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A low fetal cerebroplacental ratio confers a greater risk of intrapartum fetal compromise and adverse neonatal outcomes in low risk multiparous women at term
European Journal of Obstetrics & Gynecology and Reproductive Biology 230 (2018) 15–21
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Full length article
A low fetal cerebroplacental ratio confers a greater risk of intrapartum fetal compromise and adverse neonatal outcomes in low risk multiparous women at term$ Jessica M. Turnera,b , Christopher Flatleya , Sailesh Kumara,b,* a b
Mater Research Institute, University of Queensland, Level 3 Aubigny Place, Raymond Terrace, S. Brisbane, QLD, 4101, Australia Faculty of Medicine, University of Medicine, Whitty Building, Annerley Road, S. Brisbane, QLD, 4101, Australia
A R T I C L E I N F O
A B S T R A C T
Article history: Received 23 April 2018 Received in revised form 21 August 2018 Accepted 10 September 2018 Available online xxx
Background: A low fetal cerebroplacental ratio (CPR) and nulliparity have independently been shown to be associated with adverse obstetric and perinatal outcomes. Objectives: To assess the effect of parity on the CPR and investigate the utility of a CPR threshold of <10th centile for predicting adverse outcomes. We hypothesised that nulliparous women would have a lower CPR than multiparous women, impacting the diagnostic performance of the <10th centile threshold. This is an important consideration for interpretation of a low CPR in clinical practice. Study Design: This was a retrospective cohort study of low risk, singleton pregnancies delivering at term in Australia’s largest maternity hospital. The primary outcome was emergency caesarean section for intrapartum fetal compromise (EmCS IFC). Data was dichotomised according to parity and further by CPR <10th centile. Multiple logistic regression was performed. Results: 4737 women were included for analysis, 2333 were nulliparous and 2404 were multiparous. Overall the z-score (mean [SD])(CPR standardised for gestation) was lower in nulliparous compared to multiparous women ( 0.16 [-1.73 – 1.42] vs 0.04 [ 1.63 – 1.69], p < 0.001). Multiparous women had a non-significantly lower mean z-score for those who delivered by EmCS IFC than nulliparous women ( 0.52 [ 2.23 – 2.02] vs 0.45 [ 2.22 – 1.1]). Nulliparous women had greater odds of having a CPR <10th centile compared to the multiparous cohort (OR 1.24, 95% CI 1.02–1.5 vs. OR 0.81, 95% CI 0.7–0.98, p < 0.001). A CPR thresholdd <10th centile in nulliparous women was associated with increased odds of intrapartum fetal compromise (IFC), EmCS IFC (aOR 1.72, 95CI 1.2–2.6, p < 0.05) and birthweight <10th centile. A low CPR in multiparous women was associated with increased odds of all adverse perinatal outcomes measured: IFC, meconium stained liquor, EmCS IFC (aOR 4.99, 95%CI 2.5–9.9, p < 0.001), birthweight <10th centile, acidosis, neonatal intensive care admission and severe composite neonatal outcome. These aORs were associated with specificities of >90% and false positive rates of <10% for all outcomes in multiparous women. Conclusions: A CPR <10th centile in multiparous women confers greater odds of adverse perinatal outcomes and as such of the influence of parity should be taken into account when decisions regarding clinical management are made because of a low CPR. © 2018 Published by Elsevier B.V.
Keywords: Adverse perinatal outcomes Cerebroplacental ratio Emergency caesarean Emergency operative delivery Fetal distress Fetal doppler Intrapartum fetal compromise Multiparous Parity
Introduction
$ This work was presented as a poster presentation at the RCOG World Congress, Singapore 22–24th March 2018. * Corresponding author at: Mater Research Institute/University of Queensland, Level 3, Aubigny Place, Raymond Terrace, South Brisbane, QLD, 4101, Australia. E-mail address: [email protected] (S. Kumar).
https://doi.org/10.1016/j.ejogrb.2018.09.010 0301-2115/© 2018 Published by Elsevier B.V.
Uterine contractions in labour are associated with a 60% reduction in placental blood flow and whilst the majority of fetuses are able to cope with this lower perfusion, those that are unable to do so are at risk of intrapartum hypoxia [1,2]. Although fetal growth restriction is a major risk factor for intrapartum compromise, there is now good evidence to suggest that some apparently normally grown fetuses are also at increased risk. These fetuses have evidence of cerebral redistribution, similar to that seen in their growth restricted
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counterparts rendering them vulnerable to adverse obstetric and perinatal outcomes [3–7]. Cerebral redistribution in these fetuses is reflected by a low cerebroplacental ratio (CPR) [ratio of the fetal Middle Cerebral Artery Pulsatility index (MCA PI) to the Umbilical Artery Pulsatility Index (UA PI)], which is now believed to be a reliable surrogate marker of suboptimal fetal growth [8–10]. A low CPR is associated with a number of adverse outcomes including operative birth for intrapartum fetal compromise (IFC), low birth weight, Neonatal Intensive Care Unit (NICU) admission [11,12], meconium-stained liquor, non-reassuring fetal heart rate patterns, low Apgar scores, acidosis and perinatal mortality [13]. Concurrent with studies demonstrating an association between aberrant feto-placental Doppler changes and adverse outcomes there are also considerable data showing that nulliparity is strongly associated with complications related to placental dysfunction including pre-eclampsia [14], stillbirth [15], fetal growth restriction [16] as well as emergency operative delivery for IFC [17] and adverse neonatal outcomes [18–20] The aim of this study thus was to, firstly, assess the influence of parity on the CPR and secondly, ascertain if the utility of a low CPR (CPR <10thcentile) for predicting emergency caesarean for IFC and adverse neonatal outcomes differed in nulliparous compared to multiparous women. Methods Data from low risk women with singleton pregnancies, delivering at term, between 2010 and 2017 at the Mater Mothers’ Hospital, Brisbane were analysed. This is Australia’s largest maternity hospital with an annual birth rate of approximately 10,500 births. This study was approved by the hospital’s Human Research Ethics Committee (Ref no. HREC/14/MHS/37). Low risk pregnancy was defined as the absence of the following: multiple pregnancy, known genetic syndromes or congenital fetal malformations, small for gestational age/intrauterine growth restriction (defined as estimated fetal weight <10th centile on ultrasound scan, with or without fetal Doppler changes), pre-existing or gestational diabetes mellitus, renal disorders, hypertension, smoking, maternal age <18 or >40 years or BMI > 40 kg/m2. These variables are known to confer a greater risk of intrapartum fetal compromise. Women were excluded from the study if they did not have recorded ultrasound data for both the MCA PI and UA PI measured at 32 weeks gestation. Gestational age was calculated from either the last menstrual period or the earliest obstetric ultrasound scan. If a woman underwent >1 ultrasound scan, the last Doppler indices prior to delivery was used. The fetal MCA was first imaged using colour Doppler and the waveform then recorded from the proximal third of the vessel, distal to its origin at the circle of Willis [21]. The UA Doppler waveforms were recorded from a free loop of cord. The CPR was calculated by dividing the MCA PI by the UA PI. The gestation specific 10th centile CPR threshold was defined according to previously published data [7,22,23]. Intrapartum fetal heart rate patterns were classified by the treating birth suite obstetric team according to criteria detailed in the Royal Australian and New Zealand College of Obstetricians and Gynaecologists’ guidelines [24]. These are not dissimilar to those used in the United Kingdom [25] and North America [26]. The diagnosis of IFC was made contemporaneously by the treating Obstetrician based on abnormal fetal heart rate patterns and/or high fetal scalp lactate levels (>4 mmol/L). The primary outcome measure was Emergency caesarean section for IFC (EmCS IFC). Secondary outcomes included IFC, meconium stained liquor (MSL), birthweight, gestation specific birthweight <10th centile, [27], neonatal sex, severe acidosis (defined as umbilical artery pH 7.0 or Base Excess 12 mmol/L, or lactate 6 mmol/L), Apgar score 3 at 5 min, admission to NICU and perinatal death (neonatal death and
stillbirth). Serious composite neonatal outcome (SCNO) was defined as a composite of admission to NICU, severe acidosis, Apgar score 3 at 5 min and perinatal death. Data was dichotomised according to parity (P0 vs P1) and further by CPR (<10th vs. 10th centile). Statistical analysis Generalized Estimating Equations (GEE) were used to adjust for the correlation between women who birthed more than once within the study period. Multiple GEE regression adjusting for birthweight, gestation at delivery and maternal age was used to generate adjusted odds ratios (aOR), false positive rates (FPR), positive likelihood ratios (PLR), sensitivity and specificity as well as the area under the receiver operating characteristic curves (AUROC) for the outcomes of interest. Individual CPR values were standardised by calculating z-scores against previously published gestation-specific reference centiles [23]. This allowed for comparison, using the students t-test, of zscore between those who had an adverse outcome compared to those who did not (mean, [SD]) as well as a comparison between nulliparous and multiparous women. Statistical analysis was performed using Stata SE1, Release 15, for Windows (StataCorp LP, College Station, TX, USA) and R versions 3.1.1(R core team 2014) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, URL http://www.R-project.org/). Statistical significance was defined as p < 0.05. Results A total of 4737 women were included in the analysis 2333 were nulliparous (P0) and 2404 were multiparous (P1). The CPR 10th centile values were significantly different at all gestation points (p < 0.001) between nulliparous and multiparous women. (Table 3) (Fig. 1) Of these, 284 (12.2%) nulliparous women and 223 (9.3%) multiparous women had a CPR <10th centile. Median maternal age, BMI and birthweight were different between the two cohorts according to parity (30 years vs. 32 years, 21.8 kg/m2 vs. 22.9 kg/m2 and 3240 g vs. 3370 g respectively, p < 0.001). For nulliparous
Fig. 1. CPR median, IQR and 10th centile threshold by ultrasound gestation and parity. This figure demonstrates the differences in CPR values between nulliparous and multiparous women at different ultrasound gestations (p < 0.05 at 35, 36, 37 and 40 weeks gestation) and the differences in 10th centile threshold at each gestation (p < 0.001 at every gestation). CPR, cerebroplacental ratio; US gestation, ultrasound gestation; IQR, interquartile range. * p < 0.05; ** p < 0.001.
