Drugs in pregnancy. Antihypertensives.

Fifty per cent of pregnancies are unplanned, and 1-6% of young women have pre-existing hypertension. However, no commonly used antihypertensive agent is known to be teratogenic. ACE inhibitors (and angiotensin-receptor antagonists) should be discontinued due to fetotoxicity. Five to 10% of pregnant women have hypertension, of which pre-existing hypertension is but one type. There is consensus that severe maternal hypertension (blood pressure >or=170/110 mmHg) should be treated to minimize the risk of acute cerebrovascular complications. Parenteral hydralazine may be associated with a higher risk of maternal hypotension, and intravenous labetalol with neonatal bradycardia. There is no consensus that mild-to-moderate hypertension in pregnancy should be treated. Clinical trials indicate that transient severe hypertension, antenatal hospitalization, proteinuria at delivery and neonatal respiratory distress syndrome may be decreased by normalizing blood pressure, but intrauterine fetal growth restriction may be increased. Methodological problems with published trials warrant cautious interpretation of these findings. Methyldopa and beta-blockers have been used most extensively, although atenolol may impair fetal growth in particular and should be avoided.     

Antihypertensives

Fifty per cent of pregnancies are unplanned, and 1—6% of young women have pre-existing hypertension. However, no commonly used antihypertensive agent is known to be teratogenic. ACE inhibitors (and angiotensin-receptor antagonists) should be discontinued due to fetotoxicity.Five to 10% of pregnant women have hypertension, of which pre-existing hypertension is but one type. There is consensus that severe maternal hypertension (blood pressure →170/110 mmHg) should be treated to minimize the risk of acute cerebrovascular complications. Parenteral hydralazine may be associated with a higher risk of maternal hypotension, and intravenous labetalol with neonatal bradycardia. There is no consensus that mild-to-moderate hypertension in pregnancy should be treated. Clinical trials indicate that transient severe hypertension, antenatal hospitalization, proteinuria at delivery and neonatal respiratory distress syndrome may be decreased by normalizing blood pressure, but intrauterine fetal growth restriction may be increased. Methodological problems with published trials warrant cautious interpretation of these findings. Methyldopa and β-blockers have been used most extensively, although atenolol may impair fetal growth in particular and should be avoided.     

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.     

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.     

Hypertension in pregnancy.

Pregnancies complicated by hypertension require a well-formulated management plan. Women with chronic hypertension should be evaluated prior to pregnancy. At onset of pregnancy, they should be classified into low-risk and high-risk groups. The majority of pregnant women identified as low-risk hypertensives will have good perinatal outcome without the use of antihypertensive drugs. In general, antihypertensive medications should be reserved for those considered as having high-risk hypertension. In either case, all these women should have close follow-up of maternal and fetal conditions throughout pregnancy. All women with diagnosed preeclampsia should be hospitalized at the time of diagnosis for evaluation of maternal and fetal well-being. Subsequent management will then depend on gestational age and the severity of the disease process. An individualized management plan and a referral to a tertiary care center will improve maternal and perinatal outcome in those women who are remote from term and in those with the HELLP syndrome.     

Antihypertensive drugs in pregnancy

When mean arterial pressure exceeds 140 mmHg (equivalent to 180/120), there is a significant risk of maternal cerebral vascular damage. Therefore it is recommended that blood pressures greater than 170/110 should be treated with urgency, aiming to maintain the blood pressure at all times at less than 170/110 but not lower than 130/90. Parenteral hydralazine is effective and safe therapy. Labetalol (intravenously or orally) appears to be as effective and as safe, and causes fewer troublesome side effects; however, clinical experience of its use is more limited, particularly in relation to its safety for the fetus and neonate. Delivery of the fetus is usually the definitive management of severe hypertension in pregnancy. However, this action may not reduce the blood pressure immediately. After initial treatment with rapid-acting agents, it is often advantageous to maintain control of arterial pressure with ongoing oral therapy (methyldopa, labetalol). In addition to the protective effect on the mother, such therapy may allow delivery of the fetus to be deferred; this should be considered only if the fetus is significantly premature (e.g., less than 34 weeks), there is no other evidence of maternal or fetal distress, and there can be meticulous monitoring of the maternal and fetal state proceeding to prompt delivery if deterioration occurs. The indications for treatment of mild or moderate hypertension in pregnancy are less clear. Severe hypertensive episodes can be reduced by several drugs (methyldopa, labetalol, beta-blockers). Methyldopa appears to reduce the small risk of mid-trimester abortions seen in association with early hypertension. Other benefits may be possible with other individual drugs; however, none of these have been found consistently in controlled studies to date. There seems, therefore, to be no definite indication for treatment of mild hypertension in pregnancy; treatment of moderate hypertension may be reasonable but its value is unproved at present. Antihypertensive drugs are valuable in pregnancy to reduce the risks directly due to elevated blood pressure. These drugs are not expected to affect the evolution of preeclampsia nor to treat the other complications of this condition.     

