Cluver C, Novikova N, Koopmans CM, West HM. Planned early delivery versus expectant management for hypertensive disorders from 34 weeks gestation to term. Cochrane Database Syst Rev. 2017;1(1):CD009273. Published 2017 Jan 15. doi:10.1002/14651858.CD009273.pub2

Systematic Review and Meta-Analysis

Background

Hypertensive disorders in pregnancy are significant contributors to maternal and perinatal morbidity and mortality. These disorders include well‐controlled chronic hypertension, gestational hypertension (pregnancy‐induced hypertension) and mild pre‐eclampsia. The definitive treatment for these disorders is planned early delivery and the alternative is to manage the pregnancy expectantly if severe uncontrolled hypertension is not present, with close maternal and fetal monitoring. There are benefits and risks associated with both, so it is important to establish the safest option.

Objectives

To assess the benefits and risks of a policy of planned early delivery versus a policy of expectant management in pregnant women with hypertensive disorders, at or near term (from 34 weeks onwards).

Search methods

We searched Cochrane Pregnancy and Childbirth Trials Register (12 January 2016) and reference lists of retrieved studies.

Selection criteria

Randomised trials of a policy of planned early delivery (by induction of labour or by caesarean section) compared with a policy of delayed delivery (“expectant management”) for women with hypertensive disorders from 34 weeks’ gestation. Cluster‐randomised trials would have been eligible for inclusion in this review, but we found none.

Studies using a quasi‐randomised design are not eligible for inclusion in this review. Similarly, studies using a cross‐over design are not eligible for inclusion, because they are not a suitable study design for investigating hypertensive disorders in pregnancy.

Data collection and analysis

Two review authors independently assessed eligibility and risks of bias. Two review authors independently extracted data. Data were checked for accuracy.

Main results

We included five studies (involving 1819 women) in this review.

There was a lower risk of composite maternal mortality and severe morbidity for women randomised to receive planned early delivery (risk ratio (RR) 0.69, 95% confidence interval (CI) 0.57 to 0.83, two studies, 1459 women (evidence graded high)). There were no clear differences between subgroups based on our subgroup analysis by gestational age, gestational week or condition. Planned early delivery was associated with lower risk of HELLP syndrome (RR 0.40, 95% CI 0.17 to 0.93, 1628 women; three studies) and severe renal impairment (RR 0.36, 95% CI 0.14 to 0.92, 100 women, one study).

There was not enough information to draw any conclusions about the effects on composite infant mortality and severe morbidity. We observed a high level of heterogeneity between the two studies in this analysis (two studies, 1459 infants, I2 = 87%, Tau2 = 0.98), so we did not pool data in meta‐analysis. There were no clear differences between subgroups based on our subgroup analysis by gestational age, gestational week or condition. Planned early delivery was associated with higher levels of respiratory distress syndrome (RR 2.24, 95% CI 1.20 to 4.18, three studies, 1511 infants), and NICU admission (RR 1.65, 95% CI 1.13 to 2.40, four studies, 1585 infants).

There was no clear difference between groups for caesarean section (RR 0.91, 95% CI 0.78 to 1.07, 1728 women, four studies, evidence graded moderate), or in the duration of hospital stay for the mother after delivery of the baby (mean difference (MD) ‐0.16 days, 95% CI ‐0.46 to 0.15, two studies, 925 women, evidence graded moderate) or for the baby (MD ‐0.20 days, 95% CI ‐0.57 to 0.17, one study, 756 infants, evidence graded moderate).

Two fairly large, well‐designed trials with overall low risk of bias contributed the majority of the evidence. Other studies were at low or unclear risk of bias. No studies attempted to blind participants or clinicians to group allocation, potentially introducing bias as women and staff would have been aware of the intervention and this may have affected aspects of care and decision‐making.

The level of evidence was graded high (composite maternal mortality and morbidity), moderate (caesarean section, duration of hospital stay after delivery for mother, and duration of hospital stay after delivery for baby) or low (composite infant mortality and morbidity). Where the evidence was downgraded, it was mostly because the confidence intervals were wide, crossing both the line of no effect and appreciable benefit or harm.