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women there was no significant difference in demographic variables between those with a CPR <10th centile and those with a CPR 10th centile except for the interval between ultrasound scan and delivery whilst for the multiparous cohort, there was a significant difference in ethnicity. (Table 1) The overall incidence of EmCS IFC was 4.1%–6.7% in the nulliparous cohort and 1.6% in the multiparous cohort. There was a significantly greater incidence of all the adverse outcomes (except 5-minute Apgar score <3 and perinatal death) in the nulliparous cohort. In the nulliparous group, women with a CPR <10th centile were significantly more likely to experience IFC (13.0% vs. 8.3%, p < 0.05), undergo EmCS IFC (11.3% vs. 6.1%, p < 0.05) and have an infant with a birthweight <10th centile (29.6% vs. 16.9%, p < 0.001) compared to those with a CPR 10th centile. Multiparous women with a CPR <10th centile were significantly more likely to experience IFC (7.2% vs 2.7%, p < 0.001), undergo an EmCS IFC
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(6.3% vs 1.2%, p < 0.001), deliver an infant with a birthweight <10th centile (15.3% vs. 8.8%, p < 0.05) and to have higher NICU admission rates (12.6% vs. 7.5%, p < 0.05). (Table 2) The overall mean CPR z-score for nulliparous women was lower compared to multiparous women (-0.16 [-1.73 – 1.42] vs 0.04 [-1.63 – 1.69], p < 0.001). It was also lower for women who delivered by mode of birth other than EmCS IFC (-0.14 [-1.7 – 1.43] vs. 0.04 [-1.59 – 1.69], p < 0.001). Both nulliparous and multiparous women had a significantly lower z-score associated with the outcomes of IFC, EmCS IFC and birthweight <10th centile (p < 0.05). In addition, nulliparous women had a significantly lower mean z-score associated with perinatal death (PND) (p < 0.05) whilst multiparous women demonstrated a significantly lower mean z-score associated with NICU admission and SCNO (p < 0.05). Interestingly the mean z-score associated with EmCS IFC was higher in nulliparous women compared to multiparous women ( 0.45
Table 1 Maternal Demographics. Demographic
All Women
Nulliparous
CPR10th% 2181
CPR <10th% 223
p
4737
CPR <10th% 284
p
n.
CPR10th% 2049
Multiparous
P (P0 vs P1)
CPR Maternal age, years BMI, kg/m2 Ethnicity Caucasian ATSI Asian Other Gestation at USS (weeks) Interval between USS and delivery (days) Parity P0 P1 P2 P3
1.99 (1.67–2.34) 31 (27–34) 22.3 (20.1–25.6)
2.02 (1.74–2.33) 30 (26–33) 21.9 (19.8–24.9)
1.32 (1.18–1.44) 30 (27–33) 21.5 (19.6–24.2)
<0.001 NS NS NS
2.10 (1.81–2.45) 32 (28–35) 22.9 (20.5–26.3)
1.35 (1.21–1.47) 32 (28–35) 22.5 (20–26.1)
<0.001 NS NS <0.05
<0.001 <0.001 <0.001 NS
2404 (50.8) 75 (1.6) 1431 (30.2) 825 (17.4) 36 (34–37) 20 (9–32)
1019 (49.7) 29 (1.4) 700 (34.2) 301 (14.7) 35.9 (34.9–36.9) 20 (9–33)
141 (49.7) 4 (1.4) 101 (35.6) 38 (13.4) 36 (35–37) 16 (7–30)
NS <0.001
1146 (54.6) 39 (1.8) 559 (25.7) 435 (20.0) 35.9 (33.9–36.9) 20 (10–32)
98 (44) 3 (1.4) 71 (31.8) 51 (22.9) 36 (34–37) 21 (8–34)
NS NS
<0.001 NS
2333 (49.3) 1551 (32.7) 528 (11.1) 325 (6.9)
2049 (100)
284 (100)
NS
0 1401 (64.2) 482 (22.1) 298 (13.7)
0 150 (67.3) 46 (20.6) 27 (12.1)
NS
CPR, cerebroplacental ratio; BMI, body mass index; ASTI, Aboriginal and Torres Strait Islanders; USS, ultrasound scan; P0; nulliparous; P 1, multiparous. Data reported as n (%), median (IQR) as appropriate.
Table 2 Perinatal outcomes. Outcomes
All Women
Nulliparous Women
CPR10th% 2181
CPR <10th% 223 (9.3)
P
4737
CPR <10th% 284 (12.2)
P
n. (%)
CPR10th% 2049
Multiparous Women
Gestation at delivery (weeks) IFC MSL Mode of delivery SVD Instrumental FTP Instrumental other ElCS EmCS other EmCS IFC Male gender Birthweight, g
39 (38–40) 281 (5.9) 737 (15.6)
39 (38–40) 170 (8.3) 386 (18.9)
39 (38–40) 37 (13.0) 50 (17.6)
<0.05 <0.05 NS
39 (38–40) 58 (2.66) 264 (12.1)
39 (38–39) 16 (7.2) 37 (16.6)
NS 0.001 NS
2481 (52.4) 345 (7.3) 375 (7.9) 799 (16.9) 541 (11.4) 196 (4.1) 2390 (50.5) 3301 (2995–3640)
857 (41.8) 265 (12.9) 258 (12.6) 243 (11.9) 301 (14.7) 125 (6.1) 1035 (50.5) 3266 (2980–3584)
<0.05
NS <0.05
1378 (63.18) 42 (1.93) 65 (2.98) 477 (21.87) 194 (8.9) 25 (1.15) 1096 (50.3_ 3380 (3062–3718)
134 (60.1) <0.001 2 (0.9) 9 (4.0) 48 (21.5) 16 (7.2) 14 (6.3) 118 (52.9) NS NS 3202 (2868–3535) NS <0.001
BW <10th centile 5 min Apgar <3 Acidosis NICU admission Perinatal death SCNO
656 (13.9) 14 (0.3) 343 (7.2) 440 (9.3) 6 (0.38) 694 (14.7)
346 (16.9) 6 (0.3) 229 (11.2) 217 (10.6) 2 (0.1) 386 (18.8)
112 (39.4) 36 (12.7) 43 (15.1) 31 (10.9) 30 (10.6) 32 (11.3) 141 (49.7) 3090.5 (2781.5– 3400) 84 (29.6) 0 40 (14.1) 32 (11.3) 1 (0.4) 63 (22.2)
<0.001 NS NS NS NS NS
192 (8.8) 8 (0.4) 62 (2.8) 163 (7.5) 2 (0.1) 207 (9.5)
34 (15.3) 0 12 (5.4) 28 (12.6) 1 (0.45) 38 (17.0)
<0.05 NS NS <0.05 NS NS
P (P0 vs P1)
<0.001 <0.001 <0.001
<0.001 NS <0.001 0.001 NS <0.001
Outcomes reported as n.(%) or mean(SD) or median (IQR) as appropriate. NS; non-significant; CPR, cerebroplacental ratio; P0, nulliparous women; P 1, multiparous women; IFC, intrapartum fetal compromise; MSL, meconium stained liquor; SVD, spontaneous vaginal delivery; FTP, failure to progress; ElCS, elective caesarean section; EmCS, emergency caesarean section; IFC, intrapartum fetal compromise; BW, birthweight; Acidosis, umbilical artery pH 7.0 or Base Excess 12 mmol/L, or lactate 6 mmol/L ; NICU, neonatal intensive care unit; perinatal death, intrauterine fetal demise or neonatal death; SCNO, severe composite neonatal outcome (umbilical artery pH < 7.0, base excess 12 mmol/L and/or lactate 6 mmol/L, Apgar score 3 at 5 min, neonatal intensive care admission, perinatal death).
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Table 3 Cerebroplacental ratios according to parity at different gestations. US Gestation (weeks)
32 33 34 35 36 37 38 39 40 41 42
Nulliparous
Multiparous
n.
Median (IQR)
n.
Median (IQR)
146 115 304 237 554 445 274 145 87 20 5
2.06 (1.8–2.4) 2.17 (1.8–2.6) 2.14 (1.8–2.4) 2.06 (1.7–2.4) 1.94 (1.6–2.3) 1.9 (1.5–2.2) 1.85 (1.5–2.2) 1.74 (1.4–2.0) 1.6 (1.3–1.9) 1.48 (1.3–1.8) 1.6 (1.3–1.7)
196 147 313 290 628 408 257 95 47 15 8
2.17 (1.8–2.4) 2.2 (1.9–2.5) 2.18 (1.9–2.5) 2.13 (1.8–2.5) 2.04 (1.7–2.4) 1.99 (1.7–2.3) 1.82 (1.5–2.2) 1.79 (1.4–2.1) 1.75 (1.4–2.1) 1.7 (1.2–2) 1.83 (1.6–2.0)
P value
0.5 0.5 0.3 0.03 <0.001 <0.001 0.6 0.5 0.02 0.5 0.5
US, ultrasound; IQR, interquartile range.
[ 2.22 – 1.1] vs. 0.52 [ 2.23 – 2.02]) although this difference did not reach statistical significance. (Table 4) Fig. 2 demonstrates the effect of parity upon z-score (mean, 95% CI) for those delivering by EmCS IFC compared to other modes of birth. The z-score was significantly lower among those delivering by EmCS IFC for those who were P0 and P1. Interestingly this difference was significantly greater for women who were P1 than P0 (0.66 [0.25–1.06] vs. 0.31 [0.15-0.47], p < 0.001). The odds of having a CPR <10th centile for nulliparous women was significantly greater than that for multiparous women (OR 1.24, 95%CI 1.02–1.5 vs. OR 0.81, 95%CI 0.7-0.98, p < 0.001). Amongst nulliparous women, a CPR <10th centile threshold was significantly associated with higher odds of IFC (aOR 1.46, 95%CI 1.0–2.1, p < 0.05), EmCS IFC (aOR 1.73, 95%CI 1.2–2.6, p < 0.05) and birthweight <10th centile (aOR 2.12, 95%CI 1.6–2.8, p < 0.001). The specificities of this CPR threshold for all these outcomes were >88%. The corresponding sensitivities were 17.9% (IFC), 20.4% (EmCS IFC) and 19.6% (birthweight <10th centile) respectively and FPR of <12%. The corresponding PLR and AUROC were 1.54 and 0.53 (IFC), 1.76 and 0.54 (EmCS IFC) and 1.86 and 0.55 (birthweight <10th centile). For the other adverse outcomes (meconium stained liquor, NICU admission and SCNO) the aORs did not reach statistical significance. (Table 5) For multiparous women, a CPR <10th centile threshold was significantly associated with higher odds of IFC (aOR 2.46, 95%CI 1.4–4.3, p < 0.05), MSL (aOR 1.61, 95% CI 1.1–2.4, p < 0.05), EmCS IFC (aOR 4.99, 95%CI 2.5–9.9, p < 0.001), birthweight <10th centile (aOR 1.9, 95%CI 1.3–2.8, p = 0.01), severe acidosis (aOR 2.02, 95%CI 1.1– 3.8, p < 0.05), NICU admission (aOR 1.8, 95%CI 1.2–2.7, p < 0.05) and the composite SCNO (aOR 1.91, 95%CI 1.30–2.75, p < 0.001). The
Fig. 2. Relationship between parity and z-score (mean, 95% CI) according to mode of delivery. This figure demonstrates the difference in z-score mean and 95% CI between for those delivering by EmCS IFC compared to other mode of birth according to parity. 95% CI, 95% confidence interval; *, p < 0.05; EmCS IFC, emergency caesarean section for intrpartum fetal compromise; other MoDel, mode of delivery other than EmCS IFC.
