Term planned delivery based on fetal growth assessment with or without the cerebroplacental ratio in low-risk pregnancies (RATIO37): an international, multicentre, open-label, randomised controlled trial.

BACKGROUND: The cerebroplacental ratio is associated with perinatal mortality and morbidity, but it is unknown whether routine measurement improves pregnancy outcomes. We aimed to evaluate whether the addition of cerebroplacental ratio measurement to the standard ultrasound growth assessment near term reduces perinatal mortality and severe neonatal morbidity, compared with growth assessment alone. METHODS: RATIO37 was a randomised, open-label, multicentre, pragmatic trial, conducted in low-risk pregnant women, recruited from nine hospitals over six countries. The eligibility criteria were designed to be broad; participants were required to be 18 years or older, with an ultrasound-dated confirmed singleton pregnancy in the first trimester, an alive fetus with no congenital malformations at the routine second-trimester ultrasound, an absence of adverse medical or obstetric history, and the capacity to give informed consent. Women were randomly assigned in a 1:1 ratio (block size 100) using a web-based system to either the concealed group or revealed group. In the revealed group, the cerebroplacental ratio value was known by clinicians, and if below the fifth centile, a planned delivery after 37 weeks was recommended. In the concealed group, women and clinicians were blinded to the cerebroplacental ratio value. All participants underwent ultrasound at 36 + 0 to 37 + 6 weeks of gestation with growth assessment and Doppler evaluation. In both groups, planned delivery was recommended when the estimated fetal weight was below the tenth centile. The primary outcome was perinatal mortality from 24 weeks' gestation to infant discharge. The study is registered at ClinicalTrials.gov (NCT02907242) and is now closed. FINDINGS: Between July 29, 2016, and Aug 3, 2021, we enrolled 11 214 women, of whom 9492 (84·6%) completed the trial and were eligible for analysis (4774 in the concealed group and 4718 in the revealed group). Perinatal mortality occurred in 13 (0·3%) of 4774 pregnancies in the concealed group and 13 (0·3%) of 4718 in the revealed group (OR 1·45 [95% CI 0·76-2·76]; p=0·262). Overall, severe neonatal morbidity occurred in 35 (0·73%) newborns in the concealed group and 18 (0·38%) in the revealed group (OR 0·58 [95% CI 0·40-0·83]; p=0·003). Severe neurological morbidity occurred in 13 (0·27%) newborns in the concealed group and nine (0·19%) in the revealed group (OR 0·56 [95% CI 0·25-1·24]; p=0·153). Severe non-neurological morbidity occurred in 23 (0·48%) newborns in the concealed group and nine (0·19%) in the revealed group (0·58 [95% CI 0·39-0·87]; p=0·009). Maternal adverse events were not collected. INTERPRETATION: Planned delivery at term based on ultrasound fetal growth assessment and cerebroplacental ratio at term was not followed by a reduction of perinatal mortality although significantly reduced severe neonatal morbidity compared with fetal growth assessment alone. FUNDING: La Caixa foundation, Cerebra Foundation for the Brain Injured Child, Agència per la Gestió d'Ajuts Universitaris i de Recerca, and Instituto de Salud Carlos III.

Correlation of Meconium-Stained Amniotic Fluid and Adverse Pregnancy Outcomes between 37 to 39 and 40 to 42 Weeks of Gestational Age.

OBJECTIVE: We aimed at assessing the association between meconium-stained amniotic fluid (MSAF) and adverse maternal and neonatal outcomes in early-term versus late-term pregnancies. STUDY DESIGN: Early-term pregnancies (37-39 weeks of gestation) presented with MSAF were compared with late-term (40-42 weeks of gestation) pregnancies with MSAF. The groups were compared with respect to background characteristics, maternal outcomes, and neonatal outcomes. The composite neonatal outcome was the primary outcome of the study, and secondary outcomes included maternal and neonatal outcomes. RESULTS: The early-term group comprised 239 women, compared with 362 women in the late-term group. The primary outcome did not differ between groups. We found a higher prevalence of gestational diabetes (8.37 vs. 3%, p < 0.05), a shorter second stage of labor (45.61 ± 54.67 vs. 65.82 ± 62.99 minutes, p < 0.05), and a longer hospital stay (2.84 ± 2.21 vs. 2.53 ± 1.26 days, p < 0.05) in the early-term group. Other maternal and neonatal characteristics and outcomes were not significantly different between the two groups. CONCLUSION: In term pregnancies complicated by MSAF, adverse neonatal and maternal delivery outcomes are equivalent, regardless of gestational age, and therefore, any term pregnancy complicated by MSAF should be considered high risk and managed appropriately. KEY POINTS: · In term pregnancies complicated by MSAF, adverse neonatal and maternal delivery outcomes are equivalent, regardless of gestational age.. · Any term pregnancy complicated by MSAF should be considered high risk and managed appropriately.. · Deliveries presented with MSAF are typically considered to be high risk and require close fetal surveillance by a certified team with resuscitation skills.. · Our study may help to reduce the need for a close fetal surveillance and delivery interventions if MSAF is not identified as a risk factor for adverse outcomes in late-term pregnancies..