Authors’ conclusions

For women suffering from hypertensive disorders of pregnancy after 34 weeks, planned early delivery is associated with less composite maternal morbidity and mortality. There is no clear difference in the composite outcome of infant mortality and severe morbidity; however, this is based on limited data (from two trials) assessing all hypertensive disorders as one group.

Further studies are needed to look at the different types of hypertensive diseases and the optimal timing of delivery for these conditions. These studies should also include infant and maternal morbidity and mortality outcomes, caesarean section, duration of hospital stay after delivery for mother and duration of hospital stay after delivery for baby.

An individual patient meta‐analysis on the data currently available would provide further information on the outcomes of the different types of hypertensive disease encountered in pregnancy.

Bernardes TP, Zwertbroek EF, Broekhuijsen K, et al. Delivery or expectant management for prevention of adverse maternal and neonatal outcomes in hypertensive disorders of pregnancy: an individual participant data meta-analysis. Ultrasound Obstet Gynecol. 2019;53(4):443–453. doi:10.1002/uog.20224

Meta-analysis

Objective

Hypertensive disorders affect 3–10% of pregnancies. Delayed delivery carries maternal risks, while early delivery increases fetal risk, so appropriate timing is important. The aim of this study was to compare immediate delivery with expectant management for prevention of adverse maternal and neonatal outcomes in women with hypertensive disease in pregnancy.

Methods

CENTRAL, PubMed, MEDLINE and ClinicalTrials.gov were searched for randomized controlled trials comparing immediate delivery to expectant management in women presenting with gestational hypertension or pre‐eclampsia without severe features from 34 weeks of gestation. The primary neonatal outcome was respiratory distress syndrome (RDS) and the primary maternal outcome was a composite of HELLP syndrome and eclampsia. The PRISMA‐IPD guideline was followed and a two‐stage meta‐analysis approach was used. Relative risks (RR) and numbers needed to treat or harm (NNT/NNH) with 95% CI were calculated to evaluate the effect of the intervention.

Results

Main outcomes were available for 1724 eligible women. Compared with expectant management, immediate delivery reduced the composite risk of HELLP syndrome and eclampsia in all women (0.8% vs 2.8%; RR, 0.33 (95% CI, 0.15–0.73); I 2 = 0%; NNT, 51 (95% CI, 31.1–139.3)) as well as in the pre‐eclampsia subgroup (1.1% vs 3.5%; RR, 0.39 (95% CI, 0.15–0.98); I 2 = 0%). Immediate delivery increased RDS risk (3.4% vs 1.6%; RR, 1.94 (95% CI 1.05–3.6); I 2 = 24%; NNH, 58 (95% CI, 31.1–363.1)), but depended upon gestational age. Immediate delivery in the 35th week of gestation increased RDS risk (5.1% vs 0.6%; RR, 5.5 (95% CI, 1.0–29.6); I 2 = 0%), but immediate delivery in the 36th week did not (1.5% vs 0.4%; RR, 3.4 (95% CI, 0.4–30.3); I 2 not applicable).

Conclusion

In women with hypertension in pregnancy, immediate delivery reduces the risk of maternal complications, whilst the effect on the neonate depends on gestational age. Specifically, women with a‐priori higher risk of progression to HELLP, such as those already presenting with pre‐eclampsia instead of gestational hypertension, were shown to benefit from earlier delivery. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Chappell LC, Brocklehurst P, Green ME, et al. Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial. Lancet. 2019;394(10204):1181–1190. doi:10.1016/S0140-6736(19)31963-4

Randomized Control Trial

Background

In women with late preterm pre-eclampsia, the optimal time to initiate delivery is unclear because limitation of maternal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of neonatal or infant outcomes, compared with expectant management (usual care) in women with late preterm pre-eclampsia.

Methods

In this parallel-group, non-masked, multicentre, randomised controlled trial done in 46 maternity units across England and Wales, we compared planned delivery versus expectant management (usual care) with individual randomisation in women with late preterm pre-eclampsia from 34 to less than 37 weeks’ gestation and a singleton or dichorionic diamniotic twin pregnancy. The co-primary maternal outcome was a composite of maternal morbidity or recorded systolic blood pressure of at least 160 mm Hg with a superiority hypothesis. The co-primary perinatal outcome was a composite of perinatal deaths or neonatal unit admission up to infant hospital discharge with a non-inferiority hypothesis (non-inferiority margin of 10% difference in incidence). Analyses were by intention to treat, together with a per-protocol analysis for the perinatal outcome. The trial was prospectively registered with the ISRCTN registry, ISRCTN01879376. The trial is closed to recruitment but follow-up is ongoing.

