Etiology and Ontogeny of Cerebral Palsy: Implications for Practice and Research.

Cerebral palsy (CP) has been recognized as a group of neurologic disorders with varying etiologies and ontogenies. While a percentage of CP cases arises during labor, the expanded use of electronic fetal monitoring (EFM) to include prevention of CP has resulted in decades of vastly increased interventions that have not significantly reduced the incidence of CP for infants born at term in the USA. Litigation alleging that poor obstetrical practice caused CP in most of these affected children has led to contentious arguments regarding the actual etiologies of this condition and often resulted in substantial monetary awards for plaintiffs. Recent advances in genetic testing using whole exome sequencing have revealed that at least one-third of CP cases in term infants are genetic in origin and therefore not labor-related. Here, we will present and discuss previous attempts to sort out contributing etiologies and ontogenies of CP, and how these newer diagnostic techniques are rapidly improving our ability to better detect and understand such cases. In light of these developments, we present our vision for an overarching spectrum for proper categorization of CP cases into that the following groups: (1) those begun at conception from genetic causes (nonpreventable); (2) those stemming from adverse antenatal/pre-labor events (possibly preventable with heightened antepartum assessment); (3) Those arising from intrapartum events (potentially preventable by earlier interventions); (4) Those occurring shortly after birth (possibly preventable with closer neonatal monitoring); (5) Those that appear later in the postnatal period from non-labor-related causes such as untreated infections or postnatal intracranial hemorrhages.

Obstetrical outcomes following amniocentesis performed after 24 weeks of gestation: A systematic review and meta-analysis.

To evaluate obstetrical outcomes for women having late amniocentesis (on or after 24 weeks). Electronic databases were searched from inception to January 1st, 2023. The obstetrical outcomes evaluated were gestational age at delivery, preterm birth (PTB) < 37 weeks, PTB within 1 week from amniocentesis, premature prelabor rupture of membranes (pPROM), chorionamnionitis, placental abruption, intrauterine fetal demise (IUFD) and termination of pregnancy (TOP). The incidence of PTB <37 weeks was 4.85% (95% CI 3.48-6.56), while the incidence of PTB within 1 week was 1.42% (95% CI 0.66-2.45). The rate of pPROM was 2.85% (95% CI 1.21-3.32). The incidence of placental abruption was 0.91% (95% CI 0.16-2.25), while the rate of IUFD was 3.66% (95% CI 0.00-14.04). The rate of women who underwent TOP was 6.37% (95%CI 1.05-15.72). When comparing amniocentesis performed before or after 32 weeks, the incidence of PTB within 1 week was 1.48% (95% CI 0.42-3.19) and 2.38% (95% CI 0.40-5.95). Amniocentesis performed late after 24 weeks of gestation is an acceptable option for patients needing prenatal diagnosis in later gestation.

Improving the interpretation of electronic fetal monitoring: the fetal reserve index.

Electronic fetal monitoring, particularly in the form of cardiotocography, forms the centerpiece of labor management. Initially successfully designed for stillbirth prevention, there was hope to also include prediction and prevention of fetal acidosis and its sequelae. With the routine use of electronic fetal monitoring, the cesarean delivery rate increased from <5% in the 1970s to >30% at present. Most at-risk cases produced healthy babies, resulting in part from considerable confusion as to the differences between diagnostic and screening tests. Electronic fetal monitoring is clearly a screening test. Multiple attempts have aimed at enhancing its ability to accurately distinguish babies at risk of in utero injury from those who are not and to do this in a timely manner so that appropriate intervention can be performed. Even key electronic fetal monitoring opinion leaders admit that this goal has yet to be achieved. Our group has developed a modified approach called the "Fetal Reserve Index" that contextualizes the findings of electronic fetal monitoring by formally including the presence of maternal, fetal, and obstetrical risk factors and increased uterine contraction frequencies and breaking up the tracing into 4 quantifiable components (heart rate, variability, decelerations, and accelerations). The result is a quantitative 8-point metric, with each variable being weighted equally in version 1.0. In multiple previously published refereed papers, we have shown that in head-to-head studies comparing the fetal reserve index with the American College of Obstetricians and Gynecologists' fetal heart rate categories, the fetal reserve index more accurately identifies babies born with cerebral palsy and could also reduce the rates of emergency cesarean delivery and vaginal operative deliveries. We found that the fetal reserve index scores and fetal pH and base excess actually begin to fall earlier in the first stage of labor than was commonly appreciated, and the fetal reserve index provides a good surrogate for pH and base excess values. Finally, the last fetal reserve index score before delivery combined with early analysis of neonatal heart rate and acid/base balance shows that the period of risk for neonatal neurologic impairment can continue for the first 30 minutes of life and requires much closer neonatal observation than is currently being done.

