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Treatment of Hypertension : A Review

  • 1 Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville
  • 2 Division of General Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, New York
  • 3 Departments of Epidemiology and Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana
  • Original Investigation Antihypertensive Medication Reduction vs Usual Care in Short-term Blood Pressure Control James P. Sheppard, PhD; Jenni Burt, PhD; Mark Lown, MRCGP; Eleanor Temple, BSc; Rebecca Lowe, BSc; Rosalyn Fraser, MSc; Julie Allen, BSc; Gary A Ford, MB, BChir; Carl Heneghan, DPhil; F. D. Richard Hobbs, MBChB; Sue Jowett, PhD; Shahela Kodabuckus, MSc; Paul Little, MD; Jonathan Mant, MD; Jill Mollison, PhD; Rupert A. Payne, MRCGP; Marney Williams, BEd; Ly-Mee Yu, DPhil; Richard J. McManus, PhD; for the OPTIMISE Investigators JAMA
  • Original Investigation Trends in Blood Pressure Control Among US Adults With Hypertension, 1999-2000 to 2017-2018 Paul Muntner, PhD; Shakia T. Hardy, PhD; Lawrence J. Fine, MD; Byron C. Jaeger, PhD; Gregory Wozniak, PhD; Emily B. Levitan, ScD; Lisandro D. Colantonio, MD, PhD JAMA
  • Viewpoint A National Commitment to Improve the Care of Patients With Hypertension in the US Jerome M. Adams, MD, MPH; Janet S. Wright, MD JAMA
  • US Preventive Services Task Force USPSTF Recommendation: Screening for Hypertension in Adults US Preventive Services Task Force; Alex H. Krist, MD, MPH; Karina W. Davidson, PhD, MASc; Carol M. Mangione, MD, MSPH; Michael Cabana, MD, MA, MPH; Aaron B. Caughey, MD, PhD; Esa M. Davis, MD, MPH; Katrina E. Donahue, MD, MPH; Chyke A. Doubeni, MD, MPH; Martha Kubik, PhD, RN; Li Li, MD, PhD, MPH; Gbenga Ogedegbe, MD, MPH; Lori Pbert, PhD; Michael Silverstein, MD, MPH; James Stevermer, MD, MSPH; Chien-Wen Tseng, MD, MPH, MSEE; John B. Wong, MD JAMA
  • US Preventive Services Task Force USPSTF Review: Screening for Hypertension in Adults Janelle M. Guirguis-Blake, MD; Corinne V. Evans, MPP; Elizabeth M. Webber, MS; Erin L. Coppola, MPH; Leslie A. Perdue, MPH; Meghan Soulsby Weyrich, MPH JAMA
  • JAMA Patient Page Patient Information: Screening for Hypertension in Adults Jill Jin, MD, MPH JAMA
  • The Rational Clinical Examination Does This Adult Patient Have Hypertension? Anthony J. Viera, MD, MPH; Yuichiro Yano, MD, PhD; Feng-Chang Lin, PhD; David L. Simel, MD; Jonathan Yun, MD, MPH; Gaurav Dave, MD, DrPH; Ann Von Holle, PhD; Laura A. Viera, MA; Daichi Shimbo, MD; Shakia T. Hardy, PhD; Katrina E. Donahue, MD, MPH; Alan Hinderliter, MD; Christiane E. Voisin, MSLS; Daniel E. Jonas, MD, MPH JAMA
  • JAMA Insights Management of Chronic Hypertension During Pregnancy Suchitra Chandrasekaran, MD, MSCE; Martina L. Badell, MD; Denise J. Jamieson, MD, MPH JAMA
  • Original Investigation Dual Combination Therapies in Treatment of Hypertension in a Multinational Cohort Yuan Lu, ScD; Mui Van Zandt, BS; Yun Liu, PhD; Jing Li, MS; Xialin Wang, MS; Yong Chen, PhD; Zhengfeng Chen, MBBS, MMed; Jaehyeong Cho, PhD; Sreemanee Raaj Dorajoo, PhD; Mengling Feng, PhD; Min-Huei Hsu, MD, PhD; Jason C. Hsu, PhD; Usman Iqbal, PharmD, MBA, PhD; Jitendra Jonnagaddala, PhD; Yu-Chuan Li, MD, PhD; Siaw-Teng Liaw, MBBS, PhD; Hong-Seok Lim, MD, PhD; Kee Yuan Ngiam, MBBS, MMed; Phung-Anh Nguyen, PhD; Rae Woong Park, MD, PhD; Nicole Pratt, PhD; Christian Reich, MD, PhD; Sang Youl Rhee, MD; Selva Muthu Kumaran Sathappan, MSc; Seo Jeong Shin, PhD; Hui Xing Tan, MTech; Seng Chan You, MD, PhD; Xin Zhang, MS; Harlan M. Krumholz, MD, SM; Marc A. Suchard, MD, PhD; Hua Xu, PhD JAMA Network Open
  • Original Investigation Lifestyle Coaching vs Enhanced Pharmacotherapy Among Black Adults With Hypertension Mai N. Nguyen-Huynh, MD, MAS; Joseph D. Young, MD; Bruce Ovbiagele, MD; Janet G. Alexander, MSPH; Stacey Alexeeff, PhD; Catherine Lee, PhD; Noelle Blick, MPH; Bette J. Caan, DrPH; Alan S. Go, MD; Stephen Sidney, MD, MPH JAMA Network Open

Importance   Hypertension, defined as persistent systolic blood pressure (SBP) at least 130 mm Hg or diastolic BP (DBP) at least 80 mm Hg, affects approximately 116 million adults in the US and more than 1 billion adults worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (coronary heart disease, heart failure, and stroke) and death.

Observations   First-line therapy for hypertension is lifestyle modification, including weight loss, healthy dietary pattern that includes low sodium and high potassium intake, physical activity, and moderation or elimination of alcohol consumption. The BP-lowering effects of individual lifestyle components are partially additive and enhance the efficacy of pharmacologic therapy. The decision to initiate antihypertensive medication should be based on the level of BP and the presence of high atherosclerotic CVD risk. First-line drug therapy for hypertension consists of a thiazide or thiazidelike diuretic such as hydrochlorothiazide or chlorthalidone, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker such as enalapril or candesartan, and a calcium channel blocker such as amlodipine and should be titrated according to office and home SBP/DBP levels to achieve in most people an SBP/DBP target (<130/80 mm Hg for adults <65 years and SBP <130 mm Hg in adults ≥65 years). Randomized clinical trials have established the efficacy of BP lowering to reduce the risk of CVD morbidity and mortality. An SBP reduction of 10 mm Hg decreases risk of CVD events by approximately 20% to 30%. Despite the benefits of BP control, only 44% of US adults with hypertension have their SBP/DBP controlled to less than 140/90 mm Hg.

Conclusions and Relevance   Hypertension affects approximately 116 million adults in the US and more than 1 billion adults worldwide and is a leading cause of CVD morbidity and mortality. First-line therapy for hypertension is lifestyle modification, consisting of weight loss, dietary sodium reduction and potassium supplementation, healthy dietary pattern, physical activity, and limited alcohol consumption. When drug therapy is required, first-line therapies are thiazide or thiazidelike diuretics, angiotensin-converting enzyme inhibitor or angiotensin receptor blockers, and calcium channel blockers.

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Carey RM , Moran AE , Whelton PK. Treatment of Hypertension : A Review . JAMA. 2022;328(18):1849–1861. doi:10.1001/jama.2022.19590

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  • Published: 15 September 2020

Treatment adherence among patients with hypertension: findings from a cross-sectional study

  • Fahad M. Algabbani 1 &
  • Aljoharah M. Algabbani 2  

Clinical Hypertension volume  26 , Article number:  18 ( 2020 ) Cite this article

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Hypertension is a major risk factor for cardiovascular disease, which is the leading cause of mortality globally. Patient’s adherence to treatment is a cornerstone factor in controlling hypertension and its complications. This study assesses hypertension patients’ adherence to treatment and its associated factors.

This cross-sectional study conducted in Riyadh, Saudi Arabia. The study targeted outpatients aged ≥18 years who were diagnosed with hypertension. Participants were recruited using a systemic sampling technique. The two main measurements were assessing adherence rate of antihypertensive medications using Morisky scale and identifying predictors of poor medication adherence among hypertensive patients including socio-economic and demographic data, health status, clinic visits, medication side effects, medications availability, and knowledge. Descriptive and logistic regression analyses were performed to assess factors associated with poor adherence.

A total of 306 hypertensive outpatients participated in this study. 42.2% of participants were adherent to antihypertensive medications. Almost half of participants (49%) who reported having no comorbidities were adherent to antihypertensive medications compared to participants with one or more than one comorbidities 41, 39% respectively. The presence of comorbid conditions and being on multiple medications were significantly associated with medication adherence ( P -values, respectively, < 0.004, < 0.009). Patients with good knowledge about the disease and its complications were seven times more likely to have good adherence to medication ( P  <  0.001).


Non-adherence to medications is prevalent among a proportion of hypertensive patients which urges continuous monitoring to medication adherence with special attention to at risks groups of patients. Patients with comorbidities and on multiple medications were at high risk of medication non-adherence. Patients’ knowledge on the disease was one of the main associated factors with non-adherence.

Hypertension is one of the most common chronic diseases in Saudi Arabia and a rising health burden, affecting 26.1% adult population [ 1 ]. Hypertension is a major risk factor for heart failure, myocardial infarction, cerebrovascular disease, and renal failure [ 2 ]. Controlling hypertension reduces the risk of cerebrovascular accident (CVA), coronary heart disease, congestive heart failure, and mortality [ 2 , 3 ]. There are several factors that affect blood pressure control. Patients’ adherence to treatment is one of the major factors in controlling blood pressure and preventing hypertension complications [ 3 ]. The World Health Organization (WHO) defines adherence to long-term therapy as “the extent to which a person’s behavior-taking medication, following a diet, and/or executing lifestyle changes-corresponds with agreed recommendations from a healthcare provider” [ 3 ]. Patients with a high level of medication adherence were found to have better blood pressure control [ 4 ]. Still, adherence to hypertension treatment is challenging, due to the asymptomatic nature of the disease [ 5 ].

Several studies investigated the adherence rate among hypertension patients and sociodemographic factors affecting medication adherence including age, gender, comorbidities, patients’ knowledge about the disease, the number of medications. A study conducted in Saudi Arabia showed that only 34.7% of male hypertensive patients were found to be adherent to their medication [ 6 ]. The study reported a negative association between the presence of comorbidities and the adherence level [ 6 ]. A cross-sectional study on medication adherence among patients with hypertension in Malaysia, found an association between adherence and good knowledge of the medications and disease [ 7 ]. The study also found that the increase in the number of drugs patients taking has a negative effect on medication adherence [ 7 ]. Other studies had similar findings regarding the association between the number of medications and adherence [ 8 , 9 , 10 ]. In a cross-sectional study conducted in Iran, older patients reported high adherence to antihypertensive medication and better knowledge of their disease than younger patients [ 9 ]. However, number of studies reported no significant associations between age and medication adherence [ 8 , 11 ]. Female patients were more likely to adhere to their medication, compared to males [ 12 ]. Another study on the prevalence and predictors of poor antihypertensive reported that male patients were more adherent than female patients [ 13 ]. Some studies reported no relationship between gender and adherence [ 9 , 11 ].

Educational level and health literacy were shown to be associated with medication adherence. A cross-sectional study conducted in Iraq showed that adherence decreased in patients with primary and secondary school education, while no significant difference among patients with higher education and undereducated patients [ 14 ]. Similar results found in a systematic review conducted in hypertension management and medication adherence [ 15 ]. On the other hand, no association between educational level and adherence was found in a study conducted in Saudi Arabia [ 8 ]. However, good health knowledge of hypertension shown to be associated with good adherence to medication treatment in several studies [ 7 , 11 ]. Two cross-sectional studies conducted in Turkey and Algeria showed a significant association between knowledge of complications related to hypertension and good adherence to antihypertensive therapy [ 16 , 17 ].

Hypertension is one of the major health issues in Saudi Arabia; affecting more than a quarter of the Saudi adult population [ 1 ]. Only 37% of hypertensive patients on medication have their blood pressure controlled [ 18 ]. Non-adherence to antihypertensive medications is a potential contributing factor to uncontrolled hypertension. With limited studies conducted to investigate this challenging issue, this cross-sectional study aims to assess the adherence rate among hypertensive patients and associated factors affecting adherence to antihypertensive medications.

Study design and sampling

This cross-sectional study was conducted to determine the adherence rate of antihypertensive medications and the predictors of poor medication adherence among hypertensive patients at primary health clinics (PHCs) in Prince Sultan Medical City (PSMMC) in Riyadh the capital city of Saudi Arabia. Single population proportion formula was used to calculate the sample size based on the prevalence of hypertension in Saudi Arabia (26.1%) [ 1 ]. With a 95% confidence level and a 5% margin of error, a total of 306 randomly selected outpatients with hypertension following up at primary health clinics were included in this study.

Participants recruitment

Participants in this study were recruited using a systemic sampling technique. Every fourth consecutive patient who fits the criteria was included. Arabic speaker patients older than 18 years who have been diagnosed with hypertension for more than three months were included in this study. Patients who do not speak Arabic had mental retardation, secondary hypertension, or who were younger than 18 years old were excluded from the study. The data was collected using a self-administered questionnaire that was distributed in the waiting area of the pharmacy. Illiterate participants were interviewed by a trained data collector. Before participants’ recruitment in the study, informed consent was obtained from all patients after a full explanation of the study. The study was approved and supervised by the institution review board (IRB) of Prince Sultan Medical City.


The questionnaire consists of four main sections. The first section assesses participants’ socio-economic factors including age, gender, marital status, occupation, the highest level of education currently attained, occupation, and monthly income. The second section assesses the factors affecting medication adherence including comorbidities, number of medications, number of daily doses, number of clinic visits, the distance to the clinic, medication side effects, medication availability at the pharmacy. The third section aimed to assess patients’ adherence to treatment. The fourth part assesses the patients’ knowledge about hypertension.

Medication adherence was assessed using the 8- items Morisky scale [ 19 ]. Morisky scale has been validated and found to be reliable (α = .83) [ 20 ]. The scale is based on the patients’ self-response and consists of eight questions, seven items with yes or no response, and one item with a 5-point Likert scale response option. The total score ranges from 1 to 8, the patient whose adherence score was six or more is considered adherent. For linguistic validation, questions were translated forward and backward into Arabic by an independent translator.

The participant’s knowledge about hypertension was assessed using nine structured questions. The questions focused on different aspects of hypertension, namely blood pressure target, lifestyle modification effect, complications, treatment, and cure. During analysis, patients who answered < 70% were considered to have low knowledge and patient how answered ≥70% of the questions were considered to have good knowledge. The 70 % cut-off is based on the minimally acceptable level of quality control at PSMMC [ 21 ].

The questionnaire was pre-tested and then a pilot survey was conducted on 20 patients for clarity and feasibility. The questionnaire was also evaluated and reviewed by two independent family medicine consultants at Prince Sultan Medical City for validation.

Data analysis

Frequencies and percentages were used to assess participants’ characteristics. Chi-square analysis was used to determine the association between demographic, socioeconomic, and clinical factors with medication adherence. Logistic regression analysis was performed to assess factors associated with poor adherence. The variables were analyzed collectively using logistic regression to study the potential factors to avoid confounding bias. The association was considered statistically significant if the P -value was less than 0.05. Statistical Package for Social Sciences version 25 and Statistical Analysis System version 9.4 was used for data analysis.

A total of 306 outpatients who have hypertension participated in this study. Approximately 43% of the participants’ ages range was between 56 and 65. The majority of participants were married (92%), employed (61%), and had a high school diploma or above (80%). Most of the participants were middle income in the 5000–10,000 Saudi Riyal range of monthly income. Nearly one-third (28.1%) of the respondents in this study had no comorbidities while two-thirds reported having one or more comorbidities. The demographic, and socioeconomic clinical characteristics of the participants are presented in Table  1 .

