Nipocalimab in Early-Onset Severe Hemolytic Disease of the Fetus and Newborn.

BACKGROUND: In early-onset severe hemolytic disease of the fetus and newborn (HDFN), transplacental transfer of maternal antierythrocyte IgG alloantibodies causes fetal anemia that leads to the use of high-risk intrauterine transfusions in order to avoid fetal hydrops and fetal death. Nipocalimab, an anti-neonatal Fc receptor blocker, inhibits transplacental IgG transfer and lowers maternal IgG levels. METHODS: In an international, open-label, single-group, phase 2 study, we assessed treatment with intravenous nipocalimab (30 or 45 mg per kilogram of body weight per week) administered from 14 to 35 weeks' gestation in participants with pregnancies at high risk for recurrent early-onset severe HDFN. The primary end point was live birth at 32 weeks' gestation or later without intrauterine transfusions as assessed against a historical benchmark (0%; clinically meaningful difference, 10%). RESULTS: Live birth at 32 weeks' gestation or later without intrauterine transfusions occurred in 7 of 13 pregnancies (54%; 95% confidence interval, 25 to 81) in the study. No cases of fetal hydrops occurred, and 6 participants (46%) did not receive any antenatal or neonatal transfusions. Six fetuses received an intrauterine transfusion: five fetuses at 24 weeks' gestation or later and one fetus before fetal loss at 22 weeks and 5 days' gestation. Live birth occurred in 12 pregnancies. The median gestational age at delivery was 36 weeks and 4 days. Of the 12 live-born infants, 1 received one exchange transfusion and one simple transfusion and 5 received only simple transfusions. Treatment-related decreases in the alloantibody titer and IgG level were observed in maternal samples and cord blood. No unusual maternal or pediatric infections were observed. Serious adverse events were consistent with HDFN, pregnancy, or prematurity. CONCLUSIONS: Nipocalimab treatment delayed or prevented fetal anemia or intrauterine transfusions, as compared with the historical benchmark, in pregnancies at high risk for early-onset severe HDFN. (Funded by Janssen Research and Development; UNITY ClinicalTrials.gov number, NCT03842189.).

Association of amnioinfusion volume at the time of surgery for twin-twin transfusion syndrome and latency to delivery.

OBJECTIVE: To evaluate the impact of amnioinfusion and other peri-operative factors on pregnancy outcomes in the setting of Twin-twin transfusion syndrome (TTTS) treated via fetoscopic laser photocoagulation (FLP). METHODS: Retrospective study of TTTS treated via FLP from 2010 to 2019. Pregnancies were grouped by amnioinfusion volume during FLP (<1 L vs. ≥1 L). The primary outcome was latency from surgery to delivery. An amnioinfusion statistic (AIstat) was created for each surgery based on the volume of fluid infused and removed and the preoperative deepest vertical pocket. Regression analysis was planned to assess the association of AIstat with latency. RESULTS: Patients with amnioinfusion of ≥1 L at the time of FLP had decreased latency from surgery to delivery (61 ± 29.4 vs. 73 ± 28.8 days with amnioinfusion <1 L, p < 0.001) and increased preterm prelabor rupture of membranes (PPROM) <34 weeks (44.7% vs. 33.5%, p = 0.042). Amnioinfusion ≥1 L was associated with an increased risk of delivery <32 weeks (aRR 2.6, 95% CI 1.5-4.5), 30 weeks (aRR 2.4, 95% CI 1.5-3.8), and 28 weeks (aRR 1.9, 95% CI 1.1-2.3). Cox-proportional regression revealed that AIstat was inversely associated with latency (HR 1.1, 95% CI 1.1-1.2). CONCLUSION: Amnioinfusion ≥1 L during FLP was associated with decreased latency after surgery and increased PPROM <34 weeks.

Fetal and Neonatal Reticulocyte Count Response to Intrauterine Transfusion for the Treatment of Red Blood Cell Alloimmunization.

