Ultrasound Obstet Gynecol 2015; 46: 460–464 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.14758
Are fetuses that fail to achieve their growth potential at increased risk of intrapartum compromise? T. PRIOR*†, G. PARAMASIVAM*, P. BENNETT*† and S. KUMAR*†‡ *Centre for Fetal Care, Queen Charlotte’s and Chelsea Hospital, London, UK; †Institute for Reproductive and Developmental Biology, Imperial College London, London, UK; ‡Mater Research Institute/University of Queensland, South Brisbane, Queensland, Australia
K E Y W O R D S: cerebroplacental ratio; cerebro-umbilical ratio; fetal Doppler; growth potential
ABSTRACT Objective The true growth potential of a fetus is difficult to predict but recently a new definition, independent of fetal weight, using cerebroplacental (cerebro-umbilical) ratio (CPR) < 0.6765 multiples of the median (MoM), was reported. We applied this definition to a cohort of low-risk pregnancies recruited prospectively to determine if fetuses with CPR < 0.6765 are at increased risk of developing signs of intrapartum fetal compromise. Methods Recruitment to this prospective observational study took place between March 2011 and March 2014. All women with low-risk singleton pregnancies at term were eligible. Women with known or suspected placental dysfunction were excluded, as were women with fetuses with an estimated fetal weight < 10th centile. All participants underwent ultrasound examination prior to active labor (≤ 4 cm cervical dilatation), during which fetal biometry as well as umbilical artery and fetal middle cerebral artery blood flow were assessed. Following delivery, intrapartum and neonatal outcomes were compared between fetuses that had a CPR < 0.6765 MoM and those that had a CPR ≥ 0.6765 MoM. Results In total, 775 women were recruited. Fetuses with CPR < 0.6765 MoM were significantly more likely to require Cesarean delivery because of presumed fetal compromise (P < 0.001). These fetuses were also at increased risk of compromise at any time during labor and were less likely to be delivered vaginally, spontaneously or otherwise, than were those with CPR ≥ 0.6765 MoM. CPR < 0.6765 MoM gave a positive predictive value (PPV) for Cesarean delivery because of presumed fetal compromise of 36.7% and a negative predictive value of 88.7%, with a sensitivity of 18% and a specificity of 95.4%.
Conclusion Fetuses that failed to achieve their growth potential (defined as CPR < 0.6765 MoM) were at increased risk of intrapartum compromise and were less likely to be delivered vaginally. However, a low negative predictive value was observed for fetal compromise and further studies are required to support the translation of this technique into clinical practice. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
INTRODUCTION A growing body of work suggests that, amongst fetuses reaching a birth weight considered appropriate for gestational age, there exists a cohort with evidence of relatively altered umbilical and cerebral blood flow and evidence that these fetuses may be at increased risk of developing fetal compromise during labor1 – 3 . As true fetal growth potential is difficult to predict4 , clinicians generally accept an estimated fetal weight (EFW) < 10th centile to define small-for-gestational age (SGA), with concurrent abnormalities in umbilical artery blood flow required to diagnose fetal growth restriction (FGR). However, this classification is somewhat arbitrary as it fails to identify growth-restricted fetuses whose EFW, whilst > 10th centile, is not consistent with their growth potential. The distinction between SGA and FGR is important as, whilst both are associated with increased incidence of adverse neonatal outcome, the risk is more marked in fetuses for which alterations in fetal hemodynamics are present5 . It has been suggested that alterations in cerebral and umbilical blood flow associated with FGR are an adaptive response to suboptimal placental function6 , occurring prior to subsequent deterioration in growth velocity. Furthermore, in the presence of uterine contractions,
Correspondence to: Prof. S. Kumar, Mater Research Institute, University of Queensland, Level 3, Aubigny Place, Raymond Terrace, South Brisbane, Queensland 4101, Australia (e-mail: [email protected]) Accepted: 4 December 2014
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
ORIGINAL PAPER
Growth potential and fetal compromise growth-restricted fetuses undergo further acute cerebral redistribution7,8 . Our group has observed that fetuses with relatively increased cerebral blood flow, despite having grown appropriately, are at increased risk of fetal compromise during labor, of developing a pathological fetal heart rate pattern and of requiring emergency operative delivery because of presumed fetal compromise1 . Furthermore, cerebral redistribution, whilst considered protective in utero, has been found to be associated with adverse long-term neurological outcomes9 . Even in appropriately grown fetuses, cerebral redistribution is associated with subsequent reduced performance in neurobehavioral testing10 . Recently, Morales-Rosello´ et al. suggested that ‘failure to reach growth potential’ can be defined as a cerebroplacental ratio (CPR) < 0.6765 multiples of the median (MoM)11 . The CPR, which can also be referred to as the cerebro-umbilical ratio1 , denotes the ratio of the middle cerebral artery pulsatility index (MCA-PI) to the umbilical artery pulsatility index (UA-PI). In this study, we apply this new definition to a cohort of prospectively recruited, low-risk term fetuses, in which the CPR was assessed prior to the active phase of labor. The aim was to evaluate the use of this new definition as a predictor of subsequent intrapartum fetal compromise.