Only 13% of the respondents live at a distance of less than half an hour from the clinic. Of the total participants, 14.1% reported visiting the primary health clinic once in the last year, 29.4% twice, 24.2% three times. The majority of participants reported taking less than four medications a day and 31.4% reported taking four or more medications a day. As to antihypertensive medication side effects, 19.6% reported having medication side effects. Only 4.9% of the participants reported that they stop taking their antihypertensive medications when they get sick. Approximately 9% of the participants reported that they stop taking their medications when it is not available at the pharmacy. Findings show that half (50.7%) of the participants were knowledgeable about the disease. The clinical characteristics of the participants are presented in Table 1 .

Figure  1 presents the percentage of participants’ adherence to antihypertensive treatment. Based on Morisky scale test results, 42.2% of the participants in this study were adherent to antihypertensive medications, while 57.8% were not adherent.

figure 1

Distribution of patients according to their medication adherence status*

Table  2 presents the adherence rate in relation to the participants’ demographic, socioeconomic, and clinical characteristics. The presence of comorbid conditions is significantly associated with medication adherence ( P  <  0.001). Almost half of participants (49%) who reported having no comorbidities were adherent to antihypertensive medications compared to the participants with one or more than one comorbidities 41, 39% respectively. As for the number of medications, the adherence rate was found to be better among patients who were taking less than four medications (47.1%) compared to patients who were taking four or more medications (31.3%). Patients who visited the clinic once in the last year were more adherent than those who visited the clinic more than once ( p  < 0.05). No significant association between age, gender, income, educational level, and distance from home to the clinic.

The participants were asked eight questions about hypertension. Table  3 shows the distribution of the correct and incorrect answers giving by the participants. Most participants (64.4%) knew the target blood pressure for hypertensive patients and 40.8% think that hypertension can be cured. The majority (78%) knew that a low salt diet helps in lowering high blood pressure. Only 61% knew that hypertension can affect eyes and 13.4% reported that they stop taking their medication when they feel their blood pressure under control.

Adherence to antihypertensive medications among patients with good and poor knowledge levels about hypertension was assessed based on nine structured questions. Figure  2 shows the adherence to hypertension treatment among patients with good and poor knowledge level. 57.4% of patients with good knowledge levels were adherent compared to 42.6% who were not adherent. The majority (73.5%) of patients with poor knowledge levels were not adherent to treatment.

figure 2

Adherence to hypertension treatment among patients with good and poor knowledge level*

Table  4 presents the factors associated with good adherence. When conducting binary logistic regression, knowledge about the disease was found to be significantly associated with adherence. Patients with good knowledge about the disease were seven times more likely to have good adherence to antihypertensive medications than those with poor knowledge (AOR 7.4 [95% CI: 4.177–13.121], p  < 0.001).

Several studies have investigated factors affecting medication adherence. This study shows that the level of adherence to antihypertensive medications is low. In this sample the adherence rate to hypertension treatment was found to be only 42%, which is similar to the study conducted in Al-Khobar and higher than the study conducted in Taif where adherence rate was found to be 47 and 34.7%, respectively [ 6 , 8 ]. Other studies conducted in different countries reported adherence rates ranging from 15 to 88% [ 22 , 23 , 24 , 25 ]. This discrepancy in adherence rate is potentially due to the differences in population characteristics, medication adherence assessment tools, and healthcare systems.

The association between sociodemographic and socioeconomic factors and adherence level has been investigated in several studies. In a study done in Hong Kong, older patients were found to be more adherent. However, in this study, there was no association between age and adherence. In another study done in the United States, female patients were less adherent to hypertension medication compared to male patients [ 13 ]. A study conducted in Malaysia reported that female patients were more adherent than male patients [ 22 ]. Our study showed that there was no significant relationship between gender and adherence. A meta-analysis suggested that the association between age, gender, and adherence level is weak [ 26 ]. The results of our study also demonstrate no significant relationship between marital status and educational level with adherence, which is similar to findings reported by other studies [ 9 , 27 ].

Previous research found that shorter traveling time from residence to the healthcare facility could increase patients’ adherence [ 28 ]. A study in Ethiopia found that the adherence level was lower in patients who lived more than 10 km from healthcare facilities [ 29 ]. A cross-sectional observational study done in Northwest Ethiopia indicated that patients who live less than 10 km from the healthcare facility had an adherence rate of 74% compared to 58% for patients who live far from the healthcare facility [ 29 ]. As the authors attributed this problem to poor infrastructure and lack of transportation in Ethiopia, the study suggested that shorter traveling time from residence to the healthcare facility could increase patients’ adherence [ 29 ]. In this study, distance from home to the clinic was not associated with hypertensive treatment. These differences may be due to the higher level of car ownership in Saudis Arabia which makes it easier to access health care facilities [ 30 ].

Only 8.8% of the participants reported not taking their medication when it is not available at the hospital pharmacy. This low percentage may be explained by the multiple community health centers in Saudi Arabia which provide free health care including medications dispensing. Moreover, the medication cost at private pharmacies in Saudi Arabia is affordable for most patients. According to the published Saudi Hypertension Management Guidelines the prices of the antihypertensive medications ranges between 7 to 118 Saudi Riyal (about 2 to 31 US Dollar) [ 31 ].

Many patients with hypertension will need two or more antihypertensive medications to achieve goal blood pressure [ 2 ]. In this sample significant association was observed between the number of medications and adherence level. The adherence rate among patients taking less than four medications was 47.1% compared to 31.3% to those who take four or more medications. Similarly, other studies reported the negative association between the number of medication and adherence levels [ 29 , 32 ].

Findings indicate that patients with multiple comorbidities were less adherent to antihypertensive medication, which is inconsistent with a previous study done in Taif which showed a negative association between the presence of comorbidity and adherence level [ 6 ]. This may be related to the fact that most patients with multiple comorbidities require taking multiple complex medications.

The result of our study showed that the patient who visited the clinic once in the last year were more adherent than the patient who visited the clinic more than once. This could be explained by that most patients with multiple comorbidities and on multiple medications frequently visit the clinic for issues related to their disease and to refill prescriptions.

Our study demonstrated the positive association between knowledge and adherence levels. Patients who had good knowledge were more adherent to the treatment [ 29 ]. Previous studies showed that patients who know the ideal target blood pressure level were more adherent to their medications [ 16 , 20 ]. In this study, only 64.4% of the participants knew the ideal target of blood pressure and 40.8% of the patients believe that hypertension can be cured. A study conducted in Rajshahi, Bangladesh found that 65.8% of the patients believe that hypertension is curable. Patients how have been educated by their physicians and healthcare providers were more adherents to treatment as they have a better understanding of the disease nature, the ideal target of blood pressure, and the complications of hypertension [ 33 ]. Therefore, patient education in disease nature and management is considered a key factor in the treatment of hypertension.

The study findings were based on self-reported survey. Self-reported data is a common method used in a cross-sectional study. However, self-reported data is subjected to biases such as response and recall biases that can lead to under- or overestimation of findings. On the other hand, adherence in this study was measured based on a validated self-report adherence scale and knowledge was tested based on evaluated and reviewed assessment items by two independent family medicine consultants. Moreover, this study conducted in one of the largest medical cities that serves a large community in the capital city Riyadh. Due to the study design and sampling method, study findings cannot be generalized and temporal relationships cannot be established between risk factors and adherence. Nevertheless, this study provides a snapshot of adherence to antihypertensive medication status and associated determinates among outpatients. Future large scale longitudinal studies will contribute to a better understanding of adherence status and associated factors among hypertensive patients.

Non-adherence to medications is prevalent in proportion of patients with hypertension. Therefore, there is an urge to continually monitor patients’ adherence to antihypertensive medication using a standardized scale. Patients with comorbidities and on multiple medications were at higher risk of non-adherence. There is a need to encourage patients on multiple medications to use adherence aids such as weekly pill organizers and medication alarm devices. Hypertensive patients’ knowledge of the disease and its complications was one of the main factors affecting patients’ adherence to treatment. Implementation of health awareness interventions and education programs intended for hypertensive patients will help improve medication adherence.

Availability of data and materials

The data sets generated during and/or analyzed during the current study are available from the corresponding authors on reasonable request.


Adjusted odd ratio

Confidence interval

Blood pressure

Prince Sultan Medical City

primary health clinic

institution review board

Cerebrovascular accident

The World Health Organization

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The study design was conceptualized by FA and AA. Data collection was managed by FA and data analysis and interpretation were conducted by FA and AA. All authors participated in writing and editing the manuscript. All authors read and approved the final manuscript.

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Algabbani, F.M., Algabbani, A.M. Treatment adherence among patients with hypertension: findings from a cross-sectional study. Clin Hypertens 26 , 18 (2020). https://doi.org/10.1186/s40885-020-00151-1

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Hypertension literature review

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Anggi L Wicaksana , Anggi L Wicaksana

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Hypertension means high pressure in the arteries; it is commonly known as high blood pressure. Blood pressure from 120/80 mmHg to 139/89 mmHg is called pre-hypertension, blood pressure greater than or equal to 140/90 mmHg is considered high. Elevated systolic and/or diastolic blood pressure increases the risk of developing heart disease, kidney disease, hardening of the arteries, eye damage and stroke. These complications of hypertension are often called target organ damage, because damage to these organs is the end result of chronic high blood pressure. Most people with hypertension do not have any symptoms in the early stages, symptoms only appear after target organs are damaged. These symptoms are usually due to target organ damage and their manifestations depend on the affected organ. For this reason, regular screening of people with symptoms is essential for early diagnosis, treatment, and control of high blood pressure. Early diagnosis, treatment, and optimal control of hypertension are essential to reduce morbidity and mortality from hypertension-related diseases. A family history of hypertension shows that people with high blood pressure are nearly 6 times more likely to have high blood pressure than people with high blood pressure. People without the disease and those with high income levels are three times more likely to have high blood pressure. The greater the body mass, the more blood is needed to supply oxygen and nutrients to muscles and other tissues. Salt consumption and hypertension Sodium and salt intake remains controversial as a risk factor for hypertension, although it is true that some people are particularly sensitive to sodium. Physical activity and hypertension Inactive adolescents are more likely to have high blood pressure. Excessive consumption of saturated fatty acids and trans fatty acids is a risk factor for cardiovascular diseases, including hypertension.

International Journal of Community Medicine and Public Health Anwar S et al. Int J Community Med Public Health. 2019 Feb;6(2):488-494 http://www.ijcmph.com

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Background: According to the Oman World Health Survey in 2008, the prevalence of hypertension in Oman is about 40%. Hypertension is associated with old people, male gender, smoker and impaired glucose tolerance. The objective of the study was to find out the important predictors of hypertension in Oman. Methods: A cross sectional study in Omani adults more than 18 years of age was conducted. Blood pressure was measured and participants were classified as having hypertension. Height and weight was measured and body mass index was used to classify obesity by WHO guidelines. Multiple logistic regression was used to find the predictors of hypertension. Results: Increase in age and body mass index were found to be important covariates of hypertension. People in the age group of 30 to 50 years were at high risk of hypertension (OR 1.6, p<0.05); likelihood increased to three times in more than 50 years age group (p<0.01) in univariate analysis. Overweight had almost 2 times (p<0.05) and obese had five times (p<0.01) more likelihood of hypertension than normal weight people. People with less education had more likelihood of hypertension. Smokers (OR 2.9, p<0.01) and males (OR 1.5, p<0.05) were at a higher risk of hypertension than non-smokers and females in multivariate analysis. Percentage accuracy of classification was 67.4%. Conclusions: Age more than 50 years, male gender, BMI more than 30 and smoking were important predictors of hypertension in the study population. Keywords: Hypertension, Predictors, Obesity, Smoking, Overweight

Opaleke S Sketcher

This seminar report comprises of the introduction to hypertension, the history of hypertension, prognosis and the aims and objective in chapter one, chapter two is on the literature review which entails the causes of hypertension, the sign and symptoms and the hypertension diagnosis, and chapter three entails the treatment or management of hypertension and the prevention of hypertension and chapter four covers the conclusion and recommendation.

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Prevalence, risk factors and awareness of hypertension in India: a systematic review

  • P Devi 1 , 2 ,
  • M Rao 1 , 2 ,
  • A Sigamani 1 , 2 ,
  • A Faruqui 1 , 2 ,
  • R Gupta 3 ,
  • P Kerkar 4 ,
  • R K Jain 5 ,
  • R Joshi 6   nAff14 ,
  • N Chidambaram 7 ,
  • D S Rao 8 ,
  • S Thanikachalam 9 ,
  • S S Iyengar 10 ,
  • K Verghese 11 ,
  • V Mohan 12 ,
  • P Pais 2 , 13 &
  • D Xavier 1 , 2  

Journal of Human Hypertension volume  27 ,  pages 281–287 ( 2013 ) Cite this article

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  • Epidemiology
  • Hypertension
  • Risk factors

Indians have high rates of cardiovascular disease. Hypertension (HTN) is an important modifiable risk factor. There are no comprehensive reviews or a nationally representative study of the burden, treatments and outcomes of HTN in India. A systematic review was conducted to study the trends in prevalence, risk factors and awareness of HTN in India. We searched MEDLINE from January 1969 to July 2011 using prespecified medical subject heading (MeSH) terms. Of 3372 studies, 206 were included for data extraction and 174 were observational studies. Prevalence was reported in 48 studies with sample size varying from 206 to 167 331. A significant positive trend ( P <0.0001) was observed over time in prevalence of HTN by region and gender. Awareness and control of HTN (11 studies) ranged from 20 to 54% and 7.5 to 25%, respectively. Increasing age, body mass index, smoking, diabetes and extra salt intake were common risk factors. In conclusion, from this systematic review, we record an increasing trend in prevalence of HTN in India by region and gender. The awareness of HTN in India is low with suboptimal control rates. There are few long-term studies to assess outcomes. Good quality long-term studies will help to understand HTN better and implement effective prevention and management programs.

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We acknowledge the contribution of Ms Puneet Kaur and Ms Nidhi Rai, from the Division of Clinical Trials, St John’s Research Institute for their assistance in literature search and data extraction. We also thank Mrs Nisha George and Mrs Seena Thomas, statisticians at St John’s Research Institute, Bangalore for their contributions. This work was supported by an unrestricted educational grant from AstraZeneca, India.

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Present address: 14Current address: Department of Medicine, Sikkim Manipal Institute of Medical Sciences, Gangtok, Sikkim, India.,

Authors and Affiliations

Department of Pharmacology, Division of Clinical Trials, St John’s Medical College, St John's Research Institute, St John’s National Academy of Health Sciences, Bangalore, India

P Devi, M Rao, A Sigamani, A Faruqui, M Jose & D Xavier

Division of Clinical Trials, St John’s Research Institute, Bangalore, India

P Devi, M Rao, A Sigamani, A Faruqui, P Pais & D Xavier

Department of Medicine, Fortis Escorts Hospital, Jaipur, India

Department of Cardiology, KEM Hospital, Mumbai, India

Department of Cardiology, Krishna Institute of Medical Sciences, Secunderabad, India

Department of Medicine, Mahatma Gandhi Institute of Medical Sciences, Wardha, India

Department of Medicine, Rajah Muthiah Medical College, Annamalainagar, India

N Chidambaram

Department of Cardiology, Krishna Institute of Medical Sciences, Hyderabad, India

Cardiac Care Centre, Sri Ramachandra University, Chennai, India

S Thanikachalam

Department of Cardiology, Manipal Hospital, Bangalore, India

S S Iyengar

Department of Cardiology, St John’s Medical College, Bangalore, India

Dr Mohan’s Diabetes Specialities Centre and Madras Diabetes Research Foundation, Chennai, India

Department of Medicine, St John’s Medical College, Bangalore, India

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Correspondence to D Xavier .

