Drugs used in hypertensive diseases in pregnancy

PURPOSE OF REVIEW: This review will summarize results derived from the most recent publications on the use of drugs in women with hypertensive diseases in pregnancy. RECENT FINDINGS: There is consensus that severe hypertension should be treated without delay to reduce maternal risks of acute cerebrovascular complications. There is no consensus that antihypertensive drugs improve maternal or fetal outcome in mild to moderate hypertension. Evidence exists that antihypertensive drugs may halve the risk of severe hypertension in pregnancy. No proof exists that antihypertensive drugs reduce perinatal mortality or development of preeclampsia, and such drugs have not been associated with improved fetal growth. Clinical trials indicate non-consistent data concerning antihypertensive treatment on antenatal rate of hospitalization, proteinuria at delivery and neonatal respiratory distress syndrome. Hydralazine has for many years been regarded as the first drug of choice for treatment of severe hypertension in pregnancy. Recent findings indicate that the calcium antagonist nifedipine might be a better alternative. Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists should be discontinued due to fetotoxicity. The beta1-selective adrenoceptor blocker atenolol in the first trimester is associated with low birth weight. SUMMARY: Large randomized controlled trials are urgently needed to determine whether antihypertensive therapy in pregnancy results in greater benefit than risks for mother and fetus.     

Diagnosis and management of gestational hypertension and preeclampsia

Gestational hypertension and preeclampsia are common disorders during pregnancy, with the majority of cases developing at or near term. The development of mild hypertension or preeclampsia at or near term is associated with minimal maternal and neonatal morbidities. In contrast, the onset of severe gestational hypertension and/or severe preeclampsia before 35 weeks' gestation is associated with significant maternal and perinatal complications. Women with diagnosed gestational hypertension-preeclampsia require close evaluation of maternal and fetal conditions for the duration of pregnancy, and those with severe disease should be managed in-hospital. The decision between delivery and expectant management depends on fetal gestational age, fetal status, and severity of maternal condition at time of evaluation. Expectant management is possible in a select group of women with severe preeclampsia before 32 weeks' gestation. Steroids are effective in reducing neonatal mortality and morbidity when administered to those with severe disease between 24 and 34 weeks' gestation. Magnesium sulfate should be used during labor and for at least 24 hours postpartum to prevent seizures in all women with severe disease. There is an urgent need to conduct randomized trials to determine the efficacy and safety of antihypertensive drugs in women with mild hypertension-preeclampsia. There is also a need to conduct a randomized trial to determine the benefits and risks of magnesium sulfate during labor and postpartum in women with mild preeclampsia.     

Trends in using beta-blockers and methyldopa for hypertensive disorders during pregnancy in a Canadian population

Objective

To describe trends in and patterns of antihypertensive drug use in a general obstetric population.

Study design

Historical cohort study. A total of 18,117 women who gave birth in a Saskatchewan hospital between January 1, 1980 and December 31, 2005 with a diagnosis of hypertensive disorders in pregnancy were identified and included in the analysis.

Results

The rate of treatment with antihypertensive drugs for pregnant women with chronic hypertension rose from 19.94% in 1980–1984 to 37.63% in 2000–2005. There were similar increases in antihypertensive drug use from 1.51% to 14.47% for gestational hypertension/non-severe preeclampsia, and from 1.56% to 20.86% for severe preeclampsia/eclampsia. Methyldopa was the most frequently used drug, followed by beta-blockers, with other antihypertensive drugs accounting for about 18.43% of total uses. The use of both methyldopa and labetalol has increased in recent years while the use of other antihypertensive drugs has decreased. Other antihypertensive drugs were more commonly prescribed in earlier gestation, while methyldopa and labetalol were generally prescribed in later gestation.

Conclusion

The use of antihypertensive drugs in pregnancy is relatively common and is increasing, with the liberal use of methyldopa and (especially) labetalol contributing appreciably to this increase.     