METHODS This was a prospective observational study carried out over a 2-year period between March 2011 and March 2014. Participants were recruited at Queen Charlotte’s and Chelsea Hospital, London, a tertiary referral maternity unit with a birth rate in excess of 6000 per year. Participants were approached in early labor (≤ 4 cm cervical dilatation) or immediately prior to induction of labor. Of the potential participants undergoing induction of labor, only those with an indication for induction of postdates pregnancy (with gestational age < 42 weeks) or those for whom induction had been planned for social reasons were included. Maternal demographic and pregnancy data for all participants, including age, ethnicity, gestational age and body mass index, were collected. Exclusion criteria included: known FGR (EFW < 10th centile with UA-PI > 95th centile), known SGA (EFW < 10th centile), known fetal anomaly, maternal hypertensive disease/pre-eclampsia, multiple pregnancy, cervical dilatation > 4 cm, ruptured membranes with meconium-stained amniotic fluid or evidence of intrauterine infection. Recruited participants were provided with an information sheet and informed written consent for inclusion in the study was recorded. All participants underwent ultrasound assessment, during which fetal biometry, umbilical and middle cerebral artery Doppler and amniotic fluid volume were assessed. The target population was therefore women with uncomplicated term pregnancy who would deliver within 72 hours of recruitment. Ethical approval for the study
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
461
was granted by the London Research Ethics Committee (Ref No: REC 10/H0718/26). The method of ultrasound assessment has been reported previously1,2 . All assessments were performed by a single trained individual using a portable GE Voluson ultrasound machine (GE Healthcare Ultrasound, Milwaukee, WI, USA) with an AB2-7-RS curvilinear transabdominal transducer. Participants were examined in a supine position, with the head of the bed elevated to 45◦ to prevent aortocaval compression. All measurements were taken in triplicate, with the mean of these used for subsequent data analysis. Doppler waveforms were acquired from all vessels with an angle of acquisition as close to 0◦ as possible and always < 30◦ . The angle correction tool was used to adjust for any angle of acquisition that was not 0◦ . Doppler waveforms were not acquired during fetal breathing or during uterine contractions. The CPR was calculated as a ratio of the MCA-PI to the UA-PI and MoM was calculated using the formula described by Morales-Rosello´ et al.11 . Intrapartum outcomes including mode of and indication for delivery, incidence of cardiotocography recordings considered pathological according to National Institute for Health and Care Excellence (NICE) criteria and the presence of meconium-stained amniotic fluid were compared between cases with a CPR < 0.6765 MoM and those with a CPR ≥ 0.6765 MoM. Neonatal outcomes, including Apgar score, umbilical artery pH at delivery and neonatal unit admission were also compared between the two groups. In all cases the diagnosis of intrapartum compromise was made contemporaneously by the obstetricians managing labor and was based on abnormal fetal heart rate patterns, fetal blood sampling or both. In our institution all cases of Cesarean delivery because of presumed fetal compromise are reviewed by two senior obstetricians. All obstetricians making decisions regarding delivery are blinded to ultrasound findings.
RESULTS A total of 775 women were recruited to the study. All women delivered live infants and delivery was within 72 hours of ultrasound assessment in 96.1% of cases (745/775). Mode of delivery and maternal demographics for all study participants are documented in Table 1. When cases were divided according to a CPR < 0.6765 MoM or a CPR ≥ 0.6765 MoM, fetuses with a CPR < 0.6765 MoM were found to be at a significantly increased risk of Cesarean delivery because of fetal distress (P < 0.001), with a relative risk above three. These fetuses were also at increased risk of fetal compromise at any time during labor, and less likely to be delivered vaginally, spontaneously or otherwise, than those with a CPR ≥ 0.6765 MoM. Furthermore, fetuses with a CPR < 0.6765 MoM were more likely to be diagnosed with a pathological heart rate pattern and meconium-stained amniotic fluid during labor was
Ultrasound Obstet Gynecol 2015; 46: 460–464.
Prior et al. Data are given as n (%), mean [range] or median (range). *P-values were determined using ANOVA or chi-square test. BMI, body mass index; FD, fetal distress; FTP, failure to progress; CS, Cesarean section; SVD, spontaneous vaginal delivery.
0.99 0.97 100 (84.7) 18 (15.3) 82 (82.0) 18 (18.0) 638 (82.3) 137 (17.7)
123 (81.5) 28 (18.5)
233 (82.3) 50 (17.7)
100 (81.3) 23 (18.7)
0.37 0.29 0.006 0.80 77 (65.3) 24 (20.3) 14 (11.9) 3 (2.5) 54 (54.0) 22 (22.0) 18 (18.0) 6 (6.0) 531 (68.5) 132 (17.0) 79 (10.2) 33 (4.3)
111 (73.5) 28 (18.5) 6 (4.0) 6 (4.0)
200 (70.7) 37 (13.1) 33 (11.7) 13 (4.6)
89 (72.4) 21 (17.1) 8 (6.5) 5 (4.1)
< 0.001 0.14 0.07 < 0.001 112 (94.9) 33.5 [22–46] 25 (18–40) 41.1 (37.0–42.0) 113 (91.9) 32.1 [18–43] 24 (16–41) 41.4 (37.0–42.0) 95 (95.0) 32.0 [18–43] 25 (19–42) 41.4 (37.7–42.0)
Primiparous Maternal age (years) BMI (kg/m2 ) Gestational age (weeks) Ethnicity Caucasian Asian Afro-Caribbean Other Mode of onset of labor Induction Spontaneous
626 (80.8) 32.4 [16–47] 24 (16–43) 41 (37.0–42.0)
142 (94.0) 32.7 [16–45] 24 (18–35) 40.8 (37.0–42.0)
163 (57.6) 32.1 [18–47] 24 (17–43) 40.7 (37.0–42.0)
Emergency CS: other (n = 118) Characteristic
Overall (n = 775)
Emergency CS: FD (n = 100)
Instrumental: FD (n = 151)
Delivery
Table 1 Maternal demographics according to mode-of-delivery group in 775 low-risk singleton pregnancies
SVD (n = 283)
Instrumental: FTP (n = 123)
P*
462
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
more likely to be present (Table 2). No significant differences in maternal demographic characteristics were found between the two groups (Table 3). In this cohort, a CPR < 0.6765 MoM gave a positive predictive value for Cesarean delivery because of presumed fetal compromise of 36.7% and a negative predictive value of 88.7%, with a sensitivity of 18% and a specificity of 95.4%. Neonatal outcome variables were also examined (Table 4). Fetuses with a CPR ≥ 0.6765 MoM had a greater birth weight and birth-weight centile. Mean CPR-MoM values were compared among cases grouped according to birth-weight centile (Table 5). Neonates with the highest birth-weight centile correspondingly had the highest CPR-MoM values, with a trend toward decreasing CPR-MoM values as the birth-weight centile decreased. This finding was significant when compared using one-way ANOVA (P < 0.001). No significant differences were observed in the other neonatal outcome variables.