specificities of this CPR threshold for all these outcomes were >90% with associated sensitivities of 21.6% (IFC), 12.3% (MSL), 35.9% (EmCS IFC), 15.0% (birthweight <10th centile), 16.2% (severe acidosis), 14.7% (NICU admission) and 15.5% (SCNO) respectively and FPRs of <10%. The corresponding PLR and AUROC were 2.4 and 0.55 (IFC), 1.4 and 0.52 (MSL), 4.1 and 0.64 (EmCS IFC), 1.8 and 0.54 (severe acidosis), 1.7 and 0.53 (NICU admission) and 1.8 and 0.53 (SCNO) respectively. A CPR 10th centile was protective in nulliparous women against IFC (aOR 0.68, 95% CI 0.5–1.0, p = 0.05), EmCS IFC (aOR 0.58, 95%CI 0.40.9, p < 0.05) and birthweight <10th centile (aOR 0.47, 95%CI 0.4-0.6, p < 0.001). A CPR 10th centile in multiparous women was significantly protective for all adverse outcomes - IFC (aOR 0.4, 95%CI 0.2-0.7, p < 0.05), MSL (aOR 0.62, 95%CI 0.4-0.9, p < 0.05), EmCS IFC (aOR 0.2, 95%CI 0.1-0.4, p < 0.001), birthweight <10th centile (aOR 0.53, 95%CI 0.4-0.8, p = 0.001), severe acidosis (aOR 0.5, 95%CI 0.3-0.94, p < 0.05), NICU admission (aOR 0.56, 95%CI 0.4-0.9, p < 0.05), and SCNO (aOR 0.5, 95%CI 0.3-0.7, p < 0.001). (Table 5) Given the significant difference seen in CPR values and 10th centile threshold between nulliparous and multiparous women, a further analysis was performed assessing the diagnostic performance of a low CPR using a CPR <10th threshold specific to the woman’s parity.
Table 4 Z scores associated with adverse outcomes. Outcome
Nulliparous
n.
z-score outcome 2333
All women IFC MSL EmCS IFC BW <10th centile 5 min Apgar <3 Acidosis NICU admission Perinatal death SCNO
0.16 ((-1.73 – 1.42) 0.39 (-2.2 – 1.12) 0.18 (-1.69 – 1.36) 0.45 (-2.22 – 1.1) 0.51 (-2.15 – 1.13) 0.15 (-1.18 – 1.03) 0.16 (-1.85 – 1.47) 0.18 (-1.87 – 1.48) 1.18 (-2.6- -0.78) 0.17 (-1.94 – 1.48)
Multiparous z-score non-outcome
0.14 (-1.7 – 1.43) 0.15 (-1.75 – 1.42) 0.14 (-1.7 – 1.43) 0.08 (-1.59 – 1.45) 0.16 (-1.73 – 1.42) 0.16 (-1.71 – 1.38) 0.16 (-1.72 – 1.40) 0.13 (-0.88 – 0.5) 0.16 (-1.69 – 1.36)
P
<0.001 NS <0.001 <0.001 NS NS NS <0.05 NS
z-score outcome 2404 0.04 (-1.63 – 1.69) 0.27 (-2.07 - 1.56) 0.03 (-1.75 – 1.81) 0.52 (-2.23 – 2.02) 0.35 (-2.06 – 1.42) 0.58 (-0.83 – 1.40) 0.17 (-1.82 – 1.42) 0.19 (-2.11 – 1.53) 0.83 (-1.55 - -0.55) 0.2 (-2.06 – 1.49)
z-score non- outcome
0.04 0.04 0.04 0.08 0.03 0.04 0.05 0.05 0.06
(-1.6 – 1.7) (-1.61-1.68) (-1.59 – 1.69) (-1.55 – 1.72) (-1.63 – 1.70) (-1.61 – 1.71) (-1.57 – 1.72) (-0.63 – 0.71) (-1.54 – 1.72)
P
<0.05 NS <0.001 <0.001 NS NS <0.05 NS <0.001
P between z-score for outcome by parity
<0.001 NS <0.05 NS NS NS NS NS NS NS
Z-scores were generated by standardising CPR for gestation specific reference centiles. Reported as mean (95% CI). IFC, intrapartum fetal compromise; MSL, meconium stained liquor; EmCS IFC emergency caesarean for intrapartum fetal compromise; MoDel, mode of delivery; BW, birthweight; NICU, neonatal intensive care unit; SCNO, severe composite neonatal outcome (umbilical artery pH < 7.0, base excess 12 mmol/L and/or lactate 6 mmol/L, Apgar score 3 at 5 min, neonatal intensive care admission, perinatal death).
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Table 5 Diagnostic performance of CPR <10th centile according to parity for prediction of adverse outcomes. Outcome
n (%)
aOR (95% CI)
P
CPR <10th Nulliparous Multiparous
284 (12.2) 223 (9.3)
1.24 (1.02–1.5) 0.81 (0.7–0.98)
<0.05 <0.05
Intrapartum fetal compromise Nulliparous CPR10th Multiparous CPR10th Nulliparous CPR<10th Multiparous CPR<10th
170 (8.3) 58 (2.7) 37 (13) 16 (7.2)
0.68 (0.5–1.0) 0.41 (0.2–0.7) 1.46 (1.0–2.1) 2.46 (1.4–4.3)
Meconium stained liquor Nulliparous CPR10th Multiparous CPR10th Nulliparous CPR<10th Multiparous CPR<10th
386 (18.8) 264 (12.1) 50 (17.6) 37 (16.6)
EmCS IFC Nulliparous CPR10th Multiparous CPR10th Nulliparous CPR<10th Multiparous CPR<10th
Sensitivity (95% CI)
Specificity (95% CI)
FPR
PLR
AUROC (95% CI)
0.05 <0.05 0.05 <0.05
17.87 (12.9–23.8) 21.62 (12.9–32.7)
88.38 (86.9–89.7) 91.12 (89.9-92.2)
11.62 8.88
1.54 2.43
0.53 (0.5–0.56) 0.56 (0.52–0.61)
1.0 (0.7–1.4) 0.62 (0.4–0.9) 1.0 (0.7–1.4) 1.61 (1.1–2.4)
NS <0.05 NS <0.05
11.47 12.29
87.65 91.14
12.35 8.86
0.93 1.39
0.5 (0.48–0.51) 0.52 (0.5–0.54)
125 (6.1) 25 (1.15) 32 (11.3) 14 (6.3)
0.58 (0.4–0.9) 0.2 (0.1–0.4) 1.73 (1.2–2.6) 4.99 (2.5–9.9)
<0.05 <0.001 <0.05 <0.001
20.38 (14.4–27.5) 35.9 (21.2–52.8)
88.42 (86.99–89.7) 91.16 (89.9–92.3)
11.58 8.84
1.76 4.06
0.54 (0.51–0.58) 0.64 (0.56–0.71)
Birthweight <10th% Nulliparous CPR10th Multiparous CPR10th Nulliparous CPR<10th Multiparous CPR<10th
345 (16.8) 192 (8.8) 84 (29.6) 34 (15.2)
0.47 (0.4–0.6) 0.53 (0.4–0.8) 2.12 (1.6–2.8) 1.9 (1.3–2.8)
<0.001 0.001 <0.001 0.001
19.58 (15.9–23.7) 15.04 (10.6-20.4)
89.5 (88.0–90.8) 91.32 (90.1-92.5)
10.5 8.68
1.86 1.73
0.55 (0.53–0.6) 0.53 (0.51-0.56)
Severe Acidosis Nulliparous CPR10th Multiparous CPR10th Nulliparous CPR<10th Multiparous CPR<10th
229 (11.2) 62 (2.8) 40 (14.1) 12 (5.4)
0.8 (0.6–1.2) 0.5 (0.3–0.94) 1.25 (0.9–1.8) 2.02 (1.1–3.8)
NS <0.05 NS <0.05
14.87 (10.8–19.7) 16.22 (8.7–26.6)
88.18 (86.7–89.5) 90.94 (89.7–92.1)
11.82 9.06
1.26 1.79
0.52 (0.49–0.54) 0.54 (0.49–0.58)
NICU admission Nulliparous CPR10th Multiparous CPR10th Nulliparous CPR<10th Multiparous CPR<10th
217 (10.6) 163 (7.5) 32 (11.3) 28 (12.6)
0.92 (0.6–1.4) 0.56 (0.4–0.9) 1.08 (0.7–1.6) 1.8 (1.2–2.7)
NS <0.05 NS <0.05
12.85 (8.96-17.7) 14.66 (9.97-20.5)
87.91 (86.4-89.3) 91.19 (89.9-92.3)
12.09 8.81
1.06 1.66
0.5 (0.48–0.53) 0.53 (0.5–0.56)
SCNO Nulliparous CPR10th Multiparous CPR10th Nulliparous CPR<10th Multiparous CPR<10th
386 (18.8) 207 (9.5) 63 (22.2) 38 (17)
0.83 (0.6–1.1) 0.5 (0.3–0.7) 1.2 (0.9–1.6) 2.0 (1.4–2.9)
NS <0.001 NS <0.001
14.03 (10.95-17.6) 15.51 (11.2-20.7)
88.27 (86.7-89.7) 91.43 (90.2-92.6)
11.73 8.57
1.2 1.81
0.51 (0.49–0.53) 0.53 (0.51–0.56)
aOR, Adjusted Odds Ratio adjusts for birthweight, maternal age and gestation at delivery, gestation at ultrasound scan; CI, confidence interval; CPR, cerebroplacental ratio; FPR, false positive rate; PLR, positive likelihood ratio; AUROC, area under the receiver operators characteristic curve; CPR, cerebroplacental ratio; EmCS IFC, emergency caesarean section for intrapartum fetal compromise; NICU, neonatal intensive care unit; SCNO, severe composite neonatal outcome (umbilical artery pH < 7.0, base excess 12 mmol/L and/or lactate 6 mmol/L, Apgar score 3 at 5 min, neonatal intensive care admission, perinatal death).
