Soluble fms-like tyrosine kinase-1/placental growth factor ratio at 36 weeks' gestation: association with spontaneous onset of labor and intrapartum fetal compromise in low-risk pregnancies.

BACKGROUND: Previous evidence showed that placental dysfunction triggers spontaneous preterm or term births and intrapartum fetal compromise and often requires urgent delivery, thereby exposing both the fetus and the mother to significant risks. Predicting spontaneous labor onset and intrapartum fetal compromise could improve obstetrical management and outcomes, but this is currently difficult, particularly in low-risk populations. OBJECTIVE: The objective of this study was to examine whether placental dysfunction, as assessed at 36 weeks' gestation by the soluble fms-like tyrosine kinase-1 to placental growth factor ratio, is associated with the interval to spontaneous onset of labor and intrapartum fetal compromise that requires cesarean delivery in a routinely examined population. STUDY DESIGN: This was a retrospective analysis of prospectively collected data of women with singleton pregnancies who underwent routine assessment at 35+0 to 36+6 weeks' gestation at the King's College Hospital (London, England). Using a general linear model, the study examined the outcomes related to the soluble fms-like tyrosine kinase-1/placental growth factor ratio, including the time interval from testing to spontaneous onset of labor and the subsequent rate of fetal compromise that required a cesarean delivery. Patients who underwent induction of labor or prelabor cesarean deliveries were excluded from the study. Competing risks regression and Cox regression models were used to estimate the cumulative incidence and the risk of the outcomes of interest. RESULTS: In the screened population of 45,375 patients, 23,831 (52.5%) had spontaneous onset of labor and were included in the analysis. Cases with an soluble fms-like tyrosine kinase-1/placental growth factor ratio >50 delivered about 1 week earlier than those with a ratio of ≤50 (39.2 vs 40.0 weeks' gestation; P<.001). The general linear model showed that a larger soluble fms-like tyrosine kinase-1/placental growth factor ratio was associated with earlier spontaneous onset of labor (P<.001), particularly among multiparous women. The soluble fms-like tyrosine kinase-1/placental growth factor ratio was significantly associated, as expected, with cases of preeclampsia and advanced maternal age. The cumulative incidence of spontaneous onset of labor was significantly higher in cases with an soluble fms-like tyrosine kinase-1/placental growth factor ratio >50 than in those with a ratio 50 (P<.001). Cox regression showed that the risk for spontaneous onset of labor increased with an soluble fms-like tyrosine kinase-1/placental growth factor ratio >50 (hazard ratio, 1.424; 95% confidence interval, 1.253-1.618; P<.001) and, as expected, the risk was mitigated over time from when the soluble fms-like tyrosine kinase-1/placental growth factor ratio was measured to spontaneous labor onset (P<.001). Cases with intrapartum fetal compromise had a higher mean soluble fms-like tyrosine kinase-1/placental growth factor ratio than those without intrapartum fetal compromise (21.79 vs 17.67; P<.001). Qualitative addition of fetal compromise to the general linear model showed a higher soluble fms-like tyrosine kinase-1/placental growth factor ratio in cases with fetal compromise than in those without fetal compromise (P=.014). Competing risks regression showed a positive dose-response effect for fetal compromise with increasing soluble fms-like tyrosine kinase-1/placental growth factor ratios (P<.001). Above and below the optimal cutoff of 50, the quoted cumulative incidences were 6.7% and 4.7%, respectively (P<.001). The effect of the soluble fms-like tyrosine kinase-1/placental growth factor ratio remained significant even after adjusting for preeclampsia, which is a well-known major risk factor for fetal compromise. Finally, the proportion of cases with intrapartum fetal compromise who had an soluble fms-like tyrosine kinase-1/placental growth factor ratio >50 decreased from 35% to 0% with advancing gestation. CONCLUSION: This study showed that an increased soluble fms-like tyrosine kinase-1/placental growth factor ratio at 36 weeks' gestation is associated with an earlier gestational age at spontaneous onset of labor and higher rates of intrapartum fetal compromise. There are 2 major implications, namely an soluble fms-like tyrosine kinase-1/placental growth factor ratio >50 indicates imminent labor onset with about a 40% mean risk increase and immediate clinical translation for term pregnancy monitoring. In addition, an increased soluble fms-like tyrosine kinase-1/placental growth factor ratio increases the risk for intrapartum fetal compromise, although outcome variability indicates reassessment within multimarker models.

Exploring the potential cost-effectiveness of a new computerised decision support tool for identifying fetal compromise during monitored term labours: an early health economic model.