DISCUSSION Following the publication by Morales-Rosello´ et al. that defines a fetus as failing to achieve its growth potential if the CPR is < 0.6765 MoM11 , we sought to investigate whether use of this definition could improve identification of fetuses at risk of developing fetal compromise during labor. We applied this cut-off to a prospectively recruited cohort of low-risk term pregnancies, comparing intrapartum and neonatal outcomes between fetuses with a CPR < 0.6765 MoM and CPR ≥ 0.6765 MoM. Significant variations in the incidence of Cesarean section because of presumed fetal compromise, abnormal fetal heart rate patterns and the incidence of meconium-stained amniotic fluid during labor were found between the groups. Fetuses to whom the Morales-Rosello´ et al.11 definition of ‘failure to meet growth potential’ applies were more than three times more likely to require Cesarean delivery because of presumed fetal compromise. These results support the notion that a reduction in placental function, even in appropriately grown fetuses, may be evidenced by changes in fetal hemodynamics. The degree of alteration in fetoplacental blood flow that should be considered abnormal remains a matter for consideration. Interestingly, the use of a cut-off of < 0.6765 MoM as suggested by Morales-Rosello´ et al.11 yields a similar positive predictive value for Cesarean section because of presumed fetal compromise as reported in our original study, in which a CPR cut-off < 10th centile was used1 (36.2% vs 36.4%). However, use of a single cut-off value to denote high- and low-risk groups does not result in a high negative predictive value, as more than 10% of fetuses with a CPR ≥ 0.6765 MoM in the study cohort still required delivery by emergency Cesarean section because of presumed fetal compromise. It should be noted that the cut-off reported by Morales-Rosello´ et al. was derived in a cohort with an examination-to-delivery interval < 14 days, whilst in the
Ultrasound Obstet Gynecol 2015; 46: 460–464.
Growth potential and fetal compromise
463
Table 2 Intrapartum outcome according to cerebroplacental ratio (CPR) group in 775 low-risk singleton pregnancies CPR Delivery category Cesarean section for fetal compromise Fetal compromise diagnosed at any time during labor Spontaneous vaginal delivery Vaginal delivery of any kind Cesarean section: other Pathological FHR patterns Meconium-stained AF
Overall (n = 775)
< 0.6765 MoM (n = 49)
≥ 0.6765 MoM (n = 726)
100 (12.9)
18 (36.7)
82 (11.3)
< 0.001
3.25 (2.14–4.95)
251 (32.4)
29 (59.2)
222 (30.6)
< 0.001
1.94 (1.50–2.50)
283 (36.5) 557 (71.9) 118 (15.2) 154 (19.9) 76 (12.6)†
8 (16.3) 24 (49.0) 7 (14.3) 20 (40.8) 11 (22.4)
275 (37.9) 533 (73.4) 111 (15.3) 134 (18.5) 83 (11.4)
0.02 0.05 0.86 < 0.001 0.03
0.43 (0.23–0.82) 0.67 (0.50–0.89) 1.00 (0.49–2.02) 2.21 (1.53–3.20) 1.96 (1.12–3.43)
Relative risk (95% CI)
P*
Data are given as n (%). *P-values were determined using chi-square test. †Data available for only 604. AF, amniotic fluid; FHR, fetal heart rate; MoM, multiples of the median.
Table 3 Maternal demographics according to cerebroplacental ratio (CPR) group in 775 low-risk singleton pregnancies CPR Characteristic Primiparous Maternal age (years) BMI (kg/m2 ) Gestational age (weeks) Ethnicity Caucasian Asian Afro-Caribbean Other Mode of onset of labor Induction Spontaneous
Overall (n = 775)
< 0.6765 MoM (n = 49)
≥ 0.6765 MoM (n = 726)
P*
626 (80.8) 32.4 [16–47] 24 (16–43) 41 (37.0–42.0)
46 (93.9) 32.8 [18–43] 25.2 (18–40) 40.5 (37–42)
580 (79.9) 32.4 [16–47] 24.9 (16–43) 40.5 (37–42)
0.29 0.28 0.35 0.76
531 (68.5) 132 (17.0) 79 (10.2) 33 (4.3)
35 (71.4) 6 (12.2) 5 (10.2) 3 (6.1)
496 (68.3) 126 (17.4) 74 (10.2) 30 (4.1)
0.80 0.41 0.99 0.51
638 (82.3) 137 (17.7)
35 (71.4) 14 (28.6)
603 (83.1) 123 (16.9)
0.39 0.06
Data are given as n (%), mean [range] or median (range). *P-values were determined using ANOVA or chi-square test. BMI, body mass index; MoM, multiples of the median.
