Differences in RCTs study design and size are likely to impact outcomes

This first article in a series of two, addresses the quality of the five randomized controlled trials(RCTs) comparing CTG+ST vs. CTG (Plymouth trial 1993, Swedish trial 2001, Finnish trial 2006, French trial 2007 and Dutch trial 2010). The following issues are reviewed: power calculation, pre-study training, inclusion criteria, randomization and recruitment pace, intrapartum management protocols, intrapartum interventions, cord blood and early neonatal metabolic acidosis, and neonatal outcomes.

All but the Swedish trial were underpowered for metabolic acidosis, and the majority of trials even for their primary outcome. All trials offered pre-training, but with more thorough implementation in the Plymouth, Swedish and Dutch trials whereby the risk of human error was likely decreased. The most important difference in inclusion criteria was noted in the French trial as only patients with suspicious or pathological CTG were recruited, which in many cases was a violation of the Stan guidelines. The use of Stan monitors for both groups were only stipulated in the Swedish trial, while monitoring techniques varied in the control groups in the other trials. There were considerable variations in duration of the trials and the Plymouth, Swedish and Finnish trials enrolled patients less than half the duration of the two others. Only the Plymouth and Dutch trials had guidelines for the use of FBS but it was optional in all five trials. The use of FBS also varied greatly, but a reduction was seen in the CTG+ST arm in all trials. There was a significant reduction of operative deliveries for fetal distress in the Plymouth and Swedish trials, with a significant reduction of total operative deliveries (including caesarean) in the Swedish trial.

Cord metabolic acidosis was an outcome parameter in all trials but the definition of metabolic acidosis and validation criteria were not uniform, and the authors describe why it is an absolute requisite that the same base deficit algorithm must be used for correct comparison. The Swedish trial (revised version) is the only that reports a standardized intention-to-treat analysis and a significant reduction of metabolic acidosis in the CTG+ST group. None of the trials reported significant differences in admission to NICU and as the definition of neonatal encephalopathy differed between the trials, this outcome parameter cannot be evaluated for all cases included in the trials. All studies were underpowered to evaluate perinatal mortality. See below a summary of strengths and weaknesses of each of the trials.

 

Trial Strength Weakness
Plymouth
  • Single center RCT, suggesting lower risk of inconsistent management
  • Power calculation related to met. acidosis and ODFD
  • Well defined inclusion criteria, strict FBS guidelines
  • Interim analysis
  • Short study period, high recruitment pace, large trial
  • Underpowered to evaluate met. acidosis
  • Recruitments started from 34 weeks of gestation
  • Not standardized ITT analysis
  • Neonatal encephalopathy, seizures, deaths not reported
Swedish
  • Power calculation related to met. acidosis
  • Internal Stan monitors in both trial arms
  • Short trial period, high recruitment pace, large trial
  • Interim analysis
  • Revised article published with single vessel, neonatal and imputed cord blood gas data
  • Standardized ITT analysis of metabolic acidosis
  • Exposed to external review of crude data
  • No clear guidelines for FBS use
  • Errors in number of met. acidosis in original article
Finnish
  • Single center RCT, suggesting lower risk of inconsistent management
  • Short trial period, high recruitment pace
  • Primarily not aimed to show met. acidosis difference
  • Recruitment goal not achieved for primary outcome
  • Inclusion criterion provides no information on fetal risk
  • No clear guidelines for FBS use
  • Internal or external FHR monitoring in CTG group
  • Not standardized ITT
  • BD and met. acidosis calculated using a different algorithm
French
  • Confirmed that ST analysis had no benefit in addition to conventional CTG in labors with pre-existing evidence of fetal compromise
  • Underpowered for evaluation of met. acidosis
  • Inclusion criterion a violation of clinical guidelines
  • Long trial period, low recruitment pace, small trial
  • Not standardized ITT
  • No clear guidelines for FBS use
  • Internal or external monitoring in CTG group
  • Poor quality of cord blood samples, unreliable blood gas data
Dutch
  • Power calculation related to met. acidosis
  • Safety committee watch of serious adverse events
  • Well defined inclusion criteria
  • Strict guidelines for FBS
  • Internal electronic monitoring in CTG group
  • Largest RCT
  • Not completely standardized ITT , but missing data in only 0.25%
  • Revised data article published with corrected and imputed cord blood gas data
  • Underpowered for met. acidosis, recruitment goal not achieved
  • Long trial period, low recruitment pace, many centers involved
  • Errors in number of metabolic acidosis in original article

 From Olofsson et al. Acta Obstet Gynecol Scand 2014; 93:556–569.

 

The authors conclude that the perfect RCT to evaluate CTG+ST is yet to be performed. The great variations in conduct of these RCTs contribute to the drawback of any subsequent meta-analyses, which is further addressed in part two of this article series.

Abstract – Olofsson et al. 2014

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