BACKGROUND: Around 60% of term labours in the UK are continuously monitored using cardiotocography (CTG) to guide clinical labour management. Interpreting the CTG trace is challenging, leading to some babies suffering adverse outcomes and others unnecessary expedited deliveries. A new data driven computerised tool combining multiple clinical risk factors with CTG data (attentive CTG) was developed to help identify term babies at risk of severe compromise during labour. This paper presents an early health economic model exploring its potential cost-effectiveness. METHODS: The model compared attentive CTG and usual care with usual care alone and simulated clinical events, healthcare costs, and infant quality-adjusted life years over 18 years. It was populated using data from a cohort of term pregnancies, the literature, and administrative datasets. Attentive CTG effectiveness was projected through improved monitoring sensitivity/specificity and potential reductions in numbers of severely compromised infants. Scenario analyses explored the impact of including litigation costs. RESULTS: Nationally, attentive CTG could potentially avoid 10,000 unnecessary alerts in labour and 2400 emergency C-section deliveries through improved specificity. A reduction of 21 intrapartum stillbirths amongst severely compromised infants was also predicted with improved sensitivity. Attentive CTG could potentially lead to cost savings and health gains with a probability of being cost-effective at £25,000 per QALY ranging from 70 to 95%. Potential exists for further cost savings if litigation costs are included. CONCLUSIONS: Attentive CTG could offer a cost-effective use of healthcare resources. Prospective patient-level studies are needed to formally evaluate its effectiveness and economic impact in routine clinical practice.

Association between Doppler assessment and secondary cesarean delivery for intrapartum fetal compromise in small-for-gestational-age fetuses.

PURPOSE: To elucidate the association between arterial and venous Doppler ultrasound parameters and the risk of secondary cesarean delivery for intrapartum fetal compromise (IFC) and neonatal acidosis in small-for-gestational-age (SGA) fetuses. METHODS: This single-center, prospective, blinded, cohort study included singleton pregnancies with an estimated fetal weight (EFW) < 10th centile above 36 gestational weeks. Upon study inclusion, all women underwent Doppler ultrasound, including umbilical artery (UA) pulsatility index (PI), middle cerebral artery (MCA) PI, fetal aortic isthmus (AoI) PI, umbilical vein blood flow (UVBF), and modified myocardial performance index (mod-MPI). Primary outcome was defined as secondary cesarean section due to IFC. RESULTS: In total, 87 SGA pregnancies were included, 16% of which required a cesarean section for IFC. Those fetuses revealed lower UVBF corrected for abdominal circumference (AC) (5.2 (4.5-6.3) vs 7.2 (5.5-8.3), p = 0.001). There was no difference when comparing AoI PI, UA PI, ACM PI, or mod-MPI. No association was found for neonatal acidosis. After multivariate logistic regression, UVBF/AC remained independently associated with cesarean section due to IFC (aOR 0.61 [0.37; 0.91], p = 0.03) and yielded an area under the curve (AUC) of 0.78 (95% CI, 0.67-0.89). A cut-off value set at the 50th centile of UVBF/AC reached a sensitivity of 86% and specificity of 58% for the occurrence of cesarean section due to IFC (OR 8.1; 95% CI, 1.7-37.8, p = 0.003). CONCLUSION: Low levels of umbilical vein blood flow (UVBF/AC) were associated with an increased risk among SGA fetuses to be delivered by cesarean section for IFC.

A case-control study of the interaction of fetal heart rate abnormalities, fetal growth restriction, meconium in the amniotic fluid and tachysystole, in relation to the outcome of labour.

OBJECTIVE: To quantify the incidence of intrapartum risk factors in labours with an adverse outcome, and compare them with the incidence of the same indicators in a series of consecutive labours without adverse outcome. DESIGN: Case-control study. SETTING: Twenty-six maternity units in the UK. POPULATION OR SAMPLE: Sixty-nine labours with an adverse outcome and 198 labours without adverse outcome. METHODS: Observational study. MAIN OUTCOME MEASURES: Incidence of risk factors in hourly assessments for 7 hours before birth in the two groups. RESULTS: A risk score combining suspected fetal growth restriction, tachysystole, meconium in the amniotic fluid and fetal heart rate abnormalities (baseline rate and variability, presence of decelerations) gave the best indication of likely outcome group. CONCLUSIONS: Accurate risk assessment in labour requires fetal heart rate abnormalities to be considered in context with additional intrapartum risk factors.

Effect of intrapartum epidural analgesia on rate of emergency delivery for presumed fetal compromise: nationwide registry-based cohort study.

OBJECTIVES: To determine the rate of emergency delivery for presumed fetal compromise after epidural analgesia (EDA) compared with that after alternative analgesia or no analgesia, and to assess whether this rate is increased in pregnancies with reduced placental reserve. METHODS: This was a nationwide registry-based cohort study of 629 951 singleton pregnancies delivered at 36 + 0 to 42 + 0 weeks of gestation that were recorded in the Dutch national birth registry between 2014 and 2018, including 120 426 cases that received EDA, 86 957 that received alternative analgesia and 422 568 that received no analgesia during labor. Pregnancies with congenital anomaly, chromosomal abnormality, fetal demise, planned Cesarean delivery, non-cephalic presentation at delivery and use of multiple forms of analgesia were excluded. The primary outcome was emergency delivery for presumed fetal compromise. Secondary outcomes included delivery characteristics and neonatal outcome. Negative binomial regression analysis was stratified by parity and results are presented according to birth-weight centile, after adjusting for confounding. RESULTS: Among women who received EDA, 13.2% underwent emergency delivery for presumed fetal compromise, compared with 4.1% of women who had no analgesia (relative risk (RR), 3.23 (95% CI, 3.16-3.31)) and 7.0% of women who received alternative analgesia (RR, 1.72 (95% CI, 1.67-1.77)). Independent of birth weight, the RR of presumed fetal compromise after EDA vs no analgesia was higher in parous women (adjusted RR (aRR), 2.15 (95% CI, 2.04-2.27)) compared with nulliparous women (RR, 1.88 (95% CI, 1.84-1.94)). Stratified for parity, the effect of EDA was modified significantly by birth-weight centile (interaction P-value, < 0.001 for nulliparous and 0.004 for parous women). The emergency delivery rate following EDA was highest in those with a birth weight < 5th centile (25.2% of nulliparous and 16.6% of parous women), falling with each increasing birth-weight centile category up to the 91st -95th centile (11.8% of nulliparous and 7.2% of parous women). CONCLUSIONS: Intrapartum EDA is associated with a higher risk of emergency delivery for presumed fetal compromise compared with no analgesia and alternative analgesia, after adjusting for relevant confounding. The highest rate of emergency delivery for presumed fetal compromise was observed at the lowest birth-weight centiles. RRs of emergency delivery for presumed fetal compromise after EDA were modestly but consistently modified by birth-weight centile, supporting the hypothesis that the adverse effects of EDA are exacerbated by reduced placental function. While EDA provides effective pain relief during labor, alternative strategies for pain management may be preferable in pregnancies with a high background risk of fetal compromise. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Uterine artery Doppler in early labor and perinatal outcome in low-risk term pregnancy: prospective multicenter study.

