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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access Full Text Article  Research Article

Assessment of Prescribing Pattern and Clinical Outcomes among Women with Risk Factor for Preeclampsia

Shaivi Parashar ^1,2, Sumeet Gupta ², Vaishali Verma ², Ankit Goel ¹, Vikas Sharma ¹, Renu Sharma ¹_, Rahul Kaushik ¹, Krishan Kumar Verma ¹

¹ Department of Pharmacy, Metro College of Health Sciences and Research, Plot No. 41, Knowledge Park III, Greater Noida, U.P., 201310, India

² Department of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, 133207, India

 

 

1. INTRODUCTION

Inappropriate and irrational use of medicines is a widespread problem across healthcare systems in developing countries. Irrational prescribing adds to the economic burden on patients and increases the risk of adverse drug reactions and drug resistance.¹ Prescription pattern (drug utilization) studies are the best available tool to examine how medicines are prescribed, dispensed and used in a population, and they help in understanding rational drug use, drug quality and patient compliance with treatment guidelines.² The World Health Organization (WHO) promotes drug utilization research as a means of improving prescribing practices and rational drug use in healthcare facilities, and defines it broadly as the marketing, distribution, prescription and use of medicines in society, along with their medical, social and economic consequences.¹

Drug utilization research is chiefly concerned with the prescribing, dispensing, administration and consumption of medicines, and with the outcomes-beneficial or adverse-that follow.^11,12,13 The field dates back to the early 1960s⁷¹ and is broadly divided into prospective, concurrent and retrospective studies; prospective designs, of the type used here, allow the most comprehensive assessment of prescribing behaviour, while concurrent studies run alongside dispensing and retrospective studies review data after the fact.⁷³ Beyond describing what is prescribed, such studies help measure the effect of regulatory and pricing interventions, evaluate the efficacy and safety of treatment, and flag over-use, under-dosing or misuse of medicines,⁷³ making them a routine part of quality assurance in clinical care. Findings from drug utilization research increasingly feed into the wider fields of pharmacoepidemiology, pharmacovigilance, pharmaco-economics and pharmacogenetics.²⁰

1.1 Preeclampsia: Burden and Epidemiology

Preeclampsia is a pregnancy-specific hypertensive disorder, defined by new-onset hypertension with proteinuria (or other evidence of end-organ dysfunction) after 20 weeks of gestation. It ranks among the leading causes of maternal morbidity and mortality worldwide, with an estimated global incidence of 3-10%.²⁶ WHO data for 2003-2009 attributed 14% of maternal deaths to hypertensive disorders, second only to haemorrhage (27.1%),²⁷ and in low- and middle-income countries preeclampsia accounts for 10-15% of maternal deaths, with hypertensive disorders responsible for roughly one in ten maternal deaths across Asia and Africa. In India, preeclampsia affects an estimated 8-10% of pregnant women.⁶ Risk is markedly higher in women with a prior history of preeclampsia (2-5 fold) and in nulliparous women (occurring in 3-7% of nulliparous versus 1-3% of multiparous pregnancies); high altitude has also been associated with a higher incidence, possibly through placental hypoxia and reduced uterine arterial blood flow.²⁸

1.2 Etiology

No single cause of preeclampsia has been identified; proposed contributors include placental abnormalities, genetic predisposition, abnormal blood vessel development, immunological factors, and oxidative stress.⁷

1.3 Clinical Manifestations and Risk Stratification

Common clinical features include headache, oedema, excessive weight gain, blurred vision, upper abdominal pain, and elevated blood pressure. On the basis of blood pressure and proteinuria, patients are commonly stratified into mild, moderate and severe risk categories, which in turn guide the decision to initiate low-dose aspirin prophylaxis (Table 1).

 

 

Table 1: Clinical risk stratification for preeclampsia (ACOG guidelines, 2018){{9}}

 

 

1.4 Pathophysiology

The pathophysiology of preeclampsia is not fully understood, but abnormal placentation and multifactorial vascular endothelial dysfunction are considered central to disease onset and progression (Figure 1). 

Figure 1: Pathophysiology of preeclampsia

 

1.5 Diagnosis

Preeclampsia is diagnosed in women with new-onset hypertension after 20 weeks of gestation together with one or more of the following: proteinuria, thrombocytopenia, hepatic dysfunction, renal impairment (excluding proteinuria), pulmonary oedema, headache, or visual disturbance. Confirmatory work-up typically includes blood tests for hepatic, renal and platelet function; 24-hour urinary protein estimation or the protein-creatinine ratio; and fetal ultrasound or biophysical profile scoring, usually performed after 28 weeks of gestation, to assess fetal wellbeing.³⁷

1.6 Biomarkers

A range of biological markers has been investigated to aid the early identification of preeclampsia, spanning angiogenic, immunologic, metabolic and endocrine pathways (Table 2).

 

 

Table 2: Biomarker categories relevant to preeclampsia. VEGF: vascular endothelial growth factor; PlGF: placental growth factor; sFlt-1: soluble fms-like tyrosine kinase-1; sEng: soluble endoglin; PP-13: placental protein-13; PAPP-A: pregnancy-associated plasma protein-A.

