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.

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.

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.

Refining the Prediction and Prevention of Emergency Operative Deliveries with the Fetal Reserve Index.

Electronic fetal monitoring (EFM) is a poor predictor of outcomes attributable to delivery problems. Contextualizing EFM by adding maternal, obstetrical, and fetal risk-related information to create an index called the Fetal Reserve Index (FRI) improves the predictive capacity and facilitates the timing of interventions. Here, we test critical assumptions of FRI as a clinical tool. Our conceptualization implies that the earlier one reaches the red zone (FRI ≤25) and the longer one spends in the red zone, the greater the likelihood of emergency operative deliveries (EOD). METHODS: We analyzed 1,402 patients using logistic regression predicting the probability of EOD and employed qualitative methodology techniques to refine predictive capabilities. RESULTS: Reaching the red zone early and staying there > 1 h increases the probability of EOD. When these risk factors are paired with intrauterine resuscitation (IR) in Stage 1, the reduction of EOD is substantial. CONCLUSION: FRI is a capable predictor of EOD because it accurately identifies the level of malleable risk. FRI analysis increases the risk of using IR in Stage 1. Matching risk and resources dramatically reduces the chances of EOD. Earlier IR improves the outcomes if the calculated risk is high.

The epidemic of abnormal copy number variant cases missed because of reliance upon noninvasive prenatal screening.

OBJECTIVE: To assess the implications of increasing utilization of noninvasive prenatal screening (NIPS), which may reach 50% with the concomitant decrease in diagnostic procedures (DPs) for its impact on detection of chromosomal abnormalities. METHODS: We studied our program's statistics over 5 years for DPs and utilization of array comparative genomic hybridization (aCGH). We then modeled the implications in our program if DP had not fallen and nationally of a 50% DP and aCGH testing rate using well-vetted expectations for the diagnosis of abnormal copy number variants (CNVs). RESULTS: Our DP fell 40% from 2013-2017. Utilization of aCGH for DP nearly tripled. We detected 28 abnormal CNVs. If DP had not fallen, we likely would have detected 60. With 4 million US births per year, 2 million DPs would detect 30 000 abnormal CNVs and 4000 standard aneuploidies. At a 1/500 complication-pregnancy loss rate, the detection/complication ratio is 8.5/1. CONCLUSIONS: Noninvasive prenatal screening has significantly changed the practice of prenatal screening. However, while increasing the detection of Down syndrome, the concomitant decrease in DP and lack of aCGH results in missing many more abnormalities than the increase in Down syndrome and complications of DP combined. From a public health perspective, such represents a missed opportunity for overall health care delivery.

The impact of third-trimester genetic counseling.

OBJECTIVE: To evaluate the impact of genetic counseling (GC) during the third trimester by analyzing changes in pregnancy management and the correlation with postnatal findings. METHODS: This was a retrospective study. Pregnancy course and neonatal follow-up were analyzed according to the reason for referral and implementation of recommendations. RESULTS: The records of neonates born to 181 women were retrieved. Fifty-two women (group 1-29%) qualified for pregnancy termination under Israeli guidelines and laws, and 129 (group 2-71%) were not at the time they were referred. By another division: 104 women (group 3-57%) followed the physician's diagnostic recommendations completely after counseling including amniocentesis, fetal MRI, targeted ultrasound scans, fetal echocardiography. Seventy-seven declined amniocentesis (group 4-43%). Additional abnormalities were detected postpartum in all groups without statistically difference: 3/52 (10%) in group 1, 9/129 (7%) in group 2, 6/104 (6%) in group 3, and 6/77 (8%) in group 4). CONCLUSION: GC in the third trimester of pregnancy provided the couple with a sharper more focused picture and assisted them to perceive the significance of new, significant fetal findings which attest to the value of the GC.

Folic Acid Supplementation to Prevent Recurrent Neural Tube Defects: 4 Milligrams Is Too Much.