Resistance to Change.

Advances in medical technology do not follow a smooth process and are highly variable. Implementation can occasionally be rapid, but often faces varying degrees of resistance resulting at the very least in delayed implementation. Using qualitative comparative analysis, we have evaluated numerous technological advances from the perspective of how they were introduced, implemented, and opposed. Resistance varies from benign - often happening because of inertia or lack of resources to more active forms, including outright opposition using both appropriate and inappropriate methods to resist/delay changes in care. Today, even public health has become politicized, having nothing to do with the underlying science, but having catastrophic results. Two other corroding influences are marketing pressure from the private sector and vested interests in favor of one outcome or another. This also applies to governmental agencies. There are a number of ways in which papers have been buried including putting the thumb on the scale where reviewers can sabotage new ideas. Unless we learn to harness new technologies earlier in their life course and understand how to maneuver around the pillars of obstruction to their implementation, we will not be able to provide medical care at the forefront of technological capabilities.

Fetal reduction for everyone?

Infertility treatments have benefited millions of couples to have their own children; however, the complication of multiple pregnancies with their increased morbidity and mortality has created significant problems. Fetal reduction (FR) was developed to ameliorate these issues. Over 30 years of publications show that FR has been highly successful in substantially reducing both mortality and morbidity. As with most radically new techniques, initial cases were in the "nothing to lose" category. With experience, indications liberalize, and quality of life issues increase as a proportion of cases. Overall risks for twins are not twice as those for singletons, but they are approximately 4- to 5-fold higher. In experienced hands, the combination of genetic testing by CVS followed by FR has made most multiples behave statistically as if they were originally the lower number. The use of microarray analysis to better determine fetal genetic health before deciding on which fetus(es) to keep or reduce further improves pediatric outcomes. With increasing experience and lower average starting numbers, the proportion of FRs to a singleton has increased considerably. Twins to a singleton FR now constitute an increasing proportion of cases performed. Data on such cases show improved outcomes, and we believe FR should be at least discussed and offered to all patients with a dichorionic twin pregnancy or higher. eSET is not a panacea because of the resultant monochorionic twins.

Fetal reduction of triplet pregnancies to twins vs singletons: a meta-analysis of survival and pregnancy outcome.

OBJECTIVE: This systematic review and meta-analysis aimed to compare the fetal survival rate and perinatal outcomes of triplet pregnancies after selective reduction to twin pregnancies vs singleton pregnancies. DATA SOURCES: PubMed, Web of Science, Scopus, and Embase were systematically searched from the inception of the databases to January 16, 2022. STUDY ELIGIBILITY CRITERIA: Studies comparing the survival and perinatal outcomes between reduction to twin pregnancies and reduction to singleton pregnancies were included. The primary outcomes were fetal survival, defined as a live birth at >24 weeks of gestation. The secondary outcomes were gestational age at birth, preterm birth at <32 and <34 weeks of gestation, early pregnancy loss (<24 weeks of gestation), low birthweight, and rate of neonatal demise (up to 28 days after birth). METHODS: The random-effect model was used to pool the mean differences or odds ratios and the corresponding 95% confidence intervals. To provide a range of expected effects if a new study was conducted, 95% prediction intervals were calculated for outcomes presented in >3 studies. RESULTS: Of note, 10 studies with 2543 triplet pregnancies undergoing fetal reduction, of which 2035 reduced to twin pregnancies and 508 reduced to singleton pregnancies, met the inclusion criteria. Reduction to twin pregnancies had a lower rate of fetal survival (odds ratio, 0.61; 95% confidence interval, 0.40-0.92; P=.02; 95% prediction interval, 0.36-1.03) and comparable rates of early pregnancy loss (odds ratio, 0.89; 95% confidence interval, 0.58-1.38; P=.61; 95% prediction interval, 0.54-1.48) and neonatal demise (odds ratio, 0.57; 95% confidence interval, 0.09-3.50; P=.55) than reduction to singleton pregnancies. Reduction to twin pregnancies had a significantly lower gestation age at birth (weeks) (mean difference, -2.20; 95% confidence interval, -2.80 to -1.61; P<.001; 95% prediction interval, -4.27 to -0.14) than reduction to singleton pregnancies. Furthermore, reduction to twin pregnancies was associated with lower birthweight and greater risk of preterm birth at <32 and <34 weeks of gestation. CONCLUSION: Triplet pregnancies reduced to twin pregnancies had a lower fetal survival rate of all remaining fetuses, lower gestational age at birth, higher risk of preterm birth, and lower birthweight than triplet pregnancies reduced to singleton pregnancies; reduction to twin pregnancies vs reduction to singleton pregnancies showed no substantial difference for the rates of early pregnancy loss and neonatal death.