Category	Representative biomarkers
Maturation (angiogenic) biomarkers	Pro-angiogenic: VEGF, PlGF; Anti-angiogenic: sFlt-1, sEng
Angiotensin biomarkers	Agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA)
Immunologic biomarkers	PP-13, PAPP-A
Metabolic biomarker	Visfatin
Endocrine biomarkers	Activin A, Inhibin A

 

 

Angiogenic markers (sFlt-1 and sEng)

Normal placental vascular development depends on the pro-angiogenic factors VEGF and PlGF, which support trophoblast growth and implantation.³⁹ PlGF concentrations normally rise across the first 30 weeks of gestation but are reduced in preeclampsia,³⁸ while free VEGF is present at concentrations too low to measure reliably by standard ELISA.⁴¹ sFlt-1, an anti-angiogenic peptide that binds and neutralises PlGF and VEGF, begins rising before the clinical onset of preeclampsia and correlates with disease severity;^42,43 levels are further elevated in nulliparous women.^44,45 sEng, a soluble form of the TGF-β1/β2 receptor, impairs nitric-oxide-mediated vasodilation and endothelial proliferation; its levels rise in the second trimester in women who go on to develop preeclampsia and fall after delivery.^46,47 Together, sFlt-1 and sEng are thought to drive the systemic endothelial dysfunction underlying the hypertension and proteinuria of preeclampsia (Figure 2).

 

 

 

Figure 2: Effect of sEng and sFlt-1 on endothelial function

 

 

Angiotensin-related markers

The renin-angiotensin system regulates blood pressure, fluid-electrolyte balance and cardiac output.⁴⁹ While normal pregnancy is associated with resistance to the vasoconstrictive effects of angiotensin II, this resistance is lost in preeclampsia.⁵⁰ Two mechanisms have been proposed for the resulting rise in blood pressure, oedema and proteinuria: formation of angiotensin-bradykinin B2 receptor heterodimers, and generation of agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AA).^51,52 AT1-AA levels are raised in preeclampsia and can remain elevated post-partum in women with a prior history of the disease,⁵³ and have also been detected in fetal cord blood, where they are used to assess intrauterine growth restriction.⁵⁴

Immunologic markers: PP-13 and PAPP-A

Placental protein-13 (PP-13), a dimeric protein abundant in placental tissue, is involved in implantation and maternal vascular remodelling.⁵⁵ First-trimester PP-13 concentrations (11-13 weeks) are reduced in women who subsequently develop preeclampsia or intrauterine growth restriction,⁵⁶ and low levels early in pregnancy have been proposed as a marker for early-onset (though not severe) disease.⁵⁷ Combining maternal serum PP-13 with uterine artery Doppler improves prediction of severe preeclampsia.⁵⁵ PAPP-A, a glycosylated protein synthesised by trophoblasts, is similarly reduced in the first trimester in preeclampsia and other pregnancy complications,^58,59,60 though it is regarded as a stronger marker of intrauterine growth restriction than of preeclampsia specifically; combining PAPP-A with uterine artery Doppler is again recommended to improve prediction.⁶¹

Metabolic marker: visfatin

Visfatin, a nicotinamide phosphoribosyltransferase expressed in adipose tissue, participates in nicotinamide biosynthesis and glucose homeostasis; abnormal circulating levels have been linked to insulin resistance, obesity, fetal growth restriction and gestational diabetes.⁶² Reported changes in maternal visfatin levels in preeclampsia are inconsistent-both increases and decreases have been described-so its value as a diagnostic marker remains unresolved and requires confirmation in larger studies.^63,64

Endocrine markers: activin A and inhibin A

Activin A and inhibin A are glycoproteins of the transforming growth factor-β family, released by the fetoplacental unit; activin A participates in several organ-level processes while inhibin A suppresses FSH synthesis.^65,66 Both rise through the third trimester of normal pregnancy, with levels roughly ten-fold higher in severe preeclampsia, and placental hypoxia is thought to drive activin A release from placental and endothelial cells.⁶⁷ Second-trimester serum and amniotic-fluid inhibin A correlates with disease severity,⁶⁸ and urinary activin A and inhibin A are also raised in preeclampsia,⁶⁶ though inhibin A has shown limited predictive value when measured in the first trimester.^69,70

1.7 Complications of Preeclampsia

Maternal complications include placental abruption, disseminated intravascular coagulopathy, HELLP syndrome (haemolysis, elevated liver enzymes, low platelets), oedema, renal impairment, hepatic rupture, jaundice, intracerebral haemorrhage, and eclampsia/seizures. Fetal complications include intrauterine growth restriction, preterm birth, and fetal death, while affected neonates are at increased risk of hypoxia, brain injury, and perinatal death.

Given this burden, and the central role of antihypertensive and prophylactic drug therapy in limiting maternal and fetal complications, an assessment of prescribing patterns and clinical outcomes among women at risk of preeclampsia was undertaken at a tertiary care teaching hospital, with the objective of characterising drug utilization against WHO prescribing indicators and documenting the associated maternal-fetal outcomes.

2. MATERIALS AND METHODS

A prospective observational study was conducted in the Department of Obstetrics and Gynaecology, Maharishi Markandeshwar Institute of Medical Sciences and Research (MMIMSR), Mullana, Haryana, India, over a six-month period from October 2019 to March 2020. Case records of women attending the antenatal outpatient clinic were screened, and those diagnosed with, or carrying risk factors for, preeclampsia were reviewed in detail. Women aged 18-45 years with moderate-to-high risk factors for preeclampsia, including those with IVF pregnancies, were included; outpatient prescriptions were also captured. Women managed outside the Department of Obstetrics and Gynaecology, those in active labour, and those showing evidence of non-compliance were excluded.

