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Clinical Reviews


Preeclampsia: 3 preemptive tactics

A strategy to prevent preeclampsia or minimize severity—starting before conception if possible—is the best way to reduce adverse outcomes.

February 2005 · Vol. 17, No. 2

We routinely use every means possible to overcome the complications of hypertensive disorders and related preterm births. Yet our best opportunity to reduce morbidity and mortality could be before preeclampsia develops.

Preemptive tactics can be effective in preventing or reducing severity of preeclampsia. The patient’s active cooperation is a must, but the effort to recruit her cooperation can mean a better outcome.

If a diabetic or hypertensive woman doesn’t take her medications properly or if an obese woman postpones weight loss until after preeclampsia develops, it is too late to reduce the level of risk.

At-risk patients can benefit from being informed of any other ways to reduce risk as well; for example, by controlling the number of fetuses transferred via assisted reproductive techniques.

Trends that are driving up the prevalence of risk factors will only increase the number of preconception and obstetric cases with high-risk potential:

  • The increased proportion of births among nulliparous women and women older than 35 years.
  • The increased proportion of multifetal gestation as a result of assisted reproductive therapy.
  • The increased prevalence of obesity in women, which is likely to lead to greater frequency of gestational diabetes, insulin resistance, and chronic hypertension.

Step 1Start risk-reducing tactics as early as possible

Retrospective studies have identified factors that multiply the risk of preeclampsia. Some are identifiable—and modifiable—before conception or beginning at the first prenatal visit (TABLE 1).

PREEMPTIVE TACTICS

  1. Identify risk factors and recruit the patient’s efforts to reduce risks—before conception whenever possible.
  2. Set up prenatal care to watch closely for signal findings and make a prompt diagnosis.
  3. Develop a delivery plan that balances maternal and fetal needs. Identify indications for delivery.

Preconception risk factors

Obesity carries a 10 to 15% risk for preeclampsia. Prevention or effective treatment can greatly reduce risk.

Hypertension.Women with uncontrolled hypertension should have their blood pressure controlled prior to conception and as early as possible in the first trimester. In these women, the risk of preeclampsia may be reduced to below the 10 to 40% rate, depending on severity.

Renal disease. Risk for an adverse pregnancy outcome depends on maternal renal function at time of conception. Women should be encouraged to conceive while serum creatinine is less than 1.2 mg/dl.

Pregestational diabetes mellitus. Risk for preeclampsia and adverse outcomes depends on duration of diabetes, as well as vascular complications and blood sugar control prior to conception and early in pregnancy. Encourage these women to complete childbearing as early as possible and before vascular complications develop, and to aggressively control their diabetes and hypertension (if present) at least a few months prior to conception and throughout pregnancy.

Maternal age older than 35 years increases risk depending on associated medical conditions, nulliparity, and need for assisted reproductive therapy. These women are more likely to be nulliparous, overweight, chronically hypertensive, and to require assisted reproductive therapy. ART may involve multifetal gestation and donor insemination or oocyte donation—both of which increase risk and severity of preeclampsia. Therefore, these patients need to be made aware of their risks and helped to take steps to minimize risks.

TABLE 1

Preconception risk factors for preeclampsia

20 to 30%

Previous preeclampsia

50%

Previous preeclampsia at 28 weeks

15 to 25%

Chronic hypertension

40%

Severe hypertension

25%

Renal disease

20%

Pregestational diabetes mellitus

10 to 15%

Class B/C diabetes

35%

Class F/R diabetes

10 to 40%

Thrombophilia

10 to 15%

Obesity/insulin resistance

10 to 20%

Age >35 years

10 to 15%

Family history of preeclampsia

6 to 7%

Nulliparity/primipaternity

Pregnancy-related risk factors

Many risk factors may be identified for the first time during pregnancy (TABLE 2). It is important to realize that the magnitude of risk depends on number of risk factors.

Nulliparity and primipaternity. Over the past decade, several epidemiologic studies suggested that immune maladaptation plays an important pathogenetic role in development of preeclampsia.