This demonstrated a reduction in the odds of nulliparous women having a CPR <10th centile (aOR 1.24 vs. aOR 1.01) and an increase in odds in multiparous women (aOR 0.81 vs. aOR 0.99). There was an increase in aOR for birthweight <10th centile in both nulliparous and multiparous women (aOR 2.12 vs. 2.5 and aOR 1.9 vs. 2.0 respectively) and a reduction in the aOR for EmCS IFC in both cohorts (aOR 1.73 vs. 1.63 and aOR 4.99 vs. 4.15 respectively). Additionally, in multiparous women there was a reduction in the odds of acidosis (aOR 2.02, 95% CI 1.1–3.8 vs. aOR 1.9, 95% CI 1.01–3.6) and odds of SCNO (aOR 2.0, 95%CI 1.4–2.9 vs 1.7, 95% CI 1.1–2.4). (Supplement 1) Discussion Principal findings and implications for practice This study demonstrates that parity not only has a significant impact upon the CPR but also on the diagnostic utility of a CPR <10th centile threshold for predicting adverse intrapartum and neonatal outcomes. Our results from this low risk cohort show that multiparous women have a higher mean z-score and
significantly lower odds of a CPR <10th centile than nulliparous women. Furthermore, we demonstrate the somewhat surprising and novel finding that for multiparous women with a CPR <10thcentile, the odds of adverse outcomes including IFC, meconium stained liquor, EmCS IFC, and SCNO are greater than nulliparous women. Our data also suggest that the FPR of a CPR <10thcentile in multiparous women for the prediction of adverse outcomes is less than 10%, lower than previous reported studies [7]. Conversely, a CPR >10thcentile appears to be protective for all these adverse outcomes in multiparous women but this effect was only seen for IFC, EmCS IFC and low birthweight in nulliparous women. Our findings thus strongly suggest that a low CPR in a multiparous woman is a greater risk factor for adverse outcomes than a similar finding in a nulliparous counterpart. The findings of our study suggest that the development of any algorithm for predicting adverse perinatal outcomes should take into account parity and perhaps different thresholds to define high and low risk. Historically parity has been treated as a dichotomous variable for pregnancy risk assessment, however more recent proposals
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suggest that parity should be included into a multiple-level approach when stratifying for obstetric risks - nulliparity, low multiparity (para 1–3) and grand multiparity ( para 4) [18]. Our results support this suggestion given that the difference in mean zscore for those delivering by EmCS IFC was greatest for women who were P1-3. (Fig. 1) A low CPR is a marker of cerebral redistribution that results from adaptive changes in the fetal circulation generally in response to placental dysfunction [28]. Nulliparity is thought to affect placental function due to poorer placentation in the first trimester - placentae from multiparous women exhibit a significantly greater proportion of decidual vessels with endovascular trophoblastic invasion [29] as well as higher levels of vascular endothelial growth factor (VEGF) expression [30]. It is hypothesised that this arises due to permanent changes in the spiral artery architecture that occurs during the first pregnancy, thereby modifying subsequent vascular remodelling in the next pregnancy [31], in essence a form of “endometrial priming”. Our data supports this postulation - multiparous women are less likely to have placental dysfunction and hence have a higher median CPR. Crucially however, our findings suggest that if in a multiparous woman, the CPR falls to <10th centile this indicates significant fetal compromise (compared to a fetus in a nulliparous woman) and enhanced vulnerability to the stresses of labour and worse neonatal outcomes. Strengths and limitations The limitations of this study are mainly due to its retrospective design. At our institution low risk women as defined in this study do not routinely have third trimester ultrasound scans. Therefore, for the majority of the study cohort, there would have been a clinical indication for requesting an ultrasound including reduced fetal movements, antepartum bleeding, concerns about fetal size or growth and assessment of presentation. Thus, the women included into this study may not reflect a truly low risk population. An additional limitation was the variation in gestation at which the ultrasound was performed. We adjusted for this by using CPR thresholds specific for gestational age and standardised comparisons with the use of z-scores [22]. A possible further limitation is the arbitrary dichotomization of the CPR. As the CPR is a continuous variable, setting a single threshold may risk underestimating the severity of disease in the study cohort. Indeed some investigators argue that the use of interval thresholds provides a more accurate classification system as it allows for greater than two possible outcomes [32]. Despite this limitation, many studies do indeed use a threshold of <10th centile [7,8,13] to define an atrisk cohort. Previous studies have addressed the limitations of universal ultrasound screening for the prevention of adverse perinatal outcomes [33,34]. A recent systematic review assessing the value of the CPR for predicting adverse perinatal outcomes concluded that whilst the CPR had a strong association with adverse perinatal outcomes, there was insufficient high-quality evidence at this stage to advocate its use as a stand-alone test [11]. In our view, the relatively underwhelming performance of a low CPR as defined in this study, suggests that it should be used with caution particularly for low risk women. Currently the CPR is widely used to decide obstetric management in late pregnancy, with many clinicians using an isolated low CPR an indication for early term birth. Given the now clearly appreciated neonatal and longer-term risks of early term birth this practice should be discouraged without good evidence to the contrary, preferably from adequately powered randomised controlled trials [35,36]. Our results however, underscore the potential importance of parity when evaluating a low CPR in late third trimester.
Conflict of interest The authors report no conflicts of interest. Acknowledgement The authors acknowledge research support by the Mater Foundation. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi: https://doi.org/10.1016/j. ejogrb.2018.09.010. References [1] Janbu T., Nesheim BI. Uterine artery blood velocities during contractions in pregnancy and labour related to intrauterine pressure. Br J Obstet Gynaecol 1987;94(12):1150–5. [2] RCOG. The investigation and management of the small-for-gestational-age fetus. London (UK): Royal College of Obstetricians and Gynaecologists; 2013 2013; Green-top guideline no.31. [3] Sabdia S, Greer RM, Prior T, Kumar S. Predicting intrapartum fetal compromise using the fetal cerebro-umbilical ratio. Placenta 2015;36(5):594–8. [4] Khalil AA, Morales-Rosello J, Morlando M, et al. Is fetal cerebroplacental ratio an independent predictor of intrapartum fetal compromise and neonatal unit admission? Am J Obstet Gynecol 2015;213(1) 54 e51-10. [5] Morales-Rosello J, Khalil A. Fetal cerebral redistribution: a marker of compromise regardless of fetal size. Ultrasound Obstet Gynecol 2015;46 (4):385–8. [6] Morales-Rosello J, Khalil A, Morlando M, Bhide A, Papageorghiou A, Thilaganathan B. Poor neonatal acid-base status in term fetuses with low cerebroplacental ratio. Ultrasound Obstet Gynecol 2015;45(2):156–61. [7] Bligh LN, Al Solai A, Greer RM, Kumar S. Diagnostic performance of cerebroplacental ratio thresholds at term for prediction of low birthweight and adverse intrapartum and neonatal outcomes in a term, low-risk population. Fetal Diagn Ther 2018;43(3):191–8. [8] 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(2) 124 e121-126. [9] 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(1) 61 e61-68. [10] 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 (3):303–10. [11] Dunn L, Sherrell H, Kumar S. Review: systematic review of the utility of the fetal cerebroplacental ratio measured at term for the prediction of adverse perinatal outcome. Placenta 2017;54:68–75. [12] DeVore GR. The importance of the cerebroplacental ratio in the evaluation of fetal well-being in SGA and AGA fetuses. Am J Obstet Gynecol 2015;213(1):5– 15. [13] Khalil A, Morales-Rosello J, Townsend R, et al. Value of third-trimester cerebroplacental ratio and uterine artery Doppler indices as predictors of stillbirth and perinatal loss. Ultrasound Obstet Gynecol 2016;47(1):74–80. [14] Long PA, Abell DA, Beischer NA. Parity and pre-eclampsia. Aust N Z J Obstet Gynaecol 1979;19(4):203–6. [15] Gardosi J, Madurasinghe V, Williams M, Malik A, Francis A. Maternal and fetal risk factors for stillbirth: population based study. BMJ 2013;346:f108. [16] Cnattingius S, Axelsson O, Eklund G, Lindmark G, Meirik O. Factors influencing birthweight for gestational age, with special respect to risk factors for intrauterine growth retardation. Early Hum Dev 1984;10(1–2):45–55. [17] Schuit E, Kwee A, Westerhuis ME, et al. A clinical prediction model to assess the risk of operative delivery. BJOG 2012;119(8):915–23. [18] Bai J, Wong FW, Bauman A, Mohsin M. Parity and pregnancy outcomes. Am J Obstet Gynecol 2002;186(2):274–8. [19] Cnattingius S, Forman MR, Berendes HW, Graubard BI, Isotalo L. Effect of age, parity, and smoking on pregnancy outcome: a population-based study. Am J Obstet Gynecol 1993;168(Pt. 1):16–21. [20] Prior T, Mullins E, Bennett P, Kumar S. Influence of parity on fetal hemodynamics and amniotic fluid volume at term. Ultrasound Obstet Gynecol 2014;44(6):688–92. [21] Mari G, Deter RL, Carpenter RL, et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med 2000;342(1):9–14. [22] Flatley C, Greer RM, Kumar S. The magnitude of change in the fetal cerebroplacental ratio in the third trimester and the risk of adverse pregnancy outcome. Ultrasound Obstet Gynecol 2016.
J.M. Turner et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 230 (2018) 15–21 [23] Flatley C, Kumar S, Greer RM. Reference centiles for the middle cerebral artery and umbilical artery pulsatility index and cerebro-placental ratio from a lowrisk population - a Generalised Additive Model for Location, shape and Scale (GAMLSS) approach. J Matern Fetal Neonatal Med 2018;1–8. [24] RANZCOG. The Royal Australian and New Zealand college of obstetricians and gynaecologists: intrapartum fetal surveillance, clinical guideline - third addition. 2014. [25] NICE. National Institute of Health and care excellence: intrapartum care: interpretation of cardiotocograph traces (NICE guideline CG190). 2014. [26] ACOG. American College of Obstetricians and Gynecologists Practice Bulletin No. 106: intrapartum fetal heart rate monitoring: nomenclature, interpretation, and general management principles. Obstet Gynecol 2009;114(1):192– 202. [27] Dobbins TA, Sullivan EA, Roberts CL, Simpson JM. Australian national birthweight percentiles by sex and gestational age, 1998-2007. Med J Aust 2012;197(5):291–4. [28] Cruz-Martinez R, Figueras F. The role of Doppler and placental screening. Best Pract Res Clin Obstet Gynaecol 2009;23(6):845–55. [29] Prefumo F, Ganapathy R, Thilaganathan B, Sebire NJ. Influence of parity on first trimester endovascular trophoblast invasion. Fertil Steril 2006;85(4):1032–6.
