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RANDOMISED CONTROLLED TRIAL
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Doppler ultrasound of umbilical and middle cerebral artery in third trimester small-for-gestational age fetuses to decide on timing of delivery for suspected fetal growth restriction: A cohort with nested RCT (DRIGITAT)

Mauritia C. Marijnen

Corresponding Author

Mauritia C. Marijnen

Department of Obstetrics and Gynaecology, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands

Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands

Correspondence

M. C. Marijnen, Department of Obstetrics and Gynaecology, Amsterdam University Medical Centres, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.

Email: [email protected]

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Hester D. Kamphof

Hester D. Kamphof

Department of Obstetrics and Gynaecology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands

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Stefanie E. Damhuis

Stefanie E. Damhuis

Department of Obstetrics and Gynaecology, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands

Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands

Department of Obstetrics and Gynaecology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands

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Maddy Smies

Maddy Smies

Department of Obstetrics and Gynaecology, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands

Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands

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Aleid G. Leemhuis

Aleid G. Leemhuis

Department of Neonatology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

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Hans Wolf

Hans Wolf

Department of Obstetrics and Gynaecology, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands

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Sanne J. Gordijn

Sanne J. Gordijn

Department of Obstetrics and Gynaecology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands

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Wessel Ganzevoort

Wessel Ganzevoort

Department of Obstetrics and Gynaecology, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands

Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands

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DRIGITAT Trial Group

DRIGITAT Trial Group

DRIGITAT Trial Group members are presented in Appendix  1.

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First published: 05 February 2024

Sanne Jehanne Gordijn and Wessel Ganzevoort are co-last authors and have contributed equally to this manuscript.

Abstract

Objective

To assess the association of the umbilicocerebral ratio (UCR) with adverse perinatal outcome in late preterm small-for-gestational age (SGA) fetuses and to investigate the effect on perinatal outcomes of immediate delivery.

Design

Multicentre cohort study with nested randomised controlled trial (RCT).

Setting

Nineteen secondary and tertiary care centres.

Population

Singleton SGA pregnancies (estimated fetal weight [EFW] or fetal abdominal circumference [FAC] <10th centile) from 32 to 36+6 weeks.

Methods

Women were classified: (1) RCT-eligible: abnormal UCR twice consecutive and EFW below the 3rd centile at/or below 35 weeks or below the 10th centile at 36 weeks; (2) abnormal UCR once or intermittent; (3) never abnormal UCR. Consenting RCT-eligible patients were randomised for immediate delivery from 34 weeks or expectant management until 37 weeks.

Main outcome measures

A composite adverse perinatal outcome (CAPO), defined as perinatal death, birth asphyxia or major neonatal morbidity.

Results

The cohort consisted of 690 women. The study was halted prematurely for low RCT-inclusion rates (n = 40). In the RCT-eligible group, gestational age at delivery, birthweight and birthweight multiple of the median (MoM) (0.66, 95% confidence interval [CI] 0.59–0.72) were significantly lower and the CAPO (n = 50, 44%, p < 0.05) was more frequent. Among patients randomised for immediate delivery there was a near-significant lower birthweight (p = 0.05) and higher CAPO (p = 0.07). EFW MoM, pre-eclampsia, gestational hypertension and Doppler classification were independently associated with the CAPO (area under the curve 0.71, 95% CI 0.67–0.76).

Conclusions

Perinatal risk was effectively identified by low EFW MoM and UCR. Early delivery of SGA fetuses with an abnormal UCR at 34–36 weeks should only be performed in the context of clinical trials.

Author-Provided Video

Doppler ultrasound of umbilical and middle cerebral artery in third trimester small-for-gestational age fetuses to decide on timing of delivery for suspected fetal growth restriction: A cohort with nested RCT (DRIGITAT)

by Marijnen et al.

1 INTRODUCTION

Fetal growth restriction (FGR) is a condition in which the fetus does not reach its intrinsic growth potential, mainly concentrated in the lowest weight centiles.1 The most frequent underlying pathophysiological mechanism is placental insufficiency resulting in malnutrition and hypoxia. The associated chronic and acute-on-top-of-chronic hypoxia leads to acute perinatal morbidity and mortality and poor neurodevelopmental outcome.2-5 The imminent hypoxia that poses a severe threat of stillbirth is only prevented by timely delivery.5 In its prevention, the (low) risk and high impact of fetal demise should be balanced against the (high) risk and relatively low impact of unmet fetal needs to mature.6

There is a long-standing search for methods to differentiate growth-restricted fetuses, who are at risk for reduced placental nutritional supply and hypoxia, from fetuses that are constitutionally small for their gestational age (SGA). Generally, the 10th centile of a reference chart for estimated fetal weight (EFW) and/or fetal abdominal circumference (FAC) is used to screen for FGR and to select women who need additional surveillance and possibly timely delivery.7 Unfortunately, this method not only selects FGR fetuses, but also healthy SGA fetuses, who do not need additional surveillance and most likely will be harmed by early delivery.8

