Associations between hysterectomy and metabolic syndrome: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Metabolic syndrome is linked to an increased risk of incident cardiovascular disease and all-cause mortality. Notable associations exist between hysterectomy with bilateral salpingo-oophorectomy and metabolic syndrome. However, there is emerging evidence that even with ovarian conservation, hysterectomy may be independently associated with long-term cardiovascular disease risk. OBJECTIVE: To examine the associations between hysterectomy with ovarian preservation and metabolic syndrome risk in a multiethnic cohort. STUDY DESIGN: We studied 3367 female participants in the Multi-Ethnic Study of Atherosclerosis who had data on self-reported history of hysterectomy, oophorectomy, hystero-oophorectomy, and metabolic syndrome at baseline (2000-2002). We used adjusted logistic regression to assess the cross-sectional associations between hysterectomy and or oophorectomy subgroups and prevalent metabolic syndrome at baseline. Furthermore, we investigated 1355 participants free of baseline metabolic syndrome and used adjusted Cox regression models to evaluate incident metabolic syndrome from examinations 2 (2002-2004) to 6 (2016-2018). RESULTS: The mean age was 59.0±9.5 years, with 42% White, 27% Black, 19% Hispanic, and 13% Chinese American participants. 29% and 22% had a history of hysterectomy and oophorectomy, respectively. Over a median follow-up of 10.5 (3.01-17.62) years, there were 750 metabolic syndrome events. Hysterectomy (hazard ratio, 1.32 [95% confidence interval, 1.01-1.73]) and hystero-oophorectomy (hazard ratio, 1.40 [95% confidence interval, 1.13-1.74]) were both associated with incident metabolic syndrome compared with having neither hysterectomy nor oophorectomy. CONCLUSION: Hysterectomy, even with ovarian preservation, may be independently associated with a higher risk of metabolic syndrome. If other studies confirm these findings, screening and preventive strategies focused on females with ovary-sparing hysterectomies and the mechanisms underpinning these associations may be explored.

Evaluating Injury Severity in Neonatal Encephalopathy Using Automated Quantitative Electroencephalography Analysis: A Pilot Study.

Quantitative analysis of electroencephalography (qEEG) is a potential source of biomarkers for neonatal encephalopathy (NE). However, prior studies using qEEG in NE were limited in their generalizability due to individualized techniques for calculating qEEG features or labor-intensive pre-selection of EEG data. We piloted a fully automated method using commercially available software to calculate the suppression ratio (SR), absolute delta power, and relative delta, theta, alpha, and beta power from EEG of neonates undergoing 72 h of therapeutic hypothermia (TH) for NE between April 20, 2018, and November 4, 2019. We investigated the association of qEEG with degree of encephalopathy (modified Sarnat score), severity of neuroimaging abnormalities following TH (National Institutes of Child Health and Development Neonatal Research Network [NICHD-NRN] score), and presence of seizures. Thirty out of 38 patients met inclusion criteria. A more severe modified Sarnat score was associated with higher SR during all phases of TH, lower absolute delta power during all phases except rewarming, and lower relative delta power during the last 24 h of TH. In 21 patients with neuroimaging data, a worse NICHD-NRN score was associated with higher SR, lower absolute delta power, and higher relative beta power during all phases. QEEG features were not significantly associated with the presence of seizures after correction for multiple comparisons. Our results are consistent with those of prior studies using qEEG in NE and support automated qEEG analysis as an accessible, generalizable method for generating biomarkers of NE and response to TH. Additionally, we found evidence of an immature relative frequency composition in neonates with more severe brain injury, suggesting that automated qEEG analysis may have a use in the assessment of brain maturity.

Quantification of Diffusion Magnetic Resonance Imaging for Prognostic Prediction of Neonatal Hypoxic-Ischemic Encephalopathy.