妊娠期高血压性心脏病的防与治

妊娠期高血压性心脏病是在妊娠期高血压疾病基础上发生的心脏泵血功能减退,严重者甚至出现以左心衰竭为主的全心衰竭综合征,其病情凶险,病死率高,发病隐匿,早期症状易被忽略。对于妊娠期高血压疾病患者要采取积极降压等治疗,动态进行心功能评估,积极纠正高危因素,预防心力衰竭（心衰）的发生。已发生急性心衰者,按照一般急性心衰的原则治疗的同时应治疗导致子痫前期的原发病,并及时终止妊娠。     

Hypertensive disorders of pregnancy.

OBJECTIVES: This study was undertaken to determine the prevalence of hypertensive disorders of pregnancy and evaluate their effects on the mothers and fetuses at Jahrom, a city in southern Iran. METHODS: A retrospective survey was performed on 2300 pregnant women who had referred to Shahid Motahhari Hospital of Jahrom School of Medical Sciences from 22 September 2002 to 21 September 2003. Diagnosis of hypertensive disorders of pregnancy and their probable complications were made according to medical recording files. RESULTS: Among the studied patients, 3.3% were diagnosed as having hypertensive disorders of pregnancy, of which 96% were cases of preeclampsia/eclampsia or transient hypertension. In hypertensive patients, the overall maternal mortality rate was 1.3 per 10,000 and perinatal mortality rate was 53 per 1000 births. Low birth weight neonates were observed in 20% of cases. CONCLUSION: Hypertensive disorders of pregnancy commonly complicate pregnancy and have great influences on maternal and neonatal morbidity and mortality rates and more attention and precision is needed to evaluate the pregnant women for detecting and preventing the complications.     

Prevalence of Hypertension During Pregnancy in Portugal

Objective: To estimate the prevalence of maternal hypertensive disorders in Portugal and to assess their impact on obstetric outcomes. Methods: A national survey on hypertension in pregnancy was conducted in Portuguese public maternity wards and included 6726 pregnancies. Results: Six percent of women presented with a hypertensive disorder during pregnancy or puerperium: 1.5% with chronic hypertension, 2.5% with gestational hypertension, 1.4% with preeclampsia, 0.2% with superimposed preeclampsia, 0.1% with eclampsia, and 0.1% with HELLP syndrome. Preterm birth, small-for-gestational-age infants and fetal death were significantly more frequent among women with preeclampsia/eclampsia and HELLP syndrome. Conclusion: In Portugal, the prevalence of hypertensive disorders diagnosed during pregnancy seems to be lower than that reported in most countries, but these disorders have a significant effect on pregnancy outcomes.     

Pregnancy and severe chronic hypertension: maternal outcome.

OBJECTIVE: To determine the maternal outcome associated with severe chronic hypertension during the second half of pregnancy. METHODS: An analysis of data obtained of women with severe chronic hypertension (> or = 160/110 mm Hg) and > or = 20 weeks' gestation who were hospitalized and delivered during a 5-year period. The pregnancy outcome data were collected retrospectively from medical records. Each patient was observed closely throughout hospitalization with intensive monitoring of the clinical status of both mother and fetus. Antihypertensive drugs were used for systolic or diastolic blood pressure > or = 160 and > or = 110 mm Hg, respectively. Women with superimposed preeclampsia received magnesium sulfate. The main outcome measures were peak of blood pressure, superimposed preeclampsia, and major maternal complications. RESULTS: Of 154 women studied, 111 (72%) had pregestational chronic hypertension, and 120 (78%) developed superimposed preeclampsia. The mean weeks' gestation was 34.5 +/- 4.6. Overall, 110 (71.4%) pregnancies were delivered by cesarean section. Maternal age and parity were significantly higher among women who had pregestational chronic hypertension than those who had chronic hypertension diagnosed during the first half of pregnancy. Abruptio placentae (8.4%), HELLP syndrome (8.4%), acute renal insufficiency (3.9%), pulmonary edema (1.3%), and postpartum hypertensive encephalopathy (1.3%) were the most frequent maternal complications. There were no maternal deaths, disseminated intravascular coagulation, or eclampsia. CONCLUSION: Three-quarters of women with severe chronic hypertension in the second half of pregnancy developed superimposed preeclampsia. Intensive monitoring of the clinical status of the mother was associated with low maternal morbidity and the absence of maternal deaths. Pregestational chronic hypertension does not change the maternal prognosis.     