In 2016, a Delphi procedure led to a widely adopted international FGR consensus definition that incorporated Doppler measurements, including the cerebroplacental ratio (CPR), the inverse of the umbilicocerebral ratio (UCR), and decline in fetal growth centile as parameters of placental function.9 A high UCR reflects decreased resistance in the middle cerebral artery (MCA) and/or increased resistance in the umbilical artery (UmbA), indicating redistribution of the fetal circulation, an adaptation mechanism to scarcity of nutrients and oxygen, also called ‘brain sparing’.10 The UCR has shown diagnostic accuracy for short-term adverse outcomes of early preterm FGR and short-term adverse outcomes of late preterm FGR, mostly in retrospective studies.11, 12 Long-term associations are less established.13, 14 The biomarkers placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) are proposed as markers for placental insufficiency and may play a role in the diagnosis of FGR.15

If earlier delivery reduces the risk of hypoxia, better perinatal outcome can be hypothesised, but cannot be proven from observational studies. Therefore, we designed a randomised controlled trial (RCT) in a cohort of late preterm SGA pregnancies that randomised the cases with abnormal fetal Doppler indices between immediate delivery and expectant management.16 A second objective was to assess the association of criteria used for randomisation, with adverse perinatal outcomes in the cohort. In this paper, we describe short-term perinatal outcomes of this study. A video abstract (Video S1) has been created by the authors to summarise the paper's findings.

2 METHODS

2.1 Study setting

The DRIGITAT trial was a nationwide multicentre nested RCT in the Dutch Obstetric Consortium, a collaboration of perinatal secondary and tertiary care centres in the Netherlands. The study protocol has been previously published.16 Briefly, the trial design was a cohort study of SGA pregnancies of at least 32+0 weeks of gestation with a nested RCT including fetuses with two consecutive abnormal UCRs >0.8, and/or UmbA pulsatility index (PI) above the 90th centile. Fetal Doppler index centiles were calculated according to Arduini and Rizzo.17 Patient recruitment, patient monitoring and data collection were performed by the treating obstetricians, residents, midwives and research staff of participating sites. Patient organisations Hellp stichting and Care4Neo (Vereniging van Ouders Couveusekinderen) had an advisory role in the development of the trial.

2.2 Participants (cohort)

Pregnant women from 32+0 weeks up to 36+6 weeks of gestation with a singleton pregnancy were eligible for inclusion in the cohort if they had a fetus with an EFW, calculated by the Hadlock algorithm or an FAC below the 10th centile based on the Hadlock fetal growth chart and the Verburg FAC reference curve.18-20

Exclusion criteria were maternal age below 18 years, unwillingness or inability to give informed consent, uncertainty about the estimated due date (no first-trimester dating scan), chromosomal abnormalities or suspicion of congenital anomalies that could influence the prognosis of the pregnancy or health of the fetus independent of the growth problem.

2.3 Routine protocol

Participants were requested to complete a baseline characteristics survey at inclusion. Routine care after recruitment was according to local hospital protocol. According to study protocol, a biometry scan was performed at least every 2 weeks and a Doppler ultrasound scan at least every week, including PI of the UmbA and MCA. The UCR was calculated by dividing the values of the UmbA PI by the MCA PI. In many publications, the ratio of the UmbA PI and MCA PI is presented as CPR; the mathematical inverse of the CPR is the UCR. In this study, we used the UCR, as we have previously demonstrated that there may be some advantages to the use of UCR,21 which are of particular relevance when fetal Doppler changes become increasingly abnormal: with lower MCA and higher UmbA impedance CPR tends towards zero, whereas UCR tends towards infinity, thus allowing improved observation of differences. Cardiotocography was indicated on the discretion of the treating healthcare team. Guidance and safety net criteria were provided for timing of delivery in the cohort and in the expectant monitoring arm of the RCT. Delivery was indicated when:
  1. Cardiotocography was suggestive of fetal distress (International Federation of Obstetrics & Gynecology [FIGO] criteria).22
  2. Doppler ultrasound of the UmbA suggested high antenatal risks:

    1. Reversed end-diastolic flow in the UmbA on two consecutive occasions with a significant interval (minimum of 15 hours) from a gestational age of more than 32 weeks;
    2. Absent end-diastolic flow in the UmbA on two consecutive occasions with a significant interval from a gestational age of more than 34 weeks;
    3. PI of the UmbA above the 95th centile with positive end-diastolic flow on two occasions with a significant interval from a gestational age of more than 37 weeks.

  3. The EFW and/or FAC was below the 3rd centile from a gestational age of 37 weeks.
  4. The EFW and/or FAC was between the 3rd and 10th centiles from a gestational age of 40 weeks.
  5. The presence of other clinical signs that urged short-term delivery according to local hospital protocol, such as development of hypertension, pre-eclampsia or (repetitive) episodes of reduced fetal movements.

2.4 Blood sample storage and biomarker analysis

Maternal blood samples (serum and plasma) were drawn at inclusion and stored at −80°C for biomarker analysis of PlGF and sFlt-1 in the centres with facilities for biobanking. All blood samples were analysed for PlGF and sFlt-1, in batches after completion of the inclusions, at the University Medical Centre in Groningen using Roche Elecsys assays on the electrochemiluminescence immunoassay platform Cobas e601-module (Roche Diagnostics, Basel, Switzerland). Based on earlier publications, the PlGF cutoff value for abnormality was ≤99 and the cutoff for an abnormal sFlt-1:PlGF ratio was >33.23-25 Abnormal values at inclusion were calculated. Evaluation of the use of biomarkers in predicting adverse outcomes will follow in a secondary analysis and is beyond the scope of this paper.