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[30] Litwin S, Cortina ME, Barrientos GL, Prados MB, Roux ME, Miranda SE. Multiparity increases trophoblast invasion and vascular endothelial growth factor expression at the maternal-fetal interface in mice. J Reprod Immunol 2010;85(2):161–7. [31] Khong TY, Adema ED, Erwich JJ. On an anatomical basis for the increase in birth weight in second and subsequent born children. Placenta 2003;24(4):348–53. [32] Brown MD, Reeves MJ. Evidence-based emergency medicine/skills for evidence-based emergency care. Interval likelihood ratios: another advantage for the evidence-based diagnostician. Ann Emerg Med 2003;42(2):292–7. [33] RCOG. The investigation and management of the small-for-gestational-age fetus (Green-top guideline No.31). RCOG, NICE; 2014. [34] Bricker L, Medley N, Pratt JJ. Routine ultrasound in late pregnancy (after 24 weeks’ gestation). Cochrane Database Syst Rev 2015(6) CD001451. [35] Madden JV, Flatley CJ, Kumar S. Term small-for-gestational-age infants from low risk women are at significantly greater risk of adverse neonatal outcomes. Am J Obstet Gynecol 2018. [36] Sengupta S, Carrion V, Shelton J, et al. Adverse neonatal outcomes associated with early-term birth. JAMA Pediatr 2013;167(11):1053–9.
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Full length article
A low fetal cerebroplacental ratio confers a greater risk of intrapartum fetal compromise and adverse neonatal outcomes in low risk multiparous women at term$ Jessica M. Turnera,b , Christopher Flatleya , Sailesh Kumara,b,* a b
Mater Research Institute, University of Queensland, Level 3 Aubigny Place, Raymond Terrace, S. Brisbane, QLD, 4101, Australia Faculty of Medicine, University of Medicine, Whitty Building, Annerley Road, S. Brisbane, QLD, 4101, Australia
A R T I C L E I N F O
A B S T R A C T
Article history: Received 23 April 2018 Received in revised form 21 August 2018 Accepted 10 September 2018 Available online xxx
Background: A low fetal cerebroplacental ratio (CPR) and nulliparity have independently been shown to be associated with adverse obstetric and perinatal outcomes. Objectives: To assess the effect of parity on the CPR and investigate the utility of a CPR threshold of <10th centile for predicting adverse outcomes. We hypothesised that nulliparous women would have a lower CPR than multiparous women, impacting the diagnostic performance of the <10th centile threshold. This is an important consideration for interpretation of a low CPR in clinical practice. Study Design: This was a retrospective cohort study of low risk, singleton pregnancies delivering at term in Australia’s largest maternity hospital. The primary outcome was emergency caesarean section for intrapartum fetal compromise (EmCS IFC). Data was dichotomised according to parity and further by CPR <10th centile. Multiple logistic regression was performed. Results: 4737 women were included for analysis, 2333 were nulliparous and 2404 were multiparous. Overall the z-score (mean [SD])(CPR standardised for gestation) was lower in nulliparous compared to multiparous women ( 0.16 [-1.73 – 1.42] vs 0.04 [ 1.63 – 1.69], p < 0.001). Multiparous women had a non-significantly lower mean z-score for those who delivered by EmCS IFC than nulliparous women ( 0.52 [ 2.23 – 2.02] vs 0.45 [ 2.22 – 1.1]). Nulliparous women had greater odds of having a CPR <10th centile compared to the multiparous cohort (OR 1.24, 95% CI 1.02–1.5 vs. OR 0.81, 95% CI 0.7–0.98, p < 0.001). A CPR thresholdd <10th centile in nulliparous women was associated with increased odds of intrapartum fetal compromise (IFC), EmCS IFC (aOR 1.72, 95CI 1.2–2.6, p < 0.05) and birthweight <10th centile. A low CPR in multiparous women was associated with increased odds of all adverse perinatal outcomes measured: IFC, meconium stained liquor, EmCS IFC (aOR 4.99, 95%CI 2.5–9.9, p < 0.001), birthweight <10th centile, acidosis, neonatal intensive care admission and severe composite neonatal outcome. These aORs were associated with specificities of >90% and false positive rates of <10% for all outcomes in multiparous women. Conclusions: A CPR <10th centile in multiparous women confers greater odds of adverse perinatal outcomes and as such of the influence of parity should be taken into account when decisions regarding clinical management are made because of a low CPR. © 2018 Published by Elsevier B.V.
Keywords: Adverse perinatal outcomes Cerebroplacental ratio Emergency caesarean Emergency operative delivery Fetal distress Fetal doppler Intrapartum fetal compromise Multiparous Parity
Introduction
$ This work was presented as a poster presentation at the RCOG World Congress, Singapore 22–24th March 2018. * Corresponding author at: Mater Research Institute/University of Queensland, Level 3, Aubigny Place, Raymond Terrace, South Brisbane, QLD, 4101, Australia. E-mail address: [email protected] (S. Kumar).
https://doi.org/10.1016/j.ejogrb.2018.09.010 0301-2115/© 2018 Published by Elsevier B.V.
Uterine contractions in labour are associated with a 60% reduction in placental blood flow and whilst the majority of fetuses are able to cope with this lower perfusion, those that are unable to do so are at risk of intrapartum hypoxia [1,2]. Although fetal growth restriction is a major risk factor for intrapartum compromise, there is now good evidence to suggest that some apparently normally grown fetuses are also at increased risk. These fetuses have evidence of cerebral redistribution, similar to that seen in their growth restricted
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counterparts rendering them vulnerable to adverse obstetric and perinatal outcomes [3–7]. Cerebral redistribution in these fetuses is reflected by a low cerebroplacental ratio (CPR) [ratio of the fetal Middle Cerebral Artery Pulsatility index (MCA PI) to the Umbilical Artery Pulsatility Index (UA PI)], which is now believed to be a reliable surrogate marker of suboptimal fetal growth [8–10]. A low CPR is associated with a number of adverse outcomes including operative birth for intrapartum fetal compromise (IFC), low birth weight, Neonatal Intensive Care Unit (NICU) admission [11,12], meconium-stained liquor, non-reassuring fetal heart rate patterns, low Apgar scores, acidosis and perinatal mortality [13]. Concurrent with studies demonstrating an association between aberrant feto-placental Doppler changes and adverse outcomes there are also considerable data showing that nulliparity is strongly associated with complications related to placental dysfunction including pre-eclampsia [14], stillbirth [15], fetal growth restriction [16] as well as emergency operative delivery for IFC [17] and adverse neonatal outcomes [18–20] The aim of this study thus was to, firstly, assess the influence of parity on the CPR and secondly, ascertain if the utility of a low CPR (CPR <10thcentile) for predicting emergency caesarean for IFC and adverse neonatal outcomes differed in nulliparous compared to multiparous women. Methods Data from low risk women with singleton pregnancies, delivering at term, between 2010 and 2017 at the Mater Mothers’ Hospital, Brisbane were analysed. This is Australia’s largest maternity hospital with an annual birth rate of approximately 10,500 births. This study was approved by the hospital’s Human Research Ethics Committee (Ref no. HREC/14/MHS/37). Low risk pregnancy was defined as the absence of the following: multiple pregnancy, known genetic syndromes or congenital fetal malformations, small for gestational age/intrauterine growth restriction (defined as estimated fetal weight <10th centile on ultrasound scan, with or without fetal Doppler changes), pre-existing or gestational diabetes mellitus, renal disorders, hypertension, smoking, maternal age <18 or >40 years or BMI > 40 kg/m2. These variables are known to confer a greater risk of intrapartum fetal compromise. Women were excluded from the study if they did not have recorded ultrasound data for both the MCA PI and UA PI measured at 32 weeks gestation. Gestational age was calculated from either the last menstrual period or the earliest obstetric ultrasound scan. If a woman underwent >1 ultrasound scan, the last Doppler indices prior to delivery was used. The fetal MCA was first imaged using colour Doppler and the waveform then recorded from the proximal third of the vessel, distal to its origin at the circle of Willis [21]. The UA Doppler waveforms were recorded from a free loop of cord. The CPR was calculated by dividing the MCA PI by the UA PI. The gestation specific 10th centile CPR threshold was defined according to previously published data [7,22,23]. Intrapartum fetal heart rate patterns were classified by the treating birth suite obstetric team according to criteria detailed in the Royal Australian and New Zealand College of Obstetricians and Gynaecologists’ guidelines [24]. These are not dissimilar to those used in the United Kingdom [25] and North America [26]. The diagnosis of IFC was made contemporaneously by the treating Obstetrician based on abnormal fetal heart rate patterns and/or high fetal scalp lactate levels (>4 mmol/L). The primary outcome measure was Emergency caesarean section for IFC (EmCS IFC). Secondary outcomes included IFC, meconium stained liquor (MSL), birthweight, gestation specific birthweight <10th centile, [27], neonatal sex, severe acidosis (defined as umbilical artery pH 7.0 or Base Excess 12 mmol/L, or lactate 6 mmol/L), Apgar score 3 at 5 min, admission to NICU and perinatal death (neonatal death and
stillbirth). Serious composite neonatal outcome (SCNO) was defined as a composite of admission to NICU, severe acidosis, Apgar score 3 at 5 min and perinatal death. Data was dichotomised according to parity (P0 vs P1) and further by CPR (<10th vs. 10th centile). Statistical analysis Generalized Estimating Equations (GEE) were used to adjust for the correlation between women who birthed more than once within the study period. Multiple GEE regression adjusting for birthweight, gestation at delivery and maternal age was used to generate adjusted odds ratios (aOR), false positive rates (FPR), positive likelihood ratios (PLR), sensitivity and specificity as well as the area under the receiver operating characteristic curves (AUROC) for the outcomes of interest. Individual CPR values were standardised by calculating z-scores against previously published gestation-specific reference centiles [23]. This allowed for comparison, using the students t-test, of zscore between those who had an adverse outcome compared to those who did not (mean, [SD]) as well as a comparison between nulliparous and multiparous women. Statistical analysis was performed using Stata SE1, Release 15, for Windows (StataCorp LP, College Station, TX, USA) and R versions 3.1.1(R core team 2014) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, URL http://www.R-project.org/). Statistical significance was defined as p < 0.05. Results A total of 4737 women were included in the analysis 2333 were nulliparous (P0) and 2404 were multiparous (P1). The CPR 10th centile values were significantly different at all gestation points (p < 0.001) between nulliparous and multiparous women. (Table 3) (Fig. 1) Of these, 284 (12.2%) nulliparous women and 223 (9.3%) multiparous women had a CPR <10th centile. Median maternal age, BMI and birthweight were different between the two cohorts according to parity (30 years vs. 32 years, 21.8 kg/m2 vs. 22.9 kg/m2 and 3240 g vs. 3370 g respectively, p < 0.001). For nulliparous
Fig. 1. CPR median, IQR and 10th centile threshold by ultrasound gestation and parity. This figure demonstrates the differences in CPR values between nulliparous and multiparous women at different ultrasound gestations (p < 0.05 at 35, 36, 37 and 40 weeks gestation) and the differences in 10th centile threshold at each gestation (p < 0.001 at every gestation). CPR, cerebroplacental ratio; US gestation, ultrasound gestation; IQR, interquartile range. * p < 0.05; ** p < 0.001.