Epidemiology of preeclampsia in Mauritius island

In Mauritius, the maternal mortality rate (MMR) was 21 per 100000 live births for the year 2001 and this is comparable with figures from developed countries. There has been poor documentation in the area of hypertensive disorders of pregnancy until recently in the island. Consequently, we analysed data from the Ministry of Health. Hypertensive disorders of pregnancy occurred in 6.7% gravidas in 2001. Out of four maternal deaths recorded in 2001, two occurred due to severe eclampsia. In the second part of our study, we scrutinised also the obstetric notes and interviewed 862 hospitalised women from four main hospitals of the island between 1995 and 1997. The majority of women were affected by non-proteinuric hypertension (70%), followed by preeclampsia (24%) and chronic hypertension (6%). Preeclamptic primi and multigravidas developed the condition earlier and also gave birth to growth-retarded babies. Highly significant results supported the relationship between growth retardation and preeclampsia in different parities, irrespective of the length of exposure of the baby in utero. Preeclampsia affects both Indo-Mauritians and Creoles to the same extent, but the latter are much more prone to gestational hypertension. In addition, hypertensive disorders of pregnancy are more a problem of multigravid women in Creoles while they are more classically a condition of primigravidae in Indians.     

Severe Maternal Morbidity Associated with Hypertensive Disorders in Pregnancy in the United States

Objectives: This study was to report the incidence of severe maternal morbidity associated with hypertensive disorders of pregnancy in the United States. Study Design: We used data from the National Hospital Discharge Survey, a nationally representative sample of discharge records, from 1988 to 1997. The database consisted of approximately 300,000 deliveries, which represented 39 million births during the 10‐year period. Results: The overall incidence of hypertensive disorders in pregnancy was 5.9% [95% confidence interval (CI): 5.2 to 6.5%]. Eclampsia was reported at 1.0 per 1000 deliveries (95% CI: 0.8 to 1.2). The incidence of eclampsia, severe preeclampsia, and superimposed preeclampsia remained unchanged during the 10‐year period. Women with preeclampsia and eclampsia had a 3‐ to 25‐fold increased risk of severe complications, such as abruptio placentae, thrombocytopenia, disseminated intravascular coagulation, pulmonary edema, and aspiration pneumonia. More than half of women with preeclampsia and eclampsia had cesarean delivery. African American women not only had higher incidence of hypertensive disorders in pregnancy but also tended to have a greater risk for most severe complications. Preeclamptic and eclamptic women younger than 20 years or older than 35 years had substantially higher morbidity. Conclusion: Preeclampsia and eclampsia carry a high risk for severe maternal morbidity. Compared to Caucasians, African Americans have higher incidence of hypertensive disorders in pregnancy and suffer from more severe complications.     

重度妊娠期高血压疾病的降压治疗新进展

妊娠期高血压疾病是一个世界关注的孕产妇健康问题,是导致发展中国家孕产妇死亡的主要原因之一。在妊娠期高血压疾病的各个时期都可能发生重度高血压。为了降低血管意外尤其是脑卒中和(或)其他中枢系统并发症的发生率,改善预后,应当积极、有效地治疗持续重度的高血压。而何时开始治疗、如何治疗仍然需要探讨。现有的文献资料显示,肼苯哒嗪和硝苯地平已不再是妊娠期高血压疾病降压治疗的一线药物,而拉贝洛尔、尼卡地平也许是更好的选择。     

