Precarious hope: Ethical considerations for offering experimental fetal therapies outside of research after initial studies in humans.

OBJECTIVE: Risks and benefits of experimental fetal therapies can remain uncertain after initial clinical studies, especially long-term effects. Nevertheless, pregnant individuals may request them, hoping to benefit their future child. Guidance about offering experimental fetal therapies outside research (as "innovative therapy") is limited, despite their ethical complexity. We propose points for clinicians and reviewers to consider when deciding whether and how to offer experimental fetal therapies as innovative therapies after initial clinical studies. METHOD: We used conceptual analysis and a current case to develop points for consideration, grounded in broader debates on innovative therapy and the unique challenges associated with experimental fetal therapies. RESULTS: Clinicians should evaluate whether offering experimental fetal therapies as innovative therapy is appropriate for a pregnant individual and their fetus. The anticipated risk-benefit ratio for the fetus should be favorable. For the pregnant individual, risks may outweigh benefits, within reasonable limits. Medical resources should be sufficient to ensure appropriate care. Clinicians should support pregnant individuals in making informed choices. Clinicians offering innovative therapies with more than minimal risk should collect and report data on outcomes. Independent review should take place. CONCLUSION: Considering these points may advance the interests of fetuses, future children, and their families.

A curious case of acute respiratory distress syndrome.

Gestational acute respiratory distress syndrome (ARDS) is a complicated problem with the potential to gravely harm both mother and fetus. This case report describes a young woman in her second trimester of pregnancy who developed progressive respiratory failure in the setting of newly diagnosed influenza, diffuse alveolar hemorrhage and lymphangioleiomyomatosis. The patient's condition was refractory to conventional interventions and required extracorporeal membrane oxygenation (ECMO) support. Her course was further complicated by preeclampsia requiring preterm delivery with cesarean section while on ECMO. Through novel therapies and a multidisciplinary approach to care, both the patient and her child would overcome these unique and challenging conditions and survive.

Herpes Simplex Virus Cervicitis Mimicking Preterm Premature Rupture of Membranes.

BACKGROUND: The diagnosis of preterm premature rupture of membranes (PROM) is based on pooling, ferning, and Nitrazine tests; definitive diagnosis is made with a blue dye test. CASE: A 21-year-old woman, gravida 1 para 0, at 25 5/7 weeks of gestation was admitted for preterm PROM with positive findings of pooling, Nitrazine, and ferning. Her cervix was bluish with white plaques. Amniotic fluid volume was normal. On hospital day 8, her discharge ceased; examination was negative for pooling, Nitrazine, and ferning. A blue dye tampon test was negative. A Pap test result from her hospitalization returned consistent with herpes infection. CONCLUSION: The diagnosis of preterm PROM should be constantly reevaluated in the setting of a normal amniotic fluid volume.

Trisomy 18 and complex congenital heart disease: seeking the threshold benefit.

A prenatal diagnosis of ductal-dependent, complex congenital heart disease was made in a fetus with trisomy 18. The parents requested that the genetic diagnosis be excluded from all medical and surgical decision-making and that all life-prolonging therapies be made available to their infant. There was conflict among the medical team about what threshold of neonatal benefit could outweigh maternal and neonatal treatment burdens. A prenatal ethics consultation was requested.

Vaginal breech delivery in very low birth weight (VLBW) neonates: experience of a single center.

AIMS: To compare the short-term maternal and neonatal outcomes of very low birth weight (VLBW) breech singletons by mode of delivery. METHODS: All breech fetuses born from 24-0/7 to 26-6/7 weeks' gestation at our institution between 2000 and 2008 were eligible for the study. Abstracted medical record data included maternal demographics, delivery data, and neonatal outcomes. RESULTS: There were 26 vaginal and 39 cesarean deliveries. Maternal age did not differ between groups; gestational age was greater in the cesarean group by five days. Short-term neonatal outcomes did not differ between groups. Of the 39 cesarean deliveries, 27 involved classical uterine incisions. Estimated blood loss (732 mL vs. 362 mL) and postpartum infection rate (26% vs. 4%) were greater with cesarean delivery. CONCLUSION: Neonatal outcome is not improved in VLBW infants born by cesarean section. Given the morbidity of classical cesarean sections, vaginal delivery of the breech VLBW infant may be safely considered.

Successful diagnostic and therapeutic intrauterine fetal interventions by natural orifice transluminal endoscopic surgery (with videos).