Neonatal hypoxic-ischemic encephalopathy (HIE) is the leading cause of acquired neonatal brain injury with the risk of developing serious neurological sequelae and death. An accurate and robust prediction of short- and long-term outcomes may provide clinicians and families with fundamental evidence for their decision-making, the design of treatment strategies, and the discussion of developmental intervention plans after discharge. Diffusion tensor imaging (DTI) is one of the most powerful neuroimaging tools with which to predict the prognosis of neonatal HIE by providing microscopic features that cannot be assessed by conventional magnetic resonance imaging (MRI). DTI provides various scalar measures that represent the properties of the tissue, such as fractional anisotropy (FA) and mean diffusivity (MD). Since the characteristics of the diffusion of water molecules represented by these measures are affected by the microscopic cellular and extracellular environment, such as the orientation of structural components and cell density, they are often used to study the normal developmental trajectory of the brain and as indicators of various tissue damage, including HIE-related pathologies, such as cytotoxic edema, vascular edema, inflammation, cell death, and Wallerian degeneration. Previous studies have demonstrated widespread alteration in DTI measurements in severe cases of HIE and more localized changes in neonates with mild-to-moderate HIE. In an attempt to establish cutoff values to predict the occurrence of neurological sequelae, MD and FA measurements in the corpus callosum, thalamus, basal ganglia, corticospinal tract, and frontal white matter have proven to have an excellent ability to predict severe neurological outcomes. In addition, a recent study has suggested that a data-driven, unbiased approach using machine learning techniques on features obtained from whole-brain image quantification may accurately predict the prognosis of HIE, including for mild-to-moderate cases. Further efforts are needed to overcome current challenges, such as MRI infrastructure, diffusion modeling methods, and data harmonization for clinical application. In addition, external validation of predictive models is essential for clinical application of DTI to prognostication.

Serum brain injury biomarkers are gestationally and post-natally regulated in non-brain injured neonates.

BACKGROUND: To determine the association of gestational age (GA) and day of life (DOL) with the circulating serum concentration of six brain injury-associated biomarkers in non-brain injured neonates born between 23 and 41 weeks' GA. METHODS: In a multicenter prospective observational cohort study, serum CNS-insult, inflammatory and trophic proteins concentrations were measured daily in the first 7 DOL. RESULTS: Overall, 3232 serum samples were analyzed from 745 enrollees, median GA 32.3 weeks. BDNF increased 3.7% and IL-8 increased 8.9% each week of gestation. VEGF, IL-6, and IL-10 showed no relationship with GA. VEGF increased 10.8% and IL-8 18.9%, each DOL. IL-6 decreased by 15.8% each DOL. IL-10 decreased by 81.4% each DOL for DOL 0-3. BDNF did not change with DOL. Only 49.67% of samples had detectable GFAP and 33.15% had detectable NRGN. The odds of having detectable GFAP and NRGN increased by 53% and 11%, respectively, each week after 36 weeks' GA. The odds of having detectable GFAP and NRGN decreased by 15% and 8%, respectively, each DOL. CONCLUSIONS: BDNF and IL-8 serum concentrations vary with GA. VEGF and interleukin concentrations are dynamic in the first week of life, suggesting circulating levels should be adjusted for GA and DOL for clinically relevant assessment of brain injury. IMPACT: Normative data of six brain injury-related biomarkers is being proposed. When interpreting serum concentrations of brain injury biomarkers, it is key to adjust for gestational age at birth and day of life during the first week to correctly assess for clinical brain injury in neonates. Variation in levels of some biomarkers may be related to gestational and postnatal age and not necessarily pathology.

Assisted reproductive technology: Short- and long-term outcomes.

Assisted reproductive technology (ART) includes fertility treatment in which either eggs or embryos are handled outside a female's body to promote successful pregnancies and healthy offspring. Current ART procedures encompass in vitro fertilization with or without intracytoplasmic sperm injection. The most common complication of ART is related to the consequences of multiple pregnancy, which can be prevented or minimized by reducing the number of embryos transferred to the uterus, commonly single embryo transfer. ART has been shown to be variably associated with adverse short- and long-term perinatal outcomes, including cerebral palsy, autism, neurodevelopmental imprinting disorders, and cancer. However, there is uncertainty as to whether reported problems are related to the ART procedure itself, to factors related to infertility, to other medical and environmental factors, or a combination thereof. From a pathophysiological perspective, whether ART alters epigenetic mechanisms of gene expression, leading to later developmental, medical, and behavioral disorders, is an area of active investigation. With the meticulously conducted short- and long-term outcome studies completed so far, overall, and after controlling for multiple gestations and preterm delivery, the results suggest that ART is a safe procedure, offering hope to many parent(s) wishing for a healthy child. This paper highlights ART methods and the risk factors and confounders in the interpretation of short- and long-term outcome data, providing the reader with a means to evaluate findings and conclusions of outcome studies. WHAT THIS PAPER ADDS: Assisted reproductive technology (ART) is a relatively safe procedure. Single embryo implantation optimizes outcome. Informed consent, including the risks and benefits of ART, should be required. Ongoing longitudinal studies are necessary to fully understand ART outcomes.

