By John C. Hobbins, MD

Professor, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora

Dr. Hobbins reports no financial relationships relevant to this field of study.

SYNOPSIS: A recent study suggested that sildenafil could temporarily stabilize patients with preeclampsia, while improving blood flow to and from the placenta.

SOURCE: Trapani A, Goncalves LF, Trapani TF, et al. Perinatal and hemodynamic evaluation of sildenafil citrate for preeclampsia treatment. Obstet Gynecol 2016;128:253-259.

Preeclampsia complicates 3-5% of all pregnancies and is the second most common cause of maternal death. Fetal effects can be devastating. Its etiology has been hard to crack. However, recently there have been a flurry of clinical papers dealing with the prediction, prevention, and treatment of preeclampsia. This recent study serves as a catalyst for a short discussion of what is new in preeclampsia investigation.

Trapani et al initiated a double-blind, placebo-controlled trial in Brazil involving 100 patients diagnosed with preeclampsia between 24 and 33 weeks of gestation. One-half were treated with sildenafil every eight hours and the other half received a placebo. All patients had uterine artery, umbilical artery, and middle cerebral artery waveforms obtained before and after treatment. Management and delivery decision-making were conducted by a common protocol. If needed, blood pressures were treated with beta-blockers in addition to methyldopa.

Data were available on all 50 patients in each group. The sildenafil-treated group (SG) spent four more days pregnant (14.4 days vs. 10.4 days; 95% confidence interval, 12.5-16.6). The SG group had a 22.5% and 18.5% reduction in pulsatility indices in the uterine and umbilical arteries, respectively, vs. 2.1% and 2.3% reductions in the controls. Mean maternal arterial pressures were significantly lower after treatment in the SG group. Two patients in the control group and one patient from the SG were dropped from the study because of possible side effects (headaches). There were no differences in immediate neonatal outcomes.

COMMENTARY

A variety of maternal serum markers have been studied, but recently tyrosine kinase and placental growth factor (PGIF) have emerged as being rather efficient late predictors of true preeclampsia in patients suspected of developing the condition.1 Uterine artery waveforms have fallen in and out of favor through the years as early preeclampsia predictors. Although the data suggest them to be only of modest efficacy as predictors of preeclampsia, in general, these waveforms in the second trimester do identify with good reliability patients destined to have preeclampsia severe enough to warrant delivery prior to 34 weeks.2,3

One of the reasons that there has been inconsistent enthusiasm for any predictor of preeclampsia is that attempts to prevent or treat the condition have yielded either unexciting or somewhat confusing results. The one medication that has gotten unfair treatment is low-dose acetylsalicylic acid (ASA). Despite earlier meta-analyses showing efficacy in preventing preeclampsia,4 it was not until Bujold et al5 showed that low-dose ASA had its greatest benefit when administered prior to 17 weeks that clinicians began to pay attention.6 However, not all of the results have been positive. For example, a recent meta-analysis, in which Bujold was an author, suggested no benefit from a lower dose (60 mg) of ASA. Yet, to add to the confusion, in another paper published at about the same time, low-dose ASA was found to be cost-effective in high-risk patients.7

So, what is the clinician to think? All in all, the bulk of data do suggest the benefit of low-dose ASA (a baby aspirin of 81 mg) in patients at higher risk for pulmonary thromboembolism. In fact, in an effort to add icing on the cake, another group has even added low molecular weight heparin to an ASA regimen with some success.8

Others have attempted to go in another direction. Adult cardiovascular disease has some pathological similarities to preeclampsia, so why not try to approach the condition through that route? In a small pilot randomized trial,9 the safety of using pravastatin to prevent the condition was seemingly validated. Efficacy studies undoubtedly soon will follow.

This sildenafil study makes some sense since preeclampsia causes peripheral vasoconstriction and, in addition to keeping the process at bay for an average of four days longer than controls, there was evidence sildenafil improved fetal and maternal blood flow on both sides of the placenta and there was a significant drop in maternal blood pressure. Who would have guessed that the very pricey “little blue pill” might have this completely different therapeutic potential?

There are other preventive and therapeutic investigative activities in process, so stay tuned because breakthroughs may be on the horizon for preeclampsia.

REFERENCES

  1. Duckworth S, Griffin M, Seed PT, et al. Diagnostic biomarkers in women with suspected preeclampsia in a prospective multicenter study. Obstet Gynecol 2016;128:245-252.
  2. Bower S, Schuchter K, Cambell S. Doppler ultrasound screening as part of routine antenatal scanning: Prediction of preeclampsia and intrauterine growth retardation. Br J Obstet Gynaecol 1993;100:989-994.
  3. Conde-Aguello A, Villar J, Lindheimer M, et al. WHO systematic review of screening test for preeclampsia. Obstet Gynecol 2004;104:1367-1391.
  4. Coomarasamy A, Honest H, Papaioannau S, et al. Aspirin for prevention of preeclampsia in women with historical risk factors: A systematic review. Obstet Gynecol 2003;101:1319-1332.
  5. Bujold E, Roberge S, Lacasse Y, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: A meta-analysis. Obstet Gynecol 2010;116:402-414.
  6. Roberge S, Sibai B, McCaw-Binns A, Bujold E. Low-dose aspirin in early gestation for prevention of preeclampsia and small for gestational age neonates: A meta-analysis of large randomized trials. Am J Perinatol 2016;33:781-785.
  7. Werner EF, Hauspurg AK, Rouse DJ. A cost-benefit analysis of low-dose aspirin prophylaxis for the prevention of preeclampsia in the United States. Obstet Gynecol 2015;126:1242-1250.
  8. Roberge S, Demers K, Nicolaides H, et al. Prevention of preeclampsia by low molecular weight heparin in addition to aspirin: A meta-analysis. Ultrasound Obstet Gynecol 2016;47:548-553.
  9. Constantine MM, Cleary K, Hebert MF, et al. Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in the high risk pregnant women: A pilot randomized controlled trial. Am J Obstet Gynecol 2016;216:720.e1-17.