Circulating Endothelin-1 Is Not Increased in Severe Preeclampsia

Endothelin-1 is a potent vasoconstrictor peptide released by vascular endothelial cells. Preeclampsia is a unique hypertensive disorder of pregnancy. Endothelial (ET) cell injury has been implicated in the pathophysiology of this disorder. Endothelial cell injury has been shown in vitro to cause the release of endothelin-1. Therefore, we conducted a prospective study of pregnant patients with hypertensive disorders and a control population to examine whether circulating levels of endothelin-1 are elevated in these disorders. We studied 21 patients with the following diagnoses: severe preeclampsia (n = 9); chronic hypertension (n = 6), two of whom had superimposed preeclampsia; and control patients (n = 6). The mean maternal and gestational ages were similar in these three groups. More importantly, severe preeclamptic patients were selected by strict criteria and most had evidence of thrombocytopenia. Endothelin was extracted immediately after the collection of blood and measured by a standard radioimmunoassay (RIA). There were no differences between the endothelin-1 levels (mean ± SEM) in patients with severe preeclampsia (2.1 ± 0.6), in patients with chronic hypertension without superimposed preeclampsia (1.9 ± 0.8), and in the control population (1.7 ± 0.6). Our results are consistent with the current concept that endothelin-1 does not function as a circulating hormone. However, because of its prolonged duration of action and function as a locally acting hormone, demonstration of elevated circulating levels of ET-1 is not necessary to support its participation in the vasospasm of preeclampsia.     

The possible role of endothelial cells in hypertensive disorders during pregnancy.

OBJECTIVE: To clarify the role of endothelial cells in pregnancy-related hypertensive disorders, we studied the cytotoxic effect of sera from normal pregnant women and from gravidas with various hypertensive complications of pregnancy. METHODS: We obtained serum samples from 84 Japanese women: 17 with preeclampsia, ten with gestational hypertension, six with chronic hypertension, five with chronic hypertension with superimposed preeclampsia, 21 normal gravidas, and 25 healthy nonpregnant women. Endothelial cell injury was measured by the release of radiolabeled chromium from the cells into the culture medium. RESULTS: The mean (+/- standard error of the mean) values of chromium 51 release in preeclampsia, gestational hypertension, chronic hypertension, chronic hypertension with superimposed preeclampsia, normal pregnancy, and healthy nonpregnant women were: 21.9 +/- 2.1, 10.0 +/- 2.0, 9.2 +/- 2.3, 12.9 +/- 0.8, 8.4 +/- 1.4, and 7.3 +/- 1.6%, respectively. Normal pregnant and nonpregnant subjects did not differ with respect to endothelial cell injury. Sera from women with preeclampsia demonstrated significantly greater endothelial cell injury than did sera from normal gravidas. Subjects with the three other categories of hypertensive disorders did not differ significantly from normal gravidas. CONCLUSION: Preeclampsia is characterized by the presence of a serum factor cytotoxic to endothelial cells. Therefore, the mechanism responsible for the increase in blood pressure differs between women with preeclampsia and those with other hypertensive disorders in pregnancy.     

Chronic hypertension in pregnancy

Chronic hypertension in pregnancy is associated with increased rates of adverse maternal and fetal outcomes both acute and long term. These adverse outcomes are particularly seen in women with uncontrolled severe hypertension, in those with target organ damage, and in those who are noncompliant with prenatal visits. In addition, adverse outcomes are substantially increased in women who develop superimposed preeclampsia or abruptio placentae. Women with chronic hypertension should be evaluated either before conception or at time of first prenatal visit. Depending on this evaluation, they can be divided into categories of either "high risk" or "low risk" chronic hypertension. High-risk women should receive aggressive antihypertensive therapy and frequent evaluations of maternal and fetal well-being, and doctors should recommend lifestyle changes. In addition, these women are at increased risk for postpartum complications such as pulmonary edema, renal failure, and hypertensive encephalopathy for which they should receive aggressive control of blood pressure as well as close monitoring. In women with low-risk (essential uncomplicated) chronic hypertension, there is uncertainty regarding the benefits or risks of antihypertensive therapy. In my experience, the majority of these women will have good pregnancy outcomes without the use of antihypertensive medications. Antihypertensive agents are recommended and are widely used in these women despite absent evidence of either benefits or harm from this therapy. These recommendations are based on dogma and consensus rather than on scientific evidence. There is an urgent need to conduct randomized trials in women with mild chronic hypertension in pregnancy.     