Plasma Biomarkers of Evolving Encephalopathy and Brain Injury in Neonates with Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: The objective of the study was to evaluate the relationship between a panel of candidate plasma biomarkers and (1) death or severe brain injury on magnetic resonance imaging (MRI) and (2) dysfunctional cerebral pressure autoregulation as a measure of evolving encephalopathy. STUDY DESIGN: Neonates with moderate-to-severe hypoxic-ischemic encephalopathy (HIE) at 2 level IV neonatal intensive care units were enrolled into this observational study. Patients were treated with therapeutic hypothermia (TH) and monitored with continuous blood pressure monitoring and near-infrared spectroscopy. Cerebral pressure autoregulation was measured by the hemoglobin volume phase (HVP) index; a higher HVP index indicates poorer autoregulation. Serial blood samples were collected during TH and assayed for Tau, glial fibrillary acidic protein, and neurogranin. MRIs were assessed using National Institutes of Child Health and Human Development scores. The relationships between the candidate biomarkers and (1) death or severe brain injury on MRI (defined as a National Institutes of Child Health and Human Development score of ≥ 2B) and (2) autoregulation were evaluated using bivariate and adjusted logistic regression models. RESULTS: Sixty-two patients were included. Elevated Tau levels on days 2-3 of TH were associated with death or severe injury on MRI (aOR: 1.06, 95% CI: 1.03-1.09; aOR: 1.04, 95% CI: 1.01-1.06, respectively). Higher Tau was also associated with poorer autoregulation (higher HVP index) on the same day (P = .022). CONCLUSIONS: Elevated plasma levels of Tau are associated with death or severe brain injury by MRI and dysfunctional cerebral autoregulation in neonates with HIE. Larger-scale validation of Tau as a biomarker of brain injury in neonates with HIE is warranted.

Development of a composite diffusion tensor imaging score correlating with short-term neurological status in neonatal hypoxic-ischemic encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is the most common cause of neonatal acquired brain injury. Although conventional MRI may predict neurodevelopmental outcomes, accurate prognostication remains difficult. As diffusion tensor imaging (DTI) may provide an additional diagnostic and prognostic value over conventional MRI, we aimed to develop a composite DTI (cDTI) score to relate to short-term neurological function. Sixty prospective neonates treated with therapeutic hypothermia (TH) for HIE were evaluated with DTI, with a voxel size of 1 × 1 × 2 mm. Fractional anisotropy (FA) and mean diffusivity (MD) from 100 neuroanatomical regions (FA/MD *100 = 200 DTI parameters in total) were quantified using an atlas-based image parcellation technique. A least absolute shrinkage and selection operator (LASSO) regression was applied to the DTI parameters to generate the cDTI score. Time to full oral nutrition [short-term oral feeding (STO) score] was used as a measure of short-term neurological function and was correlated with extracted DTI features. Seventeen DTI parameters were selected with LASSO and built into the final unbiased regression model. The selected factors included FA or MD values of the limbic structures, the corticospinal tract, and the frontotemporal cortices. While the cDTI score strongly correlated with the STO score (rho = 0.83, p = 2.8 × 10-16), it only weakly correlated with the Sarnat score (rho = 0.27, p = 0.035) and moderately with the NICHD-NRN neuroimaging score (rho = 0.43, p = 6.6 × 10-04). In contrast to the cDTI score, the NICHD-NRN score only moderately correlated with the STO score (rho = 0.37, p = 0.0037). Using a mixed-model analysis, interleukin-10 at admission to the NICU (p = 1.5 × 10-13) and tau protein at the end of TH/rewarming (p = 0.036) and after rewarming (p = 0.0015) were significantly associated with higher cDTI scores, suggesting that high cDTI scores were related to the intensity of the early inflammatory response and the severity of neuronal impairment after TH. In conclusion, a data-driven unbiased approach was applied to identify anatomical structures associated with some aspects of neurological function of HIE neonates after cooling and to build a cDTI score, which was correlated with the severity of short-term neurological functions.

A predictive clinical model for moderate to severe intraventricular hemorrhage in very low birth weight infants.