2.5 Participants (RCT)

An abnormal fetal Doppler measurement was defined by a UCR >0.8 (equals a CPR of less than 1.25) based on a previous meta-analysis,21 or an UmbA PI >90th centile on two consecutive occasions with an interval >15 hours. Women were eligible for randomisation from 34+0 until 36+6 weeks if they had an abnormal fetal Doppler in combination with an EFW and/or FAC below the 3rd centile and from 36+0 until 36+6 weeks in case of an EFW and/or FAC below the 10th centile. Women who were RCT-eligible but declined RCT participation were managed according to local protocol.

2.6 Randomisation and blinding

RCT-eligible women who provided informed consent were randomly allocated to immediate delivery or expectant monitoring. Randomisation was centrally organised using the online computerised randomisation service of Castor (last updated version 2023.4.0.1).26 Randomisation was done using variable block sizes of 4 and 6, stratified by gestational age (dichotomous; before or after 36 weeks) and participating hospital. Participating sites were able to access the randomisation service 24 hours per day. Blinding of participants, obstetricians or outcome assessors was not possible because of the nature of the intervention.

Participants allocated to immediate delivery were planned for immediate induction of labour or caesarean section (CS), unless the intervention was refused by the participant. Participants allocated to the expectant management group were monitored with biometry at least every 2 weeks, at least twice weekly follow up by Doppler ultrasound scan and daily cardiotocography. Timing of birth was according to local hospital protocol and based on study safety net criteria.

2.7 Outcomes

The primary outcome of the RCT was set at neurological development at 2 years of age, to be assessed by a Bayley-III test in all children born in the RCT and a subset of children born in the cohort (delivery >38 weeks, normal Doppler) randomly selected from Castor and will be published later.27 A short-term composite adverse perinatal outcome, based on the intention to treat, was the primary outcome for this report. It was defined by (1) adverse condition at birth and/or (2) major neonatal morbidity or mortality.
  1. Adverse condition at birth: fetal death or signs of asphyxia: a 5-minute Apgar score <7, an umbilical artery pH <7.0, or a venous pH <7.1, or neonatal resuscitation by ventilation, thoracic compressions or need for vasoactive medication.
  2. Major neonatal morbidity: cerebral morbidity (intracranial haemorrhage grade ≥3, periventricular leukomalacia grade ≥2, convulsions), respiratory morbidity necessitating respiratory support, circulatory morbidity, sepsis, necrotising enterocolitis or perinatal mortality (defined as neonatal death within the first 28 days).

All other items of the relevant core outcome set were collected.28

2.8 Sample size RCT

The sample size was calculated based on a clinically relevant difference of seven points on the primary outcome of the Bayley-III assessment at 2 years of age.27 With a standard deviation of 15 points in both treatment groups, an α of 0.05 and a desired power of 80% for a two-sample t test, 74 participants had to be recruited in each arm of the nested RCT. Assuming a 20% loss to follow up of randomised participants (because of the long interval before assessment of the primary outcome), 185 women had to be included in the RCT. Assuming a 20% incidence of abnormal UCR within the SGA cohort and accounting for an RCT inclusion rate of 60%, we calculated the need for a cohort of 1542 patients.

2.9 Statistical analysis

This paper presents short-term outcomes of the complete study cohort. For these analyses the cohort was divided into the following subgroups, based on Doppler classification:
  1. Eligible for randomisation (abnormal Doppler twice consecutive and EFW/FAC <3rd centile at 34+0–36+6 weeks or EFW/AC <10th centile at 36+0–36+6 weeks):

    1. Randomised to immediate delivery;
    2. Randomised to expectant management;
    3. No consent for randomisation.

  2. Not eligible for randomisation, but an abnormal Doppler once or intermittent.
  3. Never an abnormal Doppler in the study period of 32+0 to 36+6 weeks.

Categorical baseline characteristics were summarised by presenting number and column percentages and compared using chi-square test. Continuous variables were summarised as medians with interquartile ranges (IQR) and compared using non-parametric Kruskal–Wallis test. A multiple logistic regression analysis was performed with the composite adverse perinatal outcome as dependent variable and EFW multiple of the median (MoM) at inclusion, pre-eclampsia, gestational hypertension and the Doppler group classification.29 To assess the performance of this model, receiver operating characteristics (ROC) curves and area under the ROC curve (AUC) with 95% confidence interval (CI) were calculated. Differences with a p value less than 0.05 were considered statistically significant. Statistical analyses were performed using SPSS software (version 28.0; IBM, Armonk, NY, USA).

3 RESULTS

Cohort recruitment ran from 1 January 2018 until 1 January 2022. RCT recruitment ran from the start and continued until 25 April 2022. In total, 19 hospitals participated, of which 12 were secondary care centres and seven were tertiary care centres. A total of 692 women were included in the cohort (Figure 1). Two cohort participants were excluded from analyses because of missing biometry and Doppler measurements, leaving 690 women for analyses. On 25 April 2022, the Data Safety Monitoring Board recommended that the study be halted completely because of low RCT-inclusion rates. At the time of halting the trial, 18 RCT participants had been randomly allocated to immediate delivery and 22 participants had been allocated to expectant management. After randomisation for immediate delivery, one participant declined the intervention.