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Competing interests.

Drs Xavier, Pais and Sigamani have received research funds from AstraZeneca, India. Dr Pais has received consultancy fees from AstraZeneca. All the three of them received these funds in to the Institution (St John’s) account. Remaining authors declare no conflict of interest.

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Devi, P., Rao, M., Sigamani, A. et al. Prevalence, risk factors and awareness of hypertension in India: a systematic review. J Hum Hypertens 27 , 281–287 (2013). https://doi.org/10.1038/jhh.2012.33

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Received : 23 May 2012

Revised : 09 July 2012

Accepted : 18 July 2012

Published : 13 September 2012

Issue Date : May 2013

DOI : https://doi.org/10.1038/jhh.2012.33

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Revisiting Hypertension Treatment in Patients With Chronic Kidney Disease


  • 1 Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, CA.
  • 2 Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, CA. Electronic address: [email protected].
  • PMID: 38735770
  • DOI: 10.1016/j.semnephrol.2024.151514

Despite being the world's top risk factor for death and disability, hypertension awareness and control within the chronic kidney disease (CKD) population have decreased. This is particularly important considering the heightened severity and management challenges of hypertension in CKD patients, whose outcomes are often worse compared with persons with normal kidney function. Therefore, finding novel therapeutics to improve blood pressure control within this vulnerable group is paramount. Although medications that target the renin-angiotensin-aldosterone system remain a mainstay for blood pressure control in most stages of CKD, we discuss novel approaches that may expand their use in advanced CKD. We also review newer tools for blood pressure management that have emerged in recent years, including aldosterone synthase inhibitors, endothelin receptor antagonists, and renal denervation. Overall, the future of hypertension management in CKD appears brighter, with a growing arsenal of tools and a deeper understanding of this complex disease.

Keywords: CKD; Chronic kidney disease; RAS inhibitors; high blood pressure; hypertension; nephrology.

Copyright © 2024 Elsevier Inc. All rights reserved.

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  • Sam Amin 1 ,
  • http://orcid.org/0000-0002-1114-8495 Marie Monaghan 1 ,
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  • http://orcid.org/0000-0001-5207-5731 William P Whitehouse 7 , 7 ,
  • http://orcid.org/0000-0001-6937-3399 Deepa Krishnakumar 8
  • 1 University Hospitals Bristol and Weston NHS Foundation Trust , Bristol , UK
  • 2 NHS Greater Glasgow and Clyde , Glasgow , UK
  • 3 Cambridge University Hospitals NHS Foundation Trust , Cambridge , UK
  • 4 Hull University Teaching Hospitals NHS Trust , Hull , UK
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  • 7 School of Human Development , University of Nottingham , Nottingham , UK
  • 8 Addenbrooke's Hospital , Cambridge , UK
  • Correspondence to Dr Marie Monaghan, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK; marie.monaghan{at}uhbw.nhs.uk

Background Idiopathic intracranial hypertension (IIH) is a potentially disabling condition. There is a lack of evidence and national guidance on how to diagnose and treat paediatric IIH, leading to variation in clinical practice. We conducted a national Delphi consensus via the Children’s Headache Network to propose a best-practice diagnostic and therapeutic pathway.

Methods The Delphi process was selected as the most appropriate methodology for examining current opinion among experts in the UK. 104 questions were considered by 66 healthcare professionals, addressing important aspects of IIH care: assessment, diagnosis, treatment, follow-up and surveillance. General paediatricians, paediatric neurologists, ophthalmologists, opticians, neuroradiologists and neurosurgeons with a clinical interest or experience in IIH, were invited to take part.

Results The Delphi process consisted of three rounds comprising 104 questions (round 1, 67; round 2, 24; round 3 (ophthalmological), 13) and was completed between March 2019 and August 2021. There were 54 and 65 responders in the first and second rounds, respectively. The Delphi was endorsed by the Royal College of Ophthalmologists, which engaged 59 ophthalmologists for round 3.

Conclusions This UK-based Delphi consensus process reached agreement for the management of paediatric IIH and has been endorsed by the Children’s Headache Network and more broadly, the British Paediatric Neurology Association. It provides a basis for a pragmatic clinical approach. The recommendations will help to improve clinical care while minimising under and over diagnosis.

  • Paediatrics
  • Primary Health Care
  • Ophthalmology
  • Neurosurgery

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.


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The Incidence of paediatric idiopathic intracranial hypertension (IIH) is increasing.

Absence of randomised controlled trials on the management of paediatric IIH.

Management of IIH depends on treating physician, local/national policies and funding.


Recommendations to guide the management of paediatric IIH based on consensus.

The recommendations are pragmatic and can be implemented in most healthcare systems around the world.


These new UK guidelines for the management and surveillance of IIH provide consensus guidance for the delivery of the best clinical care.

The results will help policymakers and planners to plan and allocate budgets for the management of patients with IIH.


Idiopathic intracranial hypertension (IIH) is characterised by elevated cerebrospinal fluid (CSF) pressure, without a known cause, typically presenting with headaches and visual disturbance and papilloedema, but otherwise normal neurological examination. 1 The most reported symptom, in 75–99% of cases, is headache. 2

Pseudotumour cerebri syndrome (PTCS) is an alternative term, encompassing secondary causes. 3 The condition was first reported in the late 19th century by Heinrich Quincke who believed the condition was due to overproduction of CSF. 4 The condition saw several name changes; ‘pseudotumor cerebri’ in 1904, 5 and later, ‘benign intracranial hypertension’(1955), prior to reports of visual loss, invalidating ‘benign’. Subsequently referred to as PTCS or IIH. 4

The classical modified Dandy criteria, 6 suggest that for a diagnosis of IIH, an individual must have: (1) symptoms of increased intracranial pressure (ICP); (2) a lack of localising neurological signs, except for unilateral or bilateral sixth nerve palsies; (3) increased CSF opening pressure with normal CSF; (4) normal brain imaging with no hydrocephalus; and (5) no other cause of raised ICP. Some have suggested that these criteria are sufficient. 7

Alternative criteria are Friedman’s criteria. 3 Per Friedman’s criteria ( online supplemental table 1 ), 3 required features for a definite diagnosis of IIH are;

Supplemental material


Normal neurological examination except for cranial nerve abnormalities.

Neuroimaging: Normal brain parenchyma without evidence of hydrocephalus, mass or structural lesion and no abnormal meningeal enhancement on MRI, with and without gadolinium, for typical patients (women and obese) and MRI, with and without gadolinium, and magnetic resonance venogram (MRV) for others; if MRI is unavailable or contraindicated, contrast-enhanced CT may be used.

Normal CSF composition.

Elevated lumbar puncture opening pressure (≥280 mm CSF in children (250 mm CSF if the child is not sedated and not obese)) in a properly performed lumbar puncture.

A diagnosis of IIH can still be made based on the Friedman’s criteria if there is an absence of papilloedema, as long as there is an abducens nerve palsy and all of the criteria B–E. IIH can also be diagnosed if criteria B–E are met, in combination with at least three of four of the following neuroimaging criteria:

Empty sella.

Flattening of the posterior aspect of the globe.

Distension of the perioptic subarachnoid space with or without a tortuous optic nerve.

Transverse venous sinus stenosis.

A ‘probable’ diagnosis is possible if criteria A–D are met, with bilateral papilloedema, even if the CSF pressure (criterion E) is not diagnostically elevated.

IIH requires the absence of underlying structural causes, such as malignancies or autoimmune conditions. Neuroimaging findings, if any, include secondary empty sella syndrome, 8 flattened globes, abnormal optic nerve sheaths, optic nerve protrusion, posterior globe flattening, and transverse sinus stenosis. 9 10

A cohort-based UK study found an incidence of IIH of 0.71 per 100 000 in ages 1–16 years, increasing with age and weight to 4.18 and 10.7 per 100 000 in obese 12–15 years old boys and girls, respectively. 11 The estimated incidence in the paediatric population ranges from 0.17 to 1.32 per 100 000 children. 12 13

The goals of treatment are the preservation of vision and the amelioration of headaches. In adults, weight control is effective. 14 15 Medication typically consists of acetazolamide or topiramate. Research on topiramate’s effect on weight loss may be beneficial, though yet to be demonstrated in larger studies. 16

Surgical options consist of CSF diversion (eg, by ventriculoperitoneal shunt (VPS), lumboperitonral shunt, optic nerve sheath fenestration (ONSF), or venous sinus stenting (VSS). Interventions are decided on symptomatic presentation, degree of visual loss 17 and local availability. The role of lumbar puncture (LP) has been explored both diagnostically and therapeutically. 18 Doubts about the efficacy of LPs 19 have led to an interest in surgical options. There remains uncertainty as to the practical method of pressure measurement and the clinical response to elevated pressures.

In the absence of randomised control trials on the management of paediatric IIH, this triple-round Delphi study reviewed paediatric IIH diagnosis, investigation and management, aiming to provide clinicians with recommendations from experienced professionals. This study follows international consensus recommendations in the adult population. 20

Study design Delphi

An Ovid literature search was performed to inform the Delphi survey. The output included paediatric IIH-related mortality, morbidities, diagnosis, treatment and surveillance. A core group was established through the British Paediatric Neurology Association Childhood Headache Network specialist interest group. This group consisted of 11 experts including paediatric neurologists, paediatricians and ophthalmologists, who reviewed the literature, selected questions and consulted patient groups during the process.

Delphi consensus method

A Delphi process provides consensus recommendations. At least 15–20 expert participants are recommended. 21 Thresholds may be as low as 51%, 22 though higher may be preferred. 23 Predefined thresholds reduce the potential for bias. 24 For this Delphi, a priori consensus was defined as 70% agreement. The analysis excluded responses of ‘do not know’ or ‘do not feel qualified to answer’.

The core group included paediatric: neurologists, ophthalmologists, neurodisability specialists, community paediatricians, general paediatricians, neurosurgeons, neuroradiologists and other representatives of IIH management. All were sent a weekly reminder for 3 months. No questions were repeated in subsequent rounds. Questions in the second and third rounds were derived from answers obtained from the previous round.

Three rounds were performed. In the first round, there were 67 questions, following which the core group decided areas needing further clarification, and set new questions for the second round. In the second round, 24 questions were posed. The questions in round 2 were refinements based on answers from round 1. After round 2, there was no repeat of earlier rounds. Round 3 specifically targeted ophthalmologists as the questions were relevant to their specialty and expertise. The Delphi was endorsed by the Royal College of Ophthalmologists, with round 3 sent to UK paediatric ophthalmologists, via their network. 13 ophthalmological questions were asked. No invited responder was excluded from any rounds.

Survey respondents

In round 1, 114 email invitations were sent and 54 responders completed the survey. These comprised paediatric neurologists 33 (61%), general paediatricians 5 (9%), neurosurgeons 5 (9%), ophthalmologists 4 (7%), neuroradiologists 2 (4%), a general paediatrician with a special interest in neurology (2%), an optometrist (2%), a community paediatrician (2%) and a patient group representative (2%). In Round 2, 127 email invitations were sent and 65 responders completed the survey. In Round 3, 59 paediatric ophthalmologists completed the survey.

The following includes recommendations derived from areas of consensus (recommendations summarised in online supplemental table 2 ), all survey questions and findings in online supplemental table 3 ).


The condition should be referred to as ‘Idiopathic Intracranial Hypertension’.

Timing of initial assessment—for patients with possible IIH, without red flags

Patients should be seen in the hospital for diagnosis and further management within two weeks.

Recording of auxology

A patient’s weight and height should be checked at baseline and their body mass index (BMI) and BMI centile chart recorded, with Royal College of Paediatrics and Child Health (RCPCH) Growth Charts (UK-WHO). 25 Patients with suspected/confirmed IIH should be assessed for obstructive sleep apnoea if clinically indicated.

Diagnostic criteria

Friedman’s diagnostic criteria should be used for the diagnosis of IIH ( online supplemental table 1 ).

LP and CSF pressure related to diagnosis of IIH

If suspected IIH, LP should be performed for diagnosis, unless contraindicated.

In cases of acute visual loss associated with suspected IIH, perform the first LP (if no contraindications) ‘within 48 hours’.

LP opening pressure <20 cm CSF (15 mm Hg) indicates normal CSF pressure.

A transducer should be used to record CSF pressure, if available.


Children with suspected raised ICP (early morning headache vomiting/visual disturbance/focal neurology) should have neuroimaging, ideally MRI (or CT, if unavailable) within 24 hours.

Children with suspected IIH with normal vision should have a brain MRI scan unless contraindicated.

Children with suspected IIH should have an MRI and MRV within 7 days.

MDT meetings for diagnosis of IIH

Those who did not meet the diagnostic criteria but had features of IIH should be discussed at a multidisciplinary team (MDT) meeting involving paediatric neurologists, ophthalmologists and neuroradiologists.

The minimum age for a diagnosis of IIH without prompting discussion at an MDT meeting was selected as 10 years.

Baseline laboratory investigations: thyroid function tests, sodium, potassium, creatinine, urea, liver function, calcium, phosphate, magnesium, glucose, vitamin D, and full blood count.

Children with BMI >25 kg/m 2 should have a lipid profile test at baseline.

Ophthalmological assessment

B-scan should be done at baseline where available. Opticians should refer children with suspected papilloedema urgently to an ophthalmologist.

Children should:

be seen by an ophthalmologist with training and expertise in paediatric ophthalmology.

have a detailed ophthalmological assessment, including visual fields, colour vision and visual acuity.

have a baseline optical coherence tomography scan for diagnosis and monitoring

be reviewed by an ophthalmologist, once they have started medical treatment for IIH, 3–6 monthly.

In IIH with severe grade 4 papilloedema where vision is threatened, neurosurgical options such as VPS should be considered as emergency treatment.

A regional MDT discussion for children with suspected IIH should be held which comprises paediatricians, and/or paediatric neurologists and ophthalmologists.

LP assessment of CSF pressure: method for LP

A 10–20 min online training resource on LP for IIH would be useful.

Families should be informed about the potential complications of LP.

During LP, a conscious patient should have their knees and hips flexed.

Patients should be positioned in the left lateral decubitus position.

Patients with suspected/confirmed IIH do not need to have their clotting checked before their LP unless clinically indicated.

CSF pressure should not be measured until the CSF stops rising in the manometer tube.

CSF should be sent for microscopy, glucose and protein at the time of the first LP in suspected IIH.

CSF should be sent for autoimmune screen (aquaporin and myelin oligodendrocyte glycoprotein (MOG) antibodies) and/or cytology at the time of first LP in suspected IIH only if clinically indicated.

LP assessment of CSF pressure with local or general anaesthetic

Local anaesthetic can be used for LP.

Patients having an LP under General Anaesthetic (GA), should have their GA medications documented.

Patients with suspected IIH should have their end-tidal carbon dioxide level checked during LP under GA (*reason given in online supplemental table 4 ). Patients with suspected IIH should have their end-tidal carbon dioxide level maintained within the normal reference range, at the discretion of attending anaesthetists.

Management: therapeutic LP

CSF pressure, if over 28 cm CSF (21 mm Hg) should be reduced down to 20–25 cm CSF (15–18 mm Hg).

The maximum number of (therapeutic) LPs a patient should have over the course of their illness is five, as other therapeutic options should be instigated before this point.

Management: weight management

A dietetic service should be available for weight management for patients with IIH.

Overweight or obese patients with IIH should be referred to a dietician for weight management or to a weight management team.

Management: first-line therapy in patients with IIH who do not have visual impairment

There was no consensus on medical management but the most selected answer by 46% of responders was that acetazolamide should be considered for all patients as first-line medical treatment, regardless of their BMI. This did not reach the threshold for consensus. The leading answer after ‘acetazolamide’ (46%) or ‘other’ (26%) was ‘information, general advice, safety netting but no drug treatment for now’ (18%). A minority of respondents supported topiramate (4%), no intervention (4%) or surgical approaches (2%).