Isolated fetal echogenic bowel and iron-rich mineral water supplement: a case series and review of the literature.

Natural iron-rich mineral water (IRMW) is a supplement with a higher iron bioavailability than oral iron supplement tablets. Five (4%) of 116 women who consumed IRMW starting from 16 weeks of gestation were diagnosed as having isolated foetal echogenic bowel at a single community maternity clinic between 2012 and 2015. The workup of all the women was otherwise negative. Four women taking IRMW were re-checked after discontinuation of the supplement and had a normal-appearing foetal bowel. Our observations suggest that isolated echogenic bowel may be related to the consumption of IRMW, possibly due to the high absorption of iron, leading to the coating of the internal wall of the foetal bowel and subsequent appearance of an echogenic bowel. Although this finding appears free of harmful ramifications, its possible sonographic effects on the appearance of the foetal bowel should be considered in light of the increasing popularity of IRMW use.IMPACT STATEMENTWhat is already known on this subject? IRMW is a highly absorbed iron supplement. The differential diagnosis for foetal echogenic bowel is broad and requires thorough investigation. Iron is secreted through the maternal blood to the amniotic fluid, which is swallowed by the foetus, reaching its bowel.What do the results of this study add? IRMW consumption is a possible aetiology of an isolated foetal echogenic bowel in the second half of pregnancy, conveying no risk of foetal morbidity or mortality.What are the implications of these findings for clinical practice and/or further research? In light of the increasing popularity of IRMW, we believe that it is important to increase the level of awareness of the possible effects of its intake on the sonographic appearance of the foetal bowel.

Effect of Maternal and Fetal Characteristics in Feto-Placental Doppler and Impact of Using Adjusted Standards in the Definition of Fetal Growth Restriction at Term.

INTRODUCTION: This study aimed to determine the effect and clinical impact of physiological characteristics on the 95th/5th centile of the umbilical artery (UA) Doppler and the cerebroplacental ratio (CPR), at 36+ weeks. METHODS: From the multicenter randomized trial "Ratio37," we selected 4,505 low-risk pregnant women between June 2016 and January 2020. We registered physiological characteristics and the pulsatility indexes (PI) of the UA and middle cerebral artery (36-39 weeks). The 95th/5th centile of the UA PI and CPR was modeled by quantile regression. To evaluate the clinical impact of adjusting Doppler, we retrospectively applied gestational age (GA) and fully adjusted standards to 682 small for gestational age (SGA)-suspected fetuses (37 weeks) from a cohort of consecutive patients obtained between January 2010 and January 2020. RESULTS: Several physiological characteristics significantly influenced the 95th/5th centile of the UA and CPR PI. The fully adjusted 95th centile of the UA was higher, and the 5th centile of the CPR was lower than GA-only-adjusted standards. Of the 682 SGA fetuses, 150 (22%) were classified as late fetal growth restricted only by GA and 112 (16.4%) when we adjusted Doppler. These 38 fetuses had similar perinatal outcome than the SGA group. DISCUSSION: The 95th/5th centile of the UA and CPR PI is significantly influenced by physiological characteristics. Adjusting Doppler standards could differentiate better between FGR and SGA.

Local cerebroplacental ratio reference ranges are better predictors for adverse delivery outcomes in normal weight fetuses during pregnancy.

