Journal Club Papers
Paper 1: Term planned delivery based on fetal growth assessment with or without the cerebroplacental ratio in low-risk pregnancies (RATIO37): an international, multicentre, open-label, randomised controlled trial.
Rial-Crestelo et al. The Lancet. 10 February 2024. DOI: 10.1016/S0140-6736(23)02228-6
The cerebroplacental ratio (CPR) is increasingly used as a measure of placental insufficiency at term. The CPR is a ratio of Doppler ultrasound findings of blood flow in the fetal brain (middle cerebral artery, decreased resistance with placental insufficiency) and the umbilical artery (increased resistance with placental insufficiency). Large observational studies have demonstrated an association between a low cerebroplacental ratio and increased rates of stillbirth, perinatal death and emergency caesarean section. However, there have not been randomized trials adequately powered to investigate whether acting on a low CPR can avoid severe adverse outcomes, including perinatal death. Thus, Rial-Crestelo and colleagues undertook a large, randomized, open label multicentre pragmatic trial addressing this.
- The trial recruited low risk pregnant women across 9 hospitals and 6 countries (Spain, Israel, Poland, the Czech Republic, Chile and Mexico).
- 11,214 women were randomized around 21 weeks’ gestation to either a concealed (results not shown to the clinical team or participant) or revealed group.
- An ultrasound was performed at 36+0 – 37+6 weeks’ and the estimated fetal weight and Doppler cerebroplacental ratio (CPR) obtained.
- In the revealed group, the CPR and estimated fetal weight results were provided to the clinician. Those with a CPR value <5th centile were recommended for planned birth after 37 weeks’, irrespective of EFW centile.
- In the concealed group, only the estimated fetal weight was reported but not the CPR findings.
- For both groups, women with an estimated fetal weight <10th centile were recommended to have a planned birth after 37 weeks’. However, this differed to the published protocol, where delivery was recommended at 37 weeks if EFW was <3rd centile, and at 40 weeks if EFW was between the 3rd-10th centile with a normal CPR.
- The primary outcome was perinatal mortality after 24 weeks’ up until discharge.
- Secondary outcomes included 1) severe neurological morbidity (Intraventricular haemorrhage grade III/IV, periventricular leukomalacia or hypoxic ischaemic encephalopathy), 2) severe non-neurological morbidity (necrotising enterocolitis requiring surgery, renal failure, cardiac failure or NICU>10 days) and 3) severe morbidity overall. There were also several tertiary outcomes including milder adverse perinatal outcomes (emergency caesarean section for non-reassuring fetal status, pH <7.1, 5 min Apgar <7, admission to NICU).
Revealing the CPR and recommending birth for those with CPR <5th percentile did not alter the likelihood of perinatal mortality compared with concealing the CPR result.
- The final cohort included 9,492 women and of these, perinatal mortality occurred among 13/4774 (0.3%) pregnancies in the concealed group and 13/4718 (0.3%) in the revealed group (odds ratio [OR] 1.45 [95% CI 0.76, 2.76]).
- For secondary outcomes, there was no difference for severe neurological morbidity (13/4774 [0.3%] vs 9/4718 [0.2%]; OR 0.56 [95% CI 0.25, 1.24]). However, severe non-neurological morbidity was significantly reduced in the revealed group (23/4774 [0.5%] vs 9/4718 [0.2%]; OR 0.58 [95% CI 0.39, 0.87]). This difference was largely driven by NICU admission >10 days (21/4774 vs 9/4781). The indications for prolonged NICU admission were not reported.
- Combining severe neurological and non-neurological morbidity, the revealed group had a 42% reduced likelihood of severe morbidity overall (35/4774 (0.7%) vs 18/4718 (0.4%); OR 0.58 (95% CI 0.18, 0.85).
- For tertiary outcomes, no significant difference was found for mild adverse perinatal outcomes or, birthweight <10th or <3rd centile.
- Of note, in the revealed group among women with a CPR <5th centile, 70/261 (27%) declined planned birth. It is unclear how many in either group with a birthweight <10th declined planned birth.
