such as the need for in utero transfer) and thresholds for intervention. [2019]

4 )When using a risk prediction model, take into account that:

• fullPIERS is intended for use at any time during pregnancy

• PREP-S is intended for use only up to 34 weeks of pregnancy

• fullPIERS and PREP-S models do not predict outcomes for babies. [2019]

ROLE OF ANTI – HYPERTENSIVES:

The objectives of treating severe hypertension are to prevent congestive heart failure, myocardial ischemia, renal injury or failure, and ischemic or hemorrhagic stroke.

Antihypertensive treatment should be initiated expeditiously for acute- onset severe hypertension (systolic blood pressure of 160 mm Hg or more or diastolic blood pressure of 110 mm Hg or more, or both) that is confirmed as

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persistent (15 minutes or more). The available literature suggests that antihypertensive agents should be administered immediately.

However, it is recommended to administer antihypertensive therapy as soon as reasonably possible after the criteria for acute-onset severe hypertension are met. Intravenous hydralazine or labetalol and oral nifedipine are the three agents most commonly used for this purpose.

A recent Cochrane systematic review that involved 3,573 women found no significant differences regarding either efficacy or safety between hydralazine and labetalol or between hydralazine and calcium channel blockers ¹⁹. Thus, any of these agents can be used to treat acute severe hypertension in pregnancy^19,20 Although parenteral antihypertensive therapy may be needed initially for acute control of blood pressure, oral medications can be used as expectant management is continued. Oral labetalol and calcium channel blockers have been commonly used.

One approach is to begin an initial regimen of labetalol at 200 mg orally every 12 hours and increase the dose up to 800 mg orally every 8–12 hours as needed (maximum total 2,400 mg/ d). If the maximum dose is

inadequate to achieve the desired blood pressure goal, or the dosage is limited by adverse effect, then short-acting oral nifedipine can be added gradually.

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Table 3-Antihypertensive Agents Used for Urgent Blood Pressure Control

DRUG DOSE

LABETALOL 10–20 mg IV, then 20–80 mg every 10–30 minutes to a maximum cumulative dosage of 300 mg; or constant infusion 1–2 mg/min IV HYDRALAZINE 5 mg IV or IM, then 5–10 mg IV every 20–40 minutes to a maximum

cumulative dosage of 20 mg; or constant infusion of 0.5–10 mg/hr NIFEDIPINE 10–20 mg orally, repeat in 20 minutes if needed; then 10–20 mg every

2–6 hours; maximum daily dose is 180 mg

ROLE OF MAGNESIUM SULPHATE:

1)If a woman in a critical care setting who has severe hypertension or severe preeclampsia has or previously had an eclamptic fit, give intravenous magnesium sulfate. [2010]

2)Consider giving intravenous magnesium sulfate to women with severe preeclampsia who are in a critical care setting[2010]

3 )Consider the need for magnesium sulfate treatment, if 1 or more of the following features of severe pre-eclampsia is present:

• ongoing or recurring severe headaches

• visual scotomata

• nausea or vomiting • epigastric pain

• oliguria and severe hypertension

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• progressive deterioration in laboratory blood tests (such as rising creatinine or liver transaminases, or falling platelet count). [2010, amended 2019]

Magnesium sulphate remains the anticonvulsant of choice in any kind of set up.

Magnesium sulphate has been shown to decrease the progression of pre – eclampsia to eclampsia by more than 50% .

In a subsequent systematic review that included the Magpie study and five other studies, magnesium sulfate compared with placebo more than halved the risk of eclampsia , reduced the risk of placental abruption , and reduced the risk of maternal mortality albeit nonsignificantly . There were no differences in maternal morbidity or perinatal mortality. A quarter of women reported adverse effects with magnesium sulfate, primarily hot flushes, and the rate of cesarean delivery was increased by 5% when magnesium sulfate was used²¹

Mechanism of action

1) reduced presynaptic release of the neurotransmitter 2) blockade of glutamatergic N-methyl D-aspartate receptors 3) potentiation of adenosine action

4) improved calcium buffering by mitochondria.

5) blockage of calcium entry via voltage – gated channels.

Pritchard regime is usually followed,

Give 4g of 20% Mgso4 intravenously at a rate not to exceed 1g/min over 15-20 mins.

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Follow promptly with 10g of 50% Mgso4 ,one half (5g)injected deeply in each buttock.

Every 4 hour thereafter 5g of 50% magnesium sulphate by intramuscular route in alternative buttock given as maintenance therapy⁴⁵ .