Management: first-line therapy in patients with new visual impairment/loss of vision

If a patient is taking acetazolamide, blood urea, electrolytes and bicarbonate levels should be checked. Bicarbonate should be corrected when the value is equal to or lower than 18 mmol/L.

Management: second line

Repeated therapeutic LP should be offered when visual changes progress and there is a threat to vision on medical management and/or when symptoms are not responsive to medical management.

Management: neurosurgical

ICP bolt monitoring for 48 hours should be considered for patients with persistently raised LP opening pressure measurements (on two LPs) and papilloedema.

VSS should be considered if there is evidence of stenosis of the dominant venous sinus.

The three rounds of questions revealed areas of consensus, namely in the timing of the first assessment, auxological measurements, neuroimaging, ophthalmological assessments, aspects of management and the role of a regional MDT. The use of Friedman’s criteria ( online supplemental table 1 ) 3 was recommended, which facilitates making a diagnosis based on clinical signs and neuroimaging criteria.

Areas lacking consensus

Areas of non-consensus ( online supplemental table 4 ) included interpretation of values of CSF pressure, laboratory investigations, grading of papilloedema, aspects of LP methodology and neurosurgical management. ONSF was not supported. Historically, ONSF was considered an emergency procedure for sight preservation in IIH. 26 We question the relative indications in children, versus CSF diversion strategies, for example, VPS. 27 28 VSS has been a treatment option in adults 29 but there are no randomised control trials comparing ONSF, CSF diversion, and VSS and evidence in paediatrics is lacking.

There was no consensus on medical management though acetazolamide was the most selected response (46%) for first-line medical treatment, regardless of patient BMI. Following discussion by the Delphi working group, and exploration of the comments offered for respondents who had selected ‘other’ (eg, confirming a diagnostic/therapeutic LP had been performed, and weight management was happening in parallel), a recommendation was made for acetazolamide to be considered as first-line therapy. The recommendation is based on interpretation of the offered comments rather than consensus and is therefore an exception to the goals of the Delphi method.

Thematic agreement

Occasionally thematic agreement was identified. ‘When should the CSF pressure be read on the manometer?’ was answered by most as, ‘When the CSF stops rising in the manometer tube’ (38 responses, 81%). In round 2, ‘When should the CSF pressure be read on the manometer after the CSF stops rising?’, the leading response was ‘As soon as it stops rising’ (25 responses, 50%), followed by ‘other’ (12 responses, 24%) and ‘after 5 min’ (10 responses, 20%).

Similarly, ‘If the CSF pressure is high, should it be reduced until normal CSF pressure is achieved?”. Most responded in favour (25 responses, 57%) with some selecting ‘other’ (13 responses, 29%). Only six disagreed, suggesting 86% felt high CSF pressure should be reduced by some amount.

To manage uncertainty, we propose discussion within a regional and if required, national IIH MDT. An MDT meeting may assist in confirming diagnosis, as has been described in the UK. 30

Limitations of survey

For future studies, we propose care over question construction and methods of assessing consensus. We would recommend strategies aimed at increasing enrolment and response rate. Targeted invitations to neurosurgeons would be beneficial. The Delphi survey invited responses from UK-based professionals experienced in paediatric IIH. Due to this limited professional pool, response rates were variable, particularly in more specialist areas. Response trends based on the location of respondents and the reproducibility of responses were not assessed.

Ambiguous or uncontextualised question wording may also have affected interpretation, for example, ‘Is an LP opening pressure of greater than 28 cm CSF to be considered as diagnostic for IIH?’. Most agreed (27 responses, 56.3%) however ‘no’ may have been selected as raised ICP alone is insufficient for diagnosis and the threshold of 28 cm CSF was not contextualised. While thematic agreement was noted, such evaluation was not a primary aim, rendering interpretation subjective.

This Delphi process supplies practical guidance for clinicians aiming to improve the quality of care and service provision for children under investigation for IIH. The summary of recommendations ( online supplemental table 2 ) provides a structured approach to guide the management of paediatric IIH, referencing Friedman’s criteria ( online supplemental table 1 ). The survey findings ( online supplemental table 3 ) provides a breakdown of the areas discussed, and whether consensus was identified. This survey and its recommendations form the basis for (1) a nationally endorsed guideline, (2) a clinical audit and (3) further research to improve outcomes in paediatric IIH. The recommendations are pragmatic and can be implemented in most healthcare systems around the world.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

  • Data supplement 1
  • Data supplement 2
  • Data supplement 3
  • Data supplement 4

X @docvishalmehta

Collaborators N/A.

Contributors All individuals listed as authors meet the appropriate authorship criteria, and nobody who qualifies for authorship has been omitted from the list. The authors and contributors have approved the acknowledgement of their contributions. All the authors had complete access to the study data that supports the publication. SA, KF, PH, VM, BMukhtyar, BMuthusamy, AP, PP, WPW and DK designed the questionnaire, analysed the data and drafted the manuscript. MMonaghan and MMoran analysed the data and drafted the manuscript. SAmin is guarantor.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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  • Case report
  • Open access
  • Published: 14 May 2024

Portal vein thrombosis as extraintestinal complications of Crohn’s disease: a case report and review of literature

  • Marouf Alhalabi   ORCID: orcid.org/0000-0001-5027-2096 1 ,
  • Duaa Nasri 1 &
  • Widad Aji 1  

Journal of Medical Case Reports volume  18 , Article number:  246 ( 2024 ) Cite this article

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Thrombotic events are more than twice as common in inflammatory bowel disease patients as in the general population. We report an interesting and rare case of portal vein thrombosis as a venous thromboembolic event in the context of extraintestinal manifestations of Crohn’s disease. We also conducted a literature review on portal vein thrombosis associated with inflammatory bowel disease, with the following concepts: inflammatory bowel diseases, ulcerative colitis, Crohn’s disease, portal vein, and thrombosis.

Case presentation

A 24-year-old Syrian female with active chronic Crohn’s disease was diagnosed 11 years ago and classified as A1L3B1P according to the Montreal classification. She had no prior surgical history. Her previous medications included azathioprine and prednisolone. Her Crohn’s disease activity index was 390 points. Gastroduodenoscopy revealed grade I esophageal varices, a complication of portal hypertension. Meanwhile, a colonoscopy revealed several deep ulcers in the sigmoid, rectum, and descending colon. An investigation of portal vein hypertension revealed portal vein thrombosis. We used corticosteroids to induce remission, followed by tapering; additionally she received ustekinumab to induce and maintain remission. She began on low-molecular-weight heparin for 1 week, warfarin for 3 months, and then apixaban, a novel oral anticoagulant, after excluding antiphospholipid syndrome. Primary prophylaxis for esophageal varices was not required. After 1 year, she achieved clinical, biochemical, and endoscopic remission. Despite 1 year of treatment, a computed tomography scan revealed no improvement in portal vein recanalization.

Portal vein thrombosis is a rare and poorly defined complication of inflammatory bowel disease. It is usually exacerbated by inflammatory bowel disease. The symptoms are nonspecific and may mimic a flare-up of inflammatory bowel disease, making the diagnosis difficult. Portal vein Doppler ultrasound for hospital-admitted inflammatory bowel disease patients may contribute to the diagnosis and management of this complication.

Peer Review reports

Extraintestinal manifestations can affect almost any organ system and have a negative impact on the patient’s functional status and quality of life. Extraintestinal manifestations are most commonly observed in the joints, skin, hepatobiliary tract, eyes, heart, pancreas, and vascular system. Portal vein thrombosis (PVT) is an obscure and poorly defined complication of many diseases, including cirrhosis, intraabdominal infection, intraabdominal surgery, pancreatitis, primary hematologic disorders, and inflammatory bowel disease (IBD) [ 1 ]. The prevalence of PVT in patients with IBD ranges from 0.17% to 1.7% [ 1 ], and may be associated with inherited or acquired hypercoagulability risk factors and has a benign outcome [ 1 ]. It can be difficult to diagnose PVT in patients with IBD because its extremely generic symptoms, such as abdominal discomfort, can frequently originate from any of its triggering events. Therefore, it should come as no surprise that the diagnosis is frequently made by accident when imaging is performed to check for one of these triggering processes, also the laboratory results are nonspecific [ 1 ]. We report an interesting and uncommon case of PVT associated with Crohn’s disease that was discovered when investigating the cause of esophageal varices related to portal vein hypertension. We also conducted a literature review on portal vein thrombosis associated with inflammatory bowel disease using the following concepts: inflammatory bowel disease, ulcerative colitis, Crohn’s disease, portal vein, and thrombosis.

We evaluated a 24-year-old Syrian female with active chronic Crohn’s disease, diagnosed 11 years ago. She was classified as A1L3B1P according to the Montreal classification [ 2 ]. She had no prior surgical history; her past medications included azathioprine 2.5 mg/kg/day since diagnosis until now and prednisolone 1 mg/kg up to 40 mg during flares, then tapering [ 3 ]. Furthermore, she did not use oral contraceptive pills. Her weight was 50 kg, her height was 161 cm, and she had a body mass index of 19.29 kg/m 2 . She complained of watery, bloody diarrhea up to eight times a day, accompanied by abdominal pain in the prior month. Her Crohn’s disease activity index (CDAI) was 390 points. Initial blood tests confirmed leukocytosis, anemia, elevated fecal calprotectin (FC), and C-reactive protein (CRP) levels. Stool cultures, Clostridium difficile toxin, Escherichia coli , and Cryptosporidium , as well as microscopy for ova and parasites, all returned negative. The hypercoagulability work-up revealed negative results for anti-Beta-2 Glycoprotein-1 IgM antibodies, antinuclear antibodies (ANA), fibrinogen, protein S (activity), antithrombin III, and homocysteine, whereas lupus anticoagulant (LA1, LA2) was positive. Factor II mutation and factor V Leiden mutation were normal, whereas the methylenetetrahydrofolate reductase mutation was a homozygous mutant gene. The portal system and suprahepatic vein ultrasound revealed a thrombus that covered nearly half of the lumen of the portal vein and splenomegaly. Gogastroduodenoscopy showed grade I esophageal varices (less than 5 mm, without bleeding risk signs), which indicate portal vein hypertension owing to splenomegaly and esophageal varices. In light of the patient’s recent onset of abdominal pain and the absence of portosystemic collaterals on Doppler ultrasound, a recent PVT is a strong possibility [ 4 ]. The colonoscopy revealed several deep ulcers in the sigmoid, rectum, and descending colon Fig.  1 . The biopsies were negative for Clostridium difficile , and immunohistochemical staining was negative for cytomegalovirus (CMV) [ 3 , 5 ]. The median liver stiffness measured by FibroScan was 2.4 kPa, which suggests the absence of fibrosis. Protein electrophoresis was normal. The abdomen and pelvis contrast-enhanced computed tomography (CT) scan confirmed the PVT and displayed thickening in the descending colon (Fig.  2 ). Antiphospholipid syndrome was initially diagnosed on the basis of an antiphospholipid profile, a history of PVT (thrombotic event), and an association with Crohn’s disease [ 6 ]. She initially received corticosteroids to achieve disease remission, followed by ustekinumab to induce and maintain therapy (390 mg intravenous induction followed by 90 mg subcutaneous every 8 weeks) owing to moderate-to-severe Crohn’s disease unresponsive to azathioprine [ 7 , 8 ]. She began on low-molecular-weight heparin (LMWH) for 1 week, and warfarin for 3 months with an international normalized ratio (INR) target of 2–3. The lupus anticoagulant (LA1, LA2) was retested after 12 weeks and returned to negative [ 6 ], so we switched to apixaban, a novel oral anticoagulant (NOAC) [ 4 ]. The 1-year reevaluation indicated clinical, biochemical, and endoscopic remission with CDAI of 150 points, normal lab test, and normal endoscopy. The patient’s tests are presented in Table  1 . Despite 1 year of treatment, a CT scan revealed no improvement in portal vein recanalization. We continued 90 mg of subcutaneous (SC) ustekinumab every 8 weeks, while we stopped apixaban [ 3 , 4 ].

figure 1

Colonoscopy revealed several ulcerations in the sigmoid, rectum, and descending colon

figure 2

The contrast-enhanced computed tomography scan of the abdomen, which shows portal vein thrombosis

Review of literature

To facilitate this literature review, we used a combination of keywords and database subject headings to search the MEDLINE (through PubMed) database on 1 July 2023 for the following concepts: Crohn’s disease, ulcerative colitis, IBD, portal vein, PVT, and thrombosis. We also manually searched the reference lists of the included papers. We returned the research on 7 April 2024, and no new findings were obtained.

Eligibility criteria

We searched for any case reports, case series, observational, or interventional studies that addressed portal vein thrombosis associated with inflammatory bowel disease. Table 2 summarizes the basic features and treatment outcomes of the reported cases.

Crohn’s disease is linked to a variety of extraintestinal complications. Oral aphthous ulcers, peripheral arthritis, erythema nodosum, and episcleritis are frequently associated with active intestinal disease. Whereas uveitis and ankylosing spondylitis are usually unrelated to disease activity, pyoderma gangrenosum and primary sclerosing cholangitis have a questionable relationship to disease activity [ 9 ]. Venous thromboembolic events are fearsome manifestations that are related to disease activity and associated with significant morbidity and mortality [ 9 ]. Deep vein thrombosis (DVT) is the most prevalent thrombotic event, followed by pulmonary embolism (PE). The relative risk of thrombotic events in patients with inflammatory bowel disease was 2.03 [ 10 ]. Although inflammatory bowel disease treatment options have improved over the last three decades [ 11 ], thrombotic events among hospitalized individuals with inflammatory bowel disease continued to rise [ 12 ]. The overall thrombotic risk did not differ between sexes or between individuals who have ulcerative colitis or Crohn’s disease [ 13 ]. There have been very few reports of portal vein thrombosis in the context of inflammatory bowel disease. The presenting indications, symptoms, and laboratory data are all extremely nonspecific, and a PVT diagnosis is nearly always made by chance. It is important to note that PVT is related to disease activity, particularly IBD flare. We found that portal vein thrombosis affects both men and women, with a small male predominance. It is also more frequent in individuals with ulcerative colitis than in those with Crohn’s disease. It is a rare complication in Crohn’s disease, identified in only 14 cases. Hypercoagulability testing in a subset of patients (around half) revealed inherited or acquired hypercoagulability factors in some, with antiphospholipid antibodies and factor V Leiden mutation being the most common. Treatment for thrombosis in Crohn’s disease involves tailored anticoagulation (heparin, warfarin, DOACs) or even surgery, with outcomes ranging from successful resolution to bleeding or death. However, limitations include the use of case reports and retrospective studies, and the small number of CD cases, which hinder definitive conclusions. There are no recommendations for thrombophilia screening in cases of portal vein thrombosis; many reports, including ours, have included thrombophilia testing. Naymagon et al . suggested that thrombophilia testing is not required in cases of clearly triggered PVT, such as after recent surgery or in the setting of a recent or active intraabdominal infection or IBD-flare [ 1 ]; moreover, he suggested that thrombophilia testing should be undertaken if PVT is not induced, such as spontaneous PVT in an otherwise stable and inactive IBD patient, or patients with a history of previous venous thromboembolism or unexplained blood count abnormalities [ 1 ]. Furthermore, testing for antiphospholipid syndrome and paroxysmal nocturnal hemoglobinuria may affect management and should be considered in certain conditions, such as a history of autoimmune disease or arterial thrombosis for antiphospholipid syndrome and unexplained cytopenia or evidence of intravascular hemolysis for paroxysmal nocturnal hemoglobinuria. Other thrombophilia testing are often unnecessary because the results have little impact on therapy [ 1 ]. A mutation of JAK2 could be detected in splanchnic vein thrombosis and thus provide a marker of latent myeloproliferative neoplasms (MPNs), which are a major primary cause of abdominal vein thrombosis [ 14 ]. MPNs are made up of three key rare diseases: (1) polycythemia vera, which leads to an elevation in all blood cells, especially red blood cells; (2) essential thrombocythemia, which leads to an increase in platelets; and (3) primary myelofibrosis, a bone marrow disorder that leads to defects in blood cell production [ 14 , 15 ]. MPNs were diagnosed through a variety of criteria, including the typical alterations in peripheral blood cells [ 4 ], as she had chronic active CD with possible previous CD-flare and a normal blood profile which excludes MPNs [ 1 , 14 , 15 ]. We screened for antiphospholipid syndrome antibodies because the patient was a young female with a significant thrombotic event without a clear relationship with a Crohn’s disease flare. Although the lupus anticoagulant (LA1, LA2) was initially positive, it was found to be negative 12 weeks later. The explanations for the false positive in our instance were anticoagulant treatment, including therapy with LWMH, which is indicated to every patient admitted to the hospital with inflammatory bowel disease, and later warfarin for the management of portal vein thrombosis [ 3 , 6 , 13 ]. For PVT management, literature was unclear concerning the selection of anticoagulants. Most patients who require anticoagulation are started on LMWH, or unfractionated heparin, and then switched to vitamin K antagonists (VKAs) to maintain a goal international normalization rate of 2–3. While VKAs can be substituted orally with direct oral anticoagulants (DOACs) or novel oral anticoagulants (NOACs). These medications do not require monitoring of the INR because of their speedier onset of action and lesser risk of bleeding. DOACs are just as effective as VKAs for treating deep vein thrombosis, pulmonary embolism, and stroke prevention in patients with atrial fibrillation, and may be considered owing to potentially less frequent monitoring needs and a fixed dosing regimen, which could enhance medication adherence. However, owing to unbalanced hemostasis, patients with cirrhosis have been excluded from most trials. Our case was portal hypertension without cirrhosis; therefore, DOACs or NOACs are not contraindicated after excluding antiphospholipid syndrome. For Crohn’s disease treatment, ustekinumab was more suitable than tumor necrosis factor inhibitors (anti-TNFα), as ustekinumab had low immunogenicity (generating antidrug antibodies), so it is feasible to avoid a combination of azathioprine and ustekinumab, in contrast to anti-TNF treatment, which necessitates such a combination [ 3 , 6 , 7 , 9 ]. Ustekinumab helped to eliminate the drug interactions of azathioprine and warfarin, note that warfarin was the only therapeutic option owing to the initial diagnosis of antiphospholipid syndrome. In addition, ustekinumab had the lowest rate of serious infections among the biological treatments [ 7 ]. Esophageal varices primary prophylaxis is not required, as primary prophylaxis must be initiated upon the detection of high-risk varices, such as small varices with red signs, medium or large varices regardless of Child–Pugh classification, or small varices in patients classified as Child–Pugh C [ 16 ]. It is possible to discontinue anticoagulant treatment after a year, whether or not portal vein recanalization occurs, because a longer period of anticoagulant treatment is unlikely to enhance the probability of recanalization if it does not occur after a year [ 4 ].