A total of 100 antenatal records were screened, of which 60 women met the risk criteria for preeclampsia and were followed for six months. For each patient, demographic details, obstetric and medical history, clinical findings, laboratory results, and the number, frequency and duration of prescribed medicines were recorded on a structured case record form after obtaining written informed consent. All pregnant women attending the clinic were managed by a team of obstetricians, with laboratory investigations (blood pressure measurement, sonography, Doppler studies) and prescribed medicines explained to each patient. The study was approved by the Institutional Ethics Committee of Maharishi Markandeshwar (Deemed to be University) and conducted in accordance with the principles of the Declaration of Helsinki.

 

 

 

 

2.1 Study Design and Plan of Work

Table 3: Study plan of work

 

 

2.2 Inclusion and Exclusion Criteria

Inclusion criteria: women aged 18-45 years with moderate-to-high risk of developing preeclampsia, including IVF pregnancies; outpatient prescriptions were included.

Exclusion criteria: patients not managed under the Department of Obstetrics and Gynaecology, women in labour, and patients with evidence of non-compliance.

Drug utilization was analysed using WHO prescribing indicators. Data were compiled and analysed using appropriate statistical software, and results were evaluated against patient demographics, prescribing patterns, and maternal-fetal clinical outcomes.

3. RESULTS

Of the 100 antenatal records screened, 60 women (60%) met the risk criteria for preeclampsia and were included in the final analysis. Risk of preeclampsia was concentrated in the younger age groups: 20-25 years (50%), 26-30 years (23.3%), 31-35 years (18.3%), and 36-40 years (8.3%) (Table 4).

 

 

Table 4: Age-wise distribution of patients

 

 

On the basis of laboratory findings, past medical history, family history and concomitant illness, 55% of women were classified as high risk and 38.3% as moderate risk for preeclampsia, with the remaining 6.6% at mild risk (Table 5). 

Table 5: Risk-category distribution of patients

 

Blood pressure at presentation was mild (140/90-159/99 mmHg) in 51.6% of women, moderate (160/100-179/109 mmHg) in 33.3%, and severe (>180/100 mmHg) in 13.3% (Table 6).

Table 6: Blood pressure distribution among patients

Concomitant illness was present in 33.3% of women during the study period, most commonly diabetes mellitus (10%), hypertension (10%), thyroid disorders (6.6%), amenorrhea (5%) and seizure disorder (1.6%) (Table 7).

 

Table 7: Concomitant illnesses among study patients

 

 

Antihypertensive and prophylactic therapy prescribed for preeclampsia risk is summarised in Table 8. Labetalol was the most frequently prescribed antihypertensive (75%), followed by amlodipine/Amlong (6.6%) and telmisartan/Telma (6.6%). Low-dose aspirin (Ecosprin) was prescribed to 40% of high-risk women, and magnesium sulphate to 15% for prevention of eclamptic seizures. Supportive therapy was prescribed widely: calcium (98.3%), iron (95%), L-arginine sachets (31.6%), protein powder (31.6%) and folic acid (16.6%).

 

 

Table 8: Antihypertensive and supportive drug therapy prescribed for preeclampsia risk

 

Among women receiving treatment for concomitant illness, metformin (15%), levothyroxine (11.6%), insulin (3.3%) and methimazole (10%) were prescribed for diabetes mellitus and thyroid disorders. For maintenance of pregnancy, additional supportive drugs prescribed included Folvite (20%), domperidone/Perinorm (16.6%), vitamin K (5%), calcium citrate (3.3%) and thiamine (1.6%) (Table 9).

 

 

Table 9: Drug treatment for concomitant illness and gestational support

 

 

Overall, drug therapy in this cohort was individualised according to each patient's clinical risk profile, blood pressure severity, and concomitant illness, with treatment decisions aimed at safeguarding both maternal and fetal wellbeing.

4. DISCUSSION

Hypertensive disorders remain a major cause of maternal and perinatal mortality worldwide, and preeclampsia in particular is difficult to predict until its more advanced stages, by which point risk to both mother and fetus has already risen substantially. The diagnostic threshold used in this and most other settings-systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg, confirmed on two occasions at least four hours apart after 20 weeks of gestation-reflects this need for early, reliable identification. In developing countries, preeclampsia also contributes to longer-term cardiovascular risk: affected women face a higher lifetime risk of chronic hypertension and stroke, and children born of preeclamptic pregnancies appear to carry an increased risk of cardiovascular and metabolic disease in adulthood.

The predominance of labetalol in this cohort (75%) is consistent with its position as a first-line antihypertensive in pregnancy in both national and international guidelines, reflecting its favourable safety profile relative to other agents. The use of low-dose aspirin in 40% of women aligns with current practice of initiating prophylaxis before 16 weeks of gestation in those at moderate-to-high risk, and the use of magnesium sulphate in 15% of women is consistent with its established role in seizure prophylaxis for severe disease. The near-universal use of calcium and iron supplementation, and the frequent use of folic acid and L-arginine, reflect routine antenatal supportive care rather than preeclampsia-specific therapy, but remain relevant to overall maternal and fetal outcomes.

Although the pathophysiology of preeclampsia is not fully understood, multifactorial vascular endothelial dysfunction is considered central to disease onset, and this is broadly consistent with the biomarker literature reviewed above (notably the angiogenic imbalance involving sFlt-1, sEng, VEGF and PlGF). While biomarker testing was outside the scope of the present prescribing-pattern assessment, its growing evidence base suggests a role for future studies at this centre in combining clinical risk stratification with biochemical screening.

Taken together, these findings reinforce the value of systematic prescription-pattern assessment in pregnancy: it identifies whether prescribing is concordant with evidence-based guidelines, highlights areas where dosing, drug choice or monitoring could be standardised, and ultimately supports efforts to reduce the financial and clinical burden of inappropriate prescribing on both patient and health system.