BACKGROUND: Despite advances in the development of fetal surgery, morbidity and mortality are substantial. A natural orifice transluminal endoscopic surgery (NOTES)-guided approach to the gravid uterus may offer a less-invasive technique. OBJECTIVE: To assess the feasibility of NOTES for diagnostic and therapeutic intrauterine fetal interventions. SETTING: Survival and nonsurvival experiments on pregnant sheep. DESIGN AND INTERVENTION: Nonsurvival experiments performed in 2 pregnant sheep (80-110 days' gestation). A third ewe underwent NOTES and survived for 4 weeks. Transgastric (nonsurvival ewes) and transvaginal (1 nonsurvival and the survived ewe) peritoneoscopy was performed after standard needle-knife entry into the peritoneal cavity. Endoscopic access to the gravid uterus was assessed. EUS-guided, transuterine injection of saline solution into the fetal cardiac ventricle and vessels was attempted in all. MAIN OUTCOME MEASUREMENTS: Feasibility of NOTES- and EUS-guided intervention in a pregnant animal model, visibility of fetal parts via EUS compared with transabdominal US. RESULTS: Entry into the peritoneal cavity was achieved in each ewe. Access to and complete visualization of the gravid uterus were successful once within the abdominal cavity. Visualization of the fetal parts and the placental cotyledons by EUS was achieved in all animals. EUS-guided amniocenteses and transuterine intracardiac and intravascular injection of saline were successful. There were no complications or preterm delivery after the procedures. LIMITATIONS: Animal model. CONCLUSIONS: NOTES is technically feasible in the pregnant ewe. Intraperitoneal EUS via a NOTES approach provides excellent access and visualization of the intrauterine cavity and fetal parts.

Intrapartum electronic fetal monitoring and the identification of systemic fetal inflammation.

OBJECTIVE: To determine if intrapartum electronic fetal heart rate monitoring (EFM) can identify the fetal in utero systemic inflammatory response or neonatal sepsis, risk factors for the development of brain injury. STUDY DESIGN: This case-control study matched cases with both histologic chorioamnionitis and funisitis (75 preterm and 63 term) to the next delivery without placental or cord inflammation by gestational age and mode of L delivery. The last 2 hours of EFM prior to delivery were reviewed by 3 perinatologists blinded to placental pathology. RESULTS: Preterm and term cases had significantly increased baseline heart rates. Term cases had significant increases in tachycardia, total and late decelerations, and nonreactivity and also had fewer accelerations. EFM parameters had sensitivity of 29-65%, specificity of 46-93%, positive predictive value of 53-80% and negative predictive value of 54-58% in identifying fetal systemic inflammation in this matched, case-control sample. Of the preterm neonates, 9 with sepsis were compared to 141 with negative cultures and were found to have a significant increase in baseline fetal heart rate and tachycardia of longer duration. CONCLUSION: Although significant associations were found, EFM lacks precision in identifying the fetal in utero systemic inflammatory response and neonatal sepsis, predisposing conditions for the development of neonatal encephalopathy.

Fetomaternal alloimmune thrombocytopenia: the questions that still remain.

Fetomaternal alloimmune thrombocytopenia (FMAIT) occurs when maternal antibodies are formed to fetal platelet antigens, leading to thrombocytopenia and hemorrhagic complications. The diagnosis is frequently made only after a major hemorrhagic event has occurred during a pregnancy. Identifying patients at risk remains difficult, and the optimal treatment regimen remains to be determined.

Use of T-cell antibodies for donor dosaging in a canine model of in utero hematopoietic stem cell transplantation.

AIM: Microchimerism following canine in utero hematopoietic stem cell transplantation (IUHSCT) development of T-cell dosing regimens. OBJECTIVE: To investigate the use of anti-T-cell antibodies for cell dosing of the donor graft in a canine model of IUHSCT. STUDY DESIGN: Canine IUHSCT was performed by ultrasound-guided intraperitoneal injection in days 35-38 of fetal canines with CD34(+) cells at doses of 4.5 x 10(8) to 1.3 x 10(9) cells/kg and T cells (CD3(+) CD5(+)) at doses of 8 x 10(6) to 8.8 x 10(8) cells/kg. Postnatal studies included tissue histology and polymerase chain reaction-based chimerism analysis. RESULTS: Term survival was 86-100%. Microchimerism (0-2%) was detected in five of eight recipients in multiple tissues. Histopathology revealed no evidence of graft-versus-host disease (GVHD). CONCLUSION: Canine IUHSCT is a useful model to investigate the role of donor T cells in engraftment and GVHD. IUHSCT at early gestational ages with high doses of donor T cells in the graft yields microchimerism in multiple tissues without GVHD.

Cephalopelvic disproportion is associated with an altered uterine contraction shape in the active phase of labor.

OBJECTIVE: The purpose of this study was to determine if intrapartum contractions of a particular shape (rapid rise with slower return to baseline) are predictive of cephalopelvic disproportion (CPD). STUDY DESIGN: In an institutional review board (IRB)-approved study, cohorts of 100 women who underwent spontaneous vaginal delivery (SVD) and 100 who underwent cesarean section (C/S) for CPD or arrest of labor were consecutively identified between January 2004 and March 2005. Inclusion criteria included term, singleton pregnancies, nulliparity, and absence of fetal anomalies. One