PVT symptoms are similar to the symptoms of an inflammatory bowel disease flare. Initial tests for antiphospholipid syndrome were falsely positive [ 17 ]. The wise choice of ustekinumab as the first-line biological treatment, which aided in weaning off azathioprine, led to avoiding azathioprine–warfarin interactions. Using DOACs or NOACs for the management of portal vein thrombosis in case of portal vein hypertension. Finally, the management of esophageal varices in the context of anticoagulant treatment. The use of portal vein Doppler ultrasound, particularly during flare-ups of inflammatory bowel disease, may contribute to the diagnosis and management of this uncommon complication.

Availability of data and materials

Not applicable.


  • Portal vein thrombosis
  • Inflammatory bowel disease
  • Crohn’s disease

C-reactive protein

International normalized ratio

K antagonists

Computed tomography


Antiphospholipid syndrome

Direct oral anticoagulants

Novel oral anticoagulants

Low molecular weight heparin

Hepatitis B surface antigen

Hepatitis B surface antibody

Hepatitis B core antibody

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Alhalabi, M., Nasri, D. & Aji, W. Portal vein thrombosis as extraintestinal complications of Crohn’s disease: a case report and review of literature. J Med Case Reports 18 , 246 (2024). https://doi.org/10.1186/s13256-024-04560-w

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A Comprehensive Review of Hypertension in Pregnancy

Reem mustafa.

1 Division of Nephrology, Department of Medicine, State University of New York at Buffalo, Buffalo, NY 14215, USA

2 Renal Department, Erie County Medical Center, Buffalo, NY 14215, USA

Rocco C. Venuto

Hypertension is the most common medical disorder encountered during pregnancy. Hypertensive disorders are one of the major causes of pregnancy-related maternal deaths in the United States. We will present a comprehensive update of the literature pertinent to hypertension in pregnancy. The paper begins by defining and classifying hypertensive disorders in pregnancy. The normal vascular and renal physiological changes which occur during pregnancy are detailed. We will summarize the intriguing aspects of pathophysiology of preeclampsia, emphasizing on recent advances in this field. The existing diagnostic tools and the tests which have been proposed for screening preeclampsia are comprehensively described. We also highlight the short- and long-term implications of preeclampsia. Finally, we review the current management guidelines, goals of treatment and describe the potential risks and benefits associated with various antihypertensive drug classes. Preeclampsia still remains an enigma, and the present management focuses on monitoring and treatment of its manifestations. We are hopeful that this in depth critique will stimulate the blossoming research in the field and assist practitioners to identify women at risk and more effectively treat affected individuals.

1. Introduction

Hypertension is the most common medical disorder of pregnancy and is reported to complicate up to 1 in 10 gestations and affects an estimated 240,000 women in the United States every year [ 1 ]. Although physicians for millennia have recognized preeclampsia, relatively little is known about its pathogenesis and prevention. The primary concern about elevated blood pressure relates to the potential harmful effects on both mother and fetus. These potential adverse effects range in severity from trivial to life threatening.

2. Classification of Hypertensive Disorders of Pregnancy

The National High Blood Pressure Education Program of the NHLBI classifies hypertensive disorders of pregnancy into following categories: gestational hypertension, chronic hypertension, preeclampsia, and preeclampsia superimposed on preexisting hypertension [ 1 ] ( Table 1 ).

Classification of hypertension in pregnancy.

Hypertension in pregnancy is defined as a systolic of 140 mm Hg or greater or a diastolic of 90 mm Hg or greater. Blood pressure should be taken in the upper arm with the patient seated using an appropriately sized cuff. The patient should be at rest for at least several minutes. The blood pressure should be confirmed with another reading at least at a twenty-minute interval or even on a separate occasion. The diastolic reading is determined by the disappearance of sound and not the change in sounds. Controversy remains as to the blood pressure criteria used to define preeclampsia. Some experts of this specialized area of medicine have argued that a rapid rise in blood pressure of 30 mm Hg systolic or 15 mm Hg diastolic should be sufficient to diagnose preeclampsia. However, the current recommendations of the 2000 working group suggest that women who experienced only this change are not yet preeclamptic but do warrant close observation, especially if this finding is accompanied by proteinuria and hyperuricemia [ 2 ].

2.1. Vascular Physiology of Normal Pregnancy

Dramatic physiologic changes occur in systemic hemodynamics during pregnancy. It is essential that these differences from the nonpregnant state be appreciated when one attempts to assess blood pressure during pregnancy. In uncomplicated pregnancy, mean arterial pressure drops, reaching its nadir between the 16th and 20th weeks of gestation ( Figure 1 ). The decline in diastolic pressure is somewhat greater than that in systolic pressure. The reduction is typically 8–10 mm Hg or just less than a 10% decline from pre-pregnancy levels. The fall in blood pressure begins with the luteal phase of menstruation and progresses if conception follows. After the 20th week, mean arterial blood pressure slowly returns to prepregnancy levels at about 40-week gestation. The circadian changes in blood pressure are maintained during pregnancy as demonstrated by ambulatory blood pressure monitoring.

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Relative changes in renal hemodynamics during normal human pregnancy. Dramatic changes occur in systemic hemodynamics during physiologic pregnancy. In uncomplicated pregnancy, mean arterial pressure drops, reaching its nadir between the 16th and 20th weeks of gestation. After the 20th week, mean arterial blood pressure slowly returns to close to pre-pregnancy levels at about 40-week gestation. Changes in systemic blood pressure are paralleled by a change in cardiac output which increases dramatically. The apex is reached between the 16th and 20th weeks of gestation. Plasma volume increases substantially as well but lags behinds the increased cardiac output. MAP: mean arterial pressure. CO: cardiac output.

Changes in systemic blood pressure are paralleled by a change in cardiac output, which increases dramatically. The apex is reached between the 16th and 20th weeks of gestation, and at its apogee the increment is typically at least 40% greater than the baseline. Both stroke volume and heart rate increase to achieve this profound rise in the quantity of blood pumped into the pulmonary and systemic circulations [ 3 ]. The volume load increase in the heart results in left ventricular hypertrophy that is commensurate with the greater amount of cardiac work required to achieve the increase in cardiac output [ 4 ]. The reduction in mean arterial pressure is even more dramatic when placed in the context of the change in cardiac output. Not only does the cardiac output increase, but also plasma volume increases substantially as well ( Figure 1 ). This increased capacity of the circulation with a diminished tone has led to description of the vasculature as flaccid during gestation. The reduced smooth muscle tone is not limited to the vasculature, but is shared, for example, with the smooth muscle of the gastrointestinal and urinary tracts.

The circulating levels of the hormones that help regulate blood volume, specifically all components of the renin-angiotensin aldosterone system as well as catecholamines, are paradoxically increased during gestation. The usual physiologic stimuli for the release of these hormones are a reduction in plasma volume or diminished renal perfusion. Nonetheless, enhanced activity of the renin-angiotensin axis is a hallmark of the volume-expanded state of gestation. This has led to the description of pregnancy as a state of “decreased effective plasma volume.” Increases in both arterial compliance and venous capacitance appear to underlie this unique physiologic phenomenon [ 3 ], the understanding of which remains enigmatic. As will be discussed subsequently, it is a reversal of this pattern that characterizes the specific form of hypertension in pregnancy known as preeclampsia.

The alterations in vascular reactivity are not limited to the responses to endogenous hormones. The vasoconstrictive effect of infused pressor compounds is also substantially diminished. During gestation, pregnant women were demonstrated to be resistant to the pressor effect of angiotensin II and norepinephrine more than 40 years ago [ 5 , 6 ]. Subsequently, Gant and associates demonstrated a sequential increment in the resistance to angiotensin II as pregnancy progressed, which peaked between 24–30 weeks of gestation [ 7 ] ( Figure 2 ).

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The amount of angiotensin required to raise blood pressure by 20 mm Hg. This figure demonstrates two important findings obtained from serial observations in primiparas. Women undergoing physiologic pregnancy (■) become resistant to the pressor effect of infused angiotensin II by 14 weeks of gestation. They require significantly higher dose of angiotensin II to increase blood pressure by 20 mm of Hg. In contrast, women destined to develop preeclampsia (♦) regain their sensitivity to angiotensin II between 22–26 weeks of gestation, well before any other clinical manifestations of preeclampsia are appreciated [ 7 ].

2.2. The Kidney in Normal Pregnancy

Healthy pregnant women show marked glomerular hyperfiltration. The rapid developing rise in renal blood flow and glomerular filtration rate were documented in careful studies undertaken in humans [ 8 ]. GFR begins to increase in the first trimester of pregnancy and peaks in second half of pregnancy, wherein it is increased above normal, nongravid levels by 40–60%. Davison and his associates found that these improvements in renal hemodynamics occurred even prior to the changes in cardiac output and plasma volume ( Figure 3 ). This suggests that the mechanisms underlying these profound physiologic alterations may differ from each other or at least are not interdependent. There is no other instance in biology where such a sustained improvement of function occurs. The magnitude of the change has led many investigators to attempt to define the mechanism that underlies it so that it might be employed to treat other human conditions. Thus far no definitive explanation has been proven. If pregnancy remains uncomplicated, pregnant patients with underlying renal disease usually experience an improvement in function that is proportional to their baseline level. The reason for the physiologic change presumably is teleological and designed to accommodate the additional waste products consequent to the enlarging uterus, placenta, and fetus. Although it tends to tail off toward the end of gestation, a substantive increase in both glomerular filtration rate and renal plasma flow is sustained throughout the pregnancy. The enhanced renal function is accompanied by a reciprocal reduction in blood urea nitrogen (BUN) and serum creatinine tests commonly employed to estimate glomerular filtration rate. Low blood levels of these nitrogenous waste products are hallmarks of physiologic pregnancy ( Table 2 ). It is critical to be cognizant of these differences from the normal nonpregnant values since subtle deviations from the pregnancy levels might presage the diagnosis of preeclampsia.

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Changes in renal function during pregnancy. Kidney function also dramatically increases during pregnancy. The rapid developing rise in renal blood flow and glomerular filtration rate were documented in careful studies undertaken in humans. These increments average between 40 and 50%. Dr. Davison and his associates found that these improvements in renal hemodynamics occurred even prior to the changes in cardiac output and plasma volume. GFR: glomerular filtration rate. ERPF: effective renal plasma flow [ 8 ].

Laboratory tests of renal function during pregnancy.

Throughout pregnancy the average women will retain about 1000 mEq of sodium as she experiences the fairly steady increase in extracellular and plasma volume. Nonetheless women experiencing physiologic pregnancy will respond appropriately to sodium restriction or sodium infusion [ 3 ].

2.3. Volume and Hemodynamic Alterations in Preeclampsia

It is difficult to study totally untreated preeclampsia, and often preeclampsia is diagnosed in patients with underlying chronic medical conditions. Data generated from treated preeclamptic patients or those patients with preexisting renal disease, diabetes, or hypertension might not accurately reflect those of the uncomplicated preeclamptic patient. These concerns aside, the available data suggests that the systemic hemodynamic preeclamptics vary substantially from those of women with uncomplicated pregnancy.

Visser and Wallenburg undertook detailed hemodynamic assessments of untreated primiparous preeclamptics. Using Swan-Ganz catheters, they consistently found cardiac outputs and intravascular volumes lower and systemic vascular resistance and cardiac afterload higher in these carefully selected group of women with pregnancy-induced hypertension as compared to normal control pregnant subjects [ 3 ].

If one focuses on the properties of the arterial system in preeclampsia using impedance techniques, compliance of the large conduit arteries is reduced. This suggests that the reservoir properties of the arterial system are compromised. The left ventricle muscle mass and cardiac wall diastolic pressure in late gestation is similar between preeclamptic and controlled subjects. Limited data suggests, however, that left ventricular contractility in preeclamptics is inappropriately low given the high afterload [ 3 ].

Some changes in the systemic hemodynamics of pregnant women destined to become preeclamptic may develop prior to overt clinical manifestations of the disease. Ambulatory blood pressure readings suggest that a reduction or obliteration in the usual decrease in nocturnal blood pressure may be present in many patients who eventually become preeclamptic. Such changes usually manifest at 18 to 26 weeks of gestation. The resistance to pressor substances appears to be altered well before the systemic hypertension and proteinuria are noted. Figure 2 shows that the sensitivity to the pressor effect of infused angiotensin changes in women destined to become preeclamptic. These individuals exhibit sensitivity similar to that seen in nonpregnant women well before they clinically manifest preeclampsia. In contrast, claims that high cardiac output necessarily precedes the development of preeclampsia appear to be based on an insufficient database [ 3 ].

Renin levels actually decrease in preeclamptic patients, but remain well above those of nonpregnant individuals. Similar changes are also seen in the circulating levels of aldosterone and angiotensin II. Maintaining relatively high levels of these hormones may be critically important because most often preeclamptic patients have a relatively diminished plasma volume.