Findings

Between Sept 29, 2014, and Dec 10, 2018, 901 women were recruited. 450 women (448 women and 471 infants analysed) were allocated to planned delivery and 451 women (451 women and 475 infants analysed) to expectant management. The incidence of the co-primary maternal outcome was significantly lower in the planned delivery group (289 [65%] women) compared with the expectant management group (338 [75%] women; adjusted relative risk 0·86, 95% CI 0·79–0·94; p=0·0005). The incidence of the co-primary perinatal outcome by intention to treat was significantly higher in the planned delivery group (196 [42%] infants) compared with the expectant management group (159 [34%] infants; 1·26, 1·08–1·47; p=0·0034). The results from the per-protocol analysis were similar. There were nine serious adverse events in the planned delivery group and 12 in the expectant management group.

Interpretation

There is strong evidence to suggest that planned delivery reduces maternal morbidity and severe hypertension compared with expectant management, with more neonatal unit admissions related to prematurity but no indicators of greater neonatal morbidity. This trade-off should be discussed with women with late preterm pre-eclampsia to allow shared decision making on timing of delivery.

Funding

National Institute for Health Research Health Technology Assessment Programme.

(# of subjects/ studies, cohort definition etc. )

– Studies were from the following countries: Netherlands (2), India (1), USA (1), Egypt & Saudi Arabia (1).

– Of the two larger studies, one included 704 women between 34 and 37 weeks with hypertension(preexisting, gestational, or preeclampsia). The second included women with gestational HTN or mild pre-eclampsia between 36 and 41 weeks (756 women)

– Another study compared women with labor induction at 34 to 36 weeks and another study at 34 to 37 weeks, with a control group with expectant management.

–       The expectant management group received frequent BP monitoring, evaluation of hypertensive symptoms, UA, blood tests (renal function tests, liver function tests, platelets, hemoglobin), and fetal monitoring (via mother’s perception of fetal movements, fetal heart rate monitoring, and ultrasound).

– Primary outcomes for the neonate include fetal or neonatal death (within six weeks of expected due date),grade III/ IV intraventricular or intracerebral hemorrhage, necrotizing enterocolitis (NEC),  ARDS or grade III/IV hyaline membrane disease, small‐for‐gestational age, and neonatal seizures (Cluver et. al).

-Neither group had a higher rate of C-section or post-delivery hospital stay days.

-None of the studies that reported mortality had maternal deaths and only one fetal death was reported.

– Neither the patients nor the clinicians were blinded, allowing possibility of biases, however it would be quite difficult to do blinding in this situation.

(# of subjects/ studies, cohort definition etc. )

-The immediate delivery group included 861 women and the expectant management group included 863 women.

– Included many nations: USA, Netherlands, several other European countries

– Evaluated the outcomes of the early delivery group based on weeks of gestational age.

-Secondary outcomes included “stroke, cardiac arrest, pulmonary edema, renal failure, liver failure, disseminated intravascular coagulation (DIC), placental abruption/antenatal hemorrhage, thromboembolic disease, severe postpartum hemorrhage (> 1000 mL), Cesarean section, neonatal intensive care unit (NICU) admission” etc. (Bernardes et. al)

-Women with pre-eclampsia or increased risk of HELLP were more likely to have better outcomes with early delivery.

-There was no increase in cesarean section in either group.

(# of subjects/ studies, cohort definition etc. )

– Women had to have pre-eclampsia and a gestational age between 34 and 37 weeks to be included. This study allowed women with comorbidities to participate.

– The early delivery group consisted of 448 women and 471 infants and the expectant management group consisted of 451 women and 475 infants.

– There were no significant differences in estimated gestational age between the two groups.

– Composite perinatal outcome was perinatal deaths or NICU admission.

–       The early delivery group also had decreased progression to severe pre-eclampsia compared to the expectant management group.

-There was one maternal death, but it is not thought to be from the treatment but rather the severe nature of pre-eclampsia. Neither group had any neonatal deaths.

-This was not blinded, however it would be unreasonable to do so.