Table 4 Neonatal outcome according to cerebroplacental ratio (CPR) group in 775 low-risk singleton pregnancies CPR Characteristic Birth weight (g) Birth-weight centile Apgar score < 7 at 1 min Apgar score < 7 at 5 min Cord arterial pH < 7.20 Base excess < 8 mmol/L Neonatal unit admission Neonatal encephalopathy Composite neonatal outcome score
Overall (n = 775)
< 0.6765 MoM (n = 49)
≥ 0.6765 MoM (n = 726)
P*
Relative risk (95% CI)
3522 [1780–5062] 52.5 (1–100) 62 (8.0) 10 (1.3) 236 (30.5) 170 (21.9) 14 (1.8) 0 (0) 0.75 [0–7]
3354 [1780–4246] 43.9 (1–98) 3 (6.1) 1 (2.0) 13 (26.5) 10 (20.4) 1 (2.0) 0 (0) 0.69 [0–4]
3535 [2360–5062] 53.1 (1–100) 59 (8.1) 9 (1.2) 223 (30.7) 160 (22.0) 13 (1.8) 0 (0) 0.75 [0–7]
0.009 0.03 0.63 0.63 0.61 0.81 0.90 — 0.71
— — 0.80 (0.26–2.47) 1.76 (0.23–13.60) 0.92 (0.57–1.49) 0.99 (0.56–1.75) 1.22 (0.16–9.11) — —
Data are given n (%), mean [range] or median (range). *P-values were determined using ANOVA or chi-square test. MoM, multiples of the median.
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
Ultrasound Obstet Gynecol 2015; 46: 460–464.
Prior et al.
464 Table 5 Cerebroplacental ratio (CPR) according to birth-weight centile group in 775 low-risk singleton pregnancies
Birth-weight centile 0–9th 10th –19th 20th –29th 30th –39th 40th –49th 50th –59th 60th –69th 70th –79th 80th –89th 90th –100th
n
Mean CPR-MoM
55 68 85 83 79 82 62 87 63 111
0.93 0.91 1.03 1.05 1.06 1.08 1.03 1.07 1.08 1.14
MoM, multiples of the median. Trend for increasing CPR with birth-weight centile, tested using ANOVA, P < 0.001.
present study this interval was < 72 hours in over 95% of cases. Further investigation of this emerging technique with a large prospective study is likely to be required to establish optimal discriminatory values delineating highand low-risk populations. Neonates with the greatest birth-weight centile were found to have had significantly higher CPRs than those with lower birth-weight centiles. This finding supports those of our previous publications, suggesting that the CPR may be used as a surrogate marker of placental function, even in a low-risk cohort of appropriately grown fetuses. Recently published results of the PORTO study12 confirm that the CPR is predictive of adverse perinatal outcome in a growth-restricted cohort. The results of our study, and those of Morales-Rosello´ et al.11 , suggest that this technique may have clinical application in a low-risk cohort. Given these interesting results, the CPR may be a suitable addition to the EFW in monitoring both high- and low-risk pregnancies. Recently published data suggest that the CPR better correlates with neonatal umbilical artery pH than does birth weight13 . Whilst it has been reported that SGA fetuses, without Doppler evidence of placental dysfunction, are still at increased risk of adverse neurodevelopmental outcome14 , cases are frequently classified as SGA as opposed to FGR on the basis of umbilical artery Doppler only. However, Savchev et al. examined intrapartum outcomes in SGA fetuses with normal Doppler findings (including a CPR > 5th centile) and found that, despite normal fetal hemodynamics, cases with an EFW < 3rd centile were still at increased risk of Cesarean section because of non-reassuring fetal status15 . It is likely that a combination of EFW and CPR may improve the identification of ‘at risk’ fetuses throughout
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
the antenatal period, but also immediately prior to labor. The development of a risk score, to predict the likelihood of intrapartum fetal compromise or the need for emergency operative delivery, could improve intrapartum management and facilitate appropriate decision-making. Towards this aim, further large prospective studies are necessary to refine discriminatory values and support the translation of this technique into clinical practice.
ACKNOWLEDGMENTS T.P. was funded by Moonbeam Trust (Charity No. 1110691). All authors were funded by the Imperial College Healthcare NHS Trust comprehensive Biomedical Research Centre (BRC) scheme.
REFERENCES 1. Prior T, Mullins E, Bennett P, Kumar S. Prediction of intrapartum fetal compromise using the cerebroumbilical ratio: a prospective observational study. Am J Obstet Gynecol 2013; 208: 124.e1–6. 2. Prior T, Mullins E, Bennett P, Kumar S. Umbilical venous flow rate in term fetuses: can variations in flow predict intrapartum compromise? Am J Obstet Gynecol 2014; 210: 61.e1–8. 3. Prior T, Mullins E, Bennett P, Kumar S. Prediction of fetal compromise in labor. Obstet Gynecol Clin North Am 2014; 123: 1263–1271. 4. Deter RL, Lee W, Sangi-Haghpeykar H, Tarca AL, Yeo L, Romero R. Individualized fetal growth assessment: critical evaluation of key concepts in the specification of third trimester size trajectories. J Matern Fetal Neonatal Med 2014; 27: 543–551. 