IMPORTANCE: Intraventricular hemorrhage (IVH) occurs in 15-45% of all very low birth weight (VLBW) preterm infants. Despite improvements in the perinatal care, the incidence of IVH remains high. As more preterm infants survive, there will be a larger burden of neurodevelopmental abnormalities borne by former preterm infants. OBJECTIVE: The objective of this study was to develop a predictive clinical model of IVH risk within the first few hours of life in an effort to augment perinatal counseling and guide the timing of future targeted therapies aimed at preventing or slowing the progression of disease. DESIGN: This is a prospective observational cohort study of VLBW infants born in the NICU at John's Hopkins Children's Center from 2011 to 2019. The presence and severity of IVH was defined on standard head ultrasound screening (HUS) using the modified Papile classification. Clinical variables were identified as significant using absolute risk regression from a general linear model. The model predictors included clinically meaningful variables that were not collinear. SETTING: This study took place at the Johns Hopkins Children's Center Level IV NICU. PARTICIPANTS: The study sample included VLBW infants treated in the neonatal intensive care unit (NICU) at John's Hopkins Children's Center from 2011 to 2019. A total of 683 infants included in the study had no or grade I IVH, and 115 infants had grades II through IV IVH. Exclusion criteria included admission to the JHH NICU after 24 h of age, BW > 1500 g, and failure to consent. MAIN OUTCOME: The main outcome of this study was the presence of grades II-IV IVH on standard head ultrasound screening using the modified Papile classification [1]. RESULTS: A total of 798 VLBW infants were studied in this cohort and 14.4% had moderate to severe IVH. Fifty four percent of the cohort was black, 33% white, and half of the cohort was male. A higher gestational age, 5-min Apgar score, hematocrit, and platelet count were significantly associated with decreased incidence of IVH in a multi-predictor model (ROC 0.826). CONCLUSION AND RELEVANCE: In the face of continued lack of treatments for IVH, prevention is still a primary goal to avoid long-term developmental sequela. This model can be used for perinatal counseling and may provide important information during the narrow therapeutic window for targeted prevention therapies.

Perinatal Inflammatory Biomarkers and Respiratory Disease in Preterm Infants.

OBJECTIVE: To measure plasma levels of vascular endothelial growth factor (VEGF) and several cytokines (Interleukin [IL]-6 IL-8, IL-10) during the first week of life to examine the relationship between protein expression and likelihood of developing respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD). STUDY DESIGN: Levels of IL-6, IL-8, IL-10, and VEGF were measured from plasma obtained from preterm patients during the first week of life. Newborns were recruited from a single center between April 2009 and April 2019. Criteria for the study included being inborn, birth weight of less than 1500 grams, and a gestational age of less than 32 weeks at birth. RESULTS: The development of RDS in preterm newborns was associated with lower levels of VEGF during the first week of life. Higher plasma levels of IL-6 and IL-8 plasma were associated with an increased likelihood and increased severity of BPD at 36 weeks postmenstrual age. In contrast, plasma levels of VEGF, IL-6, IL-8, and IL-10 obtained during the first week of life were not associated with respiratory symptoms and acute care use in young children with BPD in the outpatient setting. CONCLUSIONS: During the first week of life, lower plasma levels of VEGF was associated with the diagnosis of RDS in preterm infants. Preterm infants with higher levels of IL-6 and IL-8 during the first week of life were also more likely to be diagnosed with BPD. These biomarkers may help to predict respiratory morbidities in preterm newborns during their initial hospitalization.

Photoacoustic assessment of the fetal brain and placenta as a method of non-invasive antepartum and intrapartum monitoring.

A noninvasive monitor for concurrent evaluation of placental and fetal sagittal sinus sO 2 for both antepartum surveillance at the late 2nd and 3rd trimesters and intrapartum monitoring would be a great advantage over current methods. A PA fetal brain and placental monitor has potential value to rapidly identify the fetus at risk for developing hypoxia and ischemia of a sufficient degree that brain injury or death may develop, which may be prevented by intervention with delivery and other follow-up treatments.

Transcranial photoacoustic characterization of neurovascular physiology during early-stage photothrombotic stroke in neonatal pigletsin vivo.

OBJECTIVE: Perinatal ischemic stroke is estimated to occur in 1/2300-1/5000 live births, but early differential diagnosis from global hypoxia-ischemia is often difficult. In this study, we tested the ability of a hand-held transcranial photoacoustic (PA) imaging probe to non-invasively detect a focal photothrombotic stroke (PTS) within 2 h of stroke onset in a gyrencephalic piglet brain. APPROACH: About 17 stroke lesions of approximately 1 cm2area were introduced randomly in anterior or posterior cortex via the light/dye PTS technique in anesthetized neonatal piglets (n= 11). The contralateral non-ischemic region served as control tissue for discrimination contrast for the PA hemoglobin metrics: oxygen saturation, total hemoglobin (tHb), and individual quantities of oxygenated and deoxygenated hemoglobin (HbO2and HbR). MAIN RESULTS: The PA-derived tissue oxygen saturation at 2 h yielded a significant separation between control and affected regions-of-interest (p< 0.0001), which were well matched with 24 h post-stroke cerebral infarction confirmed in the triphenyltetrazolium chloride-stained image. The quantity of HbO2also displayed a significant contrast (p= 0.021), whereas tHb and HbR did not. The analysis on receiver operating characteristic curves and multivariate data analysis also agreed with the results above. SIGNIFICANCE: This study shows that a hand-held transcranial PA neuroimaging device can detect a regional thrombotic stroke in the cerebral cortex of a neonatal piglet. In particular, we conclude that the oxygen saturation metric can be used alone to identify regional stroke lesions. The lack of change in tHb may be related to arbitrary hand-held imaging configuration and/or entrapment of red blood cells within the thrombotic stroke.