If convulsions recur, further addition of 2 to 4gm is given by intravenous route over 5 minutes. Therapeutic level of 4-6 mEq is to be maintained.

Before administrating the subsequent doses, the women should be checked for - Urine output at least 100ml over the last four hours.

- Knee jerk

- Respiratory rate of atleast 16 per minute.

If any of the above parameters are found to be abnormal, the subsequent dose should be delayed till attainment of normal status. In case of toxicity, 10ml of 10% calcium gluconate (1gm) is given by intravenous route over 10 minutes and oxygenation provided.

Table – 4-Serum Magnesium Concentration and Toxicities :

Serum magnesium concentration

mmol/L mEq/L mg/dL Effect

2-3.5 4-7 5-9 Therapeutic

range

>3.5 >7 >9 Loss of

patellar reflexes

>5 >10 >12 Respiratory

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paralysis

>12.5 >25 >30 Cardiac

arrest

Data from Duley L. Magnesium sulphate regimens for women with eclampsia: messages from the Collaborative Eclampsia Trial. Br J Obstet Gynaecol 1996;103:103–5 and Lu JF,

Nightingale CH. Magnesium sulfate in eclampsia and preeclampsia: pharmacokinetic principles. Clin Pharmacokinet 2000;38:305–14.

Mgso4 is discontinued 24 hour after delivery or the last convulsion ,whichever is later⁸¹.

In case of persistence of convulsions patient should be transferred to intensive care unit and if necessary maintained with intermittent positive pressure ventilation.

ROLE OF STEROIDS:

It is a well known fact that antenatal glucocorticoids decreases neonatal morbidity as well as mortality in a woman with severe disease at or less than 34 weeks of gestational age²⁶ .

Previously, it was uncertain whether steroids were efficacious in severe pre-eclampsia less than 34 weeks of gestation. However, a prospective

randomized trial showed that there was significant reduction in the incidence of respiratory distress syndrome in the Steroids group (receiving betamethasone) against the control group (receiving placebo)²⁶ Thus steroids help in fetal lung maturity and should be used for at least 48 hours.

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FLUID BALANCE:

Large majority of women with mild pre – eclampsia have expanded intravascular volume. Hence to avoid fluid overload, fluids should be restricted to about 1ml / kg/ hour or 80ml / hour.

Inappropriate fluid management has often been associated with pulmonary edema which has attainted significance as an important cause of maternal death¹⁴ .

Fluid expansion provides no benefit²⁹. While fluid restriction have showed good outcome³⁰. Fluid restriction is inappropriate in case of maternal hemorrhage or oliguria.

Timing of birth

- Record maternal and fetal thresholds for planned early birth before 37 weeks in women with pre-eclampsia. Thresholds for considering planned early birth could include (but are not limited to) any of the following known features of severe pre-eclampsia:

• inability to control maternal blood pressure despite using 2 or more classes of antihypertensives in appropriate doses

• maternal pulse oximetry less than 90%

• progressive deterioration in liver function, renal function, haemolysis, or platelet count

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• ongoing neurological features, such as severe intractable headache, repeated visual scotomata, or eclampsia

• placental abruption

• reversed end-diastolic flow in the umbilical artery doppler velocimetry, a nonreassuring cardiotocograph, or stillbirth.

MODE OF DELIVERY:

The mode of delivery in women with gestational hypertension or

preeclampsia (with or without severe features) should be determined by routine obstetric considerations. Vaginal delivery often can be accomplished, but with labor induction in preeclampsia with severe features this is less likely with decreasing gestational age at diagnosis.

The likelihood of cesarean delivery at less than 28 weeks of gestation could be as high as 97%, and at 28–32 weeks of gestation as high as 65%^39,40,41. For gestational hypertension or preeclampsia without severe features, vaginal delivery is preferred . Retrospective studies comparing induction of labor with cesarean delivery in women with preeclampsia with severe features remote from term concluded that induction of labor was reasonable and was not harmful to low-birth-weight infants^42,43.

The decision to perform cesarean delivery should be individualized, based on anticipated probability of vaginal delivery and on the nature and progression of preeclampsia disease state.

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EXPECTANT MANAGEMENT:

There have been 15 non randomized non controlled trials to assess the benefits of expectant management in pregnancy between 24 to 34 weeks and showed an average of 10 – 14 days prolongation of pregnancy in cases of severe preeclampsia without increase in maternal morbidity but these trials are not reliable as they lack randomization¹⁶ .

However, since 1990 only one maternal death has been reported in literature among 1677 women who underwent expectant management³¹.