Ambulatory management of chronic hypertension in pregnancy

Chronic hypertension in pregnancy is one of the most common medical diseases affecting pregnancy. It is associated with serious maternal and fetal complications, including superimposed pre-eclampsia, fetal growth restriction, premature delivery, placental abruption, and stillbirth. Baseline evaluation as early as possible is important to differentiate women with essential hypertension from those with severe hypertension, coexisting end-organ damage, and secondary causes of hypertension, as their risks of poor outcomes are increased. An optimal plan for maternal treatment and fetal surveillance can then be formulated. Coordination of care after delivery is important for long-term maternal health and future pregnancies.     

Pharmacological treatment of severe hypertension in pregnancy and the role of serotonin(2)-receptor blockers

Hypertensive disorders of pregnancy are the leading cause of maternal and perinatal mortality and morbidity in developing and developed countries. The etiology of preeclampsia is still unknown. Delivering the baby is the only definite treatment. The benefits of acute pharmacological control of severe hypertension prior to and/or post-delivery are generally accepted. Most drugs commonly used in the management of severe hypertension in pregnancy have significant maternal and/or neonatal adverse side effects. Furthermore, some are not effective to acutely lower the blood pressure in patients with a hypertensive crisis. Until recently not one of the commonly used antihypertensive drugs has been tailored to the pathophysiology of severe preeclampsia, being a clinical syndrome characterized by endothelial cell dysfunction, vasospasm and platelet aggregation. Ketanserin, a serotonin(2)-receptor blocker, is a drug that appears to be tailored for treating this pregnancy-associated enthothelial cell dysfunction. The results of several prospective trials show that there is a definite place for serotonin(2)-receptor blockers in the treatment of pregnancy-induced hypertensive disorders. This review provides a summary on the more established drugs as well as on some of the newer antihypertensive drugs used in pregnancy with emphasis on the existing experience with ketanserin.     

Neonatal acute renal failure secondary to maternal exposure to telmisartan, angiotensin II receptor antagonist.

Fetal and neonatal toxic effects of angiotensin II receptor antagonists have been described in animals and humans. Five cases of fetal or neonatal deaths have been reported following maternal use of sartans for hypertension. We report a case of neonatal transient renal failure following telmisartan therapy during pregnancy. This class of antihypertensive drugs should be avoided during pregnancy and breastfeeding.     

The efficacy and safety of asthma medications during pregnancy.

Asthma may be the most common potentialy serious medical problem to complicate pregnancy. Because severe uncontrolled asthma may cause both maternal and fetal morbidity and mortality, pharmacological asthma therapy is often necessary during pregnancy. Only 1 published randomized controlled clinical trial has evaluated the efficacy of an asthma medication (inhaled beclomethasone) during pregnancy. Human data bearing on the safety of medications during pregnancy are usually limited to observational studies, because experimental studies on the use of medications during human pregnancy would generally be unethical. Existing observational cohort data do not associate an increased risk of preeclampsia, total congenital malformations, preterm birth, or low birth weight infants with maternal exposures to inhaled beta agonists, theophylline, cromolyn, or inhaled corticosteroids. Maternal use of oral corticosteroids has been associated with reduced birth weight, an increased risk of preeclampsia, and an increased risk of oral clefts (first trimester use). Based on this information, benefit-risk considerations suggest that inhaled asthma medications and theophylline should be used when indicated for the treatment of asthma during pregnancy. Moreover, although some increased risks may be associated with the gestational use of oral corticosteroids, these risks are probably still less than the potential risks to the mother and the fetus of severe uncontrolled asthma. This articles describes recently published consensus recommendations regarding the pharmacological management of asthma during pregnancy.     