Details are in the caption following the image
Flowchart of the study population. Abnormal Doppler = umbilical artery pulsatility index above the 90th centile or umbilicocerebral ratio>0.8, and estimated fetal weight (EFW) below the 3rd centile at 32–35 weeks or EFW below the 10th centile at 36 weeks. *Including two women with absent or reverse end-diastolic flow in the umbilical artery, which precluded randomisation.

Slow accrual to the RCT was related to slightly lower than anticipated number of patients with abnormal UCR and higher than anticipated number of patients with exclusion criteria such as language barriers, further worsened by the challenges of the COVID-19 period and its aftermath, when patient recruitment was less prioritised. Also, women frequently did not want to be randomised because early delivery was not an acceptable option for them.

Study population data of all subgroups, including both randomisation groups, are presented in Table 1. Notwithstanding the low number of inclusions in the RCT, there was a significantly lower gestational age at delivery (p < 0.01) in the immediate delivery group compared with the expectant management group, and a near significant lower birthweight (p = 0.05) and higher composite adverse perinatal outcome (p = 0.07). Baseline characteristics were comparable between the groups, except that pre-eclampsia was most frequent in the women who delivered before 34 weeks of gestation, and more frequent in the Abnormal Doppler twice consecutive subgroups than in those with never, or only once or intermittent abnormal Doppler.

TABLE 1. Study population (n = 690).
Definition Delivered <34 weeks ARED flow —Immediate delivery Abnormal Doppler twice consecutive = RCT eligible Abnormal Doppler once or intermittent Never abnormal Doppler
Immediate delivery Delayed delivery Not randomised
N (%) 30 (4%) 2 (0.3%) 18 (3%) 22 (3%) 73 (11%) 108 (16%) 437 (63%)
Gestational age at inclusion (weeks+days) 32+1 (32+0–32+3) 32+1 34+1 (33+0–34+5) 33+4 (32+2–34+4) 34+0 (33+0–35+0) 34+3 (33+1–36+0) 34+3 (33+1–35+5)
EFW (g) 1206 (1101–1507) 1161 1433 (1199–1803) 1492 (1353–1787) 1602 (1391–1766) 1777a (1548–2073) 1771a (1590–1979)
EFW MoM 0.69 (0.61–0.77) 0.70 0.72 (0.63–0.76) 0.73 (0.66–0.76) 0.74 (0.65–0.79) 0.78a (0.73–0.82) 0.79a (0.75–0.81)
Pre-eclampsia 18b (60%) 0 (—) 4 (22%) 3 (14%) 20 (27%) 10 (9%) 32 (7%)
Gestational age at delivery (weeks+days) 33+1 (32+4–33+4) 34+4 35+2 (34+6–36+2) 37+1 (35+6–37+3) 37+0 (35+6–37+2) 37+4a (37+0–38+2) 38+4a (37+5–39+3)
Birthweight (g) 1377 (1203–1532) 1555 1703§ (1481–1973) 1978§ (1711–2179) 1984 (1698–2193) 2375a (2184–2567) 2615a (2350–2893)
Birthweight MoM 0.65 (0.54–0.73) 0.63 0.66 (0.56–0.72) 0.66 (0.61–0.72) 0.66 (0.60–0.73) 0.76a (0.69–0.82) 0.79a (0.73–0.84)
Composite adverse perinatal outcome 24 (80%) 2 (100%) 12 (67%) 9 (41%) 27 (37%) 23a (21%) 69a (16%)
  • Note: Abnormal Doppler = Umbilical artery pulsatility index above the 90th centile or umbilicocerebral ratio >0.8, and EFW below the 3rd centile at 32–35 weeks or below the 10th centile at 36 weeks. Table shows median (interquartile range) or number (%).
  • Abbreviations: ARED flow, absent or reversed end-diastolic flow in the umbilical artery; EFW, estimated fetal weight; MoM, multiple of the median.
  • a Significant difference (p < 0.05) with the five other columns to the left.
  • b Significant difference (p < 0.05) with all other columns.
  • Differences between randomisation arms: p = 0.00; §p = 0.05; p = 0.07.

There were six perinatal deaths in the entire cohort. Two deaths occurred in the group of women who delivered before 34 weeks, caused by congenital anomalies unknown at time of inclusion. One death occurred in the Abnormal Doppler twice consecutive group (not within the RCT group) because of placental abruption and emergency CS at 38 weeks. One late death occurred in the Abnormal Doppler once or intermittent group 138 days after delivery caused by a genetic disorder unknown at time of inclusion. Two deaths occurred in the Never Abnormal Doppler group, one caused by asphyxia during spontaneous labour at 40 weeks of gestation and one because of a congenital anomaly unknown at the time of inclusion.

Tables 2 and 3 compare baseline characteristics and perinatal outcome data of the different Doppler classification groups. The 30 women who delivered before 34 weeks and women with incomplete data were excluded from this comparison. The Abnormal Doppler twice consecutive group differed from the Abnormal Doppler once or intermittent and Never abnormal Doppler groups (Table 2): at inclusion, median EFW was significantly lower (1578 g, IQR 1351–1750 g), growth restriction was more severe, as shown by a significant lower EFW MoM (0.73, IQR 0.65–0.77) and pre-eclampsia was significantly more frequent (n = 27; 24%). PlGF at inclusion was more frequently below 99 and the sFlt-1:PlGF ratio was more frequently above 33 in the Abnormal Doppler twice consecutive group, compared with the two other groups.