5. CONCLUSION

Drug therapy prescribed to women at risk of preeclampsia at this centre was broadly consistent with WHO and ACOG recommendations for patient safety and effective maternal-fetal outcomes. Labetalol was the antihypertensive of choice (75%), with low-dose aspirin (Ecosprin 75-150 mg) used as prophylaxis in high-risk women. Supportive therapy, principally folic acid, calcium, iron and protein powder, was prescribed alongside antihypertensive treatment according to each patient's individual risk profile, and additional agents (metformin, levothyroxine, insulin, methimazole, and vitamin supplementation) were used where concomitant illness was present. Magnesium sulphate was prescribed both for seizure prophylaxis and to support fetal development and reduce the risk of intrauterine growth restriction.

These prescribing patterns are intended to reduce maternal and fetal morbidity and mortality associated with preeclampsia. A limitation of this study was incomplete follow-up of maternal-fetal outcomes owing to disruption during the COVID-19 pandemic; longer-term follow-up studies are needed to confirm the clinical outcomes associated with these prescribing patterns.

Acknowledgement: The authors thank all the contributors.

Conflict of Interest: The authors declare that they have no conflict of interest.

REFERENCES

1. Hussain S, Yadav S, Khattri S, et al. Assessment of drug prescribing pattern using world health organization indicators in a tertiary care teaching hospital: Indian Journal of Public Health. 2018; 62(2): 156-158. https://doi.org/10.4103/ijph.IJPH_429_16 PMid:29923544

2. Jain S, Upadhyaya P, Moghe V, et al. A systematic review of prescription pattern monitoring studies and their effectiveness in promoting rational use of medicines: Perspective in Clinical Research. 2015; 6(2): 86-90. https://doi.org/10.4103/2229-3485.154005 PMid:25878953 PMCid:PMC4394586

3.    American College Of Obstetrics and Gynaecologist, Task force on hypertension in pregnancy. Hypertension in pregnancy. Report on American College of Obstetrics and Gynaecologist’ Task force on hypertension in pregnancy. Obstetrics Gynecology. 2013; 122:1122.

4.    Lenfant C,working group report on high blood pressure in pregnancy: Journal Clin Hypertens (Greenwich). 2001.

5.    Wagner LK, M.D, et al. Diagnosis and Management of preeclampsia: American Family Physician. 2004; 70(12): 2317-2324.

6. Henderson JT, Whitlock EP, O’Connor, et al. Low-dose aspirin for prevention of morbidity from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2014; 160:695. https://doi.org/10.7326/M13-2844 PMid:24711050

7. Rana S, Lemoine E, Granger JP, et al. Preeclampsia pathophysiology, challenges and perspectives: Circulation Research. 2019; 124:1094-1112. https://doi.org/10.1161/CIRCRESAHA.118.313276 PMid:30920918 PMCid:PMC12042644

8. Odegard RA, Austgulen R, et al. Preeclampsia and fetal growth: Obstetrics and Gynecology. 2000; 96(6): 950-955. https://doi.org/10.1097/00006250-200012000-00016 PMid:11084184

9. American College Of Obstetrics and Gynaecologist. ACOG committee opinion number 743: Committee on obstetrics practice society for maternal-foetal medicine. Obstetrics and Gynaecology. 2018; 132(1):e44-e52. https://doi.org/10.1097/AOG.0000000000002708 PMid:29939940

10. Hladunewich M, Karumanchi SA, Lafayette R, et al. Pathophysiology of the clinical manifestations of preeclampsia: Clin Journal Am Soc Nephrol. 2007; 2(3):543-549. https://doi.org/10.2215/CJN.03761106 PMid:17699462

11. Lunde PK, Baksaas I, et al. Epidemiology of drug utilization basic concepts and methodology: Acta Med Scand Suppl. 1988; 721:7-11. https://doi.org/10.1111/j.0954-6820.1987.tb05371.x PMid:3281414

12.  Strom BL, Pharmacoepidemiology. Fourth ed: John Wiley & Sons, Ltd 2005.

13.  Costa J, Rosa MM, Ferreira JJ, Sampaio C, et al. Cardiac effects of acute poisoning with tricyclic antide-pressants: systematic review of the literature. Part I. Rev Port Cardiol. 2001; 20:671-678.

14. Strom BL, Melmon KL, Miettinen OS, et al. Postmarketing studies of drug efficacy: Arch Intern Med. 1985; 145:1791-1794. https://doi.org/10.1001/archinte.1985.00360100051005 PMid:3899034

15. Andersen M, Is it possible to measure prescribing quality using only prescription data? Basic Clin Pharmacol Toxicol. 2006; 98:314-319. https://doi.org/10.1111/j.1742-7843.2006.pto_411.x PMid:16611208

16. Wettermark B, Hammar N, MichaelFored C, Leimanis A, Otterblad Olausson P, Bergman U, et al. The new Swedish Prescribed Drug Register—opportunities for pharmacoepide-miological research: Pharmacoepidemiological Drug Safety. 2007; 16:726-735. https://doi.org/10.1002/pds.1294 PMid:16897791

17. Naqvi SH, Dunkle LM, Timmerman KJ, Reichley RM, Stanley DL, O’Connor D, et al. Antibiotic usage in a pediatric medical center: Journal of the American Medical Association.1979; 242:1981-1984. https://doi.org/10.1001/jama.1979.03300180025025 PMid:480644

18. Scheckler WE, Bennett JV, et al. Antibiotic usage in seven community hospitals: Journal of the American Medical Association. 1970; 213:264-267. https://doi.org/10.1001/jama.1970.03170280024004 PMid:5467892