This was a large and well-designed pragmatic randomized trial. Although CPR combined with estimated fetal weight assessment did not reduce perinatal mortality, it reduced the secondary outcome of severe neonatal morbidity (largely NICU admission >10 days) when compared with fetal weight assessment alone.
The authors conclude that to avoid one severe morbidity, 342 women would need to be screened and with a 5th centile cut-off, 17 would be recommended for planned birth. Notably, to reduce these NICU admissions, universal 36-week ultrasounds would need to be done.
Doppler cerebroplacental ratio assessment appears to be a useful tool to identify fetuses that may be at higher risk of NICU admission. However, ultrasound at term is not routine practice and the cost-benefit ratio for universal implementation has not been determined
Paper 2: Long-Term Blood Pressure Control After Hypertensive Pregnancy Following Physician-Optimized Self-Management: The POP-HT Randomized Clinical Trial. Kitt et al. JAMA. 11 November 2023. DOI: 10.1001/jama.2023.21523
Women who experience hypertension in pregnancy are at increased risk of cardiovascular disease later in life – this risk is particularly high among women whose blood pressure remains elevated at six weeks postpartum. The 2018 Self-Management of Postnatal Antihypertensive Treatment Trial (SNAP-HT) showed the utility of self-monitored blood pressure in lowering diastolic blood pressure during the postpartum period. The Physician Optimized Postpartum Hypertension Treatment Trial (POP-HT) aimed to evaluate whether self-monitoring of blood pressure, together with physician-optimised antihypertensive titration would improve postpartum blood pressure control.
- This was a single-centre, randomised, open-label, blinded end-point study. Women with a clinician-confirmed diagnosis of gestational hypertension or preeclampsia were randomised (1:1) to:
- Intervention: daily telemonitoring of blood pressure with physician-assisted titration of antihypertensive medication – the “self-management group”, or
- Standard National Health Service (NHS) care – this generally included a blood pressure review at 7-10 days with a community midwife and a second review at 6-8 weeks with a general practitioner. Antihypertensive titration was determined by their supervising health care professionals.
- All women had four study visits at 1-6 days, 1 week, 6 weeks, and 6-9 months postpartum. Only women who attended all four visits were included in the primary analysis.
- Primary outcome: 24-hour mean diastolic blood pressure at 6-9 months postpartum (the fourth visit), adjusted for baseline postpartum blood pressure.
- Secondary and tertiary outcomes included:
- Additional blood pressure outcomes (24-hour, diurnal, and nocturnal ambulatory blood pressure, and clinic blood pressure).
- Imaging outcomes (transthoracic echocardiography and cardiovascular magnetic resonance assessment).
- Physical activity monitoring (participants wore an accelerometer for one week), British Heart Foundation standardised diet and lifestyle assessments and quality of life questionnaires were assessed at the final visit.
- In an intention-to-treat analysis (including all women with at least one post-randomisation outcome), self-management was associated with a significant reduction in 24-hour diastolic blood pressure at 6-9 months postpartum (mean difference [MD] -5.80mmHg, 95% confidence interval [CI] -7.40, -4.20; p<0.001). There was also a significant reduction in 24-hour systolic blood pressure (MD -6.80, 95% CI -8.80, -4.22; p<0.001).
- All secondary blood pressure outcomes (as above) showed improvement among the self-management group, except for clinic-based systolic blood pressure (no difference). There was also a reduced risk of readmission to hospital for elevated blood pressure in the self-management group (8 [7%] readmitted vs 29 [27%] readmitted). There were no differences between groups in any other secondary outcomes.
This study showed that self-monitoring of blood pressure with clinician-guided medication titration can reduce blood pressure (both diastolic and systolic), with the reduction of 5mmHg in diastolic BP considered clinically significant (that is, reduced lifetime risk of heart attack and stroke in this population if this were sustained). Self-monitored blood pressure with clinician-guided antihypertensive titration should be considered in clinical practice.