TABLE 2. Data at and after inclusion.
Abnormal Doppler twice consecutiveg Abnormal Doppler once or intermittent Never abnormal Doppler All
General demographic and obstetric data
N (%) 115 (17%) 108 (16%) 437 (66%) 660
Maternal age (years) 31 (28–35) 31 (28–34) 31 (28–34) 31 (28–34)
Nulliparous 72 (64%) 53 (51%) 249 (56%) 374 (57%)
Smokingc 11 (11%) 2 (2%) 20 (5%) 33 (6%)
BMI (kg/m2) 23.6 (21.7–26.9) 22.9 (20.5–26.0) 22.8 (20.6–25.5) 22.9 (20.7–26.0)
Gestational diabetes 9 (8%) 7 (7%) 15 (3%) 31 (5%)
Gestational hypertension 14 (12%)b 8 (7%) 16 (4%) 38 (6%)
Pre-eclampsia 27 (24%)a 10 (9%) 32 (7%) 69 (11%)
At inclusion in cohort
Gestational age (weeks+days) 33+6 (32+6–34+6)a 34+3 (33+1–36+0) 34+3 (33+1–35+5) 34+2 (33+1–35+4)
Interval to delivery (days) 17 (10–23) 20 (10–30) 29 (17–39) 25 (14–36)
Interval to delivery <7 days 16 (14%) 15 (14%) 23 (5%)a 54 (8%)
EFW (g) 1578 (1351-1750)a 1777 (1548–2073) 1771 (1590–1979) 1737 (1548-1968)
EFW MoM 0.73 (0.65–0.77)a 0.78 (0.73–0.82) 0.79 (0.75–0.81) 0.78 (0.74–0.81)
Umbilical artery PI 1.32 (1.16–1.51)a 1.10 (0.96–1.23)a 0.93 (0.83–1.04) 1.00 (0.88–1.18)
Umbilical artery PI >90th centile 54 (47%)a 12 (11%) 0 (—) 66 (10%)
Middle cerebral artery PId 1.53 (1.27–1.80) 1.54 (1.32–1.92) 1.79 (1.54–2.09)a 1.72 (1.46–2.00)
Middle cerebral artery PI <5th centiled 42 (38%) 36 (34%) 43 (11%)a 121 (20%)
UCRd 0.88 (0.73–1.02)a 0.68 (0.57–0.83)a 0.52 (0.43–0.61) 0.58 (0.47–0.72)
UCR >0.8d 71 (64%)a 33 (31%) 0 (—) 104 (17%)
ARED flow 2 0 0 2
PlGF ≤99e 58 (62%)a 30 (42%)b 68 (23%) 156 (34%)
PlGF ≤99 (without PE)f 37 (54%)a 22 (36%)b 49 (18%) 108 (27%)
sFlt-1:PlGF ratio >33e 63 (68%)a 37 (52%)b 86 (30%) 186 (40%)
sFlt-1:PlGF ratio >33 (without PE)f 41 (59%)b 28 (45%)b 66 (25%) 135 (34%)
First time abnormal Doppler ≥32 weeks
Gestational age (weeks+days) 33+3 (32+3–34+5)a 35+0 (33+5–36+0)
Interval to delivery (days) 18 (11–28) 17 (10–27)
Interval to delivery <7 days 11 (10%) 17 (16%)
Umbilical artery PI 1.37 (1.19–1.52)a 1.24 (1.19–1.52)
UCR 0.90 (0.81–1.00)a 0.85 (0.81–0.91)
First time second consecutive abnormal Doppler ≥32 weeks
Gestational age (weeks+days) 34+5 (34+0–35+5)
Interval to delivery (days) 9 (4–16)
Interval to delivery <7 days 45 (39%)
UCR 0.95 (0.86–1.11)
  • Note: Abnormal Doppler = umbilical artery pulsatility index above 90th centile or umbilicocerebral ratio >0.8, and EFW below 3rd centile at 32–35 weeks or below 10th centile at 36 weeks. Table shows median (interquartile range) or number (%).
  • Abbreviations: ARED flow, absent or reversed end-diastolic flow in the umbilical artery; BMI: body mass index; EFW, estimated fetal weight; MoM, multiple of the median; PI, pulsatility index; PlGF, placental growth factor; sFlt-1:PlGF ratio, soluble fms-like tyrosine kinase-1; UCR, umbilicocerebral ratio.
  • a Significant difference (p < 0.05) with other two columns.
  • b Significant difference (p < 0.05) with [Never Abnormal Doppler].
  • c 85 missing values.