19. Psaty BM, Lee M, Savage PJ, Rutan GH, German PS, Lyles M, et al. Assessing the use of medications in the elderly: methods and initial experience in the Cardiovascular Health Study: The Cardiovascular Health Study Collaborative Research Group, Journal Clin Epidemiology .1992; 45:683-692. https://doi.org/10.1016/0895-4356(92)90143-B PMid:1607909

20. Avorn J, Soumerai SB, et al. Improving drug-therapy decisions through educational outreach-A randomized controlled trial of academically based ‘detailing’: N Engl Journal Med. 1983; 308:1457-1463. https://doi.org/10.1056/NEJM198306163082406 PMid:6406886

21. Ray WA, Schaffner W, Federspiel CF, et al. Persistence of improvement in antibiotic prescribing in office practice: Journal of the American Medical Association. 1985; 253:1774-1776. https://doi.org/10.1001/jama.1985.03350360100028 PMid:3974058

22. Schaffner W, Ray WA, Federspiel CF, Miller WO, et al. Improving antibiotic prescribing in office practice: Journal of the American Medical Association. 1983; 250: 1728-1732. https://doi.org/10.1001/jama.1983.03340130046031 PMid:6350633

23.  Chesley L, Hypertensive Disorders in Pregnancy: Elsevier. 2015; 4:221-231.

24. Myatt L, Clifton RG, Roberts JM, et al. First-trimester prediction of preeclampsia in nulliparous women at low risk: Obstetrics & Gynecology. 2012; 119(6):1234--1242. https://doi.org/10.1097/AOG.0b013e3182571669 PMid:22617589 PMCid:PMC3360523

25. Myatt L, Roberts JM, et al. Preeclampsia: Syndrome or Disease: Current Hypertension Reports.2015; 17: 83. https://doi.org/10.1007/s11906-015-0595-4 PMid:26362531

26. Ghulmiyyah L, Sibai B,et al. Maternal Mortality From Preeclampsia/Eclampsia: Seminars in Perinatology.2012; 36(1): 56-59. https://doi.org/10.1053/j.semperi.2011.09.011 PMid:22280867

27. Say L, Chou D, Gemmill A, et al. Global causes of maternal death:- a WHO systematic analysis: The Lancet Global Health. 2014; 2(6): e323--e333. https://doi.org/10.1016/S2214-109X(14)70227-X PMid:25103301 PMCid:PMC11635789

28. Uzan J, Carbonnel M, Piconne O, Asmar R, et al. Pre-eclampsia: pathophysiology, diagnosis and management: Vascular Health and Risk Management. 2011; 7: 467--474. https://doi.org/10.2147/VHRM.S20181 PMid:21822394 PMCid:PMC3148420

29. Meads CA, Cnossen JS, Meher S, et al. Methods of prediction and prevention of preeclampsia: systematic reviews of accuracy and effectiveness literature with economic modeling: Health Technol Assess. 2008; 12: 1--270. https://doi.org/10.3310/hta12060

30. Osmond C, Kajantie E, Forsén TJ, Eriksson JG, Barker DJ, et al. Infant growth and stroke in adult life: the Helsinki Birth Cohort Study. 2007; 38:264--270. https://doi.org/10.1161/01.STR.0000254471.72186.03 PMid:17218608

31. Eriksson JG, Forsén T, Tuomilheto J, Osmond C, Barker DJ, et al. Early growth and coronary heart disease in later life, longitudinal study: British Medical Journal. 2001; 322:949--953. https://doi.org/10.1136/bmj.322.7292.949 PMid:11312225 PMCid:PMC31033

32. Barker DJ, Martyn CN, Osmond C, Hales CN, et al. Growth in utero and serum cholesterol concentrations in adult life: British Medical Journal. 1993; 307:1524--1527. https://doi.org/10.1136/bmj.307.6918.1524 PMid:8274921 PMCid:PMC1679540

33. Warrington JP, George EM, Palei AC, Spradley FT, et al. Recent advances in the understanding of the pathophysiology of preeclampsia: Hypertension. 2013; 62(4):666-673. https://doi.org/10.1161/HYPERTENSIONAHA.113.00588 PMid:23897068 PMCid:PMC3856636

34. Reddy A, Suri S, Sargent IL, Redman CWG, Muttukrishna S, et al. Maternal circulating levels of activin A, inhibin A, sFlt-1 and endoglin at parturition in normal pregnancy and preeclampsia: PLoSONE.2009;4(2): e4453. https://doi.org/10.1371/journal.pone.0004453 PMid:19412349 PMCid:PMC2675175

35. Portelli M, Baro B, et al. Clinical Presentation of Preeclampsia and the Diagnostic Value of Proteins and Their Methylation Products as Biomarkers in Pregnant Women with Preeclampsia and Their Newborns: Journal of Pregnancy. 2018; 1-23. https://doi.org/10.1155/2018/2632637 PMid:30050697 PMCid:PMC6046127

36.  Wagner LK, Diagnosis and management of preeclampsia: American Family Physician. 2004; 70(12): 2317--2324.

37. Guimarães filho HA, Araujo júnior E, Nardozza LM et-al. Ultrasound assessment of the fetal biophysical profile: Eur Journal Radiol. 2008; 66 (1): 122-126. https://doi.org/10.1016/j.ejrad.2007.05.011 PMid:17587525

38. Robinson CJ, Johnson DD, et al. Soluble endoglin as a second-trimester marker for preeclampsia: Am Journal Obstet Gynecol.2007; 197(2):174:e1-5. https://doi.org/10.1016/j.ajog.2007.03.058 PMid:17689640