Paper 3: Deferred cord clamping, cord milking, and immediate cord clamping at preterm birth: a systematic review and individual participant data meta-analysis. Seidler et al. The Lancet. 9 December 2023. DOI: 10.1016/S0140-6736(23)02468-6
- A systematic review of 48 randomised controlled trials (RCTs) of preterm infants (<37 weeks’ gestation) comparing methods of umbilical cord management – (1) immediate clamping, (2) deferred clamping, and (3) cord milking. Individual participant data was pooled from 6,367 infants.
- Primary outcome: death prior to hospital discharge.
Secondary outcomes: neonatal morbidity including need for blood transfusion, hypothermia and intraventricular haemorrhage.
- Findings – deferred cord clamping:
- Deferred clamping (n=1,622) was associated with a significant reduction (32%) in neonatal death prior to discharge (OR 0.68, 95% CI [0.51, 0.91]) compared with immediate cord clamping (n=1,638).
- Among infants born before 32 weeks’ gestation, deferred clamping was associated with a reduced need for blood transfusion (OR 0.59, 95% CI [0.47, 0.73]), but increased hypothermia (infants were 0.13°C colder, 95% CI [-0.20, -0.06]), compared with immediate clamping.
- Findings – umbilical cord milking:
- Compared with immediate clamping (n=792), cord milking (n=769) did not reduce neonatal death prior to discharge (OR 0·73, 95%CI 0·44–1·20). Similarly, compared with delayed cord clamping (n=655), cord milking (n=648) did not reduce death before discharge (OR 0·95, 95%CI 0·59–1·53).
- Cord milking reduced the need for blood transfusion in infants born before 32 weeks’ gestation (OR 0.69, 95% CI [0.51, 0.93]), compared with immediate clamping.
- Cord milking may increase the likelihood of severe intraventricular haemorrhage in this cohort compared with deferred clamping (OR 2.20, 95% CI [1.13, 4.31]), though this is based on low certainty evidence.
- Deferred cord clamping reduced neonatal death and need for blood transfusion, compared with immediate clamping. Cord milking did not reduce neonatal mortality, and may in fact be harmful.
Paper 4: Short, medium, and long deferral of umbilical cord clamping compared with umbilical cord milking and immediate clamping at preterm birth: a systematic review and network meta-analysis with individual participant data. Seidler et al. The Lancet. 9 December 2023. DOI: 10.1016/S0140-6736(23)02469-8
- Compared with the paper above, this study is a network meta-analysis, which allows simultaneous comparisons between three or more interventions (rather than two). It included 47 RCTs comparing timing of deferred clamping: immediate (<15 seconds); short (15-44 seconds); medium (45-120 seconds); long (>120 seconds) and intact cord milking in preterm infants. Data from 6,094 infants born <37 weeks’ gestation were analysed.
- Primary outcome: death prior to hospital discharge.
Secondary outcomes: intraventricular haemorrhage and need for blood transfusion.
- Findings:
- Long deferral in cord clamping (>120 seconds) (n=302) reduced death prior to discharge by 69% (OR 0.31, 95% Credible Interval (CrI) [0.11, 0.80]) compared with immediate clamping (n=2,030). While there were trends towards reduced mortality, short (n=422) and medium (n=1,906) delays in cord clamping and cord milking (n=1,009) did not significantly reduce neonatal death compared with immediate clamping.
- Compared head-to-head, none of the five methods of cord management clearly reduced the odds of intraventricular haemorrhage.
- Intact cord milking and a short or medium delay in cord clamping was associated with reduced need for blood transfusion. The impact of long deferral on need for blood transfusion was inconclusive due to insufficient studies directly comparing this technique with immediate cord clamping.
These companion meta-analyses provide high certainty evidence that a longer delay in cord clamping (>120 seconds) in preterm infants is associated with a significant reduction in neonatal mortality, beyond the known benefits of a 60 second delay in cord clamping.
Data from low, middle, and high-income countries were included, reinforcing the relevance of these findings across a range of resource settings. The authors conclude that deferred cord clamping should be practiced in preterm infants provided respiratory support can be concurrently administered.