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women there was no significant difference in demographic variables between those with a CPR <10th centile and those with a CPR 10th centile except for the interval between ultrasound scan and delivery whilst for the multiparous cohort, there was a significant difference in ethnicity. (Table 1) The overall incidence of EmCS IFC was 4.1%–6.7% in the nulliparous cohort and 1.6% in the multiparous cohort. There was a significantly greater incidence of all the adverse outcomes (except 5-minute Apgar score <3 and perinatal death) in the nulliparous cohort. In the nulliparous group, women with a CPR <10th centile were significantly more likely to experience IFC (13.0% vs. 8.3%, p < 0.05), undergo EmCS IFC (11.3% vs. 6.1%, p < 0.05) and have an infant with a birthweight <10th centile (29.6% vs. 16.9%, p < 0.001) compared to those with a CPR 10th centile. Multiparous women with a CPR <10th centile were significantly more likely to experience IFC (7.2% vs 2.7%, p < 0.001), undergo an EmCS IFC
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(6.3% vs 1.2%, p < 0.001), deliver an infant with a birthweight <10th centile (15.3% vs. 8.8%, p < 0.05) and to have higher NICU admission rates (12.6% vs. 7.5%, p < 0.05). (Table 2) The overall mean CPR z-score for nulliparous women was lower compared to multiparous women (-0.16 [-1.73 – 1.42] vs 0.04 [-1.63 – 1.69], p < 0.001). It was also lower for women who delivered by mode of birth other than EmCS IFC (-0.14 [-1.7 – 1.43] vs. 0.04 [-1.59 – 1.69], p < 0.001). Both nulliparous and multiparous women had a significantly lower z-score associated with the outcomes of IFC, EmCS IFC and birthweight <10th centile (p < 0.05). In addition, nulliparous women had a significantly lower mean z-score associated with perinatal death (PND) (p < 0.05) whilst multiparous women demonstrated a significantly lower mean z-score associated with NICU admission and SCNO (p < 0.05). Interestingly the mean z-score associated with EmCS IFC was higher in nulliparous women compared to multiparous women ( 0.45
Table 1 Maternal Demographics. Demographic
All Women
Nulliparous
CPR10th% 2181
CPR <10th% 223
p
4737
CPR <10th% 284
p
n.
CPR10th% 2049
Multiparous
P (P0 vs P1)
CPR Maternal age, years BMI, kg/m2 Ethnicity Caucasian ATSI Asian Other Gestation at USS (weeks) Interval between USS and delivery (days) Parity P0 P1 P2 P3
1.99 (1.67–2.34) 31 (27–34) 22.3 (20.1–25.6)
2.02 (1.74–2.33) 30 (26–33) 21.9 (19.8–24.9)
1.32 (1.18–1.44) 30 (27–33) 21.5 (19.6–24.2)
<0.001 NS NS NS
2.10 (1.81–2.45) 32 (28–35) 22.9 (20.5–26.3)
1.35 (1.21–1.47) 32 (28–35) 22.5 (20–26.1)
<0.001 NS NS <0.05
<0.001 <0.001 <0.001 NS
2404 (50.8) 75 (1.6) 1431 (30.2) 825 (17.4) 36 (34–37) 20 (9–32)
1019 (49.7) 29 (1.4) 700 (34.2) 301 (14.7) 35.9 (34.9–36.9) 20 (9–33)
141 (49.7) 4 (1.4) 101 (35.6) 38 (13.4) 36 (35–37) 16 (7–30)
NS <0.001
1146 (54.6) 39 (1.8) 559 (25.7) 435 (20.0) 35.9 (33.9–36.9) 20 (10–32)
98 (44) 3 (1.4) 71 (31.8) 51 (22.9) 36 (34–37) 21 (8–34)
NS NS
<0.001 NS
2333 (49.3) 1551 (32.7) 528 (11.1) 325 (6.9)
2049 (100)
284 (100)
NS
0 1401 (64.2) 482 (22.1) 298 (13.7)
0 150 (67.3) 46 (20.6) 27 (12.1)
NS
CPR, cerebroplacental ratio; BMI, body mass index; ASTI, Aboriginal and Torres Strait Islanders; USS, ultrasound scan; P0; nulliparous; P 1, multiparous. Data reported as n (%), median (IQR) as appropriate.
Table 2 Perinatal outcomes. Outcomes
All Women
Nulliparous Women
CPR10th% 2181
CPR <10th% 223 (9.3)
P
4737
CPR <10th% 284 (12.2)
P
n. (%)
CPR10th% 2049
Multiparous Women
Gestation at delivery (weeks) IFC MSL Mode of delivery SVD Instrumental FTP Instrumental other ElCS EmCS other EmCS IFC Male gender Birthweight, g
39 (38–40) 281 (5.9) 737 (15.6)
39 (38–40) 170 (8.3) 386 (18.9)
39 (38–40) 37 (13.0) 50 (17.6)
<0.05 <0.05 NS
39 (38–40) 58 (2.66) 264 (12.1)
39 (38–39) 16 (7.2) 37 (16.6)
NS 0.001 NS
2481 (52.4) 345 (7.3) 375 (7.9) 799 (16.9) 541 (11.4) 196 (4.1) 2390 (50.5) 3301 (2995–3640)
857 (41.8) 265 (12.9) 258 (12.6) 243 (11.9) 301 (14.7) 125 (6.1) 1035 (50.5) 3266 (2980–3584)
<0.05
NS <0.05
1378 (63.18) 42 (1.93) 65 (2.98) 477 (21.87) 194 (8.9) 25 (1.15) 1096 (50.3_ 3380 (3062–3718)
134 (60.1) <0.001 2 (0.9) 9 (4.0) 48 (21.5) 16 (7.2) 14 (6.3) 118 (52.9) NS NS 3202 (2868–3535) NS <0.001
BW <10th centile 5 min Apgar <3 Acidosis NICU admission Perinatal death SCNO
656 (13.9) 14 (0.3) 343 (7.2) 440 (9.3) 6 (0.38) 694 (14.7)
346 (16.9) 6 (0.3) 229 (11.2) 217 (10.6) 2 (0.1) 386 (18.8)
112 (39.4) 36 (12.7) 43 (15.1) 31 (10.9) 30 (10.6) 32 (11.3) 141 (49.7) 3090.5 (2781.5– 3400) 84 (29.6) 0 40 (14.1) 32 (11.3) 1 (0.4) 63 (22.2)
<0.001 NS NS NS NS NS
192 (8.8) 8 (0.4) 62 (2.8) 163 (7.5) 2 (0.1) 207 (9.5)
34 (15.3) 0 12 (5.4) 28 (12.6) 1 (0.45) 38 (17.0)
<0.05 NS NS <0.05 NS NS
P (P0 vs P1)
<0.001 <0.001 <0.001
<0.001 NS <0.001 0.001 NS <0.001
Outcomes reported as n.(%) or mean(SD) or median (IQR) as appropriate. NS; non-significant; CPR, cerebroplacental ratio; P0, nulliparous women; P 1, multiparous women; IFC, intrapartum fetal compromise; MSL, meconium stained liquor; SVD, spontaneous vaginal delivery; FTP, failure to progress; ElCS, elective caesarean section; EmCS, emergency caesarean section; IFC, intrapartum fetal compromise; BW, birthweight; Acidosis, umbilical artery pH 7.0 or Base Excess 12 mmol/L, or lactate 6 mmol/L ; NICU, neonatal intensive care unit; perinatal death, intrauterine fetal demise or neonatal death; SCNO, severe composite neonatal outcome (umbilical artery pH < 7.0, base excess 12 mmol/L and/or lactate 6 mmol/L, Apgar score 3 at 5 min, neonatal intensive care admission, perinatal death).
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Table 3 Cerebroplacental ratios according to parity at different gestations. US Gestation (weeks)
32 33 34 35 36 37 38 39 40 41 42
Nulliparous
Multiparous
n.
Median (IQR)
n.
Median (IQR)
146 115 304 237 554 445 274 145 87 20 5
2.06 (1.8–2.4) 2.17 (1.8–2.6) 2.14 (1.8–2.4) 2.06 (1.7–2.4) 1.94 (1.6–2.3) 1.9 (1.5–2.2) 1.85 (1.5–2.2) 1.74 (1.4–2.0) 1.6 (1.3–1.9) 1.48 (1.3–1.8) 1.6 (1.3–1.7)
196 147 313 290 628 408 257 95 47 15 8
2.17 (1.8–2.4) 2.2 (1.9–2.5) 2.18 (1.9–2.5) 2.13 (1.8–2.5) 2.04 (1.7–2.4) 1.99 (1.7–2.3) 1.82 (1.5–2.2) 1.79 (1.4–2.1) 1.75 (1.4–2.1) 1.7 (1.2–2) 1.83 (1.6–2.0)
P value
0.5 0.5 0.3 0.03 <0.001 <0.001 0.6 0.5 0.02 0.5 0.5
US, ultrasound; IQR, interquartile range.