妊娠合并肺动脉高压的早期识别及管理

妊娠合并肺动脉高压(pulmonary hypertension)是一类严重危及母儿生命的妊娠合并症,目前任何原因引起的肺动脉高压均被列为妊娠禁忌证.孕产妇死亡多与肺动脉高压危象、右心衰竭、栓塞有关,对胎儿的影响主要包括胎死宫内、流产、早产、胎儿生长受限等.肺动脉高压妇女妊娠后,早期临床症状不典型,易与妊娠状态混淆,对...     

Pregnancy outcomes in women with chronic hypertension: a population-based study

OBJECTIVE: To determine the pregnancy outcomes associated with maternal chronic hypertension. STUDY DESIGN: Retrospective, population-based cohort study of maternal and infant discharge records linked to birth records in California from 1991 to 2001 were examined for demographics and pregnancy outcomes, and comparisons were made between those with and without chronic hypertension. One randomly selected pregnancy per subject was included. RESULTS: The number of women who delivered with chronic hypertension (0.69% incidence) was 29,842. As compared to non-chronic hypertensive patients, fetal and neonatal mortality and in-hospital maternal mortality were increased (ORs and 95% CIs 2.3, (2.1, 2.6); 2.3, (2.0, 2.7); and 4.8, (3.1, 7.6) respectively). Major maternal morbidity was increased: stroke, OR 5.3, (3.7, 7.5); renal failure, OR 6.0, (4.4, 8.1); pulmonary edema, OR 5.2, (3.9, 6.7); severe preeclampsia, OR 2.7, (2.5, 2.9); and placental abruption OR 2.1, (2.0, 2.3). Neonatal morbidity was increased as well: fetal growth restriction, OR 4.9, (4.7, 5.2); prematurity, OR 3.2, (3.1, 3.3); low birth weight, OR 5.4, (5.2, 5.5); very low birth weight, OR 6.5, (6.2, 6.8); and respiratory distress syndrome, OR 4.0, (3.8, 4.2). CONCLUSION: Pregnant women with chronic hypertension have significantly increased risks of maternal and perinatal morbidity and mortality. Women with this condition should be treated as high risk with appropriate maternal and fetal surveillance.     

Prognosis of hypertension first documented during labor

In order to assess the prognosis of hypertension first documented during labor, an inception cohort of all women with hypertension complicating pregnancy was assembled. In this cohort, even extreme elevations of blood pressure, regardless of the degree of proteinuria, were not associated with either maternal or fetal adverse outcomes. Therefore, some degree of hypertension during labor may be physiologic. Matched pairs analysis demonstrated that intravenous (IV) magnesium sulfate, administered to prevent seizures, was associated with an excess number of primary cesarean sections. Given the excellent prognoses in patients with good antepartum care in whom hypertension is first documented during labor, the need for any preventive measures, or for antihypertensive or anticonvulsant treatment, should be reconsidered.     

Risks and benefits of beta-receptor blockers for pregnancy hypertension: overview of the randomized trials