Therapeutic Hypothermia Modulates the Relationships Between Indicators of Severity of Neonatal Hypoxic Ischemic Encephalopathy and Serum Biomarkers.

Objective: To determine the changes due to therapeutic hypothermia (TH) exposure in the strength of association between traditional clinical and biochemical indicators of severity of neonatal hypoxic-ischemic encephalopathy (HIE) and serum biomarkers. We hypothesized that culmination of TH changes the strength of the relationships between traditional indicators of severity of HIE and serum biomarkers. Methods: This was a single-center observational cohort study of 178 neonates with HIE treated with TH and followed with serum biomarkers: (i) brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) (neurotrophins); (ii) tau and glial fibrillary acidic protein (GFAP) (neural cell injury); and (iii) interleukin 6 (IL-6), IL-8, and IL-10 (cytokines), during their first week of life. Adjusted mixed-effect models tested associations with HIE indicators in relation to TH exposure. Results: At admission, lower Apgar scores and base excess (BE) and higher lactate and nucleated red blood cell (NRBC) count correlated with higher Sarnat scores. These indicators of worse HIE severity, including higher Sarnat score, correlated with lower VEGF and higher tau, GFAP, and IL-10 levels at different time points. Within the first 24 h of life, patients with a Sarnat score >2 had lower VEGF levels, whereas only those with score of 3 also had higher GFAP and IL-10 levels. Tau levels increased during TH in patients with Sarnat score of 3, whereas tau and GFAP increased after TH in those with scores of 2. After adjustments, lower VEGF levels during TH and higher tau, GFAP, and IL-10 levels during and after TH were associated with worse Sarnat scores. Tau and GFAP relationship with Sarnat score became stronger after TH. Conclusion: Therapeutic hypothermia exerts an independent modulatory effect in the relationships between traditional indicators of severity of HIE and serum biomarkers after adjustments. Thus, the timing of biomarker testing in relation to TH exposure must be carefully considered if biomarkers are proposed for patient stratification in novel clinical trials.

Perinatal blood biomarkers for the identification of brain injury in very low birth weight growth-restricted infants.

OBJECTIVE: To determine if blood biomarkers measured at delivery and shortly after birth can identify growth-restricted infants at risk for developing severe brain injury. STUDY DESIGN: In a cohort of very low birth weight neonates, fetal growth restricted (FGR) (birth weight <10%) were compared to non-FGR neonates, and within the FGR group those with brain injury were compared to those without. Biomarkers were measured in cord blood at delivery, and daily for the 1st 5 days of life. RESULT: FGR was associated with significantly higher levels of interleukin (IL)-6, IL-8, IL-10, and lower levels of vascular endothelial growth factor (VEGF). FGR and brain injury were associated with significantly higher levels of IL-6, IL-8, IL-10, and glial fibrillary acidic protein (GFAP). CONCLUSION: Interleukins may be involved in a common pathway contributing to both the development of growth restriction and brain injury, and GFAP may help identify brain injury within this growth-restricted group.

Tiny Bodies, Big Needs: Prospective Biobanking of Neonatal Clinical Remnant Samples.

Repurposing biological samples collected for required diagnostic purposes into suitable biobanking projects is a particularly useful method for enabling research in vulnerable populations. This approach is especially appropriate for the neonate in the neonatal intensive care unit (NICU), where blood volume reductions can quickly increase beyond minimal risk for adverse events, such as iatrogenic anemia, and proxy consent provided by parents or guardians is required. The method described in this study provides a framework to prospectively collect and store blood-derived clinical samples after all clinical and regulatory requirements are fulfilled. The consent approach incorporated a 30-day window to allow parents and guardians ample consideration time with follow-up involvement with NICU embedded study team members. The study enrolled 875 participants over a 3-year period. This established a critically needed biobank to support investigator-initiated research with explicit study aims requiring samples at defined day of life frequencies within the NICU and created a normative control reference bank for case comparisons for premature and full-term neonates with brain injury.

Blood biomarkers for neonatal hypoxic-ischemic encephalopathy in the presence and absence of sentinel events.