Some medical practices have been ingrained in custom for decades, long after "proof" that they were effective was established. It is necessary to periodically reevaluate these practices, as newer theories and research may challenge the evidence upon which they were based. An example is the decades' old practice of recommending a 4-mg (4,000-µg) supplement of folic acid to women who are at risk for recurrent neural tube defect (NTD) during pregnancy. This recommendation was based on findings from a randomized clinical trial in 1991. Since then, multiple studies have confirmed the utility of 400-800 µg of folic acid in lowering both primary and recurrent risks of NTDs, but no studies have established any further reduction in risk with doses over 1 mg. Current understanding of folic acid metabolism during pregnancy suggests that at higher doses, above ∼1 mg, there is not increased absorption. Recent evidence suggests that 4 mg folic acid supplementation may not be any more effective than lower doses for the prevention of recurrent NTDs. Thus, we recommend that it is time for clinicians to reexamine their reliance on this outdated recommendation and consider using current recommendations of 400-800 µg per day for all patients in conjunction with assessment of maternal folate status.

The "Fetal Reserve Index": Re-Engineering the Interpretation and Responses to Fetal Heart Rate Patterns.

OBJECTIVE: Electronic fetal monitoring (EFM) correlates poorly with neonatal outcome. We present a new metric: the "Fetal Reserve Index" (FRI), formally incorporating EFM with maternal, obstetrical, fetal risk factors, and excessive uterine activity for assessment of risk for cerebral palsy (CP). METHODS: We performed a retrospective, case-control series of 50 term CP cases with apparent intrapartum neurological injury and 200 controls. All were deemed neurologically normal on admission. We compared the FRI against ACOG Category (I-III) system and long-term outcome parameters against ACOG monograph (NEACP) requirements for labor-induced fetal neurological injury. RESULTS: Abnormal FRI's identified 100% of CP cases and did so hours before injury. ACOG Category III identified only 44% and much later. Retrospective ACOG monograph criteria were found in at most 30% of intrapartum-acquired CP patients; only 27% had umbilical or neonatal pH <7.0. CONCLUSIONS: In this initial, retrospective trial, an abnormal FRI identified all cases of labor-related neurological injury more reliably and earlier than Category III, which may allow fetal therapy by intrauterine resuscitation. The combination of traditional EFM with maternal, obstetrical, and fetal risk factors creating the FRI performed much better as a screening test than EFM alone. Our quantified screening system needs further evaluation in prospective trials.

Challenges in non-invasive prenatal screening for sub-chromosomal copy number variations using cell-free DNA.

Non-invasive prenatal screening (NIPS) has revolutionized the approach to prenatal fetal aneuploidy screening. Many commercial providers now offer analyses for sub-chromosomal copy number variations (CNVs). Here, we review the use of NIPS in the context of screening for microdeletions and microduplications, issues surrounding the choice of disorders tested for, and the advantages and disadvantages associated with the inclusion of microdeletions to current NIPS. Several studies have claimed benefits; however, we suggest that microdeletions have not demonstrated a low enough false positive rate to be deemed practical or ethically acceptable, especially considering their low positive predictive values. Because a positive NIPS result should be confirmed using diagnostic techniques, and false positive rates are as high as 90% for some microdeletions, diagnostic testing seems preferable when the goal is to maximize the detection of microdeletion or microduplication syndromes.

Re-Thinking Elective Single Embryo Transfer: Increased Risk of Monochorionic Twinning - A Systematic Review.

BACKGROUND/OBJECTIVES: Multiple pregnancies have tripled in the United States over the past 3 decades. Attributed to increasing maternal age at delivery but more so assisted reproductive technological advances, an effort has been made to decrease twinning through elective single embryo transfer. We sought to review and evaluate risks of monochorionic twinning as a predictable consequence of increasing utilization of elective single embryo transfer on perinatal outcomes. Primary outcomes included twinning rates, fetal anomalies, growth, preterm birth, and mortality. Secondary outcomes included neurological and pulmonary disability, intrauterine growth restriction, and congenital cardiac anomalies and twin-twin transfusion syndrome. DATA SOURCES: PubMed and Embase. RESULTS: A total of 106 studies identified by systematic search met the inclusion criteria. The trend for lower numbers of embryos transferred has inadvertently led to an increase in monochorionic twinning. This is associated with worse outcomes compared to dichorionic twinning and singleton gestations for all outcomes studied. DISCUSSION: Of great concern for monochorionic twins is the risk profile of significant morbidity and mortality. Transfer of 2 embryos should be considered to avoid higher risks inherent to the shared placental phenomena related to monochorionic twins.