  • d 47 missing values.
  • e 206 missing values.
  • f 195 missing values.
  • g Including two women with ARED flow.
TABLE 3. Delivery and neonatal data.
Abnormal Doppler twice consecutivee Abnormal Doppler once or intermittent Never abnormal Doppler All
N (%) 115 (17%) 108 (16%) 437 (66%) 660
Delivery
Onset spontaneous, vaginal delivery 6 (5%) 14 (13%) 97 (22%)a 117 (18%)
Onset spontaneous, CS 4 (4%) 2 (2%) 13 (3%) 19 (3%)
Induction, vaginal delivery 51 (44%)a 68 (64%) 244 (56%) 364 (55%)
Induction, CS 34 (30%)a 16 (15%) 40 (9%) 90 (14%)
Primary CS 20 (17%) 7 (7%) 43 (10%) 70 (11%)
Ruptured membranes ≥24 h 3 (3%) 2 (2%) 17 (4%) 22 (3%)
Mode of deliveryd
Vaginal 57 (49%)a 83 (77%) 341 (78%) 481 (73%)
CS 58 (50%)a 25 (23%) 96 (22%) 179 (27%)
Indication for CSd
Fetal condition 36 (62%)a 11 (44%) 27 (28%) 74 (41%)
Labour abnormalb 11 (19%) 7 (28%) 38 (40%) 56 (31%)
Maternal condition 9 (16%)a 2 (8%) 12 (13%) 23 (13%)
Other 2 (3%) 5 (20%) 19 (20%) 26 (15%)
Non-cephalic presentation 17 (15%) 6 (6%) 54 (12%) 77 (12%)
Gestational age (weeks+days) 36+6 (35+3–37+2)a 37+4 (37+0–38+2)a 38+4 (37+5–39+3) 38+0 (37+1–39+0)
Birthweight (g) 1950 (1640–2164)a 2375 (2184–2567)a 2615 (2350–2893) 2488 (2154–2780)
Birthweight MoM 0.66 (0.59–0.72)a 0.76 (0.69–0.82)a 0.79 (0.73–0.84) 0.77 (0.69–0.82)
Male sexd 65 (57%)c 49 (45%) 155 (35%) 267 (41%)
Composite adverse condition at birthd 19 (17%)a 3 (3%) 36 (8%) 58 (9%)
Apgar at 5 min <7 4 (4%) 1 (1%) 10 (2%) 15 (2%)
pH art <7.0 or ven <7.1 1 (1%) 0 (—) 8 (2%) 9 (1%)
Resuscitationd 18 (16%)a 2 (2%) 29 (7%) 49 (7%)
Fetal death 0 (—) 0 (—) 1 (0.00) 1 (0.00)
Composite major neonatal morbidityd 41 (36%)a 22 (20%) 53 (12%) 116 (18%)
Cerebral 5 (4%) 1 (1%) 5 (1%) 11 (2%)
Respiratoryd 14 (12%)c 6 (6%) 24 (6%) 44 (7%)
Mechanical ventilation 6 (5%) 0 (—) 12 (3%) 18 (3%)
Circulation 2 (2%) 2 (2%) 5 (1%) 9 (1%)
Infectiousd 8 (7%)c 2 (2%) 7 (2%) 17 (3%)
Metabolicd 31 (27%)c 16 (15%) 32 (7%) 79 (12%)
Neonatal death <28 days 1 (0.9%) 0 (—) 1 (0.2%) 2 (0.3%)
Congenital anomaly 5 (4%) 2 (2%) 3 (1%) 10 (2%)
Composite adverse perinatal outcomed 50 (44%)a 23 (21%) 69 (16%) 142 (22%)
Composite adverse perinatal outcome after exclusion of imminent delivery groupd 38 (39%)a 23 (21%) 69 (16%) 130 (20%)
Neonatal hospital days 11 (4–20)a 3 (2–6)a 2 (2–3) 3 (2–5)
Maternal hospital days 4 (3–5)a 3 (2–4)a 2 (2–3) 3 (2–4)
  • Note: Abnormal Doppler = umbilical artery pulsatility index above the 90th centile or umbilicocerebral ratio>0.8, and estimated fetal weight below the 3rd centile at 32–35 weeks or below the 10th centile at 36 weeks. Table shows median (interquartile range) or number (%).
  • Abbreviation: CS, caesarean section.
  • a Difference with both other columns p < 0.05.
  • b Including breech presentation.
  • c Difference with group Never abnormal Doppler, p < 0.05.
  • d Pearson chi-square test, p < 0.05.
  • e Including two women with absent or reversed end-diastolic flow in the umbilical artery.