OBJECTIVE: To determine if neonatal serum biomarkers representing different pathways of injury differ for cases of HIE of unknown cause to gain insight into timing and mechanism of injury. STUDY DESIGN: In this cohort of all neonates with HIE admitted to our NICU, newborns with sentinel events were compared to those without during the 1st 3 days of life. Discard neonatal blood during the 1st 3 days of life was used for analysis. RESULTS: Of 277 babies with HIE treated with whole-body hypothermia, 190 (68.6%) had blood available for biomarker analysis. In total, 71 (37.4%) were born within our system, and 119 (62.6%) were transferred in from outside hospitals. Of these babies, 77 (40.5%) had a sentinel event and 113 (59.6%) had no sentinel event. Although the degree of metabolic acidosis was similar, repeated measures analysis showed that during the initial 3 days of life neonates born with HIE in the absence of sentinel events had 41.4% decreased VEGF (p = 0.027) and 62.5% increased IL-10 serum concentrations (p = 0.005). CONCLUSION: These changes indicate that neonatal HIE in the absence of sentinel events is not related to an unrecognized acute intrapartum event and is possibly related to chronic hypoxia of lower severity or recovery from a remote event.

Adjuvant 17-hydroxyprogesterone caproate in women withultrasound-indicated cerclage: a systematic review and meta-analysis.

Objective: To assess the additional benefits of 17-hydroxyprogesterone caproate (17-OHPC) therapy in preventing recurrent spontaneous preterm birth in women with an ultrasound-indicated cerclage.Methods: Electronic databases (Medline, Scopus, ClinicalTrials.gov, PROSPERO, Embase, Scielo, and the Cochrane Central Register of Controlled Trials) were searched for studies published before September 2018. Keywords included "preterm birth", "ultrasound-indicated cerclage", "pregnancy" and "17-hydroxyprogesterone caproate". Studies comparing ultrasound-indicated cerclage alone to cerclage plus 17-OHPC were included. The primary outcome measure was preterm birth at <35 weeks of gestation. Secondary outcome measures include preterm birth <24 weeks, <28 weeks, <32 weeks and <37 weeks of gestation, necrotizing enterocolitis (NEC), fetal birth weight, and intraventricular hemorrhage (grades III and IV). Meta-analysis was performed using the random effects model of DerSimonian and Laird. Risk of bias and quality assessment was performed using the risk of bias in nonrandomized studies of interventions (ROBINS-I).Results: Four studies met inclusion criteria and were included in the final analysis. Of the 396 women who received ultrasound-indicated cerclage, 142 (35.9%) received adjuvant 17-OHPC. The primary outcome, preterm birth <35 weeks of gestation, was present in three studies and 332/396 singleton pregnancies. Though there was a trend towards a reduced risk of preterm birth, the summary estimate of effect was not statistically significant when comparing cerclage alone to cerclage plus 17-OHPC at <35 weeks (relative risk (RR) 0.95, 95% CI 0.77-1.17). Similarly, we found no differences in preterm birth at <24 weeks (RR 0.30, 95% CI 0.06-1.60), <28 weeks (RR 0.57, 95% CI 0.13-2.53), and <32 weeks (RR 0.99, 95% CI 0.44-2.27) when comparing cerclage alone to cerclage plus 17-OHPC. There were no differences in fetal birth weight, intraventricular hemorrhage and necrotizing enterocolitis comparing cerclage alone to cerclage plus 17-OHPC.Conclusion: Intramuscular 17-OHPC in combination with ultrasound-indicated cerclage in women with prior preterm birth had no additional effect in reducing spontaneous recurrent preterm birth or improving perinatal outcomes.

Placental malperfusion in response to intrauterine inflammation and its connection to fetal sequelae.

Exposure to intrauterine inflammation (IUI) is associated with short- and long-term adverse perinatal outcomes. However, little data exist on utilizing placenta to prognosticate fetal injury in this scenario. Our study aimed to utilize imaging modalities to evaluate mechanisms contributing to placental injury following IUI exposure and correlated it to concomitant fetal brain injury. CD1 pregnant dams underwent laparotomies and received intrauterine injections of either lipopolysaccharide (LPS; a model of IUI) or phosphate-buffered saline (PBS). In utero ultrasound Doppler velocimetry of uterine and umbilical arteries and magnetic resonance imaging (MRI) of placental volumes with confirmatory immunohistochemical (vimentin) and histochemistry (fibrin) analyses were performed. ELISA for thrombosis markers, fibrinogen and fibrin was performed to analyze thrombi in placenta. Fetal brain immunohistochemistry was performed to detect microglial activation (ionized calcium-binding adaptor molecule 1, Iba1). On ultrasound, LPS group demonstrated elevated resistance indices, pulsatility indices and a greater occurrence of absent end-diastolic flow in the umbilical and uterine arteries. In the fetus, there was an increased cardiac Tei indices in the LPS group. MRI revealed decreased volume of placenta in the LPS group associated with placental thinning and placental endothelial damage on immunohistochemistry. Decreased fibrinogen content and more thrombi staining in placenta exposed to maternal LPS indicated the hypercoagulability. Furthermore, the expression of Iba1was significantly associated with placental thickness (r = -0.7890, Pearson correlation coefficient). Our data indicate that IUI can trigger events leading to maternal placental malperfusion and fetal vessel resistance, as well as predispose the developing fetus to cardiac dysfunction and brain damage. Furthermore, our data suggest that prenatal ultrasound can be a real-time clinical tool for assessing fetal risk for adverse neurologic outcomes following the potential IUI exposure.

