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Delivery or expectant management for prevention of adverse maternal and neonatal outcomes in hypertensive disorders of pregnancy: an individual participant data meta‐analysis

ABSTRACT 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.

444 Bernardes et al. Worldwide, between 80 and 120 women with a pregnancy complicated by hypertension die each day 8 .
On the other hand, prolonging pregnancies complicated by hypertensive disorders may increase maternal risk 26,27 . Managed expectantly, gestational or chronic hypertension may progress to pre-eclampsia 28,29 or to more severe complications such as eclampsia, placental abruption or HELLP syndrome.
Management strategies for hypertensive disorders of pregnancy have been evaluated at various gestational ages 27,[29][30][31] . In the HYPITAT-I trial, women with gestational hypertension or pre-eclampsia without severe features from 36 + 0 weeks of gestation were randomized to either immediate delivery or expectant management 27 . The Deliver or Deliberate trial evaluated immediate delivery vs expectant management (until the 37 th week of gestation) for women with pre-eclampsia between 34 + 0 and 36 + 6 weeks of gestation 30 . The same management strategies and gestational age range were studied in the HYPITAT-II trial 31 .
These trials evaluated different outcomes, gestational ages and hypertensive disorders and used composite outcome to overcome the rarity of severe outcomes. They also had different inclusion and exclusion criteria and intervention protocols. Therefore, general conclusions regarding optimal timing of delivery, when the benefits of immediate delivery outweigh the consequences of early delivery, are difficult to draw.
Combining individual participant data from these trials has the potential to overcome some of these drawbacks and provide stronger evidence to guide clinical practice and future research. With this aim, we performed an individual participant data meta-analysis (IPDMA) comparing immediate delivery to expectant monitoring for the prevention of adverse maternal and neonatal outcomes in pregnancies from 34 weeks of gestation complicated by a hypertensive disorder.

SUBJECTS AND METHODS
This IPDMA was registered on PROSPERO (CRD420-17083348) and its protocol was published after peer-review 32 . It is reported in accordance with the PRISMA-IPD statement 33 .

Search strategy
An electronic search of CENTRAL, PubMed, MEDLINE and ClinicalTrials.gov was performed for published or registered randomized controlled trials (RCT) comparing immediate delivery with expectant management in women presenting with gestational hypertension or pre-eclampsia without severe features from 34 weeks of gestation. The following search strategy was used: ('hypertensive disorders of pregnancy' OR 'pregnancy induced hypertension' OR 'gestational hypertension' OR ('pre-eclampsia' OR 'preeclampsia') OR ('hypertension' AND ('chronic' OR 'chronical*' OR 'pre-existent' OR 'preexistent')) AND 'pregnancy'), with the limits 'human' and 'randomized controlled trial'. The search period was from database inception to 31 December 2017. Cluster-randomized trials and quasirandom design studies were not eligible. Authors of eligible trials were asked whether they were aware of relevant studies that had not been identified in the search.

Data collection
Authors of eligible studies were approached to participate in the IPDMA, comment on the protocol draft and provide data. Supplied data were assessed for missing data, internal consistency and randomization. Summary statistics of relevant variables were checked against published results. Investigators were asked for clarification on discrepancies and a final summary was sent for verification. After resolution, individual study datasets were merged into the IPDMA dataset. All included trials were approved by the relevant committees. Details can be found in the original manuscripts.

Inclusion and exclusion criteria
Women were included with singleton or multiple pregnancy presenting from 34 weeks of gestation onwards with gestational hypertension, pre-eclampsia, deteriorating pre-existing hypertension or superimposed pre-eclampsia.
Hypertension was defined as blood pressure (BP) levels ≥ 140 mmHg systolic or ≥ 90 mmHg diastolic and pre-eclampsia as hypertension and proteinuria (300 mg or more total protein in a 24-h urine sample, recurrent positive protein dipstick test or protein/creatinine ratio of 30 mg/mmol or more). Deteriorating pre-existing hypertension was defined as the need for new or additional antihypertensive drugs after 34 weeks of gestation in women with pre-existing hypertension. Superimposed pre-eclampsia was defined as new onset proteinuria in women with pre-existing hypertension.
Participants were excluded with signs of severe disease (BP ≥ 160 mmHg systolic or ≥ 110 mmHg diastolic, proteinuria ≥ 5 g/24 h, oliguria, cerebral/visual disturbances, pulmonary edema/cyanosis, epigastric or right upper quadrant pain, impaired liver function and thrombocytopenia), as well as with diabetes mellitus, gestational diabetes requiring insulin treatment, kidney or heart disease, HELLP syndrome or HIV. Pregnancies with suspected or confirmed major structural or chromosomal abnormality were also excluded.