OBJECTIVE: The prediction of adverse perinatal outcomes in low-risk pregnancies is poor, mainly owing to the lack of reliable biomarkers. Uterine artery (UtA) Doppler is closely associated with placental function and may facilitate the peripartum detection of subclinical placental insufficiency. The objective of this study was to evaluate the association of mean UtA pulsatility index (PI) measured in early labor with obstetric intervention for suspected intrapartum fetal compromise and adverse perinatal outcome in uncomplicated singleton term pregnancies. METHODS: This was a prospective multicenter observational study conducted across four tertiary maternity units. Low-risk term pregnancies with spontaneous onset of labor were included. The mean UtA-PI was recorded between uterine contractions in women admitted for early labor and converted into multiples of the median (MoM). The primary outcome of the study was the occurrence of obstetric intervention, i.e. Cesarean section or instrumental delivery, for suspected intrapartum fetal compromise. Secondary outcomes were the occurrence of adverse perinatal outcomes, including 5-min Apgar score < 7, low cord arterial pH, raised cord arterial base excess, admission to the neonatal intensive care unit (NICU) and postnatal diagnosis of small-for-gestational-age fetus. Composite adverse perinatal outcome was defined as the occurrence of at least one of the following: acidemia in the umbilical artery, defined as pH < 7.10 and/or base excess > 12 mmol/L, 5-min Apgar score < 7 or admission to the NICU. RESULTS: Overall, 804 women were included, of whom 40 (5.0%) had abnormal mean UtA-PI MoM. Women who had an obstetric intervention for suspected intrapartum fetal compromise were more frequently nulliparous (72.2% vs 53.6%; P = 0.008), had a higher frequency of increased mean UtA-PI MoM (13.0% vs 4.4%; P = 0.005) and had a longer duration of labor (456 ± 221 vs 371 ± 192 min; P = 0.01). On logistic regression analysis, only increased mean UtA-PI MoM (adjusted odds ratio (aOR), 3.48 (95% CI, 1.43-8.47); P = 0.006) and parity (aOR, 0.45 (95% CI, 0.24-0.86); P = 0.015) were independently associated with obstetric intervention for suspected intrapartum fetal compromise. Increased mean UtA-PI MoM was associated with a sensitivity of 0.13 (95% CI, 0.05-0.25), specificity of 0.96 (95% CI, 0.94-0.97), positive predictive value of 0.18 (95% CI, 0.07-0.33), negative predictive value of 0.94 (95% CI, 0.92-0.95), positive likelihood ratio of 2.95 (95% CI, 1.37-6.35) and negative likelihood ratio of 0.91 (95% CI, 0.82-1.01) for obstetric intervention for suspected intrapartum fetal compromise. Pregnancies with increased mean UtA-PI MoM also showed a higher incidence of birth weight < 10th percentile (20.0% vs 6.7%; P = 0.002), NICU admission (7.5% vs 1.2%; P = 0.001) and composite adverse perinatal outcome (15.0% vs 5.1%; P = 0.008). CONCLUSION: Our study, conducted in a cohort of low-risk term pregnancies enrolled in early spontaneous labor, showed an independent association between increased mean UtA-PI and obstetric intervention for suspected intrapartum fetal compromise, albeit with moderate capacity to rule in, and poor capacity to rule out, this condition. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Epidural analgesia and emergency delivery for presumed fetal compromise: post-hoc analysis of RAVEL multicenter randomized controlled trial.