17α-Hydroxyprogesterone Caproate and the Risk of Glucose Intolerance in Pregnancy: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate whether 17α-hydroxyprogesterone caproate use in preventing preterm birth increases the risk of gestational diabetes mellitus (GDM). DATA SOURCES: Electronic databases (MEDLINE, Scopus, ClinicalTrials.gov, PROSPERO, EMBASE, Scielo and the Cochrane Central Register of Controlled Trials) were searched for studies published before October 2018. Keywords included "gestational diabetes," "preterm birth," "pregnancy," and "17-hydroxyprogesterone caproate." METHODS OF STUDY SELECTION: Studies comparing 17α-hydroxyprogesterone caproate with unexposed control groups in women with singleton gestation and a history of a prior spontaneous preterm birth were included. The primary outcome was the development of GDM. Secondary outcomes included abnormal 1-hour, 50-g glucose screen results and mean venous blood glucose levels. Summary estimates were reported as mean differences and 95% CI for continuous variables or relative risk (RR) with 95% CI for dichotomous outcomes. Meta-analysis was performed using the random effects model of DerSimonian and Laird. TABULATION, INTEGRATION AND RESULTS: Six studies, four of which were cohort studies, met inclusion criteria and were included in the final meta-analysis. Of the 5,053 women, 1,538 (30.4%) received 17α-hydroxyprogesterone caproate and 3,515 (69.6%) were in unexposed control groups. The overall rate of GDM in women exposed to 17α-hydroxyprogesterone caproate was 10.9% vs 6.1% in women who were not exposed (RR 1.77, 95% CI 1.22-2.55). After exclusion of the cohort studies, the summary estimate of effect was nonsignificant among women who had been randomly allocated to 17α-hydroxyprogesterone caproate (RR 1.21, 95% CI 0.63-2.36). CONCLUSION: Women with singleton gestations receiving weekly 17α-hydroxyprogesterone caproate for recurrent preterm birth prevention had a significantly higher incidence of abnormal glucose test results and GDM compared with those in unexposed control groups, a finding that did not hold among women who had been randomly allocated to 17α-hydroxyprogesterone caproate. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42016041694.

Obstetric management, tests, and technologies that impact childhood development.

Childhood brain development begins before birth, and obstetric management, tests, and technologies designed to diagnose and treat fetal conditions can have an impact on development. Preconception counseling for maternal diabetes and hypertension affect the risk of fetal congenital anomalies and growth restriction. Patients with risk factors for pre-existing maternal diabetes are offered early diabetic screening because earlier diagnosis and treatment can decrease the risk of fetal and neonatal complications. Screening for chromosomal abnormalities in the first or second trimester is offered to all females regardless of age. Cell-free fetal DNA screening can be used to test for fetal genetic abnormalities as early as 9 weeks of gestation with results available in 10 days. Ultrasound performed around 20 weeks' gestation can identify the 3% of fetuses that have a major congenital malformation. Fetal magnetic resonance imaging can be used to better assess fetal central nervous system abnormalities when neurosonography is inconclusive. Doppler ultrasound can be used to assess blood flow in the umbilical artery and fetal middle cerebral artery to aid in the management of the growth-restricted fetus. In summary, diagnosis and treatment of maternal and fetal conditions from the preconception period throughout pregnancy are important for optimizing fetal health and provide the best opportunity for optimal child development. WHAT THIS PAPER ADDS: Cell-free fetal DNA screening can identify fetal genetic abnormalities as early as 9 weeks' gestation. Ultrasound performed around 20 weeks' gestation can detect major fetal congenital malformations. Fetal magnetic resonance imaging can aid neurosonography in the assessment of fetal central nervous system abnormalities. Doppler ultrasound to assess fetal blood flow is used to successfully manage the growth-restricted fetus.