At delivery, gestational age, birthweight and birthweight MoM were significantly lower in the Abnormal Doppler twice consecutive group, and delivery was more often by CS, compared with the other two groups (Table 3). The composite adverse perinatal outcomes were significantly worse in the Abnormal Doppler twice consecutive group compared with the other groups, with significantly longer hospitalisation after delivery for both infant and mother. These differences remained significant after a sensitivity analysis that excluded the immediate delivery group from the total Abnormal Doppler twice consecutive group, in which composite adverse perinatal outcome was more frequent than in the expectant management group (Table 3).

Figure 2 shows the forest plot of the odds ratios for the composite adverse perinatal outcome. The logistic regression analysis showed that EFW MoM at inclusion, pre-eclampsia, gestational hypertension and study group classification were significantly associated with the composite adverse perinatal outcome, with an AUC in a ROC graph of 0.71 (95% CI 0.67–0.76) (Figure 2).

Details are in the caption following the image
Forest plot of the odds ratios for a composite abnormal infant outcome, calculated by logistic regression analysis. The odds ratio for the EFW MoM is calculated per 0.1 MoM. Area under the curve of a receiver operating characteristic curve 0.71 (95% confidence interval 0.67–0.76). EFW, estimated fetal weight; MoM, multiple of the median.

4 DISCUSSION

4.1 Main findings

In this SGA cohort, an abnormal UCR was significantly associated with a higher incidence of short-term perinatal adverse outcomes, meaning that this can be a useful tool to discriminate between constitutional SGA and FGR needing surveillance and timing of delivery. It is unlikely that imminent delivery based on an abnormal UCR results in better outcomes. However, the randomised trial was halted prematurely because of low inclusion rates in the RCT and therefore the study did not reach the required sample size, and also the study was not powered for this outcome.

Most eligible women who elected not to be randomised favoured expectant management. As a result of this, perinatal outcome was similar between women in the RCT, who were allocated to delayed delivery, and women who were eligible, but refused randomisation.

The expectant management group showed near significant better short-term outcomes compared with the immediate delivery group. The higher median birthweight in the expectant management group showed that infants in this group gained on average 275 g in the 13 additional days of gestation (and hence maturation) compared with the immediate delivery group. Although obviously underpowered for definitive statements, in a post-hoc power calculation, there is more than a 90% chance that immediate delivery is associated with increased composite adverse perinatal outcome. This result resonates with previous calls to caution translation of associations into interventions,30 and that earlier delivery to avoid hypoxia may be protective of hypoxia, but that this benefit may be outweighed by the burden of prematurity.6 Clinicians should refrain from immediate delivery unless in the context of clinical trials. The effects on long-term neurodevelopmental outcome (on which the study sample size was designed) will be reported in due time, although this analysis may be hampered by the small sample size.

The selection criteria based on EFW centiles with abnormal Doppler were effective in selecting those fetuses with the highest risk for composite adverse perinatal outcome. Our findings are in line with numerous observations of the associations between abnormal fetal MCA Doppler and adverse outcomes in large meta-analyses of mostly retrospective studies and recent (semi-)prospective studies.12 This result therefore supports the common conception, distilled in the Delphi consensus definition (adopted by the International Society of Ultrasound in Obstetrics and Gynecology and FIGO), that an abnormal UCR indicates the perinatal risks of abnormal placental function.9

Fetuses in the Abnormal Doppler twice consecutive group gained less weight after inclusion than in the other two groups. In this group the fetal growth restriction became worse, as shown by a lower birthweight MoM than the EFW MoM at inclusion, whereas there was no change of weight MoM in the group with never abnormal Doppler. This aligns with other recent observations that fetuses that appear to have decreasing growth velocity are at risk of adverse perinatal outcome.31, 32

Baseline characteristics of women in the cohort with an abnormal Doppler once, or intermittent, were more similar to those who never had an abnormal Doppler. This supports the strategy that Doppler results should be checked for consistency to confirm abnormality.33 Furthermore, it should be noted that also fetuses who never showed an abnormal Doppler may still develop perinatal complications, as in the case of serious asphyxia during labour at 40 weeks in this group. Although that outcome is not restricted to SGA fetuses and might occur in appropriate for gestational age (AGA) fetuses too, the fair amount of composite adverse perinatal outcome in this group suggests that watchful monitoring of women with a small fetus remains necessary, even when Doppler results are normal. Nonetheless, these cohort data suggest that provider-initiated delivery before 40 weeks may not be necessary, in contrast with the pragmatic conclusions of the previous DIGITAT trial.34

4.2 Strengths and limitations

Although this study was the first to report the UCR in third-trimester SGA fetuses in a randomised intervention trial, a limitation was that the study was halted before the planned sample size was reached because of low inclusion rates. First, preparedness among physicians, patients and their partners to participate proved to be limited. Moreover, this study was recruiting during the COVID-19 pandemic and its aftermath with restricted options for laboratory study sampling, staff shortages and the resulting increased workload, hampering inclusion rates. Because of the insufficient sample size, no definite conclusions on the primary study question could be drawn.

Another limitation is that we focused on SGA (EFW or FAC below the 10th centile) and pragmatically defined suspected FGR by an abnormal UCR or UmbA PI >90th centile. This disregards the fact that with abnormal fetal Doppler measurements but an EFW or FAC above the 10th centile FGR may be present, as highlighted in the Delphi Consensus definition.9, 35 Women with AGA fetuses with suspected FGR were not included and classification of FGR could be more accurate if AGA fetuses with a decline in fetal growth velocity and abnormal Doppler had also been included. Moreover, practice variation between different physicians in the performance of Doppler measurements might have occurred based on the experience of the physician performing the measurement.

The results might have been influenced by intervention bias, as the Doppler measurements were not blinded.6 Physicians might possibly have increased the monitoring frequency and adjusted the timing of delivery of participants with abnormal Doppler results. Also, outcomes may have shifted based on protocol management, also known as the Hawthorne effect.36, 37

A strength of this prospective multicentre cohort study is the sample size with complete data for 690 late preterm SGA pregnancies that were prospectively monitored with repeated biometry and Doppler ultrasound scans during the course of pregnancy.