Generally, preeclampsia is considered a disease of first pregnancy. Indeed, a previous miscarriage of a previous normotensive pregnancy with the same partner is has a lowered frequency of preeclampsia. This protective effect is lost, however, with change of partner, suggesting that primipaternity increases the rate of preeclampsia.

A large prospective study on the relation between duration of sperm exposure with a partner and the rate of preeclampsia showed that women who conceive after a cohabitation period of 0 to 4 months have a 10-fold rate of preeclampsia, compared to those who conceive after a cohabitation period of at least 12 months. A similar study confirmed these findings.

The protective effects of long-term sperm exposure could explain the high frequency of preeclampsia in teenage pregnancy. (These women tend to have limited sperm exposure with a partner, or multiple partners). Thus, it is important to teach these women about their risks and the need for regular prenatal care.

Multifetal gestation increases the rate as well as the severity of preeclampsia, and the rate increases with the number of fetuses. Lowering the number of embryos transferred will substantially reduce the risk of preeclampsia and adverse outcomes.

There is no therapy to prevent preeclampsia in these women; however, we should acknowledge the increased risk and develop antenatal-care programs that allow close observation and early detection of preeclampsia in these women.

Hydropic degeneration of placenta. It is well-established that pregnancies complicated by fetal hydrops or hydropic degeneration of the placenta (with or without a coexisting fetus) are at very high risk for preeclampsia. In these cases, preeclampsia usually develops in the second trimester and is usually severe, and therefore causes substantial maternal and perinatal morbidities. Development of preeclampsia in such pregnancies requires immediate hospitalization and consideration for prompt delivery.

Unexplained elevated serum markers in the second trimester. Maternal serum screening with alpha fetoprotein (AFP), human chorionic gonadotropin (HCG) and inhibin A is commonly used to identify those at risk for aneuploidy or neural tube defects.

Unexplained elevations in AFP, HCG or inhibin A have been associated with increased adverse pregnancy outcome such as fetal death, intrauterine growth restriction (IUGR), preterm delivery, and preeclampsia. However, the data on the association between abnormalities in these biomarkers and preeclampsia have been inconsistent. Nevertheless, retrospective studies suggest that elevation in these serum markers during the second trimester increases the risk of preeclampsia by at least twofold. The risk is probably higher in those who have abnormalities in more than 1 of these markers. Since unexplained abnormalities of these serum markers may reflect early placental pathology, it is suggested that these pregnancies may benefit from close obstetric surveillance.

Serum and urinary markers of abnormal angiogenesis and subsequent preeclampsia were strongly associate, in newly published studies reported by Levine and colleagues. For example, circulating soluble fms-like tyrosine kinase (sFLt1) is elevated in pregnant women prior to onset of preeclampsia, whereas urinary placental growth factor is reduced several weeks prior to clinical onset of preeclampsia. Both of these markers appear to hold some promise.

Unexplained proteinuria or hematuria. Generally, proteinuria is considered a late manifestation of preeclampsia. However, recent retrospective studies suggest that some women with preeclampsia, particularly those with HELLP syndrome, might not have hypertension (>140 mm Hg systolic or >90 mm Hg diastolic). In some women, persistent proteinuria (3+ on dipstick) or >300 mg/24 hour may be the first sign of preeclampsia or could be a marker of silent renal disease.

No prospective studies have evaluated the risk of preeclampsia in asymptomatic women with persistent proteinuria. I suggest, however, that women with this finding will benefit from intensified obstetric surveillance (more frequent prenatal visits) and/or biochemical evaluation (platelet count, liver enzymes), particularly if they have headaches, visual changes, epigastric or right upper quadrant pain, nausea or vomiting, or respiratory symptoms (chest pain or shortness of breath)—likewise, for pregnant women with persistent hematuria of unknown origin.

Unexplained fetal growth restriction. Impaired trophoblast invasion is a key features of pregnancies complicated by preeclampsia or unexplained IUGR. Preeclampsia can manifest either as a maternal syndrome (hypertension and proteinuria with or without symptoms) or a fetal abnormal growth syndrome.