Risk of bias assessment
Two investigators (H.G. and T.P.B.) independently evaluated the included trials for risk of bias. This assessment was based on criteria found in the Cochrane Handbook for Systematic Reviews of Interventions 34 . The criteria were as follows: random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; selective reporting and other bias. Each was characterized as low, unclear or high for each trial. Disagreements were resolved by consensus.

Quality of evidence
To assess systematically the quality of the evidence provided by the included studies, the approach of the GRADE Working Group was followed 35 . Scoring points were attributed according to type of evidence, quality, consistency, directness and effect size. The final score was then used to categorize evidence quality as high, moderate, low or very low.

Data analysis
Outcomes were analyzed on an intention-to-treat basis using a two-stage IPDMA approach. Aggregate outcomes were recalculated at the trial level and then standard meta-analysis techniques were used to evaluate the overall effect of the intervention (pooled relative risk (RR) with 95% CI) [36][37][38] . Heterogeneity was assessed using the I 2 statistic. Mantel-Haenszel fixed-effect model was used if statistical heterogeneity was acceptable (I 2 ≤ 30%) and trial-specific interventions were deemed sufficiently similar. Random-effects models were used otherwise. Descriptive comparisons were performed to assess between-study differences.
Predefined subgroup analyses were performed by hypertensive disorder type, gestational age, obstetric history (previous hypertensive disorder of pregnancy, Cesarean section, abortion, parity), ethnicity, multiple pregnancy, maternal age, body mass index, transvaginal sonography cervical length and Bishop score. Interactions between the intervention and subgroups were evaluated using the chi-square test and resulting interaction P-values.

RESULTS
Data were collected on five RCTs: HYPITAT-I, DIGITAT, Deliver or Deliberate, HYPITAT-II and GRIT 27,28,30,31,39 . A summary of the search can be found in Figure 1. The total number of participants in the trials was 2825. Of these, 1778 were eligible for this study. Information on non-eligible participants as well as a summary of each of the five included studies can be found in Table 1. Baseline characteristics of the 1724 women for whom the primary outcomes were available can be found in Table 2. The HYPITAT-I, HYPITAT-II and Deliver or Deliberate studies evaluated immediate delivery vs expectant management for pregnancies between 34 + 0 and 41 + 0 weeks of gestation complicated by hypertensive disorders. HYPITAT-II and Deliver or Deliberate protocols mandated delivery in the expectant management group by 37 weeks.
Chronologically, HYPITAT-I ran parallel with DIG-ITAT. Women with hypertension as well as suspected intrauterine growth restriction were preferentially included in the DIGITAT study. The GRIT trial evaluated the intervention in pregnancies with fetal compromise between 24 + 0 and 36 + 0 weeks of gestation. GRIT collected data on neonatal outcome only and its main respiratory outcome was ventilation for 24 h or more, not RDS.
Randomization to immediate delivery before 37 weeks of gestation resulted in preterm delivery in 86.0% (435/506) of women. In the expectant management group, this occurred in 61.0% (303/497). In the former group, median time to delivery after randomization was 2 days (interquartile range (IQR), 1.0-3.0) vs 7 days (IQR, 4.0-12.0) in the latter. To avoid selection bias because of fetal compromise, GRIT data were not used to calculate preterm delivery rates and median time to delivery. Studies for which IPD were provided (n = 5) Participants for whom data were provided (n = 2825) Participants for whom no data were provided (n = 0) Studies for which IPD were not provided (n = 1; 78 participants) Studies for which aggregate data were available (n = 1; 78 participants)

IPD main outcomes Studies included in analysis (n = 4)
Participants included in analysis (n = 1724) Participants excluded (n = 1101)* Aggregate data † Studies included in analysis (n = 1) Participants included in analysis (n = 78) Participants excluded (n = 0) Studies for which IPD were not sought (n = 0) Studies which were ineligible (n = 2722)