Future studies should focus on further improved diagnosis of FGR by the combination of serial ultrasound of fetal size and Doppler in combination with maternal serum biomarkers (identified or novel; single time-point and/or serial). In this paper, we only described abnormal biomarkers at baseline. The predictive value of biomarkers will be further studied in subsequent analyses. Additionally, placental pathology may reveal if differences between underlying placental lesions are reflected in different SGA and FGR phenotypes. Some of these questions will be answered in secondary analyses of the DRIGITAT dataset, exploring associations of biomarkers and placental pathology with clinical variables. In addition, the results of the TRUFFLE2 and RATIO37 RCT investigating similar hypotheses are eagerly awaited.38, 39 The RCT data of DRIGITAT will also be made available for individual patient data meta-analysis with relevant other developing datasets.38, 39 In those larger datasets, it can also be studied if subpopulations of gestational age categories or extent of fetal size abnormality have different benefit/harm ratios from early delivery.

5 CONCLUSIONS

Selection criteria based on EFW centiles and abnormal Doppler were effective in selecting those with the highest risk for composite adverse perinatal outcome in a cohort with late preterm SGA. This and subsequent analyses of these data may allow guidance of the clinical application of these monitoring parameters. This study could not answer the research question of whether early delivery improves perinatal outcomes. Our interpretation is that it is unlikely that fetuses that are SGA and show haemodynamic redistribution will benefit from early delivery at 34 up to 36+6 weeks.

AUTHOR CONTRIBUTIONS

WG and SJG designed the study and applied for funding. SED, MS and MCM performed trial management and data cleaning. MCM and HW were responsible for data analyses. MCM and HW drafted the manuscript. All authors interpreted data, contributed to the writing of the manuscript, reviewed drafts and approved the final draft of the manuscript.

ACKNOWLEDGEMENTS

We acknowledge the valuable contributions of patient organisations Hellp stichting and Care4Neo (Vereniging van Ouders Couveusekinderen) and of the employees in the participating centres in this multicentre study. We acknowledge Christoph Lees (Professor of Obstetrics at Imperial College London, UK) for his involvement in the funding application. We used the CONSORT checklist when writing our report.40

    FUNDING INFORMATION

    The DRIGITAT study was funded by ZonMw (The Netherlands organisation for health research and development), reference number 843002825. ZonMW has provided funds to perform the study according to the predefined plan.16 It had no role or authority in any of the trial activities. Roche Diagnostics International Ltd supported the study by the unconditional in-kind provision of sample kits for biomarker analyses.

    CONFLICT OF INTEREST STATEMENT

    None declared.

    ETHICS APPROVAL

    Initial ethical board approval for the execution of this trial was obtained from the medical research ethics committee of the Amsterdam UMC—location AMC on 18 January 2018 (NL62923.018.17). Written, informed consent to participate was obtained from all participants. The trial was registered in the Netherlands Trial Register, registration number NTR6663, on 14 August 2017.

    APPENDIX 1

    DRIGITAT Trial Group: Jelle M. Schaaf (Department of Obstetrics and Gynaecology, Flevo Hospital, Almere, The Netherlands); Marjon A. de Boer (Department of Obstetrics and Gynaecology, Amsterdam University Medical Centres, Amsterdam, The Netherlands); Joost J. Zwart (Department of Obstetrics and Gynaecology, Deventer Hospital, Deventer, The Netherlands); Anjoke J. M. Huisjes (Department of Obstetrics and Gynaecology, Gelre Hospital, Apeldoorn, The Netherlands); Jan H. W. Veerbeek (Department of Obstetrics and Gynaecology, Diakonessenhuis, Utrecht, The Netherlands); Judith O. E. H. van Laar (Department of Obstetrics and Gynaecology, Máxima Medical Centre, Eindhoven, The Netherlands); Salwan Al-Nasiry (Department of Obstetrics and Gynaecology, Maastricht UMC+, Maastricht, The Netherlands); Henk A. Bremer (Department of Obstetrics and Gynaecology, Reinier de Graaf Hospital, Delft, The Netherlands); Brenda B. J. Hermsen (Department of Obstetrics and Gynaecology, OLVG, Amsterdam, The Netherlands); Hedwig P. van de Nieuwenhof (Department of Obstetrics and Gynaecology, Jeroen Bosch Hospital, 's Hertogenbosch, The Netherlands); Marieke Sueters (Department of Obstetrics and Gynaecology, Leiden University Medical Centre, Leiden, The Netherlands); David P. van der Ham (Department of Obstetrics and Gynaecology, Martini Hospital, Groningen, The Netherlands), Marinka S. Post (Department of Obstetrics and Gynaecology, Medical Centre Leeuwarden, Leeuwarden, The Netherlands); Arjanne J. Kroese (Department of Obstetrics and Gynaecology, Medisch Spectrum Twente, Enschede, The Netherlands); Jan B. Derks (Department of Obstetrics and Gynaecology, University Medical Centre Utrecht, Utrecht, The Netherlands); Marko J. Sikkema (Department of Obstetrics and Gynaecology, Ziekenhuisgroep Twente, Almelo, The Netherlands); Jan Willem de Leeuw (Department of Obstetrics and Gynaecology, Ikazia Hospital, Rotterdam, The Netherlands).

    DATA AVAILABILITY STATEMENT

    The data that support the findings of this study are available from the corresponding author upon reasonable request.