5. O’Dwyer V, Burke G, Unterscheider J, Daly S, Geary MP, Kennelly MM, McAuliffe FM, O’Donoghue K, Hunter A, Morrison JJ, Dicker P, Tully EC, Malone FD. Defining the residual risk of adverse perinatal outcome in growth-restricted fetuses with normal umbilical artery blood flow. Am J Obstet Gynecol 2014; 211: 420.e1–5. 6. Baschat DAA. Fetal responses to placental insufficiency: an update. BJOG 2004; 111: 1031–1041. 7. Li H, Gudmundsson S, Olofsson P. Acute centralization of blood flow in compromised human fetuses evoked by uterine contractions. Early Hum Dev 2006; 82: 747–752. 8. Fu J, Olofsson P. Intracerebral regional distribution of blood flow in response to uterine contractions in growth-restricted human fetuses. Early Hum Dev 2007; 83: 607–612. 9. Roza SJ, Steegers EAP, Verburg BO, Jaddoe VWV, Moll HA, Hofman A, Verhulst FC, Tiemeier H. What Is Spared by Fetal Brain-Sparing? Fetal Circulatory Redistribution and Behavioral Problems in the General Population. Am J Epidemiol 2008; 168: 1145–1152. 10. Mula R, Savchev S, Parra M, Arranz A, Botet F, Costas-Moragas C, Gratacos E, Figueras F. Increased fetal brain perfusion and neonatal neurobehavioral performance in normally grown fetuses. Fetal Diagn Ther 2013; 33: 182–188. 11. Morales-Rosello´ J, Khalil A, Morlando M, Papageorghiou A, Bhide A, Thilaganathan B. Changes in fetal Doppler indices as a marker of failure to reach growth potential at term. Ultrasound Obstet Gynecol 2014; 43: 303–310. 12. Flood K, Unterscheider J, Daly S, Geary MP, Kennelly MM, McAuliffe FM, O’Donoghue K, Hunter A, Morrison JJ, Burke G, Dicker P, Tully EC, Malone FD. The role of brain sparing in the prediction of adverse outcomes in intrauterine growth restriction: results of the multicenter PORTO Study. Am J Obstet Gynecol 2014; 211: 288.e1–5. 13. Morales-Rosello´ J, Khalil A, Morlando M, Bhide A, Papageorghiou A, Thilaganathan B. Poor neonatal acid–base status in term fetuses with low cerebroplacental ratios. Ultrasound Obstet Gynecol 2015; 45: 156–161. 14. Savchev S, Sanz-Cortes M, Cruz-Martinez R, Arranz A, Botet F, Gratacos E, Figueras F. Neurodevelopmental outcome of full-term small-for-gestational-age infants with normal placental function. Ultrasound Obstet Gynecol 2013; 42: 201–206. 15. Savchev S, Figueras F, Cruz-Martinez R, Illa M, Botet F, Gratacos E. Estimated weight centile as a predictor of perinatal outcome in small-for-gestational-age pregnancies with normal fetal and maternal Doppler indices. Ultrasound Obstet Gynecol 2012; 39: 299–303.
Ultrasound Obstet Gynecol 2015; 46: 460–464.
Are fetuses that fail to achieve their growth potential at increased risk of intrapartum compromise? T. PRIOR*†, G. PARAMASIVAM*, P. BENNETT*† and S. KUMAR*†‡ *Centre for Fetal Care, Queen Charlotte’s and Chelsea Hospital, London, UK; †Institute for Reproductive and Developmental Biology, Imperial College London, London, UK; ‡Mater Research Institute/University of Queensland, South Brisbane, Queensland, Australia
K E Y W O R D S: cerebroplacental ratio; cerebro-umbilical ratio; fetal Doppler; growth potential
ABSTRACT Objective The true growth potential of a fetus is difficult to predict but recently a new definition, independent of fetal weight, using cerebroplacental (cerebro-umbilical) ratio (CPR) < 0.6765 multiples of the median (MoM), was reported. We applied this definition to a cohort of low-risk pregnancies recruited prospectively to determine if fetuses with CPR < 0.6765 are at increased risk of developing signs of intrapartum fetal compromise. Methods Recruitment to this prospective observational study took place between March 2011 and March 2014. All women with low-risk singleton pregnancies at term were eligible. Women with known or suspected placental dysfunction were excluded, as were women with fetuses with an estimated fetal weight < 10th centile. All participants underwent ultrasound examination prior to active labor (≤ 4 cm cervical dilatation), during which fetal biometry as well as umbilical artery and fetal middle cerebral artery blood flow were assessed. Following delivery, intrapartum and neonatal outcomes were compared between fetuses that had a CPR < 0.6765 MoM and those that had a CPR ≥ 0.6765 MoM. Results In total, 775 women were recruited. Fetuses with CPR < 0.6765 MoM were significantly more likely to require Cesarean delivery because of presumed fetal compromise (P < 0.001). These fetuses were also at increased risk of compromise at any time during labor and were less likely to be delivered vaginally, spontaneously or otherwise, than were those with CPR ≥ 0.6765 MoM. CPR < 0.6765 MoM gave a positive predictive value (PPV) for Cesarean delivery because of presumed fetal compromise of 36.7% and a negative predictive value of 88.7%, with a sensitivity of 18% and a specificity of 95.4%.