Preeclampsia in Low and Middle Income Countries—Health Services Lessons Learned From the PRE-EMPT (PRE-Eclampsia–Eclampsia Monitoring,Prevention & Treatment) Project

The hypertensive disorders of pregnancy, in particular preeclampsia, matter because adverse events occur in women with preeclampsia and, to a lesser extent, in women with the other hypertensive disorders. These adverse events are maternal, perinatal, and neonatal and can alter the life trajectory of each individual, should that life not be ended by complications. In this review we discuss a number of priorities and dilemmas that we perceive to be facing health services in low and middle income countries as they try to prioritize interventions to reduce the health burden related to preeclampsia. These priorities and dilemmas relate to calcium for preeclampsia prevention, risk stratification, antihypertensive and magnesium sulphate therapy, and mobile health. Significant progress has been and is being made to reduce the impact of preeclampsia in low and middle income countries, but it remains a priority focus as we attempt to achieve Millennium Development Goal 5.     

Uterine artery Doppler velocimetry in pregnant women with hypertension

Uterine and umbilical artery velocimetry was carried out on 71 women with hypertensive disorders in pregnancy. Three categories of hypertensive disease were diagnosed: chronic hypertension, preeclampsia, and chronic hypertension with superimposed preeclampsia. Clinical classifications describe the severity of disease effectively, primarily because the classification is based on the appearance of abnormal physical or laboratory findings. Doppler velocimetry of the uterine arteries shows that normal pregnancy occurs when the systolic/diastolic ratio is less than or equal to 2.6. When the ratio exceeds this level and there is a notch in the waveform, the pregnancy is complicated by stillbirth, premature birth, intrauterine growth retardation, and maternal preeclampsia. The positive and negative predictive value of the examination is 93% and 91%, respectively. It appears that this new technology will be an essential ingredient of optimum pregnancy surveillance.     

Pregnancy outcomes in systemic sclerosis, primary pulmonary hypertension, and sickle cell disease

OBJECTIVE: Systemic sclerosis, primary pulmonary hypertension, and sickle cell disease are uncommon vasculopathic diseases affecting women. We estimated the nationwide occurrence of pregnancies in women with these conditions and compared pregnancy outcomes to the general obstetric population. METHODS: We studied the 2002-2004 Nationwide Inpatient Sample, of the Healthcare Cost and Utilization Project to estimate the number of obstetric hospitalizations and deliveries among women with systemic sclerosis, primary pulmonary hypertension, sickle cell disease, and women in the general population. Pregnancy outcomes included length of hospital stay, hypertensive disorders including preeclampsia, intrauterine growth restriction (IUGR), and cesarean delivery. Multivariable regression analyses were performed using maternal age, race or ethnicity, antiphospholipid antibody syndrome, diabetes mellitus, and renal failure as covariates. RESULTS: Of an estimated 11.2 million deliveries, 504 occurred in women with systemic sclerosis, 182 with primary pulmonary hypertension, and 4,352 with sickle cell disease. Systemic sclerosis, was associated with an increased risk of hypertensive disorders including preeclampsia (odds ratio [OR] 3.71, 95% confidence interval [CI] 2.25-6.15), IUGR (OR 3.74, 95% CI 1.51-9.28), and increased length of hospital stay. Primary pulmonary hypertension was associated with an increase in the odds of antenatal hospitalization (OR 4.67, 95% CI 2.88-7.57), hypertensive disorders including preeclampsia (OR 5.62, 95% CI 2.60-12.15) and a substantial increase in length of hospital stay. Sickle cell disease was associated with an increased odds of antenatal hospitalization (OR 5.56 95% CI 5.08-6.09), hypertensive disorders including preeclampsia (OR 1.78, 95% CI 1.48-2.14), and IUGR (OR 2.91, 95% CI 2.16-3.93), with a modest increase in length of hospital stay. CONCLUSION: Women with systemic sclerosis, primary pulmonary hypertension, and sickle cell disease have significantly increased rates of adverse pregnancy outcomes, requiring extensive preconceptional counseling about the risks of pregnancy.     