Management of hemolytic disease of the fetus and newborn relies on monitoring of maternal antibody titers, fetal ultrasound, and fetal middle cerebral artery peak systolic velocity studies and is generally treated by intrauterine transfusion (IUT). Few studies have explored fetal and neonate physiological responses to IUT. Our objective was to examine fetal erythropoietic response and to examine neonatal erythropoietic effects after treatment. Thirty-six patients treated from 2005 to 2015 were identified retroactively. The time course of treatment, including gestational age and number of IUT, and timing of delivery were reviewed. Fetal reticulocyte count and neonatal hemoglobin and reticulocyte counts were analyzed for each IUT. For each gestational week, reticulocyte count decreased by ∼8.6% (95% confidence interval [CI]: 5.3-12.0). In the neonatal period, there was significant correlation between hemoglobin at birth and number of transfusions (Spearman correlation 0.473, 95% CI: 0.113-0.715, P =0.01) as well as reticulocyte count at birth and number of transfusions (Spearman correlation: 0.393, 95% CI: 0.058-0.642, P =0.02). IUT appears to have a direct and measurable effect on fetal reticulocyte production which persists in neonates.

Cell free fetal DNA to triage antenatal rhesus immune globulin: Is it really cost-effective in the United States?

OBJECTIVE: To compare the efficacy and costs of three different strategies of antenatal rhesus immune globulin (RhIG) administration in a US population. METHODS: A decision tree analysis was undertaken for universal antenatal RhIG administration based on RhD serologic paternity testing, universal administration without paternity, and selective antenatal RhIG administration using cell free fetal DNA (cfDNA) for RHD fetal typing. Rates of alloimmunization were calculated. Charges were determined for laboratory testing and obstetrical and neonatal treatments for the first pregnancy and cases of alloimmunization in the following pregnancy. RESULTS: The largest number of new RhD alloimmunization cases resulted from a strategy of universal RhIG that included paternity. Fewer cases resulted from a selective strategy; the least number of cases were associated with a universal approach that discounted paternity. When the costs of first pregnancies and alloimmunized second pregnancies were combined, a universal strategy that excludes paternity had the least costs followed by a selective strategy followed by a universal strategy that included paternity. CONCLUSION: The use of cfDNA to determine the selective use of antenatal RhIG would not be cost-effective in the United States. Universal antenatal RhIG without paternity is more effective in preventing new cases of alloimmunization than the current ACOG guideline.

Measuring the Cervical Length.

An important step toward the goal of eradicating spontaneous preterm birth was achieved with the advent of cervical sonography, a tool that advanced our knowledge of the entity of preterm parturition, improved our ability to detect women at risk for early delivery, and allowed us to prevent some of these premature births. We will describe here the correct technique for obtaining such measurements and will review the literature regarding the use of this tool in specific pregnant populations.

Hemolytic disease of the fetus and newborn due to multiple maternal antibodies.

OBJECTIVE: The objective of the study was to determine whether women with combinations of red blood cell antibodies are more likely to develop significant hemolytic disease of the fetus and newborn than those with single antibodies. STUDY DESIGN: A retrospective exposure cohort study was conducted of pregnant women with red blood cell antibodies. The development of significant hemolytic disease of the fetus and newborn was then compared between patients with single antibodies and those with multiple antibodies. Data analysis was limited to pregnancies delivering since the year 2000. RESULTS: Thirteen percent of the patients referred to our program had multiple red blood cell antibodies. Odds of developing significant hemolytic disease of the fetus and newborn for patients with anti-Rh(D) combined with at least 1 additional red blood cell antibody were 3.65 times the odds for women with anti-Rh(D) antibodies in isolation (95% confidence interval, 1.84-7.33). In the setting of multiple antibodies including anti-Rh(D), Rh-positive fetuses/neonates have an increased odds of developing significant hemolytic disease even if the fetus is negative for the other corresponding red blood cell antigen. CONCLUSION: Women with multiple red blood cell antibodies are more likely to develop significant hemolytic disease of the fetus and newborn than those with a single antibody especially in the presence of anti-(Rh)D. This pathophysiology may suggest a more aggressive immune response in women who develop more than 1 red blood cell antibody.