Conclusion Fetuses that failed to achieve their growth potential (defined as CPR < 0.6765 MoM) were at increased risk of intrapartum compromise and were less likely to be delivered vaginally. However, a low negative predictive value was observed for fetal compromise and further studies are required to support the translation of this technique into clinical practice. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
INTRODUCTION A growing body of work suggests that, amongst fetuses reaching a birth weight considered appropriate for gestational age, there exists a cohort with evidence of relatively altered umbilical and cerebral blood flow and evidence that these fetuses may be at increased risk of developing fetal compromise during labor1 – 3 . As true fetal growth potential is difficult to predict4 , clinicians generally accept an estimated fetal weight (EFW) < 10th centile to define small-for-gestational age (SGA), with concurrent abnormalities in umbilical artery blood flow required to diagnose fetal growth restriction (FGR). However, this classification is somewhat arbitrary as it fails to identify growth-restricted fetuses whose EFW, whilst > 10th centile, is not consistent with their growth potential. The distinction between SGA and FGR is important as, whilst both are associated with increased incidence of adverse neonatal outcome, the risk is more marked in fetuses for which alterations in fetal hemodynamics are present5 . It has been suggested that alterations in cerebral and umbilical blood flow associated with FGR are an adaptive response to suboptimal placental function6 , occurring prior to subsequent deterioration in growth velocity. Furthermore, in the presence of uterine contractions,
Correspondence to: Prof. S. Kumar, Mater Research Institute, University of Queensland, Level 3, Aubigny Place, Raymond Terrace, South Brisbane, Queensland 4101, Australia (e-mail: [email protected]) Accepted: 4 December 2014
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
ORIGINAL PAPER
Growth potential and fetal compromise growth-restricted fetuses undergo further acute cerebral redistribution7,8 . Our group has observed that fetuses with relatively increased cerebral blood flow, despite having grown appropriately, are at increased risk of fetal compromise during labor, of developing a pathological fetal heart rate pattern and of requiring emergency operative delivery because of presumed fetal compromise1 . Furthermore, cerebral redistribution, whilst considered protective in utero, has been found to be associated with adverse long-term neurological outcomes9 . Even in appropriately grown fetuses, cerebral redistribution is associated with subsequent reduced performance in neurobehavioral testing10 . Recently, Morales-Rosello´ et al. suggested that ‘failure to reach growth potential’ can be defined as a cerebroplacental ratio (CPR) < 0.6765 multiples of the median (MoM)11 . The CPR, which can also be referred to as the cerebro-umbilical ratio1 , denotes the ratio of the middle cerebral artery pulsatility index (MCA-PI) to the umbilical artery pulsatility index (UA-PI). In this study, we apply this new definition to a cohort of prospectively recruited, low-risk term fetuses, in which the CPR was assessed prior to the active phase of labor. The aim was to evaluate the use of this new definition as a predictor of subsequent intrapartum fetal compromise.
METHODS This was a prospective observational study carried out over a 2-year period between March 2011 and March 2014. Participants were recruited at Queen Charlotte’s and Chelsea Hospital, London, a tertiary referral maternity unit with a birth rate in excess of 6000 per year. Participants were approached in early labor (≤ 4 cm cervical dilatation) or immediately prior to induction of labor. Of the potential participants undergoing induction of labor, only those with an indication for induction of postdates pregnancy (with gestational age < 42 weeks) or those for whom induction had been planned for social reasons were included. Maternal demographic and pregnancy data for all participants, including age, ethnicity, gestational age and body mass index, were collected. Exclusion criteria included: known FGR (EFW < 10th centile with UA-PI > 95th centile), known SGA (EFW < 10th centile), known fetal anomaly, maternal hypertensive disease/pre-eclampsia, multiple pregnancy, cervical dilatation > 4 cm, ruptured membranes with meconium-stained amniotic fluid or evidence of intrauterine infection. Recruited participants were provided with an information sheet and informed written consent for inclusion in the study was recorded. All participants underwent ultrasound assessment, during which fetal biometry, umbilical and middle cerebral artery Doppler and amniotic fluid volume were assessed. The target population was therefore women with uncomplicated term pregnancy who would deliver within 72 hours of recruitment. Ethical approval for the study
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
461
was granted by the London Research Ethics Committee (Ref No: REC 10/H0718/26). The method of ultrasound assessment has been reported previously1,2 . All assessments were performed by a single trained individual using a portable GE Voluson ultrasound machine (GE Healthcare Ultrasound, Milwaukee, WI, USA) with an AB2-7-RS curvilinear transabdominal transducer. Participants were examined in a supine position, with the head of the bed elevated to 45◦ to prevent aortocaval compression. All measurements were taken in triplicate, with the mean of these used for subsequent data analysis. Doppler waveforms were acquired from all vessels with an angle of acquisition as close to 0◦ as possible and always < 30◦ . The angle correction tool was used to adjust for any angle of acquisition that was not 0◦ . Doppler waveforms were not acquired during fetal breathing or during uterine contractions. The CPR was calculated as a ratio of the MCA-PI to the UA-PI and MoM was calculated using the formula described by Morales-Rosello´ et al.11 . Intrapartum outcomes including mode of and indication for delivery, incidence of cardiotocography recordings considered pathological according to National Institute for Health and Care Excellence (NICE) criteria and the presence of meconium-stained amniotic fluid were compared between cases with a CPR < 0.6765 MoM and those with a CPR ≥ 0.6765 MoM. Neonatal outcomes, including Apgar score, umbilical artery pH at delivery and neonatal unit admission were also compared between the two groups. In all cases the diagnosis of intrapartum compromise was made contemporaneously by the obstetricians managing labor and was based on abnormal fetal heart rate patterns, fetal blood sampling or both. In our institution all cases of Cesarean delivery because of presumed fetal compromise are reviewed by two senior obstetricians. All obstetricians making decisions regarding delivery are blinded to ultrasound findings.
RESULTS A total of 775 women were recruited to the study. All women delivered live infants and delivery was within 72 hours of ultrasound assessment in 96.1% of cases (745/775). Mode of delivery and maternal demographics for all study participants are documented in Table 1. When cases were divided according to a CPR < 0.6765 MoM or a CPR ≥ 0.6765 MoM, fetuses with a CPR < 0.6765 MoM were found to be at a significantly increased risk of Cesarean delivery because of fetal distress (P < 0.001), with a relative risk above three. These fetuses were also at increased risk of fetal compromise at any time during labor, and less likely to be delivered vaginally, spontaneously or otherwise, than those with a CPR ≥ 0.6765 MoM. Furthermore, fetuses with a CPR < 0.6765 MoM were more likely to be diagnosed with a pathological heart rate pattern and meconium-stained amniotic fluid during labor was
Ultrasound Obstet Gynecol 2015; 46: 460–464.
Prior et al. Data are given as n (%), mean [range] or median (range). *P-values were determined using ANOVA or chi-square test. BMI, body mass index; FD, fetal distress; FTP, failure to progress; CS, Cesarean section; SVD, spontaneous vaginal delivery.