[ 2.22 – 1.1] vs. 0.52 [ 2.23 – 2.02]) although this difference did not reach statistical significance. (Table 4) Fig. 2 demonstrates the effect of parity upon z-score (mean, 95% CI) for those delivering by EmCS IFC compared to other modes of birth. The z-score was significantly lower among those delivering by EmCS IFC for those who were P0 and P1. Interestingly this difference was significantly greater for women who were P1 than P0 (0.66 [0.25–1.06] vs. 0.31 [0.15-0.47], p < 0.001). The odds of having a CPR <10th centile for nulliparous women was significantly greater than that for multiparous women (OR 1.24, 95%CI 1.02–1.5 vs. OR 0.81, 95%CI 0.7-0.98, p < 0.001). Amongst nulliparous women, a CPR <10th centile threshold was significantly associated with higher odds of IFC (aOR 1.46, 95%CI 1.0–2.1, p < 0.05), EmCS IFC (aOR 1.73, 95%CI 1.2–2.6, p < 0.05) and birthweight <10th centile (aOR 2.12, 95%CI 1.6–2.8, p < 0.001). The specificities of this CPR threshold for all these outcomes were >88%. The corresponding sensitivities were 17.9% (IFC), 20.4% (EmCS IFC) and 19.6% (birthweight <10th centile) respectively and FPR of <12%. The corresponding PLR and AUROC were 1.54 and 0.53 (IFC), 1.76 and 0.54 (EmCS IFC) and 1.86 and 0.55 (birthweight <10th centile). For the other adverse outcomes (meconium stained liquor, NICU admission and SCNO) the aORs did not reach statistical significance. (Table 5) For multiparous women, a CPR <10th centile threshold was significantly associated with higher odds of IFC (aOR 2.46, 95%CI 1.4–4.3, p < 0.05), MSL (aOR 1.61, 95% CI 1.1–2.4, p < 0.05), EmCS IFC (aOR 4.99, 95%CI 2.5–9.9, p < 0.001), birthweight <10th centile (aOR 1.9, 95%CI 1.3–2.8, p = 0.01), severe acidosis (aOR 2.02, 95%CI 1.1– 3.8, p < 0.05), NICU admission (aOR 1.8, 95%CI 1.2–2.7, p < 0.05) and the composite SCNO (aOR 1.91, 95%CI 1.30–2.75, p < 0.001). The
Fig. 2. Relationship between parity and z-score (mean, 95% CI) according to mode of delivery. This figure demonstrates the difference in z-score mean and 95% CI between for those delivering by EmCS IFC compared to other mode of birth according to parity. 95% CI, 95% confidence interval; *, p < 0.05; EmCS IFC, emergency caesarean section for intrpartum fetal compromise; other MoDel, mode of delivery other than EmCS IFC.
specificities of this CPR threshold for all these outcomes were >90% with associated sensitivities of 21.6% (IFC), 12.3% (MSL), 35.9% (EmCS IFC), 15.0% (birthweight <10th centile), 16.2% (severe acidosis), 14.7% (NICU admission) and 15.5% (SCNO) respectively and FPRs of <10%. The corresponding PLR and AUROC were 2.4 and 0.55 (IFC), 1.4 and 0.52 (MSL), 4.1 and 0.64 (EmCS IFC), 1.8 and 0.54 (severe acidosis), 1.7 and 0.53 (NICU admission) and 1.8 and 0.53 (SCNO) respectively. A CPR 10th centile was protective in nulliparous women against IFC (aOR 0.68, 95% CI 0.5–1.0, p = 0.05), EmCS IFC (aOR 0.58, 95%CI 0.40.9, p < 0.05) and birthweight <10th centile (aOR 0.47, 95%CI 0.4-0.6, p < 0.001). A CPR 10th centile in multiparous women was significantly protective for all adverse outcomes - IFC (aOR 0.4, 95%CI 0.2-0.7, p < 0.05), MSL (aOR 0.62, 95%CI 0.4-0.9, p < 0.05), EmCS IFC (aOR 0.2, 95%CI 0.1-0.4, p < 0.001), birthweight <10th centile (aOR 0.53, 95%CI 0.4-0.8, p = 0.001), severe acidosis (aOR 0.5, 95%CI 0.3-0.94, p < 0.05), NICU admission (aOR 0.56, 95%CI 0.4-0.9, p < 0.05), and SCNO (aOR 0.5, 95%CI 0.3-0.7, p < 0.001). (Table 5) Given the significant difference seen in CPR values and 10th centile threshold between nulliparous and multiparous women, a further analysis was performed assessing the diagnostic performance of a low CPR using a CPR <10th threshold specific to the woman’s parity.
Table 4 Z scores associated with adverse outcomes. Outcome
Nulliparous
n.
z-score outcome 2333
All women IFC MSL EmCS IFC BW <10th centile 5 min Apgar <3 Acidosis NICU admission Perinatal death SCNO
0.16 ((-1.73 – 1.42) 0.39 (-2.2 – 1.12) 0.18 (-1.69 – 1.36) 0.45 (-2.22 – 1.1) 0.51 (-2.15 – 1.13) 0.15 (-1.18 – 1.03) 0.16 (-1.85 – 1.47) 0.18 (-1.87 – 1.48) 1.18 (-2.6- -0.78) 0.17 (-1.94 – 1.48)
Multiparous z-score non-outcome
0.14 (-1.7 – 1.43) 0.15 (-1.75 – 1.42) 0.14 (-1.7 – 1.43) 0.08 (-1.59 – 1.45) 0.16 (-1.73 – 1.42) 0.16 (-1.71 – 1.38) 0.16 (-1.72 – 1.40) 0.13 (-0.88 – 0.5) 0.16 (-1.69 – 1.36)
P
<0.001 NS <0.001 <0.001 NS NS NS <0.05 NS
z-score outcome 2404 0.04 (-1.63 – 1.69) 0.27 (-2.07 - 1.56) 0.03 (-1.75 – 1.81) 0.52 (-2.23 – 2.02) 0.35 (-2.06 – 1.42) 0.58 (-0.83 – 1.40) 0.17 (-1.82 – 1.42) 0.19 (-2.11 – 1.53) 0.83 (-1.55 - -0.55) 0.2 (-2.06 – 1.49)
z-score non- outcome
0.04 0.04 0.04 0.08 0.03 0.04 0.05 0.05 0.06
(-1.6 – 1.7) (-1.61-1.68) (-1.59 – 1.69) (-1.55 – 1.72) (-1.63 – 1.70) (-1.61 – 1.71) (-1.57 – 1.72) (-0.63 – 0.71) (-1.54 – 1.72)
P
<0.05 NS <0.001 <0.001 NS NS <0.05 NS <0.001
P between z-score for outcome by parity
<0.001 NS <0.05 NS NS NS NS NS NS NS
Z-scores were generated by standardising CPR for gestation specific reference centiles. Reported as mean (95% CI). IFC, intrapartum fetal compromise; MSL, meconium stained liquor; EmCS IFC emergency caesarean for intrapartum fetal compromise; MoDel, mode of delivery; BW, birthweight; NICU, neonatal intensive care unit; SCNO, severe composite neonatal outcome (umbilical artery pH < 7.0, base excess 12 mmol/L and/or lactate 6 mmol/L, Apgar score 3 at 5 min, neonatal intensive care admission, perinatal death).
J.M. Turner et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 230 (2018) 15–21
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Table 5 Diagnostic performance of CPR <10th centile according to parity for prediction of adverse outcomes. Outcome
n (%)
aOR (95% CI)
P
CPR <10th Nulliparous Multiparous
284 (12.2) 223 (9.3)
1.24 (1.02–1.5) 0.81 (0.7–0.98)
<0.05 <0.05
Intrapartum fetal compromise Nulliparous CPR10th Multiparous CPR10th Nulliparous CPR<10th Multiparous CPR<10th
170 (8.3) 58 (2.7) 37 (13) 16 (7.2)
0.68 (0.5–1.0) 0.41 (0.2–0.7) 1.46 (1.0–2.1) 2.46 (1.4–4.3)
Meconium stained liquor Nulliparous CPR10th Multiparous CPR10th Nulliparous CPR<10th Multiparous CPR<10th
386 (18.8) 264 (12.1) 50 (17.6) 37 (16.6)
EmCS IFC Nulliparous CPR10th Multiparous CPR10th Nulliparous CPR<10th Multiparous CPR<10th
Sensitivity (95% CI)
Specificity (95% CI)
FPR
PLR
AUROC (95% CI)
0.05 <0.05 0.05 <0.05
17.87 (12.9–23.8) 21.62 (12.9–32.7)
88.38 (86.9–89.7) 91.12 (89.9-92.2)
11.62 8.88
1.54 2.43
0.53 (0.5–0.56) 0.56 (0.52–0.61)
1.0 (0.7–1.4) 0.62 (0.4–0.9) 1.0 (0.7–1.4) 1.61 (1.1–2.4)
NS <0.05 NS <0.05
11.47 12.29
87.65 91.14
12.35 8.86
0.93 1.39
0.5 (0.48–0.51) 0.52 (0.5–0.54)
125 (6.1) 25 (1.15) 32 (11.3) 14 (6.3)
0.58 (0.4–0.9) 0.2 (0.1–0.4) 1.73 (1.2–2.6) 4.99 (2.5–9.9)
<0.05 <0.001 <0.05 <0.001
20.38 (14.4–27.5) 35.9 (21.2–52.8)
88.42 (86.99–89.7) 91.16 (89.9–92.3)
11.58 8.84
1.76 4.06
0.54 (0.51–0.58) 0.64 (0.56–0.71)
Birthweight <10th% Nulliparous CPR10th Multiparous CPR10th Nulliparous CPR<10th Multiparous CPR<10th
345 (16.8) 192 (8.8) 84 (29.6) 34 (15.2)
0.47 (0.4–0.6) 0.53 (0.4–0.8) 2.12 (1.6–2.8) 1.9 (1.3–2.8)
<0.001 0.001 <0.001 0.001
19.58 (15.9–23.7) 15.04 (10.6-20.4)
89.5 (88.0–90.8) 91.32 (90.1-92.5)
10.5 8.68
1.86 1.73
0.55 (0.53–0.6) 0.53 (0.51-0.56)
Severe Acidosis Nulliparous CPR10th Multiparous CPR10th Nulliparous CPR<10th Multiparous CPR<10th
229 (11.2) 62 (2.8) 40 (14.1) 12 (5.4)
0.8 (0.6–1.2) 0.5 (0.3–0.94) 1.25 (0.9–1.8) 2.02 (1.1–3.8)
NS <0.05 NS <0.05
14.87 (10.8–19.7) 16.22 (8.7–26.6)
88.18 (86.7–89.5) 90.94 (89.7–92.1)
11.82 9.06
1.26 1.79
0.52 (0.49–0.54) 0.54 (0.49–0.58)
NICU admission Nulliparous CPR10th Multiparous CPR10th Nulliparous CPR<10th Multiparous CPR<10th
217 (10.6) 163 (7.5) 32 (11.3) 28 (12.6)
0.92 (0.6–1.4) 0.56 (0.4–0.9) 1.08 (0.7–1.6) 1.8 (1.2–2.7)
NS <0.05 NS <0.05
12.85 (8.96-17.7) 14.66 (9.97-20.5)
87.91 (86.4-89.3) 91.19 (89.9-92.3)
12.09 8.81
1.06 1.66
0.5 (0.48–0.53) 0.53 (0.5–0.56)
SCNO Nulliparous CPR10th Multiparous CPR10th Nulliparous CPR<10th Multiparous CPR<10th
386 (18.8) 207 (9.5) 63 (22.2) 38 (17)
0.83 (0.6–1.1) 0.5 (0.3–0.7) 1.2 (0.9–1.6) 2.0 (1.4–2.9)
NS <0.001 NS <0.001
14.03 (10.95-17.6) 15.51 (11.2-20.7)
88.27 (86.7-89.7) 91.43 (90.2-92.6)
11.73 8.57
1.2 1.81
0.51 (0.49–0.53) 0.53 (0.51–0.56)
aOR, Adjusted Odds Ratio adjusts for birthweight, maternal age and gestation at delivery, gestation at ultrasound scan; CI, confidence interval; CPR, cerebroplacental ratio; FPR, false positive rate; PLR, positive likelihood ratio; AUROC, area under the receiver operators characteristic curve; CPR, cerebroplacental ratio; EmCS IFC, emergency caesarean section for intrapartum fetal compromise; NICU, neonatal intensive care unit; SCNO, severe composite neonatal outcome (umbilical artery pH < 7.0, base excess 12 mmol/L and/or lactate 6 mmol/L, Apgar score 3 at 5 min, neonatal intensive care admission, perinatal death).