OBJECTIVE: Examine the benefits/risks of beta-blockers for pregnancy hypertension. STUDY DESIGN: Meta-analysis of relevant trials identified by comprehensive literature review (1966-97). RESULTS: Included were 30 trials for pregnancy hypertension, and four others for perinatal outcomes only. For mild chronic hypertension treated throughout pregnancy (n=2 trials), oral beta-blockers (compared with no therapy) were associated with an inconsistent increase in small for gestational age (SGA) infants (OR 2.46 [1.02, 5.92]). For mild-moderate 'late-onset' pregnancy hypertension (i.e. either chronic treated only late in pregnancy, or pregnancy-induced) (n=8 trials), oral beta-blockers (compared with no therapy) were associated with a decrease in severe hypertension (OR 0.27 [0.16, 0.451), borderline decrease in development of proteinuria (OR 0.69 [0.48, 1.02]), decrease in RDS (OR 0.33 [0.13, 0.85]), but a borderline increase in SGA infants (OR 1.47 [0.96, 2.26]). Beta-blockers were equivalent to other agents (n=15 trials). For severe 'late-onset' pregnancy hypertension (n=5 trials), i.v. labetalol produced less maternal hypotension (OR 0.13 [0.03, 0.71]) and fewer cesareans (OR 0.23 [0.13, 0.63]) than i.v. hydralazine/diazoxide. CONCLUSIONS: It is not clear that the benefits outweigh the risks when beta-blockers are used to treat mild to moderate chronic or pregnancy-induced hypertension, given the unknown overall effect on perinatal outcomes. For severe 'late-onset' pregnancy hypertension, i.v. labetalol is safer than i.v. hydralazine or diazoxide.     

Counseling for women with preeclampsia or eclampsia

Preconception counseling may address issues such as nutrition, prevention and prediction of preeclampsia, utility of prenatal visits and fetal surveillance, risk of superimposed preeclampsia, recurrence risks for future gestation, diagnosis of underlying predisposing factors, and potential impact on future maternal and fetal health. Although certainty is lacking in medicine, it appears that minimal risk to either mother or fetus is attributable to mild chronic hypertension complicating pregnancy. Increased maternal and fetal morbidity is associated with superimposed preeclampsia. Unfortunately, we are unable to predict which of these gravidas will have superimposed preeclampsia and thus suffer added morbidity. There appears to be a greater than 50% chance of maternal or fetal morbidity for those women entering pregnancy with severe chronic hypertension in association with other renocardiovascular complications. Unfortunately, for the majority of women whose medical condition falls between these two extremes, the current predictive value remains vague. The best option is to review the existing literature with patients in a nondirective manner, allow them their decisions, and provide them the best available prenatal care.     

l-Arginine supplementation in women with chronic hypertension: impact on blood pressure and maternal and neonatal complications

Objective.?To evaluate l-arginine (l-Arg) supplementation in pregnant women with chronic hypertension and its effects on blood pressure (BP) and maternal and neonatal complications.

Methods.?We enrolled 80 women affected by mild chronic hypertension referred to the High Risk Clinic of the Mother–Infant Department of the University of Modena and Reggio Emilia. Each woman after obtaining oral consent was randomized to receive oral l-Arg versus placebo and thereafter submitted to 24-h ambulatory BP monitoring. The primary outcome was BP change after 10–12 weeks of treatment. Secondary outcomes were as follows: percentage of women on antihypertensive treatment at delivery, maternal, and fetal outcome.

Results.?The BP changes after 10–12 weeks of treatment did not differ between groups. A lower percentage of women received antihypertensive drugs in the l-Arg group than the placebo group. The incidence of superimposed preeclampsia indicated delivery before the 34th weeks and certain neonatal complications tended to be higher in the placebo group.

Conclusions.?l-Arg supplementation in pregnant women with mild chronic hypertension does not significantly affect overall BP but is associated with less need for antihypertensive medications and a trend toward fewer maternal and neonatal complications. The results of the study were limited by the small sample size and by the exclusion of women with severe chronic hypertension. In our policy, these patients needed many hypertensive drugs and were normally managed by the cardiologist. Nevertheless, considering the promising results on maternal and fetal outcome, we believe that further studies should be performed to confirm such data and to clarify the role of l-Arg as a protective supplement in high-risk pregnancy.     

Drugs in pregnancy. Anticonvulsants and drugs for neurological disease.

The use of anticonvulsant drugs in pregnancy presents unique challenges to clinicians and their patients. The need for control of maternal epilepsy must be balanced with the fetal and neonatal risks associated with anticonvulsant drugs. Anticonvulsant drugs may have potential effects on embryogenesis, neurological development, growth and subsequent paediatric progress. Drug selection and dose adjustment must be appropriate and based on a combination of known maternal and fetal risks as well as the clinical status of the patient. Overall, no one drug can be specifically recommended but monotherapy with most of the recognized first-line drugs will result in a satisfactory outcome. Polytherapy is associated with an increase in congenital malformations and should be avoided if possible. It is possible that newer second-line agents, for example, gabapentin, may be safer as add-on therapy. Neurological disorders such as migraine, and the less common conditions of myasthenia gravis and multiple sclerosis, may require the use of drugs which have not been well studied in pregnancy. Information is provided about the use of drugs to control symptoms and prevent disease progression in these disorders during pregnancy.     