An Ethical Analysis of Therapy for Severe Congenital Kidney and Urinary Tract Anomalies.

Technological advancements before and after delivery have greatly altered the counseling of pregnant patients facing a fetal diagnosis of severe oligohydramnios or anhydramnios secondary to congenital anomalies of the kidneys and urinary tract. Once considered a nearly uniformly lethal abnormality, long-term survival may now be possible secondary to prenatal innovations aimed at restoring the amniotic fluid volume and the availability of more advanced neonatal dialysis techniques. However, these available therapies are far from perfect. The procedures are onerous for pregnant patients without a guarantee of success, and families must prepare themselves for the complex life-long medical care that will be necessary for surviving individuals. Multidisciplinary counseling is imperative to help pregnant individuals understand the complexity of these conditions and assist them in exercising their right to informed decision-making. Moreover, as with any developing field of medicine, providers must contend with ethical questions related to the treatment options, including questions regarding patient-hood, distributive justice, and the blurred lines between research, innovation, and standard care. These ethical questions are best addressed in a multidisciplinary fashion with consideration of multiple points of view from various subspecialties. Only by seeing the entirety of the picture can we hope to best counsel patients about these highly complex situations and help navigate the most appropriate care path.

Patient Survey Regarding Non-Medical Burdens of Care at a Parental Fetal Care Center.

Recognizing the paucity of literature describing the non-medical effects of care at a tertiary parental fetal care center upon families, the purpose of the study was to better examine the potential barriers that our patients face related to care in a parental fetal care center. An anonymous survey was sent via email to patients who received care from 2015 to 2021. The survey included questions regarding demographics, fetal diagnoses, non-medical expenses related to care, and the impact of care on patient relationships, employment, and other children. 453 patients (15.9%) responded out of the 2684 emails sent. 58.3% of patients traveled >100 miles to reach our referral center, with 20% traveling >300 miles. 42.6% of patients reported non-medical expenditures exceeding $1000, with nearly 1 in 10 reporting expenditures of >$5000 (8.6%). Overall, 38.2% of women reported moderate to severe financial burdens related to receiving care at the parental fetal care center. This study illuminates the financial and social burdens that care at a tertiary parental fetal care center imposes upon families. By acknowledging these barriers, we can strive to minimize them to best provide equitable access to high-quality fetal care services.

Anti-M Alloimmunization: Management and Outcome at a Single Institution.

Objective The objective of this study was to review the management strategies and outcomes in gravidas with anti-M alloimmunization over 15 years. Study Design Data collected from 195 pregnant patients with anti-M antibodies from July 2000 through June 2016 were reviewed retrospectively. We analyzed indirect antiglobulin test titer results, paternal or fetal/neonatal M antigen status, antepartum course, and perinatal outcomes. Results Anti-M antibodies were found in 146 women and 195pregnancies. Among those with positive indirect antiglobulin tests, 193 pregnancies had titers at or below 1:4. Only one patient with an initial low titer experienced a more than twofold increase to a titer 1:64. Two women underwent an amniocentesis and cordocentesis. Ninety-five (73.6%) of the 129 infants tested were positive for the M antigen. Nine infants required phototherapy. There were no cases of hemolytic disease of the fetus or newborn, mild or severe. Conclusion The incidence of severe hemolytic disease of the newborn due to anti-M is extremely low. We found no cases in our review of 195 pregnancies, despite several cases of severe hemolytic disease of the newborn reported in the literature. We have created an algorithm for the management of anti-M antibodies in pregnancy based on our data and extensive literature review.

Hemolytic Disease of the Fetus and Newborn due to Intravenous Drug Use.