OBJECTIVE: To investigate the association between epidural analgesia (EDA) vs patient-controlled remifentanil analgesia (PCRA) and emergency delivery for presumed fetal compromise, in relation to birth-weight quintile. METHODS: This was a post-hoc per-protocol analysis of the RAVEL multicenter equivalence randomized controlled trial. Non-anomalous singleton pregnancies between 36 + 0 and 42 + 6 weeks' gestation were randomized at the time of requesting pain relief to receive EDA or PCRA. The primary outcome was emergency delivery for presumed fetal compromise. Secondary outcomes included mode of delivery and neonatal outcomes. Analysis was performed according to birth-weight quintile and was corrected for relevant confounding variables. RESULTS: Of 619 pregnant women, 336 received PCRA and 283 received EDA. Among women receiving EDA, 14.8% had an emergency delivery for presumed fetal compromise, compared with 8.3% of women who received PCRA. After adjusting for parity, women receiving EDA had higher odds of presumed fetal compromise compared to those receiving PCRA (odds ratio, 1.69 (95% CI, 1.01-2.83)). A statistically significant linear-by-linear association was observed between presumed fetal compromise and birth-weight quintile (P = 0.003). The incidence of emergency delivery for presumed fetal compromise was highest in women receiving EDA and delivering a neonate with a birth weight in the lowest quintile. CONCLUSIONS: Intrapartum EDA is associated with a higher rate of emergency delivery for presumed fetal compromise compared to treatment with PCRA. Birth-weight quintile is a strong predictor of this outcome, independent of pain management method. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Outcomes of the novel Odon Device in indicated operative vaginal birth.

BACKGROUND: No new method of assisting vaginal birth has been introduced into clinical practice since the development of the vacuum extractor in the 1950s. The Odon Device is a new device that employs a circumferential air cuff over the fetal head to assist birth. In this study, the Odon Device has been used to assist vaginal birth for standard clinical indications. OBJECTIVE: This study aimed to investigate the clinical impact, safety, and acceptability of the Odon Device to women, their babies, and clinicians and to assess the feasibility of recruiting women to an interventional intrapartum research study. STUDY DESIGN: This is a nonrandomized, single-arm interventional feasibility study of the Odon Device for operative vaginal birth undertaken in a single maternity unit: Southmead Hospital, Bristol, United Kingdom. The Odon Device was used to assist birth in 40 women who required the birth to be assisted for suspected fetal compromise and/or prolonged second stage of labor. The primary clinical outcome was the proportion of births successfully assisted with the Odon Device, and the primary feasibility outcome was the proportion of eligible women who were approached and who agreed to participate. Neonatal outcome data were reviewed at day 28, and maternal outcomes were investigated up to day 90. RESULTS: Between October 2018 and January 2019, 298 of 384 approached, eligible women (77.6%) consented to participate. Of these women, 40 received the intervention-the use of the Odon Device. Birth was assisted in all cephalic (occiput anterior, occiput transverse, and occiput posterior) fetal positions, at all stations at or below the ischial spine and with or without regional analgesia. The Odon Device was effective in 19 of 40 cases (48%). Of the 40 births, 21 (52.5%) required additional assistance: 18 of 40 births (45%) were completed using nonrotational forceps, 1 of 40 births (3%) required rotational forceps, and 2 of 40 births (5%) required an emergency cesarean delivery. There was no serious maternal or neonatal adverse event related to the use of the device, and there was no serious adverse device effect. There were 4 devices (10%) that were ineffective because of a manufacturing fault. Furthermore, 39 of 40 women (98%) reported a high birth perception score. All practitioners were able to use the device as intended, although some steps in using the device were reported to be easier to perform (setup and deflation of air chamber) than others (application of the device and withdrawal of the applicator). CONCLUSION: Recruitment to an interventional study of a new device for operative vaginal birth was feasible; 78% of eligible women were willing to participate, often expressing an aspiration for an alternative to forceps and vacuum. The success rate of the Odon Device was lower than reported success rates of vacuum and forceps; however, in this study, the device had been used to assist birth for standard clinical indications. There was no significant maternal or neonatal safety concern associated with the use of the device, although the number of births studied was small. Further feasibility study to establish iterative changes to the device, technique, and clinical indications is necessary.

Does gestational age at term play a role in the association between cerebroplacental ratio and operative delivery for intrapartum fetal compromise?

INTRODUCTION: To assess the impact of gestational age at term on the association between cerebroplacental ratio (CPR) and operative delivery for intrapartum fetal compromise (IFC) and prognostic performance of CPR to predict operative delivery for IFC. MATERIAL AND METHODS: This was a retrospective cohort study including 2052 singleton pregnancies delivered between 37+0 and 41+6  weeks of gestation in a single tertiary referral center over an 8-year period. CPR was measured within 1 week of delivery. IFC was defined as the presence of persistent pathological cardiotocography pattern or the combination of pathological cardiotocography pattern and fetal scalp pH < 7.20. Operative delivery included instrumental vaginal delivery and cesarean section. Pregnancies were grouped according to birthweight (small for gestational age [SGA, birthweight <10th centile] and appropriate for gestational age [AGA, birthweight 10th-90th centile]) and gestational age by week at delivery. Rates of operative delivery were compared between the subgroups. Prognostic value of CPR was assessed using receiver operating characteristic curve. RESULTS: Of the study cohort, 308 (15%) had a CPR <10th centile, 374 (18%) operative delivery for IFC, and 298 (15%) were SGA at birth. Overall, the rates of operative delivery for IFC were higher in the low CPR group both in SGA (35% vs. 22%; p = 0.023) and in AGA (23% vs. 16%; p = 0.007). According to gestational age by week at delivery, fetuses with low CPR showed higher rates of operative delivery for IFC with advancing gestational age, mainly in pregnancies delivered at 40 weeks (54% vs. 23%; p = 0.004) and at 41 weeks (60% vs. 19%; p = 0.010) for SGA and at 41 weeks (39% vs. 20%; p = 0.001) for AGA. The predictive value of CPR remained stable throughout term and was poor both in SGA and in AGA. CONCLUSIONS: Both SGA and AGA fetuses with low CPR showed higher rates of operative delivery for IFC at term with advancing gestational age. Prognostic value of CPR throughout term was poor.