Figure 1
Flowchart summarizing search for, and analysis of, individual patient data from randomized controlled trials reporting on management of near-term women with hypertensive disorder of pregnancy. *1047 excluded due to individual participant data (IPD) meta-analysis inclusion/exclusion criteria and 54 from GRIT study 39 for which main outcomes were not collected. †Placental abruption, intrauterine growth restriction, neonatal intensive care unit admission and perinatal mortality. Only first author of each study is given. Figure 2 presents the primary outcome results by study and Table 3       (1.6%) in the 863 pregnancies managed expectantly (RR, 1.94 (95% CI, 1.05-3.59); I 2 = 24%; numbers needed to harm, 58 (95% CI, 31.1-363.1)). Table 3 presents the pooled secondary outcome results. Severe postpartum hemorrhage occurred in 8.0% of women after immediate delivery and in 10.4% of women in the expectant management group (RR, 0.77 (95% CI, 0.57-1.04); I 2 = 2%). The Deliver or Deliberate and HYPITAT-II studies tracked but did not (plan to) report on this outcome. Consequently, rates may have been underestimated in the former, as only three (1.9%) occurrences were recorded in 155 pregnancies. In the latter, severe postpartum hemorrhage occurred fewer times after immediate delivery vs expectant management (8.5% vs 13.7%; RR, 0.62 (95% CI, 0.40-0.96)).

450
Bernardes et al. Only first author of each study is given.
Seizures occurred in five infants in the immediate delivery group and in two in the expectant management group (0.7% vs 0.3%; RR, 2.49 (95% CI, 0.48-12.82)). Culture-proven sepsis rates were 0.6% and 0.1%, respectively (RR, 2.8 (95% CI, 0.65-11.88)). Three neonates in the immediate delivery group presented intraventricular hemorrhage Grade III or IV and four presented necrotizing enterocolitis; none in the expectant management group presented these outcomes. There were four cases of periventricular leukomalacia in the immediate delivery group and two in the expectant management group. There were no cases of bronchopulmonary dysplasia, intracerebral hemorrhage, cerebral infarction or hypoxic ischemic encephalopathy.
There were two perinatal deaths in the included trials, both from GRIT, one in each group. Inclusion of aggregate data from Hamed et al. 29 on placental abruption, intrauterine growth restriction, NICU admission, and perinatal mortality did not change these results significantly (Table 3). Figure 3 shows the results of the subgroup analyses of the primary maternal and neonatal outcomes. There was no evidence that the intervention effect was different for any of the subgroups.

Subgroup analyses
The subgroups of women presenting with pre-eclampsia, those at or below the median age of 29 years, those who were nulliparous and those with cervical length greater than the median of 31 mm were at increased risk of HELLP or eclampsia when managed expectantly.
Median time to delivery after randomization to expectant management at 34 weeks of gestation was 16 (IQR, 12.8-19.0) days in cases of gestational hypertension and 9.5 (IQR, 5.0-16.0) days in cases of pre-eclampsia. The equivalent medians for 35 weeks were 9.5 (IQR, 5.5-13.0) days and 10 (IQR, 6.0-12.0) days, respectively, and for 36 weeks they were 7 (IQR, 4.0-13.5) days and 5 (IQR, 4.0-8.0) days, respectively. Pregnancies selected because of fetal compromise were not included in the subgroup analysis of term birth rates and median days to delivery for those randomized preterm.

Risk of bias and quality of evidence
The results of our risk of bias evaluation of the studies based on Cochrane guidelines can be found in Table 4.
GRADE assessment of quality of evidence and further data for each outcome are available in Table 3.

Primary findings
While immediate delivery decreases the risk of a composite outcome of HELLP and eclampsia, it also increases the risk of RDS, especially if delivery occurs prior to 36 weeks of gestation.

Strengths and limitations
For this IPDMA, we collected and reanalyzed individual data from five previous RCT on the management of near-term hypertensive disorders in pregnancy. By harmonizing inclusion/exclusion criteria and using individual participant data, we were able to include hypertensive women from the DIGITAT study.
Unfortunately, we sought but did not receive, data from Hamed et al. 29 . Their trial included 76 women with chronic hypertension, which could have facilitated our evaluation of this subgroup. Furthermore, as HYPITAT-II was the only included trial that had data allowing distinction between pre-eclampsia and superimposed pre-eclampsia, we were unable to differentiate between the two in the pooled results. RDS incidence is affected by corticosteroid administration prior to delivery; of the included studies, only HYPITAT-II had available data on its use. Consequently, no adjustments were possible to account for this.
Even in our combined dataset, the low incidence of most severe adverse outcomes remained a difficult challenge. The results from two currently ongoing trials, i.e. the PHOENIX trial (ISRCTN01879376) and the WILL trial (NIHR-HTA -16/167/123) will have to be awaited to re-evaluate risks of severe outcomes.