0.99 0.97 100 (84.7) 18 (15.3) 82 (82.0) 18 (18.0) 638 (82.3) 137 (17.7)
123 (81.5) 28 (18.5)
233 (82.3) 50 (17.7)
100 (81.3) 23 (18.7)
0.37 0.29 0.006 0.80 77 (65.3) 24 (20.3) 14 (11.9) 3 (2.5) 54 (54.0) 22 (22.0) 18 (18.0) 6 (6.0) 531 (68.5) 132 (17.0) 79 (10.2) 33 (4.3)
111 (73.5) 28 (18.5) 6 (4.0) 6 (4.0)
200 (70.7) 37 (13.1) 33 (11.7) 13 (4.6)
89 (72.4) 21 (17.1) 8 (6.5) 5 (4.1)
< 0.001 0.14 0.07 < 0.001 112 (94.9) 33.5 [22–46] 25 (18–40) 41.1 (37.0–42.0) 113 (91.9) 32.1 [18–43] 24 (16–41) 41.4 (37.0–42.0) 95 (95.0) 32.0 [18–43] 25 (19–42) 41.4 (37.7–42.0)
Primiparous Maternal age (years) BMI (kg/m2 ) Gestational age (weeks) Ethnicity Caucasian Asian Afro-Caribbean Other Mode of onset of labor Induction Spontaneous
626 (80.8) 32.4 [16–47] 24 (16–43) 41 (37.0–42.0)
142 (94.0) 32.7 [16–45] 24 (18–35) 40.8 (37.0–42.0)
163 (57.6) 32.1 [18–47] 24 (17–43) 40.7 (37.0–42.0)
Emergency CS: other (n = 118) Characteristic
Overall (n = 775)
Emergency CS: FD (n = 100)
Instrumental: FD (n = 151)
Delivery
Table 1 Maternal demographics according to mode-of-delivery group in 775 low-risk singleton pregnancies
SVD (n = 283)
Instrumental: FTP (n = 123)
P*
462
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
more likely to be present (Table 2). No significant differences in maternal demographic characteristics were found between the two groups (Table 3). In this cohort, a CPR < 0.6765 MoM gave a positive predictive value for Cesarean delivery because of presumed fetal compromise of 36.7% and a negative predictive value of 88.7%, with a sensitivity of 18% and a specificity of 95.4%. Neonatal outcome variables were also examined (Table 4). Fetuses with a CPR ≥ 0.6765 MoM had a greater birth weight and birth-weight centile. Mean CPR-MoM values were compared among cases grouped according to birth-weight centile (Table 5). Neonates with the highest birth-weight centile correspondingly had the highest CPR-MoM values, with a trend toward decreasing CPR-MoM values as the birth-weight centile decreased. This finding was significant when compared using one-way ANOVA (P < 0.001). No significant differences were observed in the other neonatal outcome variables.
DISCUSSION Following the publication by Morales-Rosello´ et al. that defines a fetus as failing to achieve its growth potential if the CPR is < 0.6765 MoM11 , we sought to investigate whether use of this definition could improve identification of fetuses at risk of developing fetal compromise during labor. We applied this cut-off to a prospectively recruited cohort of low-risk term pregnancies, comparing intrapartum and neonatal outcomes between fetuses with a CPR < 0.6765 MoM and CPR ≥ 0.6765 MoM. Significant variations in the incidence of Cesarean section because of presumed fetal compromise, abnormal fetal heart rate patterns and the incidence of meconium-stained amniotic fluid during labor were found between the groups. Fetuses to whom the Morales-Rosello´ et al.11 definition of ‘failure to meet growth potential’ applies were more than three times more likely to require Cesarean delivery because of presumed fetal compromise. These results support the notion that a reduction in placental function, even in appropriately grown fetuses, may be evidenced by changes in fetal hemodynamics. The degree of alteration in fetoplacental blood flow that should be considered abnormal remains a matter for consideration. Interestingly, the use of a cut-off of < 0.6765 MoM as suggested by Morales-Rosello´ et al.11 yields a similar positive predictive value for Cesarean section because of presumed fetal compromise as reported in our original study, in which a CPR cut-off < 10th centile was used1 (36.2% vs 36.4%). However, use of a single cut-off value to denote high- and low-risk groups does not result in a high negative predictive value, as more than 10% of fetuses with a CPR ≥ 0.6765 MoM in the study cohort still required delivery by emergency Cesarean section because of presumed fetal compromise. It should be noted that the cut-off reported by Morales-Rosello´ et al. was derived in a cohort with an examination-to-delivery interval < 14 days, whilst in the
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Growth potential and fetal compromise
463
Table 2 Intrapartum outcome according to cerebroplacental ratio (CPR) group in 775 low-risk singleton pregnancies CPR Delivery category Cesarean section for fetal compromise Fetal compromise diagnosed at any time during labor Spontaneous vaginal delivery Vaginal delivery of any kind Cesarean section: other Pathological FHR patterns Meconium-stained AF
Overall (n = 775)
< 0.6765 MoM (n = 49)
≥ 0.6765 MoM (n = 726)
100 (12.9)
18 (36.7)
82 (11.3)
< 0.001
3.25 (2.14–4.95)
251 (32.4)
29 (59.2)
222 (30.6)
< 0.001
1.94 (1.50–2.50)
283 (36.5) 557 (71.9) 118 (15.2) 154 (19.9) 76 (12.6)†
8 (16.3) 24 (49.0) 7 (14.3) 20 (40.8) 11 (22.4)
275 (37.9) 533 (73.4) 111 (15.3) 134 (18.5) 83 (11.4)
0.02 0.05 0.86 < 0.001 0.03
0.43 (0.23–0.82) 0.67 (0.50–0.89) 1.00 (0.49–2.02) 2.21 (1.53–3.20) 1.96 (1.12–3.43)
Relative risk (95% CI)
P*
Data are given as n (%). *P-values were determined using chi-square test. †Data available for only 604. AF, amniotic fluid; FHR, fetal heart rate; MoM, multiples of the median.