The physiology of intrapartum fetal compromise at term.

Uterine contractions in labor result in a 60% reduction in uteroplacental perfusion, causing transient fetal and placental hypoxia. A healthy term fetus with a normally developed placenta is able to accommodate this transient hypoxia by activation of the peripheral chemoreflex, resulting in a reduction in oxygen consumption and a centralization of oxygenated blood to critical organs, namely the heart, brain, and adrenals. Providing there is adequate time for placental and fetal reperfusion between contractions, these fetuses will be able to withstand prolonged periods of intermittent hypoxia and avoid severe hypoxic injury. However, there exists a cohort of fetuses in whom abnormal placental development in the first half of pregnancy results in failure of endovascular invasion of the spiral arteries by the cytotrophoblastic cells and inadequate placental angiogenesis. This produces a high-resistance, low-flow circulation predisposing to hypoperfusion, hypoxia, reperfusion injury, and oxidative stress within the placenta. Furthermore, this renders the placenta susceptible to fluctuations and reduction in uteroplacental perfusion in response to external compression and stimuli (as occurs in labor), further reducing fetal capillary perfusion, placing the fetus at risk of inadequate gas/nutrient exchange. This placental dysfunction predisposes the fetus to intrapartum fetal compromise. In the absence of a rare catastrophic event, intrapartum fetal compromise occurs as a gradual process when there is an inability of the fetal heart to respond to the peripheral chemoreflex to maintain cardiac output. This may arise as a consequence of placental dysfunction reducing pre-labor myocardial glycogen stores necessary for anaerobic metabolism or due to an inadequate placental perfusion between contractions to restore fetal oxygen and nutrient exchange. If the hypoxic insult is severe enough and long enough, profound multiorgan injury and even death may occur. This review provides a detailed synopsis of the events that can result in placental dysfunction, how this may predispose to intrapartum fetal hypoxia, and what protective mechanisms are in place to avoid hypoxic injury.

Prelabor screening at term using the cerebroplacental ratio and placental growth factor: a pragmatic randomized open-label phase 2 trial.

BACKGROUND AND OBJECTIVE: In some women placental function may not be adequate to meet fetal growth requirements in late pregnancy or the additional demands during labor, thus predisposing these infants to intrapartum fetal compromise and subsequent serious morbidity and mortality. The objective of this study was to determine if the introduction of a prelabor screening test at term combining the cerebroplacental ratio and maternal placental growth factor level would result in a reduction in a composite of adverse outcomes. STUDY DESIGN: Single-site, nonblinded, randomized controlled trial conducted at a tertiary hospital in Brisbane, Australia. Eligible women were randomized to either receive the screening test performed between 37-38 weeks or routine obstetric care. Screen-positive women were offered induction of labor. The primary outcome was a composite of emergency cesarean delivery for nonreassuring fetal status (fetal distress) or severe neonatal acidosis or low Apgar score or stillbirth or neonatal death. RESULTS: Women were recruited and randomized (n = 501) between April 2017 and January 2019. Sixty-three of 249 subjects (25.3%) in the screened group compared to 56 of 252 (22.2%) in the control group experienced the primary outcome (relative risk = 1.14 [95% confidence interval, 0.83-1.56]; P = .418). Women who screened positive were more likely to require operative delivery for fetal distress, have meconium-stained liquor, have pathologic fetal heart rate abnormalities, and have infants with lower birthweight compared to women that screened negative. CONCLUSION: The introduction of this test did not result in improvements in intrapartum intervention rates or neonatal outcomes. However, it did show discriminatory potential, and future research should focus on refining the thresholds used.

Safety and efficacy of sildenafil citrate to reduce operative birth for intrapartum fetal compromise at term: a phase 2 randomized controlled trial.

BACKGROUND AND OBJECTIVE: Sildenafil citrate is a vasodilator used in erectile dysfunction and pulmonary hypertension. We tested whether it reduces emergency operative births for fetal compromise and improves fetal or uteroplacental perfusion in labor in a phase 2 double-blind randomized controlled trial. STUDY DESIGN: Women at term in early labor or undergoing scheduled induction of labor at Mater Mother's Hospital, Brisbane, Australia, were randomly allocated 50 mg of sildenafil citrate orally 8 hourly up to 150 mg or placebo. Intrapartum fetal monitoring followed Royal Australian and New Zealand College of Obstetricians and Gynaecologists guidelines. Primary outcomes were (1) emergency operative birth (by cesarean delivery or instrumental vaginal birth) for intrapartum fetal compromise and (2) mean indices of fetal and uteroplacental perfusion using Doppler ultrasound. Analysis was by intention-to-treat. TRIAL REGISTRATION NUMBER: ANZCTRN12615000319572 RESULTS: Between September 2015 and January 2019, 300 women were randomized equally to sildenafil citrate or placebo. Sildenafil citrate reduced the risk of emergency operative birth by 51% (18% vs 36.7%; relative risk, 0.49, 95% confidence interval, 0.33-0.73, P=.0004, number needed to treat = 5 [3-11]). There was no difference in indices of fetal and uteroplacental perfusion, but these were ascertained in only 71 women. Sildenafil citrate reduced the risk of meconium-stained liquor or pathologic fetal heart rate patterns by 43% (25.3% vs 44.7%; relative risk, 0.57, 95% confidence interval, 0.41-0.79, P=.0005), but its effects on fetal scalp sampling rates (2.0% vs 6.7%; relative risk, 0.30, 95% confidence interval, 0.08-1.07, P=.06) and adverse neonatal outcome (20.7% vs 21.3%; relative risk, 0.97, 95% confidence interval, 0.62-1.50, P=.89) were inconclusive. Only 3.6% of maternal levels of sildenafil citrate or its metabolite were detected in cord blood. No differences in maternal adverse events were seen. CONCLUSION: Sildenafil citrate reduced operative birth for intrapartum fetal compromise, but much larger phase 3 trials of its effects on mother and child are needed before it can be routinely recommended.

