The importance of the cerebro-placental ratio at term for predicting adverse perinatal outcomes in appropriate for gestational age fetuses

Study design

The study we conducted is a retrospective cohort study and has been approved by the Ethics Committee of the Friedrich-Schiller-University, Jena, Germany (Reg.-Nr. 2022-2678-Daten). The study population (Figure 1) consists of 491 children, born at the Jena University Hospital between 1 January 2015 and 31 December 2021. The anonymous use of clinical data for research and educational purposes is generally permitted under the governmental regulations of Thuringia, eliminating the need for written consent. Researchers and clinicians are legally authorized to use patient data collected during routine care for scientific and educational presentations, reports, and analyses. The data were accessed for research purposes on July 1, 2022. After this date, the authors no longer had access to any information that could identify individual participants. The ethical approval was obtained in the in the sense of these regulations.

Figure 1:

Cohort composition: from a total of n=575 with available cerebro-placental ratios (CPR) at exactly 40+0 weeks of gestation, we were able to finally include n=491 to our final cohort after applying exclusion criteria: planned C-section (n=12), small for gestational age (n=42), umbilical artery pulsatility index >95. Percentile (n=3) and large for gestational age (n=27).

All women with singleton pregnancies who gave birth in our hospital for which CPR was assessed at 40+0 weeks’ gestation (n=575) and for which spontaneous delivery was intended (n=12 with primary caesarean section excluded) were included as consecutive cases. Further exclusion criteria were a pathological umbilical Doppler (umbilical artery PI>95th percentile=1.097 according to Ciobanu et al. (n=3)) as well as expected SGA (n=42) and LGA fetuses (n=27) based on the estimated birth weight (EFD) at 40+0 weeks of gestation using Hadlock’s formula [17], 18]. We used the cut-off defined for the 40th week of pregnancy published by Ciobanu et al. as a comparison to a cut-off determined in our cohort [17].

Data collection

Data were retrieved from the available patient records. Gestational age was determined for all pregnancies based on the measurement of the fetal crown-rump length (CRL) during the first trimester and thus the calculated date of delivery (40+0), which was defined as the inclusion criterion for our cohort. Maternal body mass index (BMI) was calculated based on the height and the documented pre-pregnancy weight. The birth weight was categorized using Voigt’s percentiles [19]. Doppler examination was obtained from 40+0 weeks of gestation according to our clinical guidelines by a constant and trained group of doctors from the Department of Obstetrics at Jena University Hospital using a 2.0–6.0 MHz transabdominal transducer on a GE Voluson E10 (GE Healthcare GmbH, Solingen, Germany). Umbilical artery Doppler were assessed in a free cord loop and MCA Doppler in the proximal third of the origin of the MCA with an angle nearly to zero between direction of blood flow and ultrasound beam according to the current guidelines published by The International Society of Ultrasound in Obstetrics & Gynecology (ISUOG) [20].

Primary outcome

The primary endpoint was adverse pregnancy outcome (APO) defined as one or more of the following criteria: admission to neonatal intensive care unit (NICU), umbilical cord blood pH<7.1, 5-min APGAR score less than 7, obstetric intervention due to fetal distress (IDFD). An IDFD was defined as a need for vaginal-operative delivery or emergency caesarean section due to fetal distress, indicated by non-reassuring heart rate monitoring or in fetal scull blood testing.

Statistical methods

The statistical analysis was performed using IBM SPSS Statistics 27. 491 cases were included, which met all inclusion and no exclusion criteria. For categorical data, we applied the Chi² test or Fisher exact test. As most of the metric data did not have a normal distribution, median and interquartile range were used for data presentation. The Mann-Whitney U test was performed as a non-parametric test for group comparison of the metric data. The significance level was set at α=0.05 (two-sided).

ROC curves (receiver operator characteristic curves) were generated to assess the accuracy of the prediction of APO of the CPR and maternal age. The area under the curve (AUC) with a 95 % confidence interval was used for this purpose.

The cut-offs for CPR and also maternal age in relation to the prediction model was determined using Youden index criteria [21]. Both sensitivity and specificity were determined and used to calculate the positive predictive values (PPV) and negative predictive values (NPV) for the different CPR cut offs.

Multivariate logistic regression for analyzing the individual effects of the different CPR cut offs, parity, BMI and maternal age on the APO were performed. Adjusted ORs (adjusted for days of gestation at delivery and fetal birth weight) with a 95 % confidence interval (CI) are presented. A p-value <0.05 was considered to indicate statistical significance (2-tailed).

APO depending on the CPR cut offs

To perform group comparisons between cases with a CPR below a certain threshold and cases within the normal range we used different cut off values. The 10th percentile published by Ciobanu et al. (CPR<1.192), the in clinical routine most commonly used cut-off of a CPR<1.0 and the cut off value we retrieved from the data of this study using statistical analysis (CPR<1.269). The results are shown in Tables 2 and 3.