Fetal Treatment 2017: The Evolution of Fetal Therapy Centers - A Joint Opinion from the International Fetal Medicine and Surgical Society (IFMSS) and the North American Fetal Therapy Network (NAFTNet).

More than 3 decades ago, a small group of physicians and other practitioners active in what they called "fetal treatment" authored an opinion piece outlining the current status and future challenges anticipated in the field. Many advances in maternal, neonatal, and perinatal care and diagnostic and therapeutic modalities have been made in the intervening years, yet a thoughtful reassessment of the basic tenets put forth in 1982 has not been published. The present effort will aim to provide a framework for contemporary redefinition of the field of fetal treatment, with a brief discussion of the necessary minimum expertise and systems base for the provision of different types of interventions for both the mother and fetus. Our goal will be to present an opinion that encourages the advancement of thoughtful practice, ensuring that current and future patients have realistic access to centers with a range of fetal therapies with appropriate expertise, experience, and subspecialty and institutional support while remaining focused on excellence in care, collaborative scientific discovery, and maternal autonomy and safety.

Noninvasive prenatal screening or advanced diagnostic testing: caveat emptor.

The past few years have seen extraordinary advances in prenatal genetic practice led by 2 major technological advances; next-generation sequencing of cell-free DNA in the maternal plasma to noninvasively identify fetal chromosome abnormalities, and microarray analysis of chorionic villus sampling and amniotic fluid samples, resulting in increased cytogenetic resolution. Noninvasive prenatal screening of cell-free DNA has demonstrated sensitivity and specificity for trisomy 21 superior to all previous screening approaches with slightly lower performance for other common aneuploidies. These tests have rapidly captured an increasing market share, with substantial reductions in the number of chorionic villus sampling and amniocentesis performed suggesting that physicians and patients regard such screening approaches as an equivalent replacement for diagnostic testing. Simultaneously, many clinical programs have noted significant decreases in patient counseling. In 2012 the Eunice Kennedy Shriver National Institute of Child Health and Human Development funded a blinded comparison of karyotype with the emerging technology of array comparative genomic hybridization showing that in patients with a normal karyotype, 2.5% had a clinically relevant microdeletion or duplication identified. In pregnancies with an ultrasound-detected structural anomaly, 6% had an incremental finding, and of those with a normal scan, 1.6% had a copy number variant. For patients of any age with a normal ultrasound and karyotype, the chance of a pathogenic copy number variant is greater than 1%, similar to the age-related risk of aneuploidy in the fetus of a 38 year old. This risk is 4-fold higher than the risk of trisomy 21 in a woman younger than 30 years and 5- to 10-fold higher than the present accepted risk of a diagnostic procedure. Based on this, we contend that every patient, regardless of her age, be educated about these risks and offered the opportunity to have a diagnostic procedure with array comparative genomic hybridization performed.

Sequential Amniotic Fluid Thyroid Hormone Changes Correlate with Goiter Shrinkage following in utero Thyroxine Therapy.

Several isolated reports of fetal goiter treatment have shown limited generalizability of approaches and provide no real guidance for optimal timing, dosages, and treatment strategies. Graves' disease accounts for >60% of these cases. Maternal treatments of hyperthyroidism include antithyroid medications such as methimazole and more commonly propylthiouracil (PTU). Here, our management of a patient with a fetal thyroid goiter from maternal exposure to PTU diagnosed at 23.6 weeks' gestation and the management of other cases allow us propose a general strategy for treatment. Intrauterine therapy with 200 and then 400 µg of levothyroxine (3 weeks apart) showed an 85% reduction in fetal thyroid goiter volume. We collected amniotic fluid samples at the time of treatments and assayed thyroid hormones and associated antibodies which closely reflected the changes in thyroid goiter mass volume. Our observations suggest a weekly or biweekly therapeutic intervention schedule. Utilizing both goiter size as well as a novel approach in using amniotic fluid hormone levels to monitor therapy efficacy might improve the quality of treatments. Only with a standardized approach and collection of amniotic fluid thyroid panels do we have the opportunity to develop the database required to determine the number and timing of treatments needed.

Integrating Microarrays into Routine Prenatal Diagnosis: Determinants of Decision Making.