In clinical practice, most cases of unexplained IUGR are probably delivered before the maternal syndrome develops. In some cases, unexplained IUGR may be the first manifestation of preeclampsia, particularly those with IUGR before 34 weeks’ gestation. The absolute risk of clinical preeclampsia in such women is unknown because of lack of prospective data. Nevertheless, a woman with idiopathic IUGR prior to 34 weeks’ gestation whose pregnancy is managed expectantly is at increased risk for future preeclampsia. These women should receive intensive maternal surveillance for preeclampsia, and a diagnosis of preeclampsia should be considered in those who develop maternal symptoms or abnormal blood tests.

Abnormal uterine artery Doppler velocimetry at 18 to 24 weeks’ gestation. Several observational studies reported an association between elevated uterine artery resistance as measured by Doppler (with or without presence of a notch) in the second trimester and subsequent preeclampsia and/or IUGR. The reported rates of preeclampsia among women with abnormal Doppler results range from 6% to 40%. The risk varies depending on the site measured, gestational age at time of measurement, normal indices used, abnormality on repeat measurement, and population studied.

A systemic review of 27 studies, which included approximately 13,000 women, revealed that an abnormal uterine artery Doppler waveform increases the risk of preeclampsia by 4- to 6-fold, compared to normal Doppler results. The review concluded that uterine artery Doppler evaluation has a limited value as a screening test to predict preeclampsia.

What should the physician do when faced with an ultrasound report indicating an abnormal uterine artery Doppler finding?

Is low-dose aspirin helpful? Several randomized trials evaluated the potential role of low-dose aspirin in reducing the risk of preeclampsia in women with abnormal uterine artery Doppler indices. A meta-analysis suggested that low-dose aspirin significantly reduced the rate of preeclampsia (16% in placebo versus 10% with aspirin, odds ratio of 0.55). This analysis included a total of 498 subjects.

In contrast, a recent randomized trial in 560 women with abnormal uterine artery Doppler at 23 weeks’, who were assigned to aspirin 150 mg or placebo, found no differences in rates of preeclampsia (18% versus 19%) or in preeclampsia requiring delivery before 34 weeks’ (6% versus 8%). A similar randomized trial using 100 mg aspirin daily in 237 women with abnormal uterine artery Doppler at 22 to 24 weeks revealed no reduction in rate of preeclampsia compared to placebo.

Consequently, low-dose aspirin is not recommended for prevention of preeclamp-sia in these women.

Close surveillance is warranted. Although there is no available proven therapy to reduce the risk of preeclampsia in these women, they should be closely observed because of the increased rate of adverse outcomes, including preeclampsia.

TABLE 2

Pregnancy-related risk factors for preeclampsia

Magnitude of risk depends on the number of factors

2-fold normal

Unexplained midtrimester elevations of serum AFP, HCG, inhibin-A

10 to 30%

Abnormal uterine artery Doppler velocimetry

0 to 30%

Hydrops/hydropic degeneration of placenta

10 to 20%

Multifetal gestation (depends on number of fetuses and maternal age)

10%

Partner who fathered preeclampsia in another woman

8 to 10%

Gestational diabetes mellitus

8 to 10%

Limited sperm exposure (teenage pregnancy)

6 to 7%

Nulliparity/primipaternity

Limited data

Donor insemination, oocyte donation

Limited data

Unexplained persistent proteinuria or hematuria

Unknown

Unexplained fetal growth restriction

Step 2Watch for signal findings, diagnose preeclampsia early

Signs and symptoms may call for close surveillance at any time. Early detection of preeclampsia is the best way to reduce adverse outcomes.

Prenatal care does not prevent preeclampsia, of course. All pregnant women are at risk, some more than others. Still, adequate and proper prenatal care is the best strategy to detect preeclampsia early.

We may need to modify the frequency and type of maternal and fetal surveillance at any time. Thus, patients with multiple risk factors or risk exceeding 10% should have more frequent visits, especially beyond 24 weeks. Maternal blood pressure (both systolic and diastolic), urine protein values, abrupt and excessive weight gain, maternal symptoms, and fetal growth warrant particular attention.

Continued...
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