Comparing the groups with and without APO values below the defined cut off were significantly more frequent in the APO group for the value from Ciobanu et al. (22.1 vs. 11.9 %, p=0.008) and the one retrieved from our data (30.8 vs. 17.3 %, p=0.002), while the cut-off of below 1 did not discriminate the group with APO from the one without (3.8 vs. 1.8 %, p=0.257) (Table 2).

Table 3 shows the frequencies of APO in cases with a CPR below the different cut offs. Cases with a CPR<10th percentile according to Ciobanu had significantly more frequent APOs (33.3 vs. 19.2 %, p=0.008) and more IDFDs (24.6 vs. 12.6 %, p=0.008). Cases with a CPR below our cut-off were significantly more likely to have an APO (32.3 vs. 18.4 %, p=0.002), IDFDs (21.2 vs. 12.5 %, p=0.027) and children were significantly more likely to be transferred to NICU (11.1 vs. 4.8 %, p=0.020). There were no significant differences between groups applying a threshold of 1.0. Values for specificity, sensitivity, NPV and PPV are depicted in Table 3.

CPR, age and nulliparity are independent risk factors for APO

Multivariate regression analysis was performed including categorical information on nulliparity, obesity (BMI≥30 kg/m²), maternal age cut off >28.5 years and CPR<1.269 adjusted for gestational age at delivery and birth weight (Table 4). Results retrieved a CPR below 1.269 to be a robust risk factor for APO increasing the risk by 1.7-fold (CI: 1.007–2.905).

Main findings

In this retrospective study of 491 patients with CPR measured directly at term, we were able to establish a CPR cut-off of 1.269 that best discriminated for APO. We demonstrated a significant 1.7-fold increase in the risk of encountering an APO when the CPR measured at term was below our threshold. In contrast the so far applied cut offs for CPR at term both Ciobanu of 1.192 and of just 1 did not reveal to be of robust influence on APO in our multivariate analysis. However, being older than 28.5 years increases the risk for an APO by 2.7-fold and being nulliparous by 4-fold independently (see Table 4).

Comparison to existing literature

The role of antepartum Doppler sonography to identify fetuses at risk for adverse outcomes remains important to detect subclinical placental insufficiency [22]. Fetuses with abnormal antepartum Doppler are supposed to be at higher risk for adverse perinatal outcome [2], [3], [4], [5], [6, 9], 11]. We were able to demonstrate that fetuses with abnormal CPR values at the due date were more likely to experience APOs, including the necessity of an intervention due to fetal distress, admission to NICU and were born with lower birth weights and lower birth weight percentiles (see Table 3 and Supplemental Data).

Like Lu et al. in their prospective study with 384 term pregnancies undergoing induction of labor and the relevance of different clinical parameters prior induction, we were also unable to demonstrate an influence of CPR on fetal blood gas parameters [5]. In contrast, Akolekar et al. were able to demonstrate an association of CPR on blood gas analysis in a rather large cohort of 6,178 singleton pregnancies where CPR was measured at 35–37 weeks’ gestation [23]. The fact that we did not see a significant effect on the 5-min APGAR and the umbilical cord pH can possibly be explained by the fact that our study was a retrospective study and the decision to intervene in the delivery was made early enough to prevent the child from being compromised. However, in comparison to the national perinatal data base (Institut für Qualitätssicherung und Transparenz im Gesundheitswesen, IQTIG) the rate of fetal acidosis (Umbilical artery pH<7.1) and admission rate to NICU were markedly higher in out cohort (5.9 vs. 2.3 % for acidosis and 6.1 vs. 3.5 % for NICU admission) [24]. This demonstrates, that the rate of fetal compromises might be generally higher in a post due date cohort like the one analysed in our study.

In the multivariate analysis, a significant increase in risk was only found for the threshold value we established on the basis of our study. However, our sample is only suitable for validating this threshold value to a limited extent as it was calculated on this very sample. The value should therefore be tested on a different population to confirm its validity. In contrast to El-Sayed et al. and Ciobanu et al., we were unable to demonstrate a significant influence of maternal BMI on the occurrence of APO or CPR in our multivariate analysis [17], 25].

Our calculated value for gestational age of 280 days (1.269) falls between the values calculated by Ciobanu et al. for the time points of 276 days (1.275) and 283 days (1.192). According to Ciobanu et al. we were able to demonstrate a correlation between nulliparity, increased maternal age and low CPR.