Table 3 Maternal demographics according to cerebroplacental ratio (CPR) group in 775 low-risk singleton pregnancies CPR Characteristic Primiparous Maternal age (years) BMI (kg/m2 ) Gestational age (weeks) Ethnicity Caucasian Asian Afro-Caribbean Other Mode of onset of labor Induction Spontaneous
Overall (n = 775)
< 0.6765 MoM (n = 49)
≥ 0.6765 MoM (n = 726)
P*
626 (80.8) 32.4 [16–47] 24 (16–43) 41 (37.0–42.0)
46 (93.9) 32.8 [18–43] 25.2 (18–40) 40.5 (37–42)
580 (79.9) 32.4 [16–47] 24.9 (16–43) 40.5 (37–42)
0.29 0.28 0.35 0.76
531 (68.5) 132 (17.0) 79 (10.2) 33 (4.3)
35 (71.4) 6 (12.2) 5 (10.2) 3 (6.1)
496 (68.3) 126 (17.4) 74 (10.2) 30 (4.1)
0.80 0.41 0.99 0.51
638 (82.3) 137 (17.7)
35 (71.4) 14 (28.6)
603 (83.1) 123 (16.9)
0.39 0.06
Data are given as n (%), mean [range] or median (range). *P-values were determined using ANOVA or chi-square test. BMI, body mass index; MoM, multiples of the median.
Table 4 Neonatal outcome according to cerebroplacental ratio (CPR) group in 775 low-risk singleton pregnancies CPR Characteristic Birth weight (g) Birth-weight centile Apgar score < 7 at 1 min Apgar score < 7 at 5 min Cord arterial pH < 7.20 Base excess < 8 mmol/L Neonatal unit admission Neonatal encephalopathy Composite neonatal outcome score
Overall (n = 775)
< 0.6765 MoM (n = 49)
≥ 0.6765 MoM (n = 726)
P*
Relative risk (95% CI)
3522 [1780–5062] 52.5 (1–100) 62 (8.0) 10 (1.3) 236 (30.5) 170 (21.9) 14 (1.8) 0 (0) 0.75 [0–7]
3354 [1780–4246] 43.9 (1–98) 3 (6.1) 1 (2.0) 13 (26.5) 10 (20.4) 1 (2.0) 0 (0) 0.69 [0–4]
3535 [2360–5062] 53.1 (1–100) 59 (8.1) 9 (1.2) 223 (30.7) 160 (22.0) 13 (1.8) 0 (0) 0.75 [0–7]
0.009 0.03 0.63 0.63 0.61 0.81 0.90 — 0.71
— — 0.80 (0.26–2.47) 1.76 (0.23–13.60) 0.92 (0.57–1.49) 0.99 (0.56–1.75) 1.22 (0.16–9.11) — —
Data are given n (%), mean [range] or median (range). *P-values were determined using ANOVA or chi-square test. MoM, multiples of the median.
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
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Prior et al.
464 Table 5 Cerebroplacental ratio (CPR) according to birth-weight centile group in 775 low-risk singleton pregnancies
Birth-weight centile 0–9th 10th –19th 20th –29th 30th –39th 40th –49th 50th –59th 60th –69th 70th –79th 80th –89th 90th –100th
n
Mean CPR-MoM
55 68 85 83 79 82 62 87 63 111
0.93 0.91 1.03 1.05 1.06 1.08 1.03 1.07 1.08 1.14
MoM, multiples of the median. Trend for increasing CPR with birth-weight centile, tested using ANOVA, P < 0.001.
present study this interval was < 72 hours in over 95% of cases. Further investigation of this emerging technique with a large prospective study is likely to be required to establish optimal discriminatory values delineating highand low-risk populations. Neonates with the greatest birth-weight centile were found to have had significantly higher CPRs than those with lower birth-weight centiles. This finding supports those of our previous publications, suggesting that the CPR may be used as a surrogate marker of placental function, even in a low-risk cohort of appropriately grown fetuses. Recently published results of the PORTO study12 confirm that the CPR is predictive of adverse perinatal outcome in a growth-restricted cohort. The results of our study, and those of Morales-Rosello´ et al.11 , suggest that this technique may have clinical application in a low-risk cohort. Given these interesting results, the CPR may be a suitable addition to the EFW in monitoring both high- and low-risk pregnancies. Recently published data suggest that the CPR better correlates with neonatal umbilical artery pH than does birth weight13 . Whilst it has been reported that SGA fetuses, without Doppler evidence of placental dysfunction, are still at increased risk of adverse neurodevelopmental outcome14 , cases are frequently classified as SGA as opposed to FGR on the basis of umbilical artery Doppler only. However, Savchev et al. examined intrapartum outcomes in SGA fetuses with normal Doppler findings (including a CPR > 5th centile) and found that, despite normal fetal hemodynamics, cases with an EFW < 3rd centile were still at increased risk of Cesarean section because of non-reassuring fetal status15 . It is likely that a combination of EFW and CPR may improve the identification of ‘at risk’ fetuses throughout
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
the antenatal period, but also immediately prior to labor. The development of a risk score, to predict the likelihood of intrapartum fetal compromise or the need for emergency operative delivery, could improve intrapartum management and facilitate appropriate decision-making. Towards this aim, further large prospective studies are necessary to refine discriminatory values and support the translation of this technique into clinical practice.
ACKNOWLEDGMENTS T.P. was funded by Moonbeam Trust (Charity No. 1110691). All authors were funded by the Imperial College Healthcare NHS Trust comprehensive Biomedical Research Centre (BRC) scheme.
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