RCOG AND ACOG RECOMMENDATIONS

^:

AIM:-

To prolong pregnancy in severe preeclampsia women remote from term in order to improve perinatal outcome without increasing maternal morbidity or mortality.

Preeclampsia with severe features can result in acute and long-term complications for the woman and her newborn. Maternal complications include pulmonary edema, myocardial infarction, stroke, acute respiratory distress syndrome, coagulopathy, renal failure, and retinal injury. These complications are more likely to occur in the presence of preexistent medical disorders.

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The clinical course of preeclampsia with severe features is characterized by progressive deterioration of maternal and fetal condition. Therefore, delivery is recommended when gestational hypertension or preeclampsia with severe features is diagnosed at or beyond 34 0/7 weeks of gestation, after maternal stabilization or with labor or prelabor rupture of membranes.

Delivery should not be delayed for the administration of steroids in the late preterm period.

In women with preeclampsia with severe features at less than 34 0/7 weeks of gestation, with stable maternal and fetal condition, expectant

management may be considered. Two randomized controlled trials of delivery versus expectant management of preterm preeclampsia with severe features demonstrated that expectant management is associated with higher gestational age at delivery and improved neonatal outcomes^46,47. These observations were reiterated by a Cochrane systematic review⁴⁸.

The limited available randomized data are consistent with observational evidence suggesting that expectant management of early preeclampsia with severe features prolongs pregnancy by 1–2 weeks, has low maternal risk, and improves neonatal outcomes ⁴⁹.

In contrast, in a multicenter randomized controlled trial in Latin America, the authors found no neonatal benefit with expectant management of

preeclampsia with severe features from 28 weeks to 34 weeks of gestation⁵⁰.

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These different results may reflect the limitations in neonatal intensive care in low-resource settings.

Embarking on a course of expectant management necessitates adherence to principles of shared decision making with discussions of maternal and fetal risks and benefits, appropriate resources (levels of care), and ongoing vigilant surveillance. Close maternal and fetal clinical monitoring is necessary, and laboratory testing (complete blood count including platelets, liver enzymes, and serum creatinine) should be performed serially ⁵¹.

The expectant management of preeclampsia with severe features before 34 0/7 weeks of gestation is based on strict selection criteria of those appropriate candidates and is best accomplished in a setting with resources appropriate for maternal and neonatal care ⁵². Because expectant management is intended to provide neonatal benefit at the expense of maternal risk, expectant management is not advised when neonatal survival is not anticipated. During expectant

management, delivery is recommended at any time in the case of deterioration of maternal or fetal condition.

If delivery is indicated at less than 34 0/7 weeks of gestation,

administration of corticosteroids for fetal lung maturation is recommended ⁵¹; however, delaying delivery for optimal corticosteroid exposure may not always be advisable. Maternal or fetal deterioration may preclude completion of the course of steroid treatment.

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Previously, fetal growth restriction was considered an indication for delivery. In the setting of normal fetal parameters ( amniotic fluid volume, Doppler findings, antenatal fetal testing), continuation of expectant management may be reasonable in the absence of other, aforementioned maternal and fetal criteria.

POSTPARTUM MANAGEMENT:

Postnatal close monitoring should be done for women with severe disease . The period of hospital stay is unclear as eclampsia can occur even after 4 weeks postnatal. However after fourth postpartum day, incidence of eclampsia decrease ⁵⁶ .

Inpatient management for four or more days will be required for most women with severe disease after delivery.

Anti – hypertensive treatment should be continued and tapered stepwise after delivery. It can take even three months for blood pressure to return back to normal. No particular anti – hypertensive is recommended. But α- methyl dopa is avoided due to its side effect, like depression.

Nifedipine, labetolol, enalapril and atenolol are being used currently in breastfeeding women. Women should be further investigated in case of

persistence of high blood pressure and proteinuria.

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Some common medications and substances used in the postpartum period may potentially aggravate hypertension through three major mechanisms:

volume retention, sympathomimetic activation, and direct vasoconstriction. Of particular interest are nonsteroidal antiinflammatory drugs (NSAIDs), which are frequently prescribed as postpartum analgesics. These medications decrease prostaglandins leading to a lack of vasodilation and increased sodium retention.

Nonsteroidal anti-inflammatory medications should continue to be used preferentially over opioid analgesics; however, women with chronic

hypertension may theoretically require intensification of blood pressure monitoring and regimen adjustments when on these medications.