Objectives The objective is to present a pregnancy complication associated with intravenous drug use, namely, that of red blood cell alloimmunization and hemolytic disease of the fetus and newborn. Methods An observational case series is presented including women with red blood cell alloimmunization most likely secondary to intravenous drug abuse Results Five pregnancies were identified that were complicated by red blood cell alloimmunization and significant hemolytic disease of the fetus and newborn, necessitating intrauterine transfusion, an indicated preterm birth, or neonatal therapy. Conclusions As opioid abuse continues to increase in the United States, clinicians should be aware of the potential for alloimmunization to red blood cell antibodies as yet another negative outcome from intravenous drug abuse.

Prevention of preterm birth in modern obstetrics.

Spontaneous preterm labor is a complex process characterized by the interplay of multiple different pathways. Prevention of preterm labor and delivery is also complicated. The most effective interventions for prevention of preterm birth (PTB) are progestin prophylaxis and lifestyle modifications, with cerclage placement also playing a role in selected populations. Interventions such as activity modification, home tocometry, and routine antibiotic use have fallen out of favor because of lack of effectiveness and possibility of harm. The solution to the problem of PTB remains elusive, and researchers and clinicians must collaborate to find a cure for preterm labor.

Preterm birth rates in a prematurity prevention clinic after adoption of progestin prophylaxis.

OBJECTIVE: To evaluate whether progestin prophylaxis influenced the odds of recurrent spontaneous preterm birth among pregnant women with a previous preterm birth. METHODS: A retrospective cohort study was performed evaluating outcomes of pregnant women with one or more previous preterm births who received prenatal care in a single academic prematurity clinic. Care algorithms were determined and revised by a single supervising physician. Progestin prophylaxis was adopted in 2004 with accelerated access to the first clinic visit adopted in 2008. Rates of preterm birth before 37, 35, and 32 weeks of gestation were compared over time. RESULTS: One thousand sixty-six women with a history of one or more spontaneous preterm births received care in the prematurity clinic and were delivered between January 1, 1998, and June 30, 2012. The gestational age at initiation of prenatal care declined significantly after adoption of an accelerated appointment process (median of 19.1 weeks before 2003, 16.2 weeks from 2004 to 2007, and 15.2 weeks from 2008 to 2012, P<.01), and progestin use increased from 50.8% in 2004-2007 to 80.3% after 2008 (P<.01). After adjustment for race, smoking, cerclage, and number of prior preterm deliveries, we noted a statistically significant decreased odds of spontaneous preterm birth in years 2008-2012 compared with 1998-2007 before 37 (adjusted odds ratio [OR] 0.75, 95% confidence interval [CI] 0.58-0.97) and 35 (adjusted OR 0.70, 95% CI (.52-0.94) weeks of gestation. CONCLUSION: Adoption of prophylactic progestin treatment was associated with a decreased odds of recurrent preterm birth before 37 or 35 weeks of gestation after adoption of an aggressive program to facilitate early initiation of progestin treatment. LEVEL OF EVIDENCE: II.

Maternal preeclampsia and neonatal outcomes.

Preeclampsia is a multiorgan, heterogeneous disorder of pregnancy associated with significant maternal and neonatal morbidity and mortality. Optimal strategies in the care of the women with preeclampsia have not been fully elucidated, leaving physicians with incomplete data to guide their clinical decision making. Because preeclampsia is a progressive disorder, in some circumstances, delivery is needed to halt the progression to the benefit of the mother and fetus. However, the need for premature delivery has adverse effects on important neonatal outcomes not limited to the most premature infants. Late-preterm infants account for approximately two thirds of all preterm deliveries and are at significant risk for morbidity and mortality. Reviewed is the current literature in the diagnosis and obstetrical management of preeclampsia, the outcomes of late-preterm infants, and potential strategies to optimize fetal outcomes in pregnancies complicated by preeclampsia.