OBJECTIVE: To evaluate the predictive value of local versus external cerebroplacental ratio (CPR) reference ranges for delivery outcomes in low-risk pregnancies. METHODS: A retrospective analysis of all feto-maternal demographic and biometric data in fetuses with normal estimated fetal weight (EFW) and a CPR examination between the years 2014-2019, in a university medical center. The study group included healthy singleton pregnancies from 32-week gestation, with an examination-to-delivery interval of <31 days. The three models compared two thresholds: <5th percentile (CPR 1, CPR 3) and <10th percentile (CPR2). The CPR1 and CPR2 models both use local CPR reference ranges, while the CPR3 model uses an external CPR reference range. The main outcome was predictive accuracy for urgent cesarean delivery (CD), operative delivery (OD), and composite outcome (CO), defined as an Apgar score of <7, fetal blood pH < 7.1 or admission to the neonatal intensive care unit (NICU). RESULTS: Overall, 410 low-risk pregnancies with normal weight fetuses were enrolled in the study. All three CPR models turned out to be significant predictors of CD, with an odds ratio (OR) of 9, 95% CI (2.7-27), p < .001 for CPR1, and an OR of 2.9, 95% CI (1.1-7.4), p < .04 for CPR2, and an OR of 3.4, 95% CI (1.7-6.8), p < .001 for CPR3. All the three models were also found to be predictors of OD, and an OR of 6.9, 95% CI (2.1-22) p < .04 for CPR1, and an OR of 2.8, 95% CI (1.2-6.7), p < .04 for CPR2, and an OR of 2.8, 95% CI (1.4-5.3) p < .01 for CPR3. The positive predictive values (PPV) for CD and OD were both 50% for CPR1, versus 28% and 26% in CPR2, and 24% and 25% in CPR3. The negative predictive value (NPV) was similar, around 88% in all three models. None of the models were found to be significant predictors for CO. CONCLUSIONS: A CPR model based on local reference ranges and <5th percentile cutoffs showed the highest PPV for CD and OD. The calculation of local references for CPR should be encouraged.

Do spontaneously decreasing estradiol levels prior to triggering of ovulation adversely impact in vitro fertilization outcomes?

OBJECTIVE: The aim of this study was to explore the potential adverse effect of spontaneously decreasing serum estradiol (SE) levels on in vitro fertilization (IVF) outcomes. METHODS: This retrospective single-subject study analyzed IVF cycles conducted at a hospital IVF unit between 2010 and 2017. Overall, 2,417 cycles were analyzed. Only cycles with spontaneously decreasing SE before human chorionic gonadotropin (hCG) triggering were included. Each patient served as her own control, and subsequent cycles were analyzed for recurrent SE decreases. The main outcome was the number of oocytes retrieved. RESULTS: Cycle characteristics were similar between the study (SE decrease) and control groups, with the exception of the median SE on the day of hCG triggering (899.7 pg/mL; interquartile range [IQR], 193-2,116 pg/mL vs. 1,566.8 pg/mL; IQR, 249-2,970 pg/mL; p< 0.001). The study group, relative to the control group, had significantly fewer total oocytes (5 [IQR, 2-9] vs. 7 [IQR, 3-11]; p= 0.002) and significantly fewer metaphase II (MII) oocytes (3 [IQR, 1-6] vs. 4 [IQR, 2-8]; p= 0.001) retrieved. The study group had fewer cleavage-stage embryos than the control cycles (3 [IQR, 1-6] vs. 4 [IQR, 2-7]; p= 0.012). Compared to cycles with a ≤ 20% SE decrease, cycles with a > 20% decrease had significantly fewer total and MII oocytes retrieved. SE decrease recurred in 12% of patients. CONCLUSION: A spontaneous decrease in SE levels adversely affected IVF outcomes, with a linear correlation between the percentage decrease and the number of oocytes retrieved. SE decrease can repeat in later cycles.

Prescriptive Reference Standards of Third-Trimester Cerebroplacental Ratio and Its Physiological Determinants.

OBJECTIVE: To construct valid reference standards reflecting optimal cerebroplacental ratio and to explore its physiological determinants. METHODS: A cohort of 391 low-risk pregnancies of singleton pregnancies of nonmalformed fetuses without maternal medical conditions and with normal perinatal outcomes was created. Doppler measurements of the middle cerebral artery and umbilical artery were performed at 24-42 weeks. Reference standards were produced, and the influence of physiological determinants was explored by nonparametric quantile regression. The derived standards were validated in a cohort of 200 low-risk pregnancies. RESULTS: Maternal body mass index was significantly associated with the 5th centile of the cerebroplacental ratio. For each additional unit of body mass index, the 5th centile was on average 0.014 lower. The derived 5th, 10th, and 50th centiles selected in the validation cohort were 5, 9.5, and 51% of the measurements. CONCLUSIONS: This study provides methodologically sound prescriptive standards and suggests that maternal body mass index is a determinant of a cutoff commonly used for decision-making.