39. Thadhani R, Mutter WP, Wolf M, et al. First trimester placental growth factor and soluble Fms-like tyrosine kinase 1 and risk for preeclampsia: Journal Clin Endocrinol Metabol. 2004; 89:770--775. https://doi.org/10.1210/jc.2003-031244 PMid:14764795

40. Levine RJ, Thadhani R, Qian C, Lam C, Lim KH, et al. Urinary placental growth factor and risk of preeclampsia: Journal of the American Medical Association. 2005; 293:77-85. https://doi.org/10.1001/jama.293.1.77 PMid:15632339

41. Hagmann H, Thadhani R, Benzing T, Karumanchi S A, et al. The Promise of Angiogenic Markers for the Early Diagnosis and Prediction of Preeclampsia: journal Clin Chem. 2012; 58:837-845. https://doi.org/10.1373/clinchem.2011.169094 PMid:22431894

42. Levine RJ, Maynard SE, Qian C, Lim KH, Yu KF, et al. Circulating angiogenic factors and the risk of preeclampsia: N Engl Journal Med. 2004; 350:672-683. https://doi.org/10.1056/NEJMoa031884 PMid:14764923 PMCid:PMC12042644

43. Karumanchi SA, Lindheimer MD, et al. Preeclampsia pathogenesis: ‘Triple a rating’ autoantibodies and anti-angiogenic factors Hypertension. 2008; 51:991-992. https://doi.org/10.1161/HYPERTENSIONAHA.107.100735 PMid:18259040

44. Wolf M, Shah A, Lam C, et al. Circulating levels of the antiangiogenic marker sFLT-1 are increased in first versus second pregnancies: Am Journal Obstet Gynecol. 2005; 193:16--22. https://doi.org/10.1016/j.ajog.2005.03.016 PMid:16021053

45. Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia: Journal Clin Investig. 2003; 111:649--658. https://doi.org/10.1172/JCI17189 PMid:12618519 PMCid:PMC151901

46. Mutter WP, Karumanchi SA, et al. Molecular mechanisms of preeclampsia: Microvas Res. 2008; 75:1-8. https://doi.org/10.1016/j.mvr.2007.04.009 PMid:17553534 PMCid:PMC2241748

47. Venkatesha S, Toporsian M, Lam C, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia: Nature Med. 2006; 12:642--649. https://doi.org/10.1038/nm1429 PMid:16751767 PMCid:PMC12042644

48. Rana S, Karumanchi SA, Levine RJ, et al. Sequential changes in antiangiogenic factors in early pregnancy and risk of developing preeclampsia: Hypertension. 2007; 50:137--142. https://doi.org/10.1161/HYPERTENSIONAHA.107.087700 PMid:17515455

49. Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, et al. Inflammation and angiotensin II: Intl Journal of Biochem and Cell Biol. 2003; 35:881-900. https://doi.org/10.1016/S1357-2725(02)00271-6 PMid:12676174

50. Fujimoto Y, Sasaki T, Tsuchida A, Chayama K, et al. Angiotensin II type 1 receptor expression in human pancreatic cancer and growth inhibition by angiotensin II type 1 receptor antagonist: FEBS Letters. 2001; 495:197-200. https://doi.org/10.1016/S0014-5793(01)02377-8 PMid:11334891

51. Paul M, Mehr AP, Kreutz R, et al. Physiology of local renin angiotensin systems: Physiol Reviews. 2006; 86:747-803. https://doi.org/10.1152/physrev.00036.2005 PMid:16816138

52. Redman CW, Sargent IL, et al. Latest advances in understanding preeclampsia: Science. 2005; 308:1592-1594. https://doi.org/10.1126/science.1111726 PMid:15947178 PMCid:PMC12042644

53. Hubel CA, Wallukat G, Wolf M, Herse F, Rajakumar A, et al. Agonistic angiotensin II type 1 receptor autoantibodies in postpartum women with a history of preeclampsia :Hypertension. 2007; 49:612-617. https://doi.org/10.1161/01.HYP.0000256565.20983.d4 PMid:17210828

54. Irani RA, Zhang Y, Blackwell SC, et al. The detrimental role of angiotensin receptor agonistic autoantibodies in intrauterine growth restriction seen in preeclampsia: Journal of Exp Med. 2009; 206:2809-2822. https://doi.org/10.1084/jem.20090872 PMid:19887397 PMCid:PMC2806612

55. Nicolaides KH, Bindra R, Turan OM, et al. A novel approach to first-trimester screening for early pre-eclampsia combining serum PP-13 and Doppler ultrasound: Ultrasound Obstet Gynecol. 2006; 27:13-17. https://doi.org/10.1002/uog.2686 PMid:16374755

56. Burger O, Pick E, Zwickel J, et al. Placental protein 13 (PP-13): Effects on cultured trophoblasts, and its detection in human body fluids in normal and pathological pregnancies Placenta: British Medical Journal. 2004; 25:608-622. https://doi.org/10.1016/j.placenta.2003.12.009 PMid:15193867

57. Chaftez I, Kuhnreich I, Sammar M, et al. First trimester placental protein 13 screening for preeclampsia and intrauterine growth restriction: Am Journal Obstet Gynecol. 2007; 197:35(e1)-35(e7). https://doi.org/10.1016/j.ajog.2007.02.025 PMid:17618748

58. Bersinger NA, Smarason AK, Muttukrishna S, et al. Women with preeclampsia have increased serum levels of pregnancy-associated plasma protein A (PAPP-A), inhibin A, activin A, and soluble E-selectin: Hypertens Pregnancy. 2003; 22:45-55. https://doi.org/10.1081/PRG-120016794 PMid:12648442