2.4. Renal Alterations in Preeclampsia

The dramatic improvement in renal function experienced by women undergoing a physiologic pregnancy is abrogated in women who develop preeclampsia. The GFR and renal blood flow decline. The severity of the reduction is quite variable and correlates with the overall severity of the illness. If proteinuria develops, as is most common, and a kidney biopsy were to be undertaken, it would typically show glomerular endotheliosis. This lesion, although not limited to pregnancy, is characteristic in preeclamptic women. This endothelial abnormality is quite consistent with the notion of endothelial injury playing a key role in the pathophysiology of this systemic condition with the kidney not being spared. These hemodynamic and endothelial changes also appear to make the kidneys more vulnerable for the development of acute renal failure (acute tubular necrosis) and uncommonly a particular form of acute, often irreversible renal failure known as renal cortical necrosis. Cortical necrosis is seen almost exclusively in severe preeclamptics and rarely occurs in settings outside of pregnancy [ 9 ].

2.5. Pathophysiology of Preeclampsia

The pathophysiology of de novo hypertension and proteinuria in pregnancy known as preeclampsia remains largely undiscovered. More than 30 years ago Dr. Leon Chesley, a champion in the field of hypertension in pregnancy divided the most likely causative factor into four major categories: dietary, renal, immunologic, and placental [ 10 ]. Subsequently, the evidence that poor diet or preexisting renal abnormalities underlie the majority of episodes of preeclampsia has not been sustained. The role of immunologically mediated vascular injury, as the initiating cause remains plausible and will be explored.

Delivery of the placenta usually initiates the resolution of the acute clinical symptoms of preeclampsia, suggesting that the placenta plays a central role in preeclampsia pathogenesis. During normal pregnancy, the placenta undergoes dramatic vascularization to enable circulation between fetus and mother. Placental vascularization involves vasculogenesis, angiogenesis, and pseudovasculogenesis or maternal spiral artery remodeling. These processes require a delicate balance of proangiogenic and antiangiogenic factors. The imbalance of proangiogenic and antiangiogenic factors in preeclampsia is thought to trigger abnormal placental vascularization and disease onset.

Underlying genetic explanations for the overproduction of anti-angiogenic factors in preeclampsia are still being proposed [ 11 ].

2.6. The Role of Uteroplacental Ischemia

Altered uteroplacental blood flow has long been the focus of the pathophysiology of preeclampsia. Clinicians and research scientists have garnered a wealth of data to support the hypothesis that a reduction in uterine blood flow is the overriding factor in the etiopathogenesis of this condition ( Table 3 ). The placentae of women with preeclampsia are uniformly abnormal. The primary pathology appears to be at the maternal-fetal interface and is characterized by poor trophoblastic invasion of the uterus. The endovascular invasion of the spiral arteries is incomplete. Specifically, the failure of the cytotrophoblasts to penetrate deep and cause a “widening of the pathway” appears to explain the relative reduction in uteroplacental blood flow. Additional pathologic findings include placental infarcts. It is not surprising; consequently, that intrauterine growth retardation is frequently associated with preeclampsia. Virtually all clinical settings that favor the development of preeclampsia also favor the possibility that growth of the intrauterine contents outstrips the capacity to commensurately improve blood supply.

Observations supporting uteroplacental ischemia as a key factor in preeclampsia.

Finally, there is a wealth of data derived from experiments in various pregnant mammals spanning the spectrum from rats to primates supporting this hypothesis. When subjected to reduced uteroplacental blood flow, these animals develop findings that mimic those seen in preeclamptic women. Sustained hypertension, proteinuria, and glomerular endotheliosis, the renal lesion that characterizes preeclampsia, have all been reported in these laboratory animals following uterine constriction of blood flow [ 12 ].

2.7. Maternal Endothelial Dysfunction

Although preeclampsia appears to originate in the placenta, the tissue affected most is the maternal endothelium. The clinical manifestations of preeclampsia reflect widespread endothelial dysfunction, with vasoconstriction and end organ ischemia. Systemic hypertension, renal, hepatic, and cerebral vascular pathology are hallmarks of severe preeclampsia. Taylor, Davidge and Roberts explore in great depth the evidence placing endothelial dysfunction as the focal point of the disease [ 13 ]. They point out that endothelial “activation” and dysfunction are reflected in the inappropriate vasoconstriction and its propensity toward a hypercoagulable state and the widespread microvascular thrombi, most notably that are seen nearly uniformly in the placenta of preeclamptics. These investigators suggest that endothelial dysfunction may be manifested by the altered synthesis and release of endothelial cell products. Among the various compounds, which act on the endothelium, are the prostanoids and nitric oxide. Nitric oxide synthesis is increased in women undergoing physiologic pregnancy, whereas analysis of tissue and urine samples strongly suggest that nitric oxide production is impaired in preeclamptic women. In laboratory animals nitric oxide synthase inhibition can produce a condition, which bears many similarities to preeclampsia [ 12 ]. Likewise, there appears to be a role for possible imbalance between vasodilating and vasoconstricting prostaglandins. Synthesis of the vasorelaxant prostacyclin increases in physiologic pregnancies, whereas more of the vasoconstrictor thromboxane is produced in women whose pregnancies are complicated by high blood pressure and proteinuria. Whether these particular compounds play a primary role or are only a part of the progression of the pathophysiology is unclear. A treatment strategy, nonetheless, was devised using low-dose aspirin to attempt to confirm the relationship between thromboxane and vasodilating prostaglandins, since low-dose aspirin may selectively inhibit thromboxane synthesis. The results of studies on a large number of primiparous women who were not at high risk to develop preeclampsia failed to support a benefit from this strategy. Some advocates, however, still hold to the notion that selective treatment of women who are at extremely high risk because of preexisting hypertension or renal disease for example, may be of benefit.

2.8. Antiangiogenic Factors in Preeclampsia

There is a published body of work that has grown almost logarithmically since 2003 suggesting that circulating angiogenic factors play a key role in the pathogenesis of preeclampsia. Increased expression of soluble fms-like tyrosine kinase (sFlt1), together with decreased placental growth factor (PGF) and vascular endothelial growth factor (VEGF) signaling, were the first abnormalities described [ 14 ].

2.8.1. sFlt1: A Circulating Antagonist to VEGF and PGF

Several investigators spearheaded by Karumanchi have seized on the finding that pregnant women may produce a soluble variant of vascular endothelial growth factor receptor. This kinase has been designated sFlt1. sFlt1 consists of the extracellular ligand-binding domain of Flt1, but lacks the transmembrane and intracellular signaling domain. Hence, it is secreted into the circulation where it binds and antagonizes both vascular endothelial growth factor (VEGF) and placenta growth factor (PGF) [ 15 ]. Both are potent stimuli for the vascular expansion essential to the development of the uteroplacental unit and act via their effects on endothelial cells [ 16 ]. Even more recent clinical evidence has been gathered that supports the notion that both circulating and placental levels of this soluble receptor blocker are higher in women with preeclampsia than in women with uncomplicated pregnancy. These hypertensive women also have been demonstrated to have lower levels of PGF and VEGF. Circulating levels of sFlt1 and PGF are altered several weeks before the onset of clinical disease and are correlated with severity of the disease [ 17 , 18 ]. sFlt1 levels normalize several days after delivery, coinciding with improvement in proteinuria and hypertension. Support for the key role of this kinase in the pathophysiology of preeclampsia has been garnered from studies undertaken in a baboon model of hypertension in pregnancy induced by uteroplacental ischemia [ 19 ]. In these primates with restricted uterine arteries, a temporal link was observed between the onset of hypertension and renal dysfunction and the increase level of the kinase. This rise in the kinase was also correlated with the blunted effectiveness of PGF and VEGF. Based on the findings in preeclamptic women, assays that measure s-Flt, PGF, and VEGF have been touted as potential tools to differentiate preeclampsia from other categories of hypertension in pregnancy.

More recent studies have identified a second sFlt1 splice form expressed in cytotrophoblasts, which differs in its c-terminus and also appears to be upregulated in preeclampsia [ 20 ]. The biologic significance of the different sFlt1 variants with regards to anti-angiogenic activity and their role in the pathogenesis of preeclampsia is a subject of ongoing study. Selectively removing soluble FMS-like tyrosine kinase, using an extracorporeal adsorption technique, reduced proteinuria, stabilized blood pressure, and permitted prolongation of pregnancy in a small group of women with preeclampsia very early in pregnancy. This observation supports the notion that this protein kinase has a role in the pathophysiology of preeclampsia [ 21 ].

2.8.2. Soluble Endoglin: A Circulating Antagonist to Transforming Growth Factor-B

Proponents of the vascular endothelial growth factor-receptor antagonist hypothesis or so-called anti-angiogenic theory recognize that blocking the action of these growth factors alone was insufficient to explain all the clinical manifestations seen in severe eclampsia. Another factor, soluble endoglin (sEng), has now been also found to be upregulated in preeclampsia in a pattern similar to sFlt1. sEng is a truncated form of endoglin (CD 105), a cell surface receptor for transforming growth factor B (TGF-B), which binds and antagonizes TGF-B [ 22 ]. This compound not only potentiates the anti-angiogenic actions of s-Flt-1 kinase, but ultimately results in the decreased production of nitric oxide. This type of endothelial abnormality would be requisite to account for the disseminated intravascular coagulation and the other hematologic components seen in patients with severe preeclampsia.

As with sFlt1, circulating sEng levels are increased weeks before preeclampsia onset, and increased sEng levels are observed in the reduced uterine perfusion pressure rat model of preeclampsia [ 23 ]. Cultured placental trophoblasts from women with preeclampsia show increased sEng and sFlt1 expression, both at normoxic conditions and in response to hypoxia, as compared with normal placental trophoblasts [ 24 ].

Endoglin excess has now been incorporated into the anti-angiogenic theory. Collectively, this is an appealing hypothesis. Skeptics could say, however, we may not as yet have reached the root cause level.

3. Relaxin in Pregnancy

Relaxin, a peptide hormone secreted by the corpus luteum, circulates during pregnancy in human beings, nonhuman primates, rats, and mice [ 25 ]. The hormone also is detectable in the circulation during the luteal phase of the menstrual cycle in both women and nonhuman primates [ 25 ]. Traditionally, relaxin has been investigated in the context of the reproductive tract; however, it was suggested by Hisaw et al. that relaxin has a vasodilatory role [ 26 , 27 ], this was further shown in subsequent studies by St-Louis and Massicotte [ 28 ]. Relaxin administration to nonpregnant rats was shown to mimic the vasodilatory phenomenon of pregnancy [ 29 ]. Furthermore, immunoneutralization of relaxin or its elimination from the circulation during midterm pregnancy in rats prevents maternal systemic and renal vasodilation, and the increase in global arterial compliance [ 30 ]. Evidence suggests that the vasodilatory responses of relaxin are mediated by its major receptor, the relaxin/insulin-like family peptide 1 receptor, RFXP 1 [ 31 ], that is largely expressed in vascular smooth muscle [ 32 ]. The possibility that angiogenic growth factors may be secreted by the vascular smooth muscle upon RFXP1 activation is being entertained [ 32 ]. Jeyabalan et al. reported an association of low first trimester relaxin concentrations with increased risk of developing preeclampsia [ 33 ]. This study raised the possibility that these women may experience defective decidualization and trophoblast invasion or fail to adequately vasodilate in early pregnancy owing to low levels of circulating relaxin, thereby predisposing them to develop preeclampsia.

4. Renin Angiotensin Signaling in Preeclampsia

There is an increase in almost all the components of renin-angiotensin system during an uncomplicated pregnancy, but renin activity, angiotensin II, and aldosterone decrease in preeclampsia for reasons that are unclear. Numerous studies report the presence of angiotensin II type 1 receptor agonistic antibody (AT1-AA) found circulating in preeclamptic women [ 34 , 35 ]. Many recent studies have shown that by activating AT1 receptors on a variety of cell types, these autoantibodies could increase certain factors (including sFlt1, sEng, Plasminogen activator inhibitor-1, reactive oxygen species, tissue factor, and NADPH oxidase) that lead to preeclamptic pathophysiology such as endothelial cell dysfunction and vascular damage [ 36 , 37 ]. Granger et al. isolated AT-AA1 from the rats manipulated by reduction in uterine perfusion pressure. These rats also demonstrated development of hypertension, proteinuria, increased sFlt1, endothelin production, and endothelial dysfunction [ 38 ].

5. The Role of Alterations of the Immune System

Over the last 30 years, significant progress has been made in understanding the role of immune mechanisms in the development of preeclampsia. It remains unexplained why primiparous women are more susceptible to this condition and also why the high preeclampsia attack rate (5–7%) noted in primiparous is unchanged in women who are having a first pregnancy with a second partner. This has fostered the suspicion that the immunologic difference between the partners, embedded in the fetus triggers an immune response in pregnant women. Redman et al. have postulated that preeclampsia is the continuum of the immune-mediated inflammatory changes seen in normal pregnancy. Most investigators believe that endothelial injury, perhaps caused by cytokine release induced by inflammation is a basic mechanism underlying the pathogenesis of preeclampsia [ 39 ].

It has also been postulated that immune accommodation to the fetus needs to be learned, and this adaptation may be relatively defective in the first pregnancy leading to the higher preeclampsia attack rate which declines in but less so in subsequent pregnancies. Such conditioning might be acquired from previous pregnancy, abortion, and exposure to paternal semen and seminal plasma. Maternal exposure to fetoplacental tissues varies with gestational age, and two interfaces have been described. Interface 1, which is predominant in the first half of pregnancy, exists between maternal immune cells and invasive, extravillous HLA expressing trophoblasts in decidua. Interface 2, which predominates during the second half of pregnancy, comprises syncytiotrophoblasts that are in contact with maternal blood-borne immune cells. Syncytiotrophoblasts are HLA negative, and thus the paternal alloantigens are only expressed at interface 1, which is most active in first half of pregnancy [ 39 ].

It is tempting to suggest that those women who respond vigorously to these foreign antigens are more susceptible to develop endothelial injury that precedes preeclampsia. Women indeed often develop persistent antibodies to the fetal HLA antigens of paternal origin. The presence of these antibodies substantially increases the rate of graft rejection post transplant. It is of note that the endothelium is the major attack site of antibody-mediated rejection that develops not uncommonly in this setting.

6. Role of Genetics in Preeclampsia

Although the risk factors for preeclampsia are both genetic and environmental, the presence of preeclampsia in first degree relatives increases a woman's risk of preeclampsia by 2 to 4 fold [ 40 , 41 ]. Genetic factors may play an important role in the angiogenic imbalance found in patients with preeclampsia. Recently, several polymorphisms in sFlt1 and VEGF have been associated with severity of preeclampsia [ 42 ]. Although circulating PGF, sFlt1, and sEng levels have been shown to be important markers of preeclampsia, no causal mutations in these genes associated with preeclampsia have been identified so far [ 43 ]. However, women with trisomy 13 fetuses have a higher incidence of preeclampsia [ 44 ], suggesting that gene dosage or copy number variation may contribute to the development of preeclampsia. Notably, the Flt1 gene is located on chromosome 13.

There is some evidence to suggest that in addition to maternal genotype, paternal (or fetal) genotype may also contribute to risk of preeclampsia. The risk of fathering a preeclamptic pregnancy is increased among males who fathered a preeclamptic pregnancy with a different partner [ 45 ]. Also, men who are born from a pregnancy complicated by preeclampsia are at a higher risk of fathering a preeclamptic pregnancy [ 46 ].

7. Diagnosis of Preeclampsia

The diagnosis of preeclampsia is largely based upon meeting the characteristic clinical features outlined above which define preeclampsia. In this section, we explore various tools proposed to predict the development and/or accurately diagnose preeclampsia.

7.1. Clinical Assessment

The hallmark features in preeclampsia include developing systolic blood pressure (SBP) ≥140, or diastolic blood pressure (DBP) ≥90, and proteinuria of 0.3 grams or greater in a 24-hour urine specimen after 20 weeks of gestation in a woman who was previously normotensive. Hypertension is generally the earliest physical abnormality seen in preeclampsia and is the most important clinical clue to the presence of the disease. Since SBP and DBP readings are an essential part of the diagnosis of preeclampsia, ensuring that the optimal and appropriate ways are employed to measure BP cannot be overemphasized.