Earlier and improved screening for impending fetal compromise.

OBJECTIVE: The use of pH and base excess (FSSPHBE) from fetal scalp sampling (FSS) was abandoned when cardiotocography (CTG) was believed to be sufficiently accurate to direct patient management. We sought to understand the fetus' tolerance to stress in the 1st stage of labor and to develop a better and earlier screening test for its risk for developing acidosis. To do so, we investigated sequential changes in fetal pH and BE obtained from FSS in the 1st stage of labor as part of a research protocol from the 1970s. We then examined the utility of multiple of the median (MoM's) conversion of BE and pH values, and the capacity of Fetal Reserve Index (FRI) scores to be a proxy for such changes. We then sought to examine the predictive capacity of 1st stage FRI and its change over the course of the first stage of labor for the subsequent development of acidosis risk in the 2nd stage of labor. METHODS: Using a retrospective research database evaluation, we evaluated FSSPHBE data from 475 high-risk parturients monitored in labor and their neonates for 1 h postpartum.We categorized specimens according to cervical dilatation (CxD) at the time of FSSPHBE and developed non-parametric, multiples of the median (MOMs) assessments. FRI scores and their change over time were used as predictors of FSSPHBE. Our main outcome measures were the changes in BE and pH at different cervical dilatations (CxD) and acidosis risk in the early 2nd stage of labor. RESULTS: FSSPHBE worsens over the course of the 1st stage. The implications of any given BE are very different depending upon CxD. At 9 cm, -8 Mmol/L is 1.1 MOM; at 3 cm, it would be 2.0 MOM. The FRI level and its trajectory provide a 1st stage screening tool for acidosis risk in the second stage. CONCLUSIONS: Fetal acid-base balance ("reserve") deteriorates beginning early in the 1st stage of labor, irrespective of whether the fetus reaches a critical threshold of concern for actual acidosis. The use of MoM's logic improves appreciation of such information. The FRI and its trajectory reasonably approximate the trajectory of the FSSPHBE and appears to be a suitable screening test for early deterioration and for earlier interventions to keep the fetus out of trouble rather than wait until high risk status develops.

Fetal reduction and twins.

Infertility treatments have allowed millions of couples to have their own children, but resultant multiple pregnancies with their increased morbidity and mortality have been a significant complication. Fetal reduction was developed to ameliorate this issue. Over 30 years of publications show that fetal reduction has been highly successful in substantially reducing both mortality and morbidity related to multiple pregnancies. As with most radically new techniques, initial cases were in the "nothing to lose" category. With experience, indications liberalize, and quality of life issues gain relevance. The overall risks of twin pregnancy are not twice that of singleton pregnancy; they are about 4 to 5 times higher. In experienced hands, the combination of genetic testing by chorionic villus sampling followed by fetal reduction has made the outcomes of most multiple pregnancies statistically equivalent to those of pregnancies with lower fetal numbers. Use of microarray analysis to better determine fetal genetic health before deciding on which fetus(es) to keep or reduce further improves pediatric outcomes. With increasing experience and lower average starting numbers, the proportion of fetal reductions to a singleton has increased considerably. Twins to a singleton fetal reductions now constitute an increasing proportion of cases performed. Data on such cases show improved outcomes, and we believe fetal reduction should be at least discussed and offered to all patients with a dichorionic twin pregnancy or higher. With the increasing reliance on elective single-embryo transfers, monochorionic twins, which have much higher complication rates than dichorionic twins, have increased substantially. Furthermore, monochorionic twins cannot be readily and safely reduced, so the adverse perinatal statistics of elective single-embryo transfer are a major setback for good outcomes. Although elective single-embryo transfer is appropriate for some, we believe that for many couples, the transfer of 2 embryos is generally a more rational approach.