This demonstrated a reduction in the odds of nulliparous women having a CPR <10th centile (aOR 1.24 vs. aOR 1.01) and an increase in odds in multiparous women (aOR 0.81 vs. aOR 0.99). There was an increase in aOR for birthweight <10th centile in both nulliparous and multiparous women (aOR 2.12 vs. 2.5 and aOR 1.9 vs. 2.0 respectively) and a reduction in the aOR for EmCS IFC in both cohorts (aOR 1.73 vs. 1.63 and aOR 4.99 vs. 4.15 respectively). Additionally, in multiparous women there was a reduction in the odds of acidosis (aOR 2.02, 95% CI 1.1–3.8 vs. aOR 1.9, 95% CI 1.01–3.6) and odds of SCNO (aOR 2.0, 95%CI 1.4–2.9 vs 1.7, 95% CI 1.1–2.4). (Supplement 1) Discussion Principal findings and implications for practice This study demonstrates that parity not only has a significant impact upon the CPR but also on the diagnostic utility of a CPR <10th centile threshold for predicting adverse intrapartum and neonatal outcomes. Our results from this low risk cohort show that multiparous women have a higher mean z-score and
significantly lower odds of a CPR <10th centile than nulliparous women. Furthermore, we demonstrate the somewhat surprising and novel finding that for multiparous women with a CPR <10thcentile, the odds of adverse outcomes including IFC, meconium stained liquor, EmCS IFC, and SCNO are greater than nulliparous women. Our data also suggest that the FPR of a CPR <10thcentile in multiparous women for the prediction of adverse outcomes is less than 10%, lower than previous reported studies [7]. Conversely, a CPR >10thcentile appears to be protective for all these adverse outcomes in multiparous women but this effect was only seen for IFC, EmCS IFC and low birthweight in nulliparous women. Our findings thus strongly suggest that a low CPR in a multiparous woman is a greater risk factor for adverse outcomes than a similar finding in a nulliparous counterpart. The findings of our study suggest that the development of any algorithm for predicting adverse perinatal outcomes should take into account parity and perhaps different thresholds to define high and low risk. Historically parity has been treated as a dichotomous variable for pregnancy risk assessment, however more recent proposals
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suggest that parity should be included into a multiple-level approach when stratifying for obstetric risks - nulliparity, low multiparity (para 1–3) and grand multiparity ( para 4) [18]. Our results support this suggestion given that the difference in mean zscore for those delivering by EmCS IFC was greatest for women who were P1-3. (Fig. 1) A low CPR is a marker of cerebral redistribution that results from adaptive changes in the fetal circulation generally in response to placental dysfunction [28]. Nulliparity is thought to affect placental function due to poorer placentation in the first trimester - placentae from multiparous women exhibit a significantly greater proportion of decidual vessels with endovascular trophoblastic invasion [29] as well as higher levels of vascular endothelial growth factor (VEGF) expression [30]. It is hypothesised that this arises due to permanent changes in the spiral artery architecture that occurs during the first pregnancy, thereby modifying subsequent vascular remodelling in the next pregnancy [31], in essence a form of “endometrial priming”. Our data supports this postulation - multiparous women are less likely to have placental dysfunction and hence have a higher median CPR. Crucially however, our findings suggest that if in a multiparous woman, the CPR falls to <10th centile this indicates significant fetal compromise (compared to a fetus in a nulliparous woman) and enhanced vulnerability to the stresses of labour and worse neonatal outcomes. Strengths and limitations The limitations of this study are mainly due to its retrospective design. At our institution low risk women as defined in this study do not routinely have third trimester ultrasound scans. Therefore, for the majority of the study cohort, there would have been a clinical indication for requesting an ultrasound including reduced fetal movements, antepartum bleeding, concerns about fetal size or growth and assessment of presentation. Thus, the women included into this study may not reflect a truly low risk population. An additional limitation was the variation in gestation at which the ultrasound was performed. We adjusted for this by using CPR thresholds specific for gestational age and standardised comparisons with the use of z-scores [22]. A possible further limitation is the arbitrary dichotomization of the CPR. As the CPR is a continuous variable, setting a single threshold may risk underestimating the severity of disease in the study cohort. Indeed some investigators argue that the use of interval thresholds provides a more accurate classification system as it allows for greater than two possible outcomes [32]. Despite this limitation, many studies do indeed use a threshold of <10th centile [7,8,13] to define an atrisk cohort. Previous studies have addressed the limitations of universal ultrasound screening for the prevention of adverse perinatal outcomes [33,34]. A recent systematic review assessing the value of the CPR for predicting adverse perinatal outcomes concluded that whilst the CPR had a strong association with adverse perinatal outcomes, there was insufficient high-quality evidence at this stage to advocate its use as a stand-alone test [11]. In our view, the relatively underwhelming performance of a low CPR as defined in this study, suggests that it should be used with caution particularly for low risk women. Currently the CPR is widely used to decide obstetric management in late pregnancy, with many clinicians using an isolated low CPR an indication for early term birth. Given the now clearly appreciated neonatal and longer-term risks of early term birth this practice should be discouraged without good evidence to the contrary, preferably from adequately powered randomised controlled trials [35,36]. Our results however, underscore the potential importance of parity when evaluating a low CPR in late third trimester.
Conflict of interest The authors report no conflicts of interest. Acknowledgement The authors acknowledge research support by the Mater Foundation. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi: https://doi.org/10.1016/j. ejogrb.2018.09.010. References [1] Janbu T., Nesheim BI. Uterine artery blood velocities during contractions in pregnancy and labour related to intrauterine pressure. Br J Obstet Gynaecol 1987;94(12):1150–5. [2] RCOG. The investigation and management of the small-for-gestational-age fetus. London (UK): Royal College of Obstetricians and Gynaecologists; 2013 2013; Green-top guideline no.31. [3] Sabdia S, Greer RM, Prior T, Kumar S. Predicting intrapartum fetal compromise using the fetal cerebro-umbilical ratio. Placenta 2015;36(5):594–8. [4] Khalil AA, Morales-Rosello J, Morlando M, et al. Is fetal cerebroplacental ratio an independent predictor of intrapartum fetal compromise and neonatal unit admission? Am J Obstet Gynecol 2015;213(1) 54 e51-10. [5] Morales-Rosello J, Khalil A. Fetal cerebral redistribution: a marker of compromise regardless of fetal size. Ultrasound Obstet Gynecol 2015;46 (4):385–8. [6] Morales-Rosello J, Khalil A, Morlando M, Bhide A, Papageorghiou A, Thilaganathan B. Poor neonatal acid-base status in term fetuses with low cerebroplacental ratio. Ultrasound Obstet Gynecol 2015;45(2):156–61. [7] Bligh LN, Al Solai A, Greer RM, Kumar S. Diagnostic performance of cerebroplacental ratio thresholds at term for prediction of low birthweight and adverse intrapartum and neonatal outcomes in a term, low-risk population. Fetal Diagn Ther 2018;43(3):191–8. [8] 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(2) 124 e121-126. [9] 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(1) 61 e61-68. [10] 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 (3):303–10. [11] Dunn L, Sherrell H, Kumar S. Review: systematic review of the utility of the fetal cerebroplacental ratio measured at term for the prediction of adverse perinatal outcome. Placenta 2017;54:68–75. [12] DeVore GR. The importance of the cerebroplacental ratio in the evaluation of fetal well-being in SGA and AGA fetuses. Am J Obstet Gynecol 2015;213(1):5– 15. [13] Khalil A, Morales-Rosello J, Townsend R, et al. Value of third-trimester cerebroplacental ratio and uterine artery Doppler indices as predictors of stillbirth and perinatal loss. Ultrasound Obstet Gynecol 2016;47(1):74–80. [14] Long PA, Abell DA, Beischer NA. Parity and pre-eclampsia. Aust N Z J Obstet Gynaecol 1979;19(4):203–6. [15] Gardosi J, Madurasinghe V, Williams M, Malik A, Francis A. Maternal and fetal risk factors for stillbirth: population based study. BMJ 2013;346:f108. [16] Cnattingius S, Axelsson O, Eklund G, Lindmark G, Meirik O. Factors influencing birthweight for gestational age, with special respect to risk factors for intrauterine growth retardation. Early Hum Dev 1984;10(1–2):45–55. [17] Schuit E, Kwee A, Westerhuis ME, et al. A clinical prediction model to assess the risk of operative delivery. BJOG 2012;119(8):915–23. [18] Bai J, Wong FW, Bauman A, Mohsin M. Parity and pregnancy outcomes. Am J Obstet Gynecol 2002;186(2):274–8. [19] Cnattingius S, Forman MR, Berendes HW, Graubard BI, Isotalo L. Effect of age, parity, and smoking on pregnancy outcome: a population-based study. Am J Obstet Gynecol 1993;168(Pt. 1):16–21. [20] Prior T, Mullins E, Bennett P, Kumar S. Influence of parity on fetal hemodynamics and amniotic fluid volume at term. Ultrasound Obstet Gynecol 2014;44(6):688–92. [21] Mari G, Deter RL, Carpenter RL, et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med 2000;342(1):9–14. [22] Flatley C, Greer RM, Kumar S. The magnitude of change in the fetal cerebroplacental ratio in the third trimester and the risk of adverse pregnancy outcome. Ultrasound Obstet Gynecol 2016.
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