Using different indices of BP to predict preeclampsia has been comprehensively evaluated in a meta-analysis published by Cnossen et al. [ 47 ]. This meta-analysis included 34 studies and evaluated using SBP, DBP, mean arterial pressure, and the increase over time in BP. The data from this meta-analysis supports the conclusion that BP measurements in the first and second trimesters have only a modest ability to predict preeclampsia [ 47 ].

7.2. Laboratory Tests

(1) proteinuria —.

Although proteinuria is generally considered an essential characteristic of preeclampsia, preeclampsia should be suspected in any pregnant woman with hypertension and characteristic signs or symptoms, even if proteinuria is absent. Twenty percent of women who develop eclampsia have no proteinuria and 10 percent of women with other clinical and/or histological manifestations of preeclampsia have no proteinuria [ 48 ]. Women with proteinuria detected by urine dipstick should undergo quantitative measurement of protein excretion. Use of the urine protein: creatinine (P : C) ratio to estimate 24 h protein excretion for the diagnosis of preeclampsia has been controversial. The P : C ratio has been compared with 24 h urine collection in pregnant women with discordant conclusions. Though the earlier studies reflected that urine protein: creatinine ratios did not correlate with 24-hour urine protein excretion during gestation [ 48 ], the more recent literature suggests a significant correlation between these tests [ 49 ]. A meta-analysis involving 974 pregnant women from 10 studies showed a pooled sensitivity of 90% and specificity of 78% using P : C ratio cutoffs between 0.19 and 0.25, as compared with “gold standard” of 24 h urine protein excretion (>300 mg/day) [ 50 ]. Most misclassifications tended to occur in women with borderline proteinuria (250 to 400 mg/day) [ 51 ]. Hence it is reasonable to use the urine P : C ratio for the diagnosis of preeclampsia, with 24 h collection undertaken when the results are equivocal. Microalbuminuria and albuminuria, however, have a poor value to predict the subsequent development of preeclampsia [ 9 ].

(2) Kidney Function —

The kidney is the organ most likely to manifest endothelial injury related to preeclampsia. Although the plasma creatinine concentration is generally normal or only slightly elevated (1.0 to 1.5 mg/dL (88 to 133 mmol/L)), this could represent a decrease by 30–40% of glomerular filtration rate (GFR) for the values experienced in pregnant normotensive controls ( Table 1 ). Renal failure is an unusual complication that most often occurs in patients who develop severe preeclampsia. Distinguishing preeclampsia from an exacerbation of underlying renal disease can be challenging. This is especially true in patients with preexisting proteinuria because protein excretion almost always increases as pregnancy progresses. Preexisting renal disease is a well-described risk factor for preeclampsia, and the onset of preeclampsia in early pregnancy (before 32 weeks) is most often seen in patients with underlying kidney disease or hypertension.

(3) Serum Uric Acid —

Hyperuricemia was purportedly among the earliest manifestation described in preeclampsia. Different theories were explored trying to explain this finding [ 52 ]. In two systematic reviews published in 2006, serum uric acid was found to be a poor predictor of preeclampsia and its complications [ 53 , 54 ]. A meta-analysis by Koopmans et al. found uric acid to be useful to predict maternal complications and assist with management of pre-eclampsia [ 55 ]. First trimester elevated uric acid was associated with later preeclampsia and more strongly with preeclampsia and gestational hypertension with hyperuricemia in a prospective cohort study [ 56 ].

(4) Urinary Calcium Excretion —

Hypocalciuria has been reported in association with preeclampsia [ 57 ]. The mechanisms for this change is not clear, but multiple studies designed to evaluate urinary calcium excretion have shown that this parameter has no predictive value in the diagnosis of preeclampsia [ 9 ].

7.3. Provocative Tests

Roll over test; isometric exercise test, and angiotensin II sensitivity test [ 58 – 60 ] were devised to demonstrate the presence of abnormally increased vascular activity during gestational weeks 28–32 and before the clinical onset of preeclampsia. None of these tests are currently being used clinically because they are expensive, time-consuming, invasive, subjective, and, most important, unreliable.

7.4. Doppler Ultrasonography of the Uterine Arteries

The inadequate placental perfusion has lead to the use of Doppler ultrasonography to assess the velocity of the blood flow in the uterine arteries. A persistence of an early diastolic notch after 24 weeks of gestation or abnormal flow velocity ratio's has been associated with an inadequate trophoblast invasion. Pregnancies associated with an abnormal uterine Doppler after 24 weeks of gestation (high pulsatility index and/or presence of an early diastolic notch) are associated with a more than six-fold increase in the rate of preeclampsia [ 61 ]. Among high-risk patients with a previous preeclampsia, Doppler ultrasound of the uterine arteries has an excellent negative predictive value [ 62 ].

Current data do not support the use of Doppler ultrasonography for routine screening of patients for preeclampsia [ 63 ]. However, several studies have shown that the measurement of uterine perfusion in the second trimester and analysis of angiogenic markers have a high detection rate especially for early onset preeclampsia [ 64 , 65 ].

7.5. Biomarkers in Prediction and Diagnosis of Preeclampsia

Several markers heretofore described, might help, alone or in combination to predict and/or diagnose preeclampsia. The data, however, are derived largely from small case studies in selected population. When evaluating new screening strategies, not only sensitivity, specificity, and predictive values need to be taken into account, but costs, patient's acceptability, and quality control also must be considered.

Studies have consistently reported elevated serum levels of sFlt-1 in women with preeclampsia compared with normal pregnancies [ 66 – 68 ]. Levine et al. reported a mean sFlt-1 value of 4382 pg/mL in women with preeclampsia compared with 1643 pg/mL in the control group [ 66 ]. Similar values have been reported in other studies [ 69 – 71 ], with most concluding that the higher the sFlt-1 level, the more predictive it is of preeclampsia. Importantly, this increase in serum sFlt-1 levels may be detected up to 5 wks before the clinical onset of clinical symptoms.

Levine et al. found a mean serum PGF concentration in women with preeclampsia of 137 pg/mL compared with 669 pg/mL in controls [ 66 ]. Unfortunately, there was a substantial overlap in the sFlt-1 and PGF concentrations between patients destined to develop preeclampsia and those who will go on to have normal pregnancies. Widmer et al. also reported considerable difference in the methods of various studies and concentrations of sFlt-1 in a systematic review published in 2007 [ 72 ].

More recently, the assessment of the sFlt-1: PGF ratio in the maternal serum has been proposed as more reliable marker of overall preeclampsia risk. Preliminary data suggests that this ratio may be more accurate than sFlt-1 or PGF alone [ 70 ]. This test was launched in Europe by Roche as a second trimester screening test for preeclampsia. A financial analysis found that the cost of this test when added to the standard protocol was negated by timely management of patients who would not have been diagnosed if only existing tests had been used (false negative cases) [ 73 ].

Increased maternal serum levels of sEng were detected prior to preeclampsia onset in healthy, nulliparous women [ 74 , 75 ] as well as in high-risk pregnant population [ 76 ].

A Korean study demonstrated that the combined ratio of (sFlt-1 + soluble endoglin) : (PGF + TGF beta −1) during the second trimester had the highest odds ratio and lowest false positive rate as compared to the individual markers for prediction of preeclampsia [ 77 ].

The results of various studies, unfortunately, have been inconsistent, and larger studies in more heterogenous population are needed to better define the clinical utility of these tests. There is some data, however, to suggest that tests for these biomarkers may be of use when applied to selected high-risk patients such as those with underlying hypertension [ 78 ].

The other suggested markers for the prediction or detection of preeclampsia are

  • placental protein 13 (PP-13);
  • pregnancy-associated plasma protein A (PAPP A);
  • P-selectin;
  • cell-free fetal DNA;
  • 2-Methoxyestradiol (2-ME).

8. Consequences of Hypertension in Pregnancy

Hypertension in pregnancy is a major cause of maternal morbidity and mortality in the United States. There is approximately one maternal death due to preeclampsia-eclampsia per 100,000 live births, with a case-fatality rate of 6.4 deaths per 10,000 cases [ 79 , 80 ]. The outcome of hypertension in pregnancy is, not surprisingly, affected by multiple factors. These embrace (but are not limited to) gestational age at onset, severity of disease, and the presence of comorbid conditions including diabetes mellitus, renal disease, thrombophilia, or preexisting hypertension [ 81 ]. Adverse outcomes related to hypertension in pregnancy can be divided into short-term versus long-term complications. While short-term complications can be further subgrouped into maternal and fetal complications, long-term outcomes are mainly maternal.

8.1. Short-Term Complications

8.1.1. maternal.

Outcomes for pregnancy complicated by hypertension range from uneventful pregnancy in women with chronic, controlled hypertension to death in cases of preeclampsia-eclampsia. The major adverse outcomes include central nervous system (CNS) injuries such as seizures (eclampsia), hemorrhagic and ischemic strokes, hepatic damage ranging from transaminase elevation, the so-called “HELLP syndrome” (hemolysis, elevated liver enzymes, and low platelets), hepatic failure, renal dysfunction (spanning the gamut from a trivial reduction in glomerular filtration rate and minimal proteinuria to reversible acute renal failure or so-called acute tubular necrosis to even irreversible renal failure secondary to renal cortical necrosis) as well as increased frequency of cesarean delivery, preterm delivery, and abruptio placentae [ 2 , 80 , 81 ].

8.1.2. Fetal

The effects of chronic, controlled hypertension in pregnancy on the fetus are minimal. However, preeclampsia-eclampsia can lead to higher frequency of induced labor, fetal growth restriction, neonatal respiratory difficulties, and increased frequency admission to neonatal intensive care unit. Hypertension in pregnancy, even in its more severe forms, causes only minimal increased risk for perinatal or fetal death [ 2 , 82 ].

8.2. Long-Term Complications

Though hypertension in pregnancy/preeclampsia is usually thought of as a short-term problem that resolves itself with delivery, it still carries significant risk for remote complications. Those infants born small and premature may experience prolonged stays in neonatal intensive care units and often face developmental delays. Remote outcomes include the risk of preeclampsia in subsequent pregnancies and several long-term maternal health risks as described below.

8.2.1. Risk of Recurrence

The risk of recurrent preeclampsia in subsequent pregnancies varies with the severity and time of onset of the acute episode [ 63 ]. It is estimated that women with severe, early preeclampsia during their first pregnancy will have a high risk of recurrent preeclampsia in their subsequent pregnancies (25–65%) [ 83 , 84 ]. On the other hand, for milder forms of preeclampsia the risk of recurrent episode is still elevated, though to a lesser degree (5–7%) in comparison to women who remained normal during their first pregnancy (1%) [ 85 – 87 ]. The recurrence risk of preeclampsia is lower when the first pregnancy was a twin as compared to a singleton pregnancy [ 88 ].

8.2.2. Cardiovascular Complications

The association between preeclampsia and cardiovascular diseases is both well described and well documented. Women with history of preeclampsia are at significantly increased risk to develop hypertension, ischemic heart disease, stroke, type II diabetes, and venous thromboembolism in comparison with women without history of the disease [ 89 ]. Factors linked to increased risk of long-term cardiovascular diseases are early onset preeclampsia, recurrent preeclampsia, severe preeclampsia, gestational hypertension, or preeclampsia with onset as a multipara [ 89 ]. Peripartum cardiomyopathy more often develops in women with preeclampsia. The pathophysiologic relation between preeclampsia and subsequent late-developing cardiovascular disease is unclear. Many hypotheses have been explored including impaired endothelial function, increased insulin resistance, sympathetic overactivity, proinflammatory activity, and the abnormal lipid profile, which usually constitute an early manifestation of metabolic syndrome [ 90 – 94 ].

8.2.3. Renal Disease

More renal biopsies are undertaken in victims of preeclampsia than in unaffected women [ 95 ]. There is also an increased risk for women with history of preeclampsia to develop end-stage renal disease (ESRD), though the absolute risk appears to be low. A recently published study that evaluated data from the Norwegian national birth and ESRD registries found that the risk of subsequent ESRD increases with increased recurrent episodes of preeclampsia in two or more pregnancies [ 95 ].

8.2.4. Cancer

Multiple observational studies evaluated the possible association between hypertension in pregnancy and cancer risk. Overall, women with preeclampsia were found to be at reduced risk or had no excess risk of cancer when followed by extended periods postpartum [ 96 – 99 ]. This was confirmed by a recent systematic review that found no significant association between preeclampsia and risk of cancer. This “protective” effect of preeclampsia may be explained, at least in part, by the possible role of the immune system in the disease pathogenesis. Women with responsive immune systems may be more vulnerable to develop preeclampsia but enjoy some protection from malignancy.

9. Treatment of Hypertension

The first principle of treatment of hypertension in pregnancy is to correctly diagnose the category ( Table 1 ) and severity of the hypertension. Implicit to this guide is the aforementioned limited value of attempting to completely normalize the blood pressure in this setting. The second and perhaps even more important principle is to understand the potential vulnerability of the fetus to treatment.

9.1. Chronic Hypertension

The estimated prevalence of chronic hypertension in pregnancy in United states is 3% and has been increasing over time. This increase in prevalence has been attributed to the increased prevalence of obesity and delay in childbearing to ages, when chronic hypertension is more common [ 100 ]. Although these patients are at higher risk of superimposed preeclampsia, many will naturally experience a physiological lowering of blood pressure during pregnancy, and a reduction in the requirement for any previously prescribed antihypertensive medication. A return to blood pressure in hypertensive range in the third trimester is not unexpected. The goal of treatment is to maintain blood pressure at a level that prevents maternal cerebrovascular and cardiovascular complications. Prevention of preeclampsia is desirable; however, current evidence has not shown that either specific blood pressure targets in pregnancy, or specific antihypertensive agents modify the risk of superimposed preeclampsia in women with preexisting hypertension [ 101 ].

Women with the following conditions are at increased risk for maternal and fetal complications and should have a lower threshold for treatment [ 102 ]:

  • underlying renal disease;
  • secondary hypertension;
  • end-organ damage (e.g., ventricular dysfunction, retinopathy);
  • maternal age over forty years old;
  • microvascular disease;
  • history of stroke;
  • previous perinatal loss;

9.2. Gestational Hypertension

Gestational hypertension is elevated blood pressure, which develops after 20 weeks of gestation in a previously normotensive woman, though without proteinuria. It complicates 6% of all pregnancies. These women are at high risk for developing preeclampsia that can occur at any time including the first postpartum week and need close monitoring. Approximately 15–45% will eventually develop preeclampsia [ 103 , 104 ]. The goal of treatment is same as chronic hypertension.

9.3. Preeclampsia

The general principles as outlined to guide the treatment of women with chronic hypertension are applicable to the preeclamptic patients. Close monitoring to recognize fetal distress while receiving treatment is essential. Early onset preeclampsia (less than thirty-four weeks) requires careful use of antihypertensive medications, bed rest, and in-hospital monitoring of both mother and fetus. This approach may help delay delivery and thus improve fetal outcome. Often these patients are intravascularly depleted and are more susceptible to precipitous, drug-induced drops in blood pressure. If signs of other fetal or maternal distress are noted, delivery is the definitive treatment. Concerns about hypotension and decreased uteroplacental blood flow are central to the treatment of the preeclamptic patient, since placental ischemia is the focal point of preeclampsia pathophysiology. Furthermore, lowering of BP does not reverse the primary process. The ultimate goal of antihypertensive therapy is to reduce the main risks to the mother, which include placental abruption, accelerated hypertension requiring hospitalization, and target organ-damage including cerebrovascular and cardiovascular complications. One must be cognizant of the risk for target organ damage is increased, when a sudden change in blood pressure occurs in previously normotensive women. As is true in all dynamic clinical settings, individualization of care is often the rule. In most instances, delivery of preeclamptics is indicated after 37 weeks of gestation or when fetal lung maturity has been confirmed.