OBJECTIVES: The explosion in genetic technologies, including array comparative genomic hybridization (aCGH), has increased the complexity of genetic counseling. We now offer chorionic villus sampling (CVS) and aCGH to all first-trimester patients, as this allows the prenatal diagnosis of an additional 1% of anomalies not otherwise detectable and can detect genetic copy number variants at a much higher resolution than conventional cytogenetics. Here, we explored some of the determinants of how patients are deciding to use or not use this new technology and evaluate risk-benefit analyses for that decision. METHODS: This is a retrospective case-control study of singleton and multiples pregnancies at our center. Those having aCGH testing along with CVS were defined as 'testers' and those who declined aCGH but had the CVS were 'nontesters'. RESULTS: Demographic data of 181 educated women who chose CVS were compared. Among those carrying singletons (n = 144), older women, defined as over 35 years of age (or 'advanced maternal age'; AMA), were more likely to choose the aCGH than younger women. Further, women who had a prior history of genetic testing and who wanted to know the gender of the fetus were more likely to choose the aCGH test. In women carrying multiples (n = 37), AMA ceases to be a predictor of choice. Having had prior genetic counseling remains a strong predictor for choosing aCGH, as does wanting to know the gender of the fetus. Neither prior abortions nor having prior children were significant for women carrying singletons or multiples. CONCLUSION: Offering pregnant couples an individualized choice regarding aCGH seems an appropriate approach. There are discrete patterns associated with the choice of taking the aCGH that varied depending on whether the patient was carrying a singleton or multiples.

Long-term neurologic outcomes after common fetal interventions.

OBJECTIVE: Fetal interventions have clearly decreased mortality, but the neurological outcomes of survivors are of critical concern. Here we consolidated available data on long-term neurological outcomes after common fetal interventions to guide counseling, management, and future research. STUDY DESIGN: Published studies assessing long-term neurological outcomes after common fetal interventions from 1990 through 2014 were collected. We included all studies with a cohort of more than 5 patients and with follow-up of 1 year or longer. We divided procedures into those performed for singletons and for multiples. Singleton procedures included amnioinfusion for preterm premature rupture of membranes, intrauterine transfusion for red cell alloimmunization-associated anemia, intrauterine transfusion for parvovirus-associated anemia, vesicoamniotic shunts, thoracoamniotic shunts, ventriculoamniotic shunts, fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia, and open fetal cases by myelomeningocele and others. Multiple procedures included those done for monochorionic twins including serial amnioreduction, selective fetoscopic laser photocoagulation, and selective termination. RESULTS: Of 1341 studies identified, 28 met the inclusion criteria. We combined available literature for all procedures. Studies varied in their length of follow-up and method of assessing neurological status. Neurological outcome after intervention varied by procedure but was normal in 40-93%, mildly impaired in 3-33%, and severely impaired in 1-40%. Follow-up to school age was rare with the exception of procedures for monochorionic twins. CONCLUSION: Fetal treatments have been successful in achieving survival in previously hopeless cases, but success should also be determined by the outcomes of survivors. Except for monochorionic twins, there is a dearth of reported long-term outcomes. Standardized reporting of long-term neurological sequelae is imperative so that meaningful analysis and study comparisons can be made.

Fetal reduction: 25 years' experience.

Fetal reduction (FR) began in the 1980s to salvage the pregnancies of couples needing fertility therapy who were finally successful but with too many fetuses. Since then, it has gone from a rarity performed in only the highest risk situations to an integral fail-safe of infertility practice. Our understanding of the problems of multiple and premature births has increased - even twins carry 4-5 times more risk than singletons. Evaluation of fetuses before FR has permitted more intelligent choices and improved resultant outcomes. We now perform chorionic villus sampling in approximately 85% of cases, obtain fluorescent in situ hybridization (FISH) results overnight, and then perform FR the next day. Decisions about which to reduce prioritize anomalies, but now can include fetal gender in the decision process, as couples are now just as likely to want girls as boys. In Mendelian cases, sophisticated molecular analyses permit diagnoses before FR, and new uses such as paternity analysis can be performed. Ethical arguments have also evolved; as with many technologies in which the start was for only 'life or death cases', FR has also moved into 'quality of life' issues. FR of twins to a singleton now compromise about 30% of our cases.

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.