59. Yaron Y, Heifetz S, Ochshorn Y, Lehavi O, et al. Decreased first trimester PAPP-A is a predictor of adverse pregnancy outcome: Prenat Diagn. 2002; 22:778-782. https://doi.org/10.1002/pd.407 PMid:12224070

60. Smith GC, Stenhouse EJ, Crossley JA, et al. Early pregnancy levels of pregnancy-associated plasma protein A and the risk of intrauterine growth restriction, premature birth, preeclampsia, and stillbirth: Journal Clin Endocrinol Metabol. 2002; 87:1762--1767. https://doi.org/10.1210/jcem.87.4.8430 PMid:11932314

61. Canini S, Prefumo F, Pastorino D, et al. Association between birth weight and first-trimester free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A: Fertil and Steril. 2008; 89: 174--178. https://doi.org/10.1016/j.fertnstert.2007.02.024 PMid:17509577

62. Preiss J, Handler P, et al. Enzymatic synthesis of nicotinamide mononucleotide: Journal Biol Chem. 1957; 225:759-770. https://doi.org/10.1016/S0021-9258(18)64875-6 PMid:13416279

63. Frasshauer M, Bluher M, Stumvoll M, Tonessen P, Stepan H, et al. Differential regulation of visfatin and adiponectin in pregnancies with normal and abnormal placental function: Clin Endocrinol. 2007; 66:434-439. https://doi.org/10.1111/j.1365-2265.2007.02751.x PMid:17302880

64. Hu W, Wang Z, Wang H, Huang H, et al. Serum visfatin levels in late pregnancy and pre-eclampsia: Acta Obstet Gynaecol Scand. 2008; 87:413-418. https://doi.org/10.1080/00016340801976012 PMid:18382866

65. Luisi S, Florio P, Reis FM, Petraglia F, et al. Inhibins in female and male reproductive physiology: role in gametogenesis, conception, implantation and early pregnancy: Hum Reprod Update. 2005; 11:123--135. https://doi.org/10.1093/humupd/dmh057 PMid:15618291

66. Muttukrishna S, Hyett J, Paine M, et al. Uterine vein and maternal urinary levels of activin A and inhibin A in pre-eclampsia patients: Clin Endocrinol (Oxf). 2006; 64:469-473. https://doi.org/10.1111/j.1365-2265.2006.02476.x PMid:16584522

67. Mandang S, Maneulpillai U, Wallace EM, et al. Oxidative stress increases placental and endothelial cell activin A secretion: Journal Endocrinol. 2007; 192:485-493. https://doi.org/10.1677/JOE-06-0061 PMid:17332518

68. Kim SY, Ryu HM, Yang JH, et al. Maternal serum and amniotic fluid inhibin A levels in women who subsequently develop severe preeclampsia: Journal Korean Med Science. 2006; 21:452--456. https://doi.org/10.3346/jkms.2006.21.3.452 PMid:16778388 PMCid:PMC2729950

69. Davidson EJ, Riley SC, Roberts SA, et al. Maternal serum activin, inhibin, human chorionic gonadotrophin and alpha-fetoprotein as second trimester predictors of pre-eclampsia: British Journal Obstet Gynaecol. 2003; 110:46-52. https://doi.org/10.1016/S1470-0328(02)02937-3

70. Roes EM, Gaytant MA, Thomas CM, et al. First trimester inhibin-A concentrations and later development of preeclampsia: Acta Obstetricia Gynecologica Scandinavica. 2004; 83:117. https://doi.org/10.1080/j.1600-0412.2004.00140.x PMid:14758802

71.  Dukes MNG. Introduction. In: Drug Utilization Studies: Methods and Uses. Edited by Dukes MNG. 1992. WHO Regional Publications, European Series, No. 45, 1-4.

72.  Lee D, Bergman U, et al. Studies of Drug Utilization: Pharmaco-epidemiology: West Sussex: John Wiley & Sons, Ltd.1994; 2: 379-393.

73. Erwin WG. The Definition of Drug Utilization Review: Statement of Issues: Clinical Pharmacology & Therapeutics. 1991; 50(5, part 2, November): 596-599. https://doi.org/10.1038/clpt.1991.188 PMid:1934874

74. Sunol R, Abello C, Cels IC, et al. Studies in Utilization of Drugs: a Review of Different Methods: Quality Assurance in Health Care. 1991; 3(1):63-72. https://doi.org/10.1093/intqhc/3.1.63 PMid:1873531

75. Griffiths K, McDevitt DG, Andrew M, et al. Therapeutic Traditions in Northern Ireland, Norway and Sweden- I. Diabetes: European Journal of Clinical Pharmacology. 1986; 30:513-519. https://doi.org/10.1007/BF00542408 PMid:3530780

76. Andrew M, Griffiths K, McDevitt DG, et al. Therapeutic Traditions in Northern Ireland, Norway and Sweden- II. Hypertension: European Journal of Clinical Pharmacology. 1986; 30:521-525. https://doi.org/10.1007/BF00542409 PMid:3758139

77.  Haaijer FM, De Jong-Van den Berg LTW, et al. Drug Utilization Studies and Drug Monitoring in the Netherlands: Annali dell’ Istituto Superiore di Sanita. 1991; 27(2):217-224.

78.  National Institute for Health and Care Excellence (NICE) NICE CG 107. Manchester, UK: National Institute for Health and Clinical Excellence; 2010. [Accessed February 5, 2015]. Hypertension in pregnancy: the management of hypertensive disorders during pregnancy.