Plasma adiponectin concentration in early pregnancy and subsequent risk of hypertensive disorders

OBJECTIVE: Adiponectin is an exclusively adipose tissue-derived protein. Low plasma adiponectin levels have been found in hypertensive men. Our objective was to evaluate whether low first-trimester plasma adiponectin values were predictive of hypertensive disorders later in pregnancy. METHODS: A nested case-control study was carried out on a cohort of 1,842 pregnant women who participated in the first-trimester Down syndrome screening program; 34 developed preeclampsia and 48 gestational hypertension. A control group of 82 nonhypertensive uneventful pregnancies was selected. Plasma adiponectin was determined using an enzyme-linked immunosorbent assay (ELISA). RESULTS: Adiponectin median concentrations in the group which subsequently became hypertensive were significantly lower than those in the control group (7.6 versus 13.0 microg/mL) (P < .001). When the 2 hypertensive subgroups were considered, the plasma adiponectin median value in the preeclampsia group was significantly lower than that in the gestational hypertension group (6.6 versus 9.3 microg/mL) (P = .01). Regression analysis showed an inverse correlation between plasma adiponectin concentrations and maternal age, gestational age, body mass index, systolic blood pressure, and proteinuria. Approximately 34% of hypertensive pregnancies, compared with 7% of controls (P < .001), had plasma adiponectin concentrations less than 6.4 microg/mL (mean value of lower quartile of distribution among control patients). After adjusting for maternal age, all these women experienced a 6.6-fold (95% confidence interval 2.5-17.8) increased risk of pregnancy hypertension, compared with those women who had higher concentrations. CONCLUSION: Our findings suggest a strong association between hypoadiponectinemia and the risk of hypertensive disorders in pregnancy, especially with preeclampsia.     

降低子痫前期患者严重并发症的策略

妊娠期高血压疾病是妊娠最常见的并发症之一,尤其是临床表现严重的子痫前期、子痫和HELLP综合征,可使母亲与胎儿的发病率和死亡率增加,如何及时、准确地诊断和处理关系到患者病情的进展和预后。本文从风险预测、诊断标准和处理原则几个方面阐述了降低子痫前期患者严重并发症发生的策略,以期最大程度改善妊娠期高血压疾病患者的母儿预后。     

Expectant management of severe preeclampsia and preeclampsia superimposed on chronic hypertension between 24 and 34 weeks' gestation

BACKGROUND: Timing of delivery is difficult to judge in preeclampsia. OBJECTIVE: To compare the differences of maternal and perinatal outcome of patients with severe preeclampsia and essential hypertension with superimposed preeclampsia, with expectant management at 24-34 weeks' gestation. STUDY DESIGN: A retrospective review of a conservative regime using intravenous magnesium sulfate, glucocorticoids and antihypertensive drugs, monitored by serial liver function tests, full blood count, coagulation profile, and renal function tests. Fetal status was assessed by daily non-stress test and ultrasound twice by week. RESULTS: A total number of 100 women had severe preeclampsia and 29 superimposed preeclampsia. The average pregnancy prolongation was 8.4 and 8.5 days, respectively. Oliguria, abruption placentae and HELLP syndrome were frequent complications similar in each group. There were no cases of eclampsia or disseminated coagulopathy in either group. The total neonatal survival rate was 93% in both groups. CONCLUSION: Expectant management is equally safe in both superimposed preeclampsia and severe preeclampsia of early onset.