Clinical meaning of findings
The American College of Obstetricians and Gynecologists (ACOG) currently suggests delivery at 37 weeks of gestation in the presence of gestational hypertension or pre-eclampsia 40 . On the other hand, in the UK, The National Institute for Health and Care Excellence (NICE) guidelines recommend this only for women with pre-eclampsia. For women with gestational hypertension, timing of delivery is left to mutual agreement between patient and obstetrician 41 . Our evaluation of pooled data may contribute to further sophistication of this advice. Women with gestational hypertension more often developed HELLP syndrome after expectant management as compared to immediate delivery. Since the Deliver or Deliberate and HYPITAT-II trials allowed expectant management only until 37 weeks of gestation, occurrence of progression to HELLP or eclampsia was precluded. If allowed to continue beyond this gestational age, these pregnancies would likely have contributed to an even larger difference in our primary maternal outcome. Therefore, our findings strengthen the evidence base for the ACOG recommendation.
A recently published Cochrane review pooled aggregate results from the two HYPITAT studies and concluded that immediate delivery is associated with less composite maternal morbidity and mortality for women with a hypertensive disorder after 34 weeks' gestation 42 . However, the review authors pooled different composite outcomes, highlighting the relevance of this IPDMA. They also found that immediate delivery lowers HELLP risk, a result that is in accordance with our IPDMA. On the other hand, they found more NICU admissions after immediate delivery, which we could not confirm. From 34 weeks of gestation to term, current guidelines concur that management should be expectant as long as no severe features are present. Our results favor maintaining this recommendation.

Subgroup analyses
We found no evidence of statistically significant interaction effects present in particular subgroups. This implies that the relative effects of the intervention do not appear to differ between subgroups. However, there were subgroups with increased risks of RDS or progression to HELLP or eclampsia.
Women with a-priori higher risk of progression to HELLP, such as those already presenting with pre-eclampsia instead of with gestational hypertension, were shown to benefit from earlier delivery. For gestational and chronic hypertension, we were not able to demonstrate a statistically significant difference in HELLP syndrome and/or eclampsia between the management groups. Even in our substantial dataset, conclusions remain difficult to draw for hypertensive disorders other than pre-eclampsia due to their low prevalence.
The higher rates of the composite outcome of HELLP syndrome and/or eclampsia found in nulliparous women and in those with high cervical lengths managed expectantly are biologically plausible, as both risk factors contribute to a longer peripartum period and therefore more opportunity for deterioration. Immediate delivery at 35 weeks was the only gestational age subgroup with a significantly higher risk of RDS. This is unlikely to be a false-positive finding because of the higher prior probability of RDS at this gestational age when compared to 36 and 37 weeks. Incidence of RDS stabilizes at around 0.3% from the 38 th week of gestation onwards 43,44 . RDS risk was not elevated for those randomized at 34 weeks, which could be a false-negative finding or because of insufficient power. On the other hand, expectant management initiated in the 34 th week of gestation, i.e. between 2 + 1 weeks and 3 + 0 weeks before term, did not often result in term delivery. This was particularly apparent in those with pre-eclampsia randomized to expectant management, as only 17.1% reached term. Progression to severe disease or fetal 452 Bernardes et al.
distress before term triggered preterm iatrogenic delivery as per protocol, potentially raising RDS rates to resemble those in the immediate delivery subgroup. Similar considerations are valid for the subgroup randomized at 36 weeks with two caveats: (1) RDS rates and severity at this gestational age are lower than at 34 weeks and (2) the period of opportunity to deteriorate was, at most, 1 week because of protocol-mandated delivery at 37 weeks 44 .
In addition to women with pre-eclampsia, the HYPITAT-II trial included women with gestational hypertension. This may explain the contrast with results from Deliver or Deliberate, which did not include gestational hypertension. The lower RDS occurrence with expectant management of preterm gestational hypertension in the former study possibly occurred because more of these women were able to reach the 37 th week of gestation without clinical deterioration compared to those with pre-eclampsia.

Secondary outcome analyses
In agreement with previous RCT-based assessments, we did not find a higher Cesarean section rate when delivery was immediate 23,24 . We found no difference in other secondary maternal and neonatal outcomes. Although SGA was reduced by delivery in the HYPITAT-II study, this was not observed in the Deliver or Deliberate study, and our pooled results were not conclusive. Whether immediate delivery sufficiently alleviates prolonged fetal exposure to a hypertensive environment to decrease SGA merits further investigation.

Conclusion
Our study can inform women and clinicians in decision making on the timing of delivery. To reduce the risk of progression to HELLP or eclampsia, we recommend immediate delivery of pregnancies complicated by gestational hypertension or pre-eclampsia by 37 weeks of gestation. Despite our large database, uncertainty remains regarding effects on rare, severe outcomes. Moreover, long-term consequences of the intervention need to be investigated and more, larger trials are needed.