Changing Perspectives of Electronic Fetal Monitoring.

The delivery of healthy babies is the primary goal of obstetric care. Many technologies have been developed to reduce both maternal and fetal risks for poor outcomes. For 50 years, electronic fetal monitoring (EFM) has been used extensively in labor attempting to prevent a large proportion of neonatal encephalopathy and cerebral palsy. However, even key opinion leaders admit that EFM has mostly failed to achieve this goal. We believe this situation emanates from a fundamental misunderstanding of differences between screening and diagnostic tests, considerable subjectivity and inter-observer variability in EFM interpretation, failure to address the pathophysiology of fetal compromise, and a tunnel vision focus. To address these suboptimal results, several iterations of increasingly sophisticated analyses have intended to improve the situation. We believe that part of the continuing problem is that the focus of EFM has been too narrow ignoring important contextual issues such as maternal, fetal, and obstetrical risk factors, and increased uterine contraction frequency. All of these can significantly impact the application of EFM to intrapartum care. We have recently developed a new clinical approach, the Fetal Reserve Index (FRI), contextualizing EFM interpretation. Our data suggest the FRI is capable of providing higher accuracy and earlier detection of emerging fetal compromise. Over time, artificial intelligence/machine learning approaches will likely improve measurements and interpretation of FHR characteristics and other relevant variables. Such future developments will allow us to develop more comprehensive models that increase the interpretability and utility of interfaces for clinical decision making during the intrapartum period.

Mid forceps did not cause "compromised babies" - "compromise" caused forceps: an approach toward safely lowering the cesarean delivery rate.

OBJECTIVE: Over 5 decades, Cesarean Delivery rates (CDR) have risen 6-fold while vaginal operative deliveries [VODs] decreased from >20% to ∼3%. Poor outcomes (HIE and cerebral palsy) haven't improved. Potentiating the virtual abandonment of forceps (F), particularly midforceps (Mid), were allegations about various poor neonatal outcomes. Here, we evaluate VOD and CDR outcomes controlling for prior fetal risk metrics (PR) ascertained an hour before birth. METHODS: Our 45-year-old database from a labor research unit of moderate/high risk laboring patients (288 NSVDs, 120 Lows, 30 Mids, and 32 CDs) had multiple fetal scalp samples for base excess (BE), pH, cord blood gases (CB), and umbilical artery bloods. ANOVA established relationships between birth methods and outcomes (Cord blood BE and pH and 1 and 5 min Apgar scores); correlations, and two-step multiple regression assessed PR for delivery method and neonatal outcomes. The main outcome measures were correlations of outcome measures with fetal scalp sample BE and pH up to an hour before delivery and fetal reserve index scores scored concurrently. RESULTS: NSVDs had the best immediate neonatal outcomes with significantly higher CB pH and BE as compared to forceps and CDs. However, controlling for PR revealed: (1) PR at 1 h before delivery correlated with delivery mode, i.e. the decrements in outcomes were already present before the delivery was performed; and (2) The presumed deleterious effects of interventional deliveries, per se, were significantly reduced, and (3) Fetal Reserve Index predicted neonatal outcomes better than fetal scalp sample BE, pH, or delivery mode. CONCLUSION: The historical belief that MF deliveries caused poorer outcomes than NSVDs seems mostly backwards. Appreciating PR's impact on delivery routes, and when appropriate, properly performing VODs could safely reduce CDR. If our approach lowered CDR by only ∼2%, in the United States about 80,000 CDs might be avoided, saving ∼$750 Million yearly. In the post pandemic world, safely apportioning medical expenses will be even more critical than previously.