子痫前期合并胎儿生长受限的母儿妊娠结局分析

目的:探讨子痫前期(PE)合并胎儿宫内生长受限(FGR)的母儿结局。方法:选取591例PE孕妇,按新生儿出生体重分为小于胎龄儿组(SGA组,95例)和适于胎龄儿组(AGA组,496)。随访母体妊娠结局和新生儿结局。结果:与AGA组孕妇相比,SGA组孕妇的胎盘早剥发生率增加,因胎儿窘迫行剖宫产的比率增加(P0.05),新生儿病房收治率增加,住院时间延长,差异均有统计学意义(P0.05);其他孕妇严重并发症包括重度高血压、肺水肿、肾功能异常和HELLP综合征发生率,以及孕期和产后降压药和硫酸镁使用比率均无显著变化,差异无统计学意义。结论:PE合并FGR未导致除胎盘早剥之外母体严重不良妊娠结局的增加,但新生儿不良预后增加。     

Epidemiology of fetal death in Latin America

BACKGROUND: To identify risk factors associated with fetal death, and to measure the rate and the risk of fetal death in a large cohort of Latin American women. METHODS: We analyzed 837,232 singleton births recorded in the Perinatal Information System Database of the Latin American Center for Perinatology and Human Development (CLAP) between 1985 and 1997. The risk factors analyzed included fetal factors and maternal sociodemographic, obstetric, and clinical characteristics. Adjusted relative risks were obtained, after adjustment for potential confounding factors, through multiple logistic regression models based on the method of generalized estimating equations. RESULTS: There were 14,713 fetal deaths (rate=17.6 per 1000 births). The fetal death risk increased exponentially as pregnancy advanced. Thirty-seven percent of all fetal deaths occurred at term, and 64% were antepartum. The main risk factors associated with fetal death were lack of antenatal care (adjusted relative risk [aRR]=4.26; 95% confidence interval, 3.84-4.71) and small for gestational age (aRR=3.26; 95% CI, 3.13-3.40). In addition, the risk of death during the intrapartum period was almost tenfold higher for fetuses in noncephalic presentations. Other risk factors associated with stillbirth were: third trimester bleeding, eclampsia, chronic hypertension, preeclampsia, syphilis, gestational diabetes mellitus, Rh isoimmunization, interpregnancy interval<6 months, parity > or =4, maternal age > or =35 years, illiteracy, premature rupture of membranes, body mass index > or =29.0, maternal anemia, previous abortion, and previous adverse perinatal outcomes. CONCLUSIONS: There are several preventable factors that should be dealt with in order to reduce the gap in fetal mortality between Latin America and developed countries.     

Anticonvulsants and drugs for neurological disease

The use of anticonvulsant drugs in pregnancy presents unique challenges to clinicians and their patients. The need for control of maternal epilepsy must be balanced with the fetal and neonatal risks associated with anticonvulsant drugs. Anticonvulsant drugs may have potential effects on embryogenesis, neurological development, growth and subsequent paediatric progress. Drug selection and dose adjustment must be appropriate and based on a combination of known maternal and fetal risks as well as the clinical status of the patient. Overall, no one drug can be specifically recommended but monotherapy with most of the recognized first-line drugs will result in a satisfactory outcome. Polytherapy is associated with an increase in congenital malformations and should be avoided if possible. It is possible that newer second-line agents, for example, gabapentin, may be safer as add-on therapy.Neurological disorders such as migraine, and the less common conditions of myasthenia gravis and multiple sclerosis, may require the use of drugs which have not been well studied in pregnancy. Information is provided about the use of drugs to control symptoms and prevent disease progression in these disorders during pregnancy.