79. Lancet C, et al. low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women CLASP (Collaborative Low-dose Aspirin Study in Pregnancy): Collaborative Group. 1994; 343(8898):619--629. https://doi.org/10.1016/S0140-6736(94)92633-6

80. Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L,et al. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems: Cochrane Database System Revised. 2014;6:CD001059. https://doi.org/10.1002/14651858.CD001059.pub4

81. Myers JE, Baker PN, et al. Hypertensive diseases and eclampsia: Current Opinion Obstetrics Gynecol. 2002; 14(2):119--125. https://doi.org/10.1097/00001703-200204000-00004 PMid:11914688

82. National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy: American Journal of Obstetrics Gynecology .2000; 183: S1-22. https://doi.org/10.1067/mob.2000.107928 PMid:10920299

83. Abalos E, Duley L, Steyn D,et al. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy: Cochrane Database System Revised. 2001 ;2:CD002252. https://doi.org/10.1002/14651858.CD002252

84. American College Of Obstetrics and Gynaecologist Committee on Obstetric Practice: ACOG practice bulletin, Diagnosis and management of preeclampsia and eclampsia: ACOG Obstet Gynecol. 3002; 99:159-167. https://doi.org/10.1016/S0029-7844(01)01747-1 PMid:16175681

85. Koopmans CM, Bijlenga D, Groen H, et al. HYPITAT study group Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks’ gestation (HYPITAT): a multicentre, open-label randomised controlled trial. Lancet. 2009; 374(9694):979--988. https://doi.org/10.1016/S0140-6736(09)60736-4 PMid:19656558

86. Duley L, Meher S, Abalos E, et al. Management of pre-eclampsia: British Medical Journal. 2006; 332(7539): 463--468. https://doi.org/10.1136/bmj.332.7539.463 PMid:16497761 PMCid:PMC1382544

87. Pryde PG, Mittendorf R, et al. Contemporary usage of obstetric magnesium sulfate: indication, contraindication, and relevance of dose: Obstetrics & Gynecologist. 2009;114:669--673. https://doi.org/10.1097/AOG.0b013e3181b43b0e PMid:19701048

88.  National Institute for Health and Care Excellence (NICE) Severe Hypertension, Severe Pre-Eclampsia and Eclampsia in Critical Care---Nice Clinical Guideline. Royal College of Obstetricians and Gynaecologists; London, UK: 2015.

89. Peres G, Mariana M, Cairrao E, et al. Pre-Eclampsia and Eclampsia: An Update on the Pharmacological Treatment Applied in Portugal: Journal of Cardiovascular Development and Disease. 2018 Mar; 5(1): 3. https://doi.org/10.3390/jcdd5010003 PMid:29367581 PMCid:PMC5872351

90. Bouet PE, Brun S, Madar H, Baisson AL, Courtay V, Lasocki S, et al. Implementation of an antenatal magnesium sulfate protocol for fetal neuroprotection in preterm infants: Scientific Report. 2015; 5:14732. https://doi.org/10.1038/srep14732 PMid:26415713 PMCid:PMC4586759

91.  American College of Obstetricians and Gynecologists. Low- dose aspirin use during pregnancy Committee Opinion. Number-743. 2018.

92.  WHO. In: Who Recommendations for Prevention and Treatment of Pre-Eclampsia and Eclampsia. 2013:7: 8--27.

93. Roberge S, Villa P, Nicolaides K, Giguere Y, Vainio M, Bakthi , et al. Early administration of low-dose aspirin for the prevention of preterm and term preeclampsia: Fetal Diagnosis & Therapy 2012; 31:141--146. https://doi.org/10.1159/000336662 PMid:22441437

94. Mol BW, Roberts CT, Thangaratinam S, Magee LA, et al. Pre-eclampsia: Lancet. 2015; 387:999--1011. https://doi.org/10.1016/S0140-6736(15)00070-7 PMid:26342729

95. Tong S, Mol BW, Walker SP, et al. Preventing preeclampsia with aspirin: American Journal of Obstetrics & Gynecologist. 2017; 216:95--97. https://doi.org/10.1016/j.ajog.2016.12.003 PMid:28148451

96. Meher S, Duley L, Hunter K, Askie L, et al. Antiplatelet therapy before or after 16 weeks’ gestation for preventing preeclampsia: American Journal of Obstetrics & Gynecologist. 2017; 216:121--128. https://doi.org/10.1016/j.ajog.2016.10.016 PMid:27810551

97. Chandiraman M, Shennan Ah, et al. Modern management of postpartum hypertension: Trends in Urology, Gynaecology & Sexual Health. 2007:12: 37-42. https://doi.org/10.1002/tre.40

98. Fred A , Louise C , Fergus P, et al. Risk factors and effective management of preeclampsia: Integr Blood Pressure Control. 2015; 8: 7--12. https://doi.org/10.2147/IBPC.S50641 PMid:25767405 PMCid:PMC4354613

99. Podymow T, August P, et al. Antihypertensive drugs in pregnancy: Semin Nephrol Journal. 2011; 31(1):70--85. https://doi.org/10.1016/j.semnephrol.2010.10.007 PMid:21266266

100.  Lowe SA, Brown MA, Dekker GA, Gatt S, McLintock CK, McMahonLP,etal. Guidelines for the management of hypertensive disorders of pregnancy: Australian & New Zealand Journal of Obstetrics Gynaecology. 2009; 49(3):242-246. https://doi.org/10.1111/j.1479-828X.2009.01003.x PMid:19566552