9.4. Superimposed Preeclampsia

Superimposed preeclampsia complicates approximately 25% of pregnancies in women with chronic hypertension [ 102 ]. Principles of management are the same as outlined earlier for preeclampsia, although these women have more likelihood of developing severe hypertension, requiring multiple antihypertensive medications.

10. Goals of Treatment

10.1. mild-to-moderate hypertension in pregnancy.

The benefits of antihypertensive therapy for mild to moderately increased blood pressure in pregnancy (≤160/109 mm Hg), either chronic or de novo, have not been shown in clinical trials. A Cochrane meta-analysis concluded that there are insufficient data to determine the benefits and risks of antihypertensive therapy for mild-to-moderate hypertension (defined as blood pressure 140–160 mm Hg systolic or diastolic blood pressure 90–109 mm Hg) [ 101 ]. Of note, with antihypertensive treatment there seems to be less risk of developing severe hypertension (relative risk, 0.50; with a number needed to treat of 10) but no difference in outcomes of preeclampsia, neonatal death, preterm birth, and small for gestational age babies with treatment [ 101 ].

International guidelines for the treatment of hypertension in pregnancy vary with respect to thresholds for starting treatment and targeted BP goals. Therapy is recommended in the United states for a BP of 160/105 mm Hg or greater [ 1 ] with no set treatment target; in Canada for women with no comorbid conditions therapy is recommended for blood pressure of 140–150/90 or greater, targeting diastolic pressure to 80–90 mm Hg and in those with comorbid conditions targeting 130–139/80–89 mm Hg [ 105 , 106 ].

10.2. Severe Hypertension

There is consensus that treatment is indicated for severe hypertension in pregnancy, defined as 160/110 mm Hg or greater, to prevent intracerebral hemorrhage and maternal death [ 1 , 107 ]. Those with hypertensive encephalopathy, hemorrhage, or eclampsia require treatment with parenteral agents to lower mean arterial pressure (two-thirds diastolic + one-third systolic blood pressure) by 25% over minutes to hours, and then to further lower blood pressure to 160/100 mm Hg over subsequent hours [ 1 ].

10.3. Severe Preeclampsia

Patient with severe preeclampsia are managed differently as chances for maternal and fetal complications are much higher. The criteria for diagnosis of severe preeclampsia are outlined below:

  • sustained systolic blood pressure ≥160 mm of Hg;
  • sustained diastolic blood pressure of ≥110 mm of Hg;
  • pulmonary edema;
  • oliguria <500 mL/24 hours;
  • persistent headaches or scotoma;
  • thrombocytopenia <100,000/mm 3 ;
  • persistent right upper quadrant pain or epigastric pain;
  • intrauterine growth restriction <10th percentile.

The ultimate treatment in severe preeclampsia is prompt delivery. The timing of delivery is based on both maternal and fetal indications. If gestational age is less than 34 weeks, expectant management, when possible should be attempted with the aim of improving neonatal outcome without compromising the safety of the mother. This requires close inpatient monitoring of both mother and the fetus. If possible, delivery should be 48 hours after glucocorticoid administration to maximize fetal lung maturity and improve neonatal outcome. Prior to delivery, the focus is to improve placental perfusion by enhancing cardiac output and peripheral vasodilatation. Patient should be placed in lateral or supine position, which will optimize venous return and cardiac output. These patients are often intravascularly volume-depleted and require some degree of perfusion. Magnesium sulfate seizure prophylaxis is typically initiated in severe preeclamptics. The recommended dose for magnesium sulfate is 4–6 gm iv over 20 minutes followed by continuous infusion at 2 g/hr, which will maintain most patient at therapeutic range of >4 meq/mL. Blood pressure management is same as outlined above for severe hypertension with target BP of 150/100. Rapid vasodilatation with consequent hypotension should be obviated by adequate intravascular resuscitation. An absolute fetal or maternal indication for delivery requires immediate intervention. Delivery can be induced with oxytocin and prostaglandin. If induction fails, cesarean delivery is indicated.

11. Choice of Antihypertensive Drugs

All antihypertensive drugs cross the placenta but to variable degrees and most are agents categorized as “Category C.” There are no data from large well-designed randomized trials strong enough to mandate the use of one drug over another. Different drugs will be discussed separately based on their pharmacological actions and summarized in Table 4 [ 108 ].

Antihypertensives in pregnancy.

11.1. Sympathetic Nervous System Inhibitors

11.1.1. centrally acting agents.

Methyldopa is one of the most widely used drugs for the treatment of hypertension in pregnancy. It is a prodrug metabolized to alpha methylnorepinephrine, which then replaces norepinephrine in the neurosecretory vesicles of adrenergic nerve terminals. BP control is gradual, over six to eight hours, because of the indirect mechanism of action. It is not thought to be teratogenic based on limited data and forty-year clinical experience. Treatment with methyldopa has been reported to prevent subsequent progression to severe hypertension in pregnancy [ 109 ] and does not seem to have adverse effects on uteroplacental or fetal hemodynamics [ 110 ].

Adverse effects are based on central alpha-2 blocking effect or decreased peripheral sympathetic tone. This drug can cause decreased mental alertness and impaired sleep, leading to sense of fatigue in some or depression in others. Still other observed side effects are decreased salivation, leading to xerostomia (chronic dry mouth), elevated liver enzymes in 5%; hepatitis and hepatic necrosis have also been reported. Some patients will develop a positive antinuclear antigen or antiglobulin (Coombs') test with chronic use, which may occasionally cause clinical hemolytic anemia.

Clonidine, a selective alpha-2 agonist, acts similarly and is comparable to methyldopa with respect to safety and efficacy [ 111 ], but of some concern is a small controlled follow-up study of twenty-two neonates that reported an excess of sleep disturbance in clonidine-exposed infants [ 112 ]. In pregnancy, it is mainly used as a third-line agent for multidrug control of refractory hypertension.

11.1.2. Peripherally Acting Agents

B-blockers have been extensively used in pregnancy. Concern still remains about their safety in pregnancy based on data derived from a few small studies, which suggests an association with low birth weight infants. Atenolol, for example, in one such study started at twelve to twenty-four weeks' gestation, resulted in clinically significant fetal growth restriction and decreased placental weight compared with placebo [ 113 , 114 ]. None of the b-blockers have been associated with teratogenicity. Oral agents have been associated with nonclinically significant neonatal bradycardia. Parenteral therapy has been found to increase the risk of neonatal bradycardia in one of six newborns. Results from one-year follow-up study, which showed normal development of infants exposed to atenolol in utero, are reassuring [ 115 ]. In a recent Cochrane analysis, b-blockers were found to be more effective in lowering BP than methyldopa in ten trials.

Labetolol, a nonselective beta- and alpha-blocker has gained wide acceptance in pregnancy. Oral administration is considered safe and effective as methyldopa [ 116 , 117 ], although neonatal hypoglycemia is reported at high doses. Based on one placebo trial, it has been associated with growth restriction when used in management of preeclampsia remote from term. Parenterally it is used to treat severe hypertension, and because of a lower incidence of maternal hypotension and other side effects, many find this drug preferable to hydralazine. Reported adverse events are fatigue, lethargy, exercise intolerance, peripheral vasoconstriction, sleep disturbance, and bronchoconstriction. It has moved up to the category of a first-line agent in the opinion of many clinicians.

Peripherally acting alpha-adrenergic antagonists are second-line antihypertensive drugs in nonpregnant adults. These are indicated during pregnancy in the management of hypertension in patients suspected to have pheochromocytoma. Both prazosin and phenoxybenzamine have been used, with b-blockers used as adjunctive agents after alpha-blockade is accomplished [ 118 , 119 ]. There is only limited experience with these agents in pregnancy; therefore, their routine use cannot be advocated.

11.2. Calcium Channel Blockers

These drugs have been used to manage chronic hypertension, mild pre-eclampsia presenting late in gestation and urgent hypertension associated with preeclampsia. Both nifedipine a nondihydropyridine calcium channel blocker and verapamil are not associated with teratogenic risks to fetus exposed in first trimester [ 120 ]. Maternal adverse effects with nifedipine include tachycardia, palpitations, peripheral edema, headaches, and facial flushing. Nifedipine does not seem to cause a detectable decrease in uterine blood flow [ 121 , 122 ]. Short-acting dihydropyridine calcium antagonists, particularly when administered sublingually, are now not recommended for the treatment of hypertension in nonpregnant patients because of reports of myocardial infarction and death in hypertensive patients with coronary artery disease. In pregnant patients, these formulations are associated with maternal hypotension and fetal distress [ 123 , 124 ] and are generally not recommended. In contrast long-acting oral nifedipine in pregnant patients with severe hypertension in pregnancy has been shown to be safe and effective [ 125 ]. Dihydropyridine compounds also have a tocolytic effect and can delay the onset or slow the progression of labor. Nondihydropyridine agents such as verapamil and diltiazem may have added value in women with proteinuria because of their antiproteinuric action.

A concern with the use of calcium antagonists for BP control in preeclampsia has been the concomitant use of magnesium sulfate to prevent seizures. Drug interactions between nifedipine and magnesium sulfate were reported to cause neuromuscular blockade, myocardial depression, or, in some cases, circulatory collapse. Despite this concern, recent evaluation showed that these medications are commonly used together without increased risk.

11.3. Diuretics

Diuretics are first-line agents to be used in management of essential hypertension prior to conception and, based on their apparent safety, they may be continued during pregnancy alone or in combination with other agents especially in women more likely to have salt-responsive hypertension [ 1 ]. Concerns regarding volume contraction leading to limited fetal growth have not been supported in studies [ 126 ]. Mild volume contraction, however, may lead to hyperuricemia and in doing so invalidate serum uric acid levels as a laboratory marker that may assist in the diagnosis of superimposed preeclampsia. The adverse effects are mainly due to fluid, electrolytes, and solute disturbances.

In women already taking, hydrochlorothiazide may be continued during pregnancy; use of low-doses (12.5 to 25 mg daily) may minimize untoward metabolic effects, such as impaired glucose tolerance and hypokalemia [ 127 ]. The potassium sparing diuretics triamterene and amiloride do not appear to be teratogenic based on a small numbers of case reports [ 127 ]. On the other hand, spironolactone is not recommended because of its antiandrogenic effects during fetal development, noted in animal models, although this concern was not borne out in an isolated clinical case, where this agent was employed [ 128 ].

11.4. Direct Vasodilators

Hydralazine: selectively relaxes arteriolar smooth muscle by an as yet unknown mechanism. The most important indication is severe hypertension or a third-line agent in control of refractory hypertension. It can be used orally, intravenously, or intramuscularly. Adverse effects are due to excessive vasodilation or sympathetic activation (headache, nausea, flushing, or palpitations). Chronic use can lead to (in rare cases) a pyridoxine-responsive polyneuropathy or to immunologic reactions, including a drug-induced lupus syndrome. Hydralazine has been used in all trimesters of pregnancy, and data have not shown an association with teratogenicity, although neonatal thrombocytopenia and lupus have been reported [ 129 ]. For acute severe hypertension later in pregnancy, intravenous hydralazine has been associated with more maternal and perinatal adverse effects than intravenous labetalol or oral nifedipine. Maternal hypotension, cesarean sections, placental abruptions, Apgar scores less than 7, and oliguria occur more frequently following hydralazine. A recent meta-analysis of the use of intravenous hydralazine in severe hypertension in pregnancy concluded that parenteral labetalol or oral nifedipine were preferable first-line agents, with hydralazine as a suitable second-line agent [ 130 ].

11.4.1. Isosorbide Dinitrates

this agent has been investigated in a small study of gestational hypertensive and preeclamptic pregnant patients. It was found that cerebral perfusion pressure is unaltered by isosorbide dinitrate, despite significant changes in maternal BP, thus decreasing the risk for ischemia and infarction, when BP is lowered [ 131 ].

11.4.2. Sodium Nitroprusside

This direct nitric oxide donor, which relaxes both arteriolar and venular vascular smooth muscles. It is used only as continuous infusion and is easily titrated because of its near immediate action of onset and only three-minute duration of action. Nitroprusside metabolism releases cyanide, which can reach toxic levels when infused rapidly. Cyanide metabolizes to thiocyanate which can lead to toxicity in 24–48 hours. Adverse effects include excessive vasodilation and cardioneurogenic (i.e., paradoxical bradycardia) syncope in volume-depleted preeclamptic women [ 132 ].

N.B.: The risk of fetal cyanide intoxication remains unknown. Given the long experience with hydralazine and alternative use of parenteral labetalol or oral calcium channel blockers, this drug is considered as a last resort.

11.5. Serotonin Receptor Blockers

Serotonin-induced vasodilation is mediated by S1 receptors and subsequent release of prostacyclin and NO. Ketanserin is a selective S2 receptor-blocking agent that has been used in the nonpregnant population. Based on the data available from Australia and South Africa, it may be safe to use in pregnancy and useful in treatment of chronic hypertension in pregnancy, preeclampsia, and HELLP syndrome [ 133 , 134 ]. FDA has not approved Ketanserin for use in United States.

11.6. Angiotensin-Converting Enzyme Inhibitors (ACE-I) and Angiotensin Receptor Antagonists (ARB)

ACE-I and ARB are contraindicated in 2nd and 3rd trimesters because of severe toxicity secondary to reduced renal perfusion of the fetal kidneys. Their use has been associated with renal dysgenesis, oligohydramnios as a result of fetal oliguria, calvarial and pulmonary hypoplasia, intrauterine growth restriction, and neonatal anuric renal failure, leading to death of the fetus [ 135 , 136 ]. ARBs have also been associated with fetal demise and same concerns are applicable to the use of direct renin inhibitors. First trimester exposure to these agents has been associated with greater incidence of cardiovascular and central nervous system malformations. Whether these effects are secondary to hemodynamic effects or specific requirement of angiotensin II as a fetal growth factor is unknown. Patients should, therefore, be counseled to stop these medications while attempting to conceive. The risk of birth defects increased from 3 to 7% while on these medications at the time of conception [ 137 ].

12. Postpartum Hypertension

Some women experience a rise in their BP in the postpartum period, which typically reaches a maximum on the fifth postpartum day. This has been attributed to volume expansion and fluid mobilization in postpartum period. The time period, beyond which patients with gestational hypertension and preeclampsia are labeled chronic hypertensive, is not well defined. The threshold for treatment in these patients has not been uniformly established, but medication is generally recommended to be started when systolic BP exceeds 150 mm Hg or diastolic BP is greater than 100 mm of Hg [ 138 ]. The choice of antihypertensive agents is, of course, influenced by whether or not the patient is breast-fed. In selected patients with severe preeclampsia, especially those with hypertension accompanied by peripheral and pulmonary edema, a short course of loop diuretics may be beneficial.

NSAIDS may contribute to postpartum hypertension as per few case reports [ 139 ], and thus their use should be avoided in patients who are already hypertensive.

13. Breast Feeding

Neonatal exposure to methyldopa via nursing is likely low and is generally considered safe. Atenolol and metoprolol are concentrated in breast milk, possibly to levels that could affect the infant; by contrast, exposure to labetolol and propanolol appears low [ 140 ]. Although milk concentrations of diuretics are low and considered safe, these agents, by inducing volume contraction in mother, can decrease milk production [ 141 ]. There are reports of calcium channel blockers transfer into breast milk [ 142 ], but the relative infant dose of nifedipine, verapamil, and diltiazem is low, and all are safe during breast-feeding. Sufficient data exist for the safety of three ACE inhibitors: captopril, enalapril, and quinapril; these drugs are deemed to be compatible with breast-feeding by the American Academy of Pediatrics [ 143 ]. There are currently insufficient data on angiotensin II receptor blockers and at this time the recommendation is not to use these drugs during breast-feeding.

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