Overall, data support the safe use of NSAIDs in postpartum patients with blood pressure issues. In a randomized trial comparing use of ibuprofen to

acetaminophen in postpartum patients with preeclampsia with severe features, ibuprofen did not lengthen the duration of severe-range blood pressures ¹⁵⁵. In a cohort of 399 patients with preeclampsia with severe features, there was no association of NSAID use with postpartum blood pressure elevations⁵⁴. Further, another cohort study of postpartum patients on magnesium for seizure prophylaxis for preeclampsia did not show differences in blood pressure,

antihypertensive requirements, or other adverse events for patients managed with NSAIDs in the postpartum period ⁵⁵.

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PROPHYLAXIS:

Strategies to prevent preeclampsia have been studied extensively over the past 30 years. To date, no intervention has been proved unequivocally effective at eliminating the risk of preeclampsia. With regard to nutritional interventions, evidence is insufficient to demonstrate effectiveness for vitamins C and E⁵⁷ , fish oil⁵⁸ , garlic supplementation⁵⁹ , vitamin D⁶⁰ , folic acid⁶¹or sodium restriction⁶² for reducing the risk of preeclampsia.

A meta-analysis of 13 trials (15,730 women) reported a significant reduction in preeclampsia with calcium supplementation, with the greatest effect among women with low-baseline calcium intake ⁶³. Yet, this is not the case in the United States or other developed countries. Likewise, data do not support effectiveness of bed rest and, thus, it should not routinely be recommended ⁶⁴. Investigators hypothesized that an imbalance in prostacyclin and thromboxane A2 metabolism was involved in the pathogenesis of preeclampsia, leading to the initial studies of aspirin for preeclampsia prevention because of its preferential inhibition of thromboxane A2 at lower doses ^65,66. In a recent meta- analysis of aggregate data from 45 randomized trials, only a modest reduction in preeclampsia was noted when low-dose aspirin was started after 16 weeks of gestation but a more significant reduction in severe preeclampsia and fetal growth restriction was demonstrated when low-dose aspirin was started before 16 weeks of gestation⁶⁷.

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In contrast, in pooled individual data from 31 high-quality randomized trials, the beneficial effects of low-dose aspirin were consistent, whether treatment was started before or after 16 weeks of gestation⁶⁸. In a recent

multicenter, double blind, placebocontrolled trial, pregnant women at increased risk of preterm preeclampsia (less than 37 weeks of gestation) were randomly assigned to receive aspirin, at a higher dose (150 mg/day), or placebo from 11 weeks to 14 weeks of gestation until 36 weeks of gestation⁶⁹. Preterm

preeclampsia occurred in 1.6% of the participants in the aspirin group, as compared with 4.3% in the placebo group.

In the meantime, the use of metformin for the prevention of preeclampsia remains investigational, as is the use of sildenafil and statins . These drugs are not recommended for this indication outside of the context of clinical trials.

Table-5 Clinical risk factors and aspirin use* Level of

risk

Risk factors Recommendations

high † h/o preeclampsia Recommend low dose

aspirin if the patient has one or more of these high risk factors

Multiple gestation Chronic hypertension Type 1 or 2 diabetes Renal disease

Autoimmunedisease(SLE,APLA syndrome)

Moderate# Nulliparity Consider low dose aspirin

if the patient has more than one of these Obesity

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Family h/o preeclampsia(mother /sister)

moderate risk factors^§

Sociodemographic characteristics Age 35 years or elder

Personal

history(LBW,SGA,previous

adverse pregnancy

outcome,LCB>10 years

Low Previous uncomplicated full term delivery

Do not recommend low dose aspirin

*Includes only risk factors that can be obtained from the patient’s medical history. Clinical measures, such as uterine artery Doppler ultrasonography, are not included.

† Single risk factors that are consistently associated with the greatest risk of preeclampsia. The preeclampsia incidence rate would be approximately 8% or more in a pregnant woman with one or more of these risk factors.

# A combination of multiple moderate-risk factors may be used by clinicians to identify women at high risk of preeclampsia. These risk factors are independently associated with moderate risk of preeclampsia, some more consistently than others.

CLASP TRIAL- Low dose aspirin (60-150mg per day) is widely used and well tolerated antiplatelet treatment,which irreversibly inhibits almost all platelet cyclo-oxygenase activity , thereby blocking synthesis of the vasoconstrictor and platelet aggregating agent thrombaxane.

There was a significant trend towards progressively greater reductions in proteinuric preeclampsia and preterm delivery⁷⁹

A PROSPECTIVE STUDY OF FETOMATERNAL OUTCOME IN SEVERE PREECLAMPSIA