Maternal cardiovascular function and risk of intrapartum fetal compromise in women undergoing induction of labor: pilot study.

OBJECTIVE: Identification of the fetus at risk of intrapartum compromise has many benefits. Impaired maternal cardiovascular function is associated with placental hypoperfusion predisposing to intrapartum fetal distress. The aim of this study was to assess the predictive accuracy of maternal hemodynamics for the risk of operative delivery due to presumed fetal compromise in women undergoing induction of labor (IOL). METHODS: In this prospective cohort study, patients were recruited between November 2018 and January 2019. Women undergoing IOL were invited to participate in the study. A non-invasive ultrasonic cardiac output monitor (USCOM-1A®) was used for cardiovascular assessment. The study outcome was operative delivery due to presumed fetal compromise, which included Cesarean or instrumental delivery for abnormal fetal heart monitoring. Regression analysis was used to test the association between cardiovascular markers, as well as the maternal characteristics, and the risk of operative delivery due to presumed fetal compromise. Receiver-operating-characteristics-curve analysis was used to assess the predictive accuracy of the cardiovascular markers for the risk of operative delivery for presumed fetal compromise. RESULTS: A total of 99 women were recruited, however four women were later excluded from the analysis due to semi-elective Cesarean section (n = 2) and failed IOL (n = 2). The rate of operative delivery due to presumed fetal compromise was 28.4% (27/95). Women who delivered without suspected fetal compromise (controls) were more likely to be parous, compared to those who had operative delivery due to fetal compromise (52.9% vs 18.5%; P = 0.002). Women who underwent operative delivery due to presumed fetal compromise had a significantly lower cardiac index (median, 2.50 vs 2.60 L/min/m2 ; P = 0.039) and a higher systemic vascular resistance (SVR) (median, 1480 vs 1325 dynes × s/cm5 , P = 0.044) compared to controls. The baseline model (being parous only) showed poor predictive accuracy, with an area under the curve of 0.67 (95% CI, 0.58-0.77). The addition of stroke volume index (SVI) < 36 mL/m2 , SVR > 7.2 logs or SVR index (SVRI) > 7.7 logs improved significantly the predictive accuracy of the baseline model (P = 0.012, P = 0.026 and P = 0.012, respectively). CONCLUSION: In this pilot study, we demonstrated that prelabor maternal cardiovascular assessment in women undergoing IOL could be useful for assessing the risk of intrapartum fetal compromise necessitating operative delivery. The addition of SVI, SVR or SVRI improved significantly the predictive accuracy of the baseline antenatal model. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Correlation of short-term variation and Doppler parameters with adverse perinatal outcome in low-risk fetuses at term.

OBJECTIVE: To evaluate the association of short-term variation (STV) and Doppler parameters with adverse perinatal outcome in low-risk fetuses at term. METHODS: This was a retrospective study of 1008 appropriate-for-gestational age (AGA) term fetuses. Doppler measurements [umbilical artery (UA), middle cerebral artery (MCA), and cerebroplacental ratio (CPR)] and computerized CTG (cCTG) with STV analysis were performed prior to active labor (≤ 4 cm cervical dilatation) within 72 h of delivery. The association between Doppler indices and STV values with adverse perinatal outcome was analyzed using univariate regression analysis. RESULTS: No significant association between Doppler parameters and the need for secondary cesarean delivery (CD) or operative vaginal delivery (OVD) was shown. Regarding fetuses delivered by CD due to fetal distress, regression analyzes revealed significantly higher UA PI MoM. However, the differences in MCA PI MoM and CPR MoM were not statistically significant. Fetuses with the need for emergency CD showed significantly higher UA PI MoM, lower MCA PI MoM and lower CPR MoM. Neonates with a 5-min Apgar score < 7 had significantly lower MCA PI MoM and neonatal acidosis (UA pH ≤ 7.10) showed a significant association with UA PI MoM. None of the assessed outcome parameters were significantly associated to STV. CONCLUSION: Doppler indices assessed close to delivery in low-risk fetuses at term show a moderate association with adverse outcome parameters, whereas STV does not appear to predict poor perinatal outcome in this group of fetuses.