Third-trimester Reference Ranges for Cerebroplacental Ratio and Pulsatility Index for Middle Cerebral Artery and Umbilical Artery in Normal-growth Singleton Fetuses in the Israeli Population.

BACKGROUND: The ratio between the fetal umbilical artery pulsatility index (UA-PI) and the middle cerebral artery pulsatility index (MCA-PI) is termed the cerebroplacental ratio (CPR). The CPR represents fetal blood flow redistribution at the early stages of placental insufficiency; moreover, it has predictive value for adverse intrapartum and neonatal outcomes. However, internationally accepted reference ranges for CPR are lacking. OBJECTIVE: This study sought to establish UA-PI, MCA-PI, and CPR reference ranges in low-risk, normal-growth singleton fetuses during the third trimester of pregnancy. METHODS: A retrospective cohort cross-sectional study was performed in the obstetrics ultrasound unit of a university hospital in Israel. We reviewed all fetal and maternal electronic records of pregnant women referred for ultrasound assessment during the third trimester between January 2014 and January 2019. We included only singleton pregnancies with normal anatomy scans and a normal third-trimester estimated fetal weight. The UA-PI, MCA-PI, and CPR reference ranges were reconstructed for each of the vessels for each gestational age between 29 and 41 weeks. RESULTS: A total of 560 pregnancies met the inclusion criteria. Satisfactory waveforms and measurements were obtained in all cases. At least 18 women enrolled at each gestational week. The MCA-PI and CPR values showed a similar parabolic curve during the third trimester of pregnancy, with a peak value at 32 and 33 gestational weeks, respectively. The UA-PI showed a linear and gradual decrease over the gestational age. CONCLUSIONS: In this study we established UA-PI, MCA-PI, and CPR reference ranges in low-risk, normal-growth singleton fetuses during the third trimester based on the Israeli population.

Prolonged activation of the coagulation system during in vitro fertilization cycles.

OBJECTIVE: To investigate coagulation system changes during an in-vitro fertilization (IVF) cycle using Thromboelastogram (TEG) that enables analysis of the elastic properties of whole blood samples and provides a global assessment of the hemostatic function. STUDY DESIGN: A prospective study. TEG indices were evaluated in 23 women who underwent controlled ovarian stimulation for IVF at four points in time: 1. At the beginning of the cycle (corresponding to the lowest levels of E2), 2. On the day of hCG administration (maximal stimulation with highest E2 levels), 3. On the day of ovum pickup and 4. At the first pregnancy test (approximately 14days after ovum pickup). The main outcome measures were TEG indices including R-time (time until initial fibrin formation), K-time (time until a 20mm amplitude is achieved), α angle (the rate of clot formation), Maximum Amplitude (MA, strength of the fibrin clot), Coagulation Index (CI, calculated overall indicator of coagulation) and LY30 (the decrease in graph amplitude). RESULTS: R, K, α angle, MA and CI before hCG administration and at the time of the first pregnancy test were significantly higher compared to the baseline measurement before gonadotropins administration. No correlation was found between E2 and TEG indices. CONCLUSION: Ovarian stimulation is associated with prolonged increased coagulability that extends after the time of maximal ovarian stimulation. The lack of association between E2 levels and TEG indices suggest that additional factors may play a role in the pathogenesis of increased coagulability in women with ovarian stimulation.

A New Perspective on the Risk of Hypercoagulopathy in Ovarian Hyperstimulation Syndrome Using Thromboelastography.

Thromboelastography (TEG) provides real-time assessment of hemostasis by measuring the viscoelastic properties, coagulation factor, and platelet activity in whole blood samples. In this prospective case-control study, we wanted to investigate whether blood clot formation assessment, using TEG, can identify a hypercoagulable state in women with severe ovarian hyperstimulation syndrome (OHSS). Thirty-six women who were hospitalized with severe OHSS were allocated to the OHSS group and 32 women undergoing controlled ovarian hyperstimulation but who did not develop OHSS were allocated to the control group. The TEG indices were compared between women with severe OHSS and controls. All the coagulation indices assessed by TEG were significantly different in the OHSS group compared to the controls, depicting a hypercoagulable state. Median coagulation index was 3.6 (interquartile range: 2.80-4.15) and 1.45 (interquartile range: 0.20-2.30) in study group and controls, respectively ( P < .001). Our results show that TEG can be used to depict a hypercoagulable state in women with severe OHSS.