Dr Fergus McCarthy takes a monthly look at articles just published in the area of hypertension & pre-eclampsia…

Women with pre-eclampsia are particularly susceptible to temporary acute kidney injury which may be temporarily worsened by fluid restriction and the use of non-steroidal anti-inflammatory drugs. Viteri et al performed a retrospective cohort study at a single, tertiary centre to examine the association of non-steroidal anti-inflammatory drugs with the occurrence of postpartum hypertension in women with pre-eclampsia.¹ The study was conducted between January 2013 to December 2015. All women diagnosed with severe pre-eclampsia who remained hypertensive for greater than 24 hours after delivery were included. The primary outcome was the rate of persistent postpartum hypertension, defined as systolic blood pressure 150 mmHg or greater or diastolic 100 mmHg or greater (or both), on two occasions, at least 4 hours apart. Secondary outcomes included severe maternal morbidity: pulmonary oedema, renal dysfunction, stroke, eclampsia, and intensive care unit admission.

Of the 399 women with severe pre-eclampsia, 324 (81%) remained hypertensive 24 hours after delivery. Two hundred forty-three (75%) received NSAIDs (either ibuprofen or ketorolac) and 81 (25%) did not. The likelihood of reaching a blood pressure of 150 mmHg systolic or 100 mmHg diastolic (or both), on two occasions, at least 4 hours apart, was similar between those who received NSAIDs compared with those who did not (70% compared with 73%; adjusted OR 1.1, 95% CI 0.6-2.0).

Similarly, puerperal occurrence of pulmonary oedema (3% compared with 10%; OR 4.4, 95% CI 1.5-13.1), renal dysfunction (5% compared with 8%; OR 1.7, 95% CI 0.6-4.8), eclampsia (1% compared with 0%; P=0.34), or intensive care unit admission (3% compared with 8%; OR 2.4, 95% CI 0.8-7.1) was similar between the groups. There were no differences in the rate of narcotic use (89% compared with 75%; adjusted OR 0.6 95% CI 0.18-1.70).

It is reassuring to see that NSAIDs were not associated with increased rates of persistent postpartum hypertension. However, the study was not powered to look at renal dysfunction and although the incidence of renal dysfunction appeared similar caution must still be exercised to avoid AKI.

The optimal time for delivery of a pregnancy affected by pre-eclampsia remains contentious although HYPITAT provided good evidence to inform the decision process. The PHOENIX study is ongoing and will add further evidence to this (https://www.npeu.ox.ac.uk/phoenix). Wang et al performed a meta-analysis of RCTs examining the effectiveness and safety of elective delivery versus expectant management for women with pre-eclampsia and to assess neonatal outcomes before and after 34 weeks gestation.²

1704 citations were identified. Randomised controlled trials comparing elective delivery with expectant management for women with pre-eclampsia were included. Seven studies were included (n = 1501). Reassuringly, there were no maternal deaths.

Elective delivery lowered incidence of complications in women with pre-eclampsia or hypertension greater than 34 weeks’ gestation (n = 756; RR, 0.64; 95% CI 0.51-0.80). For women with severe pre-eclampsia less than 34 weeks’ gestation, elective delivery lowered the incidence of placental abruption (n = 483, 5 RCTs; RR, 0.43; 95% CI 0.19-0.98). For women with pre-eclampsia or hypertension greater than 34 weeks’ gestation, elective delivery also reduced the need for antihypertensive drug therapy. The need for ventilatory support and the risk of developing neonatal intraventricular haemorrhage or hypoxic ischemic encephalopathy may be increased in infants whose mothers undergo elective delivery for severe pre-eclampsia at less than 34 weeks’ gestation. However, there was no relevant evidence for women with severe pre-eclampsia over 34.

In women with pre-eclampsia or gestational hypertension beyond 34 weeks’ gestation, elective delivery can decrease the incidence of complications, severe hypertension and the need for antihypertensive drug therapy. Elective delivery can also lower the risk of placental abruption in women before 34 weeks’ gestation with severe pre-eclampsia, however, may be associated with increased risk of neonatal complications.

Finally, as the recent ISSHP European Congress has shown, there remains considerable interest in the angiogenic factors and their role in the pathophysiology and prediction of pre-eclampsia. In their publication in JCI, Burke et al investigate soluble fms-like tyrosine kinase 1(sFlt-1) and its interaction with angiotensin II in pre-eclampsia.³ The authors demonstrated that overexpression of sFlt-1 in pregnant mice induced angiotensin II sensitivity and hypertension by impairing endothelial nitric oxide synthase (eNOS) phosphorylation and promoting oxidative stress in the vasculature. Administration of the NOS inhibitor l-NAME to pregnant mice recapitulated the angiotensin sensitivity and oxidative stress observed with sFlt-1 overexpression.

Sildenafil, a phosphodiesterase 5 inhibitor that enhances NO signaling, reversed sFlt1-induced hypertension and angiotensin II sensitivity in the preeclampsia mouse model. Sildenafil treatment also improved uterine blood flow, decreased uterine vascular resistance, and improved fetal weights in comparison with untreated sFlt-1 expressing mice. Finally, sFLT-1 protein expression inversely correlated with reductions in eNOS phosphorylation in placental tissue of human preeclampsia patients. These data support the concept that endothelial dysfunction due to high circulating sFLT-1 may be the primary event leading to enhanced vasoconstrictor sensitivity that is characteristic of pre-eclampsia and suggest that targeting sFLT-1-induced pathways may be an avenue for treating pre-eclampsia and improving fetal outcomes.

References

1. Viteri OA, England JA, Alrais MA, et al. Association of Nonsteroidal Antiinflammatory Drugs and Postpartum Hypertension in Women With Preeclampsia With Severe Features. Obstetrics and gynecology. Oct 2017;130(4):830-835.
2. Wang Y, Hao M, Sampson S, Xia J. Elective delivery versus expectant management for pre-eclampsia: a meta-analysis of RCTs. Archives of gynecology and obstetrics. Mar 2017;295(3):607-622.
3. Burke SD, Zsengeller ZK, Khankin EV, et al. Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia. The Journal of clinical investigation. Jul 01 2016;126(7):2561-2574.