Relationship of prelabor fetal cardiac function with intrapartum fetal compromise and neonatal status at term.

OBJECTIVES: To investigate prospectively the relationship of fetal cardiac function and Doppler ultrasound parameters with intrapartum fetal compromise (IFC) in appropriately grown term fetuses. Secondary aims were to correlate prenatal cardiac function with neonatal acid-base status, intrapartum fetal heart rate (FHR) abnormalities and adverse neonatal outcomes. METHODS: This was a blinded, prospective, observational, cohort study of 270 women with an uncomplicated singleton pregnancy who underwent fortnightly ultrasound assessment from 36 weeks' gestation until delivery at the Mater Mother's Hospital, Brisbane, Australia. Fetal cardiac output and blood flow parameters were assessed and correlated with intrapartum and neonatal outcomes. The primary outcome was need for operative (either Cesarean or instrumental vaginal) delivery for IFC. Secondary outcome measures were acidosis at birth, 5-min Apgar score ≤ 7, suspicious or pathological FHR abnormalities and admission to the neonatal intensive care unit. RESULTS: Two hundred and seventy women were included in the analysis, of whom 51 (18.9%) had an emergency operative delivery for IFC. Fetuses that had emergency delivery for IFC showed lower mean left ventricular cardiac output (LVCO) (560 ± 44 mL/min vs 617 ± 73 mL/min; P < 0.001), lower mean LVCO/right ventricular cardiac output (RVCO) ratio (0.55 ± 0.07 vs 0.64 ± 0.11; P < 0.001), lower mean cerebroplacental ratio (CPR) (1.62 ± 0.3 vs 1.90 ± 0.5; P < 0.001) and higher mean RVCO (1026 ± 105 mL/min vs 978 ± 110 mL/min; P = 0.003) compared with those that did not develop IFC. Additionally, LVCO and CPR were lower in fetuses with adverse neonatal outcome. CONCLUSION: Term fetuses with estimated fetal weight > 10th centile that develop IFC have evidence of lower LVCO and higher RVCO, which are in turn associated with poorer condition of the newborn. Fetal CPR is positively correlated with LVCO. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Cerebroplacental ratio thresholds measured within 2 weeks before birth and risk of Cesarean section for intrapartum fetal compromise and adverse neonatal outcome.

OBJECTIVES: Prediction of intrapartum fetal compromise in uncomplicated, term pregnancies is a global obstetric challenge. Currently, no widely accepted screening test for this condition exists, although the cerebroplacental ratio (CPR) shows promise. We aimed to evaluate prospectively the screening performance of the CPR 10th centile threshold for prediction of Cesarean section for intrapartum fetal compromise (IFC) and composite adverse neonatal outcome (ANO) after 36 weeks' gestation in low-risk women, and to compare this with CPR ≤ 1 and < 5th centile thresholds described previously in the literature. METHODS: This was a blinded, prospective, observational, cohort study of 483 women with uncomplicated singleton pregnancy who underwent fortnightly CPR measurements from 36 weeks to delivery, and their intrapartum and neonatal outcomes were recorded. The CPR 10th centile threshold screening performance was calculated for emergency Cesarean section for IFC and composite ANO (defined as acidosis at birth, 5-min Apgar score < 7 and/or admission to the neonatal intensive care unit). Comparison of screening performance of CPR ≤ 1 and < 5th and < 10th centile thresholds was also undertaken for these specified outcomes. RESULTS: In total, 437 women were included in the analysis, of whom 4.1% had an emergency Cesarean section for IFC and 17.8% had a composite ANO. Sensitivity and specificity for CPR < 10th centile were, respectively, 55.6% and 87.9% for prediction of Cesarean section for IFC, and 28.2% and 88.0% for composite ANO. Compared with CPR ≤ 1 and < 5th centile, CPR < 10th centile yielded the best overall test performance for detection of Cesarean section for IFC and composite ANO, although its predictive value was only fair for Cesarean section for IFC (area under the receiver-operating characteristics curve (AUC) = 0.72) and poor for composite ANO (AUC = 0.58). CONCLUSION: The CPR 10th centile threshold may be useful as a component of a risk assessment tool for Cesarean section for IFC in low-risk pregnancies at term. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Prelabor screening for intrapartum fetal compromise in low-risk pregnancies at term: cerebroplacental ratio and placental growth factor.