Uterine contraction frequency in the last hour of labor: how many contractions are too many?

OBJECTIVE: Increased frequency of uterine contractions is a component in the cluster of causal conditions that can lead to fetal hypoxia and acidosis and increase the risk for neonatal neurologic injury. For most international obstetrical societies, 5 contractions per 10 min averaged over 30 min is considered as the upper limit of normal uterine activity. We hypothesize that it might be safer to adopt an upper limit of 4 contractions per 10 min. METHODS: We reviewed our 1970's research database containing 475 patients with closely monitored and well-documented labor and neonatal assessments that included cord blood (CB) pH, base excess (BE), and continuous recording of neonatal heart rate (NHR). Using data segregated by the proportion of the last hour before delivery when uterine contraction frequency (UCF) exceeded 4 and 5 contractions per 10 min respectively, we evaluated outcomes (CB BE, pH, Apgar scores at 1 min, the status of NHR at 16 min after birth, and the proportion of births that did not the result from normal spontaneous vaginal deliveries (NSVDs). ANOVA established relationships between UCF cutoffs and these outcomes. Our sample size is sufficiently large to provide the ability of UCF, per se, to accurately detect an alpha region of .05 88% of the time with an effect size of .15. RESULTS: During the last hour prior to delivery, a UCF cutoff at 4 contractions per 10 min performed better than a UCF cutoff at 5 contractions per 10 min to enable the earlier identification of risks for abnormal outcomes. The longer UCF was increased, the worse were the outcomes that were measured, and the region >4 but ≤5 contractions identifies the beginnings of worsening conditions in a variety of measures of poor outcomes. CONCLUSION: Lowering the recommended threshold for UCF from 5 to 4 contractions per 10-minute period as averaged over 30 min facilitates earlier detection of potentially compromised fetuses and is also an important contributor to a multicomponent contextualized approach to risk assessment.

Comparison of Genetic Profiling between Primary Tumor and Circulating Tumor Cells Captured by Microfluidics in Epithelial Ovarian Cancer: Tumor Heterogeneity or Allele Dropout?

Epithelial ovarian cancer (EOC) is a leading cause of cancer mortality among women but unfortunately is usually not diagnosed until advanced stage. Early detection of EOC is of paramount importance to improve outcomes. Liquid biopsy of circulating tumor cells (CTCs) is emerging as one of the promising biomarkers for early detection of solid tumors. However, discrepancies in terms of oncogenomics (i.e., different genetic defects detected) between the germline, primary tumor, and liquid biopsy are a serious concern and may adversely affect downstream cancer management. Here, we illustrate the potential and pitfalls of CTCs by presenting two patients of Stage I EOC. We successfully isolated and recovered CTCs by a silicon-based nanostructured microfluidics system, the automated Cell RevealTM. We examined the genomics of CTCs as well as the primary tumor and germline control (peripheral blood mononuclear cells) by whole exome sequencing. Different signatures were then investigated by comparisons of identified mutation loci distinguishing those that may only arise in the primary tumor or CTCs. A novel model is proposed to test if the highly variable allele frequencies, between primary tumor and CTCs results, are due to allele dropout in plural CTCs or tumor heterogeneity. This proof-of-principle study provides a strategy to elucidate the possible cause of genomic discrepancy between the germline, primary tumor, and CTCs, which is helpful for further large-scale use of such technology to be integrated into clinical management protocols.

Understanding False Negative in Prenatal Testing.

A false negative can happen in many kinds of medical tests, regardless of whether they are screening or diagnostic in nature. However, it inevitably poses serious concerns especially in a prenatal setting because its sequelae can mark the birth of an affected child beyond expectation. False negatives are not a new thing because of emerging new tests in the field of reproductive, especially prenatal, genetics but has occurred throughout the evolution of prenatal screening and diagnosis programs. In this paper we aim to discuss the basic differences between screening and diagnosis, the trade-offs and the choices, and also shed light on the crucial points clinicians need to know and be aware of so that a quality service can be provided in a coherent and sensible way to patients so that vital issues related to a false negative result can be appropriately comprehended by all parties.