MANEJO OBSTÉTRICO, PRUEBAS Y TECNOLOGÍAS QUE IMPACTAN EL DESARROLLO INFANTIL: El desarrollo infantil comienza antes del nacimiento, y el manejo obstétrico, las pruebas y las tecnologías diseñadas para diagnosticar y tratar las afecciones fetales pueden tener un impacto en el desarrollo. El asesoramiento previo a la concepción para la diabetes materna y la hipertensión puede modificar el riesgo de anomalías congénitas fetales y la restricción del crecimiento. A los pacientes con factores de riesgo para la diabetes materna preexistente se les ofrece la detección temprana de la diabetes debido a que un diagnóstico y tratamiento tempranos pueden disminuir el riesgo de complicaciones fetales y neonatales. El examen de detección de anomalías cromosómicas en el primer o segundo trimestre se ofrece a todas las mujeres, independientemente de su edad. La prueba de detección de ADN fetal sin células se puede usar para detectar anomalías genéticas fetales tan pronto como a las 9 semanas de gestación, con resultados disponibles en 10 días. La ecografía realizada alrededor de las 20 semanas de gestación puede identificar el 3% de los fetos que tienen una malformación congénita importante. La resonancia magnética fetal puede usarse para evaluar mejor las anomalías del sistema nervioso central fetal cuando la neurosonografía no es concluyente. La ecografía Doppler se puede usar para evaluar el flujo sanguíneo en la arteria umbilical y la arteria cerebral media fetal para ayudar en el manejo del feto con restricción de crecimiento. En resumen, el diagnóstico y el tratamiento de las afecciones maternas y fetales desde el período previo a la concepción, y durante todo el embarazo, son importantes para optimizar la salud fetal y ofrecen la mejor oportunidad para el desarrollo óptimo del niño.

MANEJO OBSTÉTRICO, TESTES E TECNOLOGIAS QUE IMPACTAM O DESENVOLVIMENTO INFANTIL.: O desenvolvimento infantil começa antes do nascimento, e o manejo obstétrico, testes e tecnologias projetados para diagnosticar e tratar condições fetais podem ter impacto no desenvolvimento. Aconselhamento pré-concepcional para diabetes materna e hipertensão afetam o risco de anomalias congênitas fetais e restrição do crescimento. Pacientes com fatores de risco para diabetes materna pré-existente recebem oferta de monitoramento precoce para diabetes porque o diagnóstico e tratamento precoces podem diminuir o risco de complicações fetais e neonatais. O monitoramento para anormalidades cromossômicas no primeiro ou segundo trimestre é oferecido para todas as mulheres independente da idade. A avaliação sem células do DNA fetal pode ser usada para testar anormalidades genéticas tão cedo como 9 semanas de gestação, com resultados disponíveis em 10 dias. O ultra-som realizado por volta de 20 semanas de gestação pode identificar os 3% de fetos que têm uma malformação congênita importante. Imagem por ressonância magnética fetal pode ser usada mara melhor avaliar anormalidades do sistema nervoso central quando a neurosonografia é inconcusiva. Ultra-som Doppler pode ser usado para avaliar o fluxo sanguíneo na artéria umbilical e artéria cerebral média fetal para ajudar no manejo de fetos com restrição de crescimento. Em resumo, o diagnóstico e tratamento de condições maternas e fetais no período pré-concepcional e durante toda a gestação são importantes para otimizar a saúde do feto e proporcionar a melhor oportunidade para o desenvolvimento infantil ótimo.

Risk Factors for Neonatal Hypoxic-Ischemic Encephalopathy in the Absence of Sentinel Events.

OBJECTIVE: Hypoxic-ischemic encephalopathy (HIE) may be associated with intrapartum sentinel events or may be unexplained. We sought to identify risk factors for unexplained HIE cases and compare their morbidity and mortality to cases associated with sentinel events. STUDY DESIGN: Retrospective cohort study of all neonates admitted with suspected HIE treated with whole-body hypothermia from January 2007 through July 2017. Cases of unexplained HIE were compared with those with a sentinel event. RESULTS: A total of 223 neonates met the inclusion criteria, of which 86 (38.6%) experienced a sentinel event and 137 (61.4%) did not. Placental histopathology was performed for 28/31 (90.3%) and 48/53 (90.6%) inborn neonates with and without sentinel events, respectively. Placentas from unexplained HIE cases more often exhibited histologic chorioamnionitis (43.8% vs. 17.9%, p = 0.02) and funisitis (25% vs. 3.6%, p = 0.02). Neonatal morbidity and mortality were similar. On multivariable regression, nulliparity (odds ratio [OR], 4.11, 95% confidence interval [CI]: 1.24-13.62) and histologic funisitis (OR, 20.33, 95% CI: 1.11-373.4) remained significant. CONCLUSION: Other than nulliparity and infection which could be identified on umbilical cord examination following delivery but not on clinical assessment prior to delivery, there are no other identifiable risk factors for HIE in the absence of a sentinel event, and morbidity and mortality are similar between groups.