OBJECTIVES: To determine the screening performance of low fetal cerebroplacental ratio (CPR), a marker of fetal adaptation to suboptimal growth, and maternal placental growth factor (PlGF) level, both in isolation and in combination, for the prediction of Cesarean section (CS) for intrapartum fetal compromise (IFC) and composite adverse neonatal outcome (CANO). METHODS: This was a prospective cohort study in low-risk women with uncomplicated singleton pregnancy from 36 weeks' gestation to delivery. CPR and PlGF were assessed fortnightly and intrapartum and neonatal outcomes were recorded. CPR and PlGF values from the final assessment for each woman were corrected for gestational age and assessed for screening performance, firstly as continuous variables and then as binary predictors. RESULTS: Of the 264 women who consented to participate in the study, 207 were included in the final analysis. Seven pregnancies required CS for IFC and 38 had CANO. Pregnancies delivered by CS for IFC had lower CPR and PlGF centiles than those in all other pregnancies. Pregnancies with CANO had a lower PlGF centile. The greatest areas under the receiver-operating characteristics curves (AUCs) for the prediction of CS for IFC (0.92; 95% CI, 0.86-0.97) and CANO (0.64; 95% CI, 0.54-0.74) were achieved by a combination of CPR 20th and PlGF 33rd centile thresholds. This produced sensitivities, specificities and positive likelihood ratios for the prediction of CS for IFC of 100%, 86% and 7.14, respectively, and 34.2%, 87.0% and 2.63, respectively, for the prediction of CANO. There was no statistical difference in the AUC for CS for IFC between the combined model and when CPR was used alone, or for CANO between the combined model and CPR or PlGF in isolation. CONCLUSIONS: This pilot proof-of-concept study describes the screening performance of CPR and maternal PlGF level for CS for IFC in low-risk women from 36 weeks' gestation. It was found that CPR and maternal PlGF improved the overall predictive utility for CS for IFC, as well as that for CANO. However, given the lack of significant difference between the combined model and its individual components, it is debatable whether the combined model is a superior screening test. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Screening Performance of Placental Growth Factor for the Prediction of Low Birth Weight and Adverse Intrapartum and Neonatal Outcomes in a Term Low-Risk Population.

INTRODUCTION: Fetuses who fail to reach their genetic growth potential are thought to have sub-optimal placental function. Low placental growth factor (PlGF) levels have been shown to be predictive of placentally mediated conditions, such as pre-eclampsia or fetal growth restriction. We investigated the screening performance of PlGF for the prediction of low birth weight (<10th centile for gestation) and adverse intrapartum and neonatal outcomes in apparently low-risk term pregnancies. MATERIALS AND METHODS: Maternal PlGF levels were measured fortnightly in a blinded, prospective, observational study from 36 weeks of pregnancy. Women and clinicians were blinded to PlGF results, and pregnancies were managed according to local policies and guidelines. Intrapartum and neonatal outcomes were recorded. PlGF was analysed for association with, and predictive capacity for, low birth weight, caesarean section for intrapartum fetal compromise (CS-IFC) and adverse neonatal outcomes. RESULTS: A total of 438 women were included in the final analysis. Lower PlGF levels were associated with low birth weight, CS-IFC and adverse neonatal outcome. For a false-positive rate of 10 and 20%, respectively, the corresponding sensitivities were 9.7-11.1% and 22.2-26.8%. CONCLUSION: As a sole predictor for low birth weight, CS-IFC and adverse neonatal outcome, PlGF was poor as a test.

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.

OBJECTIVES: To investigate the screening performance and best threshold centile (5th vs. 10th) of the cerebroplacental ratio (CPR) in low-risk, term pregnancies to predict low birthweight and adverse intrapartum and neonatal outcomes in a term, low-risk population. METHODS: This was a blinded, prospective, cross-sectional study of low-risk singleton pregnancies at term. Women attended fortnightly from 36 weeks for CPR and estimated fetal weight assessment. Intrapartum and neonatal outcomes were recorded. Primary outcomes assessed were low birthweight, cesarean section for intrapartum fetal compromise, and composite adverse neonatal outcome. RESULTS: A total of 483 women participated in the study. The CPR 10th centile (1.48) threshold resulted in the best screening performance. Sensitivities for low birthweight, cesarean section for intrapartum fetal compromise, and composite adverse neonatal outcome of 41.9, 61.1, and 38.3% were achieved for false-positive rates of 17.7, 17.7, and 15.2%, respectively. The corresponding areas under the receiver operating characteristic curves were 0.62, 0.72, and 0.62. CONCLUSION: The CPR 10th centile resulted in the best screening performance, although this would be considered fair at best. The CPR 10th centile may be useful as part of a risk stratification tool for prediction of low birthweight and adverse intrapartum and neonatal outcomes.

An investigation of the effect of placental growth factor on intrapartum fetal compromise prediction in terminduced high risk pregnancies.

OBJECTIVES: To date, there is no available test to predict the risk of intrapartum fetal compromise (IFC) during labor, either starting spontaneously or induced due to obstetrics indications. The aim of this study was to examine the effectiveness of placental growth factor (PIGF) in identifying cases that develop intrapartum fetal compromise (IFC) in term high-risk pregnancies induced for labor. MATERIAL AND METHODS: This prospective cross-sectional study was conducted on 40 IFC+ cases and 40 IFC- cases with high-risk term pregnancy and labor induction started in the Health Sciences University Gazi Yasargil Training and Research Hospital, between January 2018 and April 2018. Comparisons were made between the groups in respect of placental growth factor (PIGF) levels, and obstetric and neonatal outcomes. RESULTS: The PIGF level was found to be statistically significantly lower in the IFC+ cases compared to the IFC- cases. For a PIGF cutoff value of 32 pg/mL for the prediction of IFC+ cases, sensitivity was 74.4%, specificity 73.2%, NPV 75% and PPV 72.5%, with a statistically significant difference determined between the groups. The IFC+ development risk increased 7.91-fold in patients with PIGF ≤ 32 pg/mL. CONCLUSIONS: The PIGF levels in cases of IFC+ high risk pregnancies were found to be statistically significantly lower than those of IFC- cases. However, further, large-scale randomized controlled research is necessary to demonstrate this relationship better.