The poor predictive value of CPR for an adverse outcome (we calculated sensitivity 30.8 %, specificity 82.7 %, PPV 32.36 %, NPV 81.64 %) was also shown in other studies [2], [3], [4, 13], [26], [27], [28]. Fiolna et al. reported a sensitivity of 35 % and a specificity of 80 % for the CPR<10th percentile. The sensitivity is thus slightly higher and the specificity slightly lower compared to our cut-off. Fiolna et al. also included LGA fetuses into their study, which have an increased risk for APO compared to AGA fetuses. The higher incidence of APO might have increased the sensitivity in this study sample. Furthermore, while we included all patients admitted for spontaneous delivery, they included only pregnant women with a scheduled induction [2] which might have impaired the incidence of APO in the study sample further. Ortiz et al. also found a sensitivity of only 19 % and a specificity of 84 % for the prediction of an APO for CPR below the 10th percentile, whereby in their study the IDFD represented a separate endpoint for which CPR performed better with a sensitivity of 26 % and a specificity of 87 % [13]. In our study, however, IDFD was a component of the adverse outcome, which is a possible reason the different sensitivity and specificity determined for APO. All studies suggest that using CPR alone as a screening method for adverse outcomes lacks sufficient sensitivity and specificity. Fiolna et al. suggested that maternal and pregnancy characteristics, along with the course of labor, may play a more significant role than prenatal fetal oxygenation in the development of fetal stress and associated adverse neonatal outcomes [2].

Strength and limitations

A strength of our study is the measurement of the CPR on the exact estimated date of delivery and the substantial size of the cohort (n=491). Including maternal comorbidities like preexisting cardiovascular diseases or diabetes to establish a cut-off that is broadly applicable can be considered both a strength and also a limitation of our study. Thus, the cut-off is more universally applicable to a broader patient population but can also be significantly altered negatively by a possible higher risk of complications. Weaknesses of our study include primarily verifying the threshold value within the same cohort used for its calculation. To validate our cut-off, it should undergo testing on an independent cohort. By exclusively including cases examined at the EDD (40+0 weeks of gestation), we hoped to improve the predictive power of the calculated value, as CPR fluctuating normal values during pregnancy. Another possible source of bias in our study may be the 39 cases (7.9 %) that were incorrectly classified as AGA by ultrasound. These were also more frequently represented in the group with adverse outcome. This point once again illustrates the relevance but also the over- and underestimation of EFW, especially in SGA but also LGA fetuses, as shown by Dittkrist et al. [29].

Implications

Due to the rather poor discrimination qualities (NPV of our threshold for an APO of 81 %), CPR seems insufficient as a single criterion for a decision in favor of and especially against induction of labor. Nevertheless, fetuses with a CPR below this value were significantly more likely to have an APO, an IDFD and admission to NICU, so it can certainly be assumed that a CPR<1.269 represents a risk factor and could therefore be useful as a supplementary criterion especially in the shared decision-making process with patients at the time of EDD. The extent to which this is weighted should be the aim of further studies.

In a different attempt using Doppler sonographic assessment to predict fetal outcome uterine blood flow at an early stage of labor was determined and showed an independent association of increased mean UtA PI (Uterine Artery PI) with IDFDs and adverse perinatal outcome was shown. However, in this study as well PPV and NPV to predict APO were low (PPV of 0.18 (95 % CI, 0.07–0.33) and NPV of 0.94 (95 % CI, 0.92–0.95)) [22].

Supporting physiological birth is currently becoming more and more important in obstetrics. The ARRIVE study was performed to evaluate the value of induction of labor near term, aiming to reduce the rate of induced labor. The results of the ARRIVE study, showed that elective induction after 39 weeks’ gestation did indeed not improve the composite adverse perinatal outcome. However, fewer maternal interventions such as caesarean sections (18.6 vs. 22.2 %; relative risk (RR), 0.84; 95 % CI, 0.76 to 0.93) and assisted vaginal deliveries (7.3 vs. 8.5 %; RR 0.85; 95 % CI, 0.72–1.01) were necessary in the induction group compared to the expectant-management group [30]. In addition the RATIO37 study with a prospective design and over 9.000 cases included showed that elective labor based on a CPR<5th percentile in addition to estimated fetal weight (EFW) significantly reduced severe neonatal morbidity such as renal or cardiac failure and NICU admission >10 days compared to single use of EFW [15]. Both prospective studies demonstrate, that early term induction even regardless of CPR determination improved neonatal outcome, thus supporting our result, that induction of labor at term in cases with impaired CPR might lead to improved neonatal outcome. However, to prove this conclusion prospective designed studies are mandatory. If we apply the results of the ARRIVE and RATIO37 studies to our data, patients at the EDD who reach the CPR cut-off should be offered elective induction to maybe reduce interventions sub partu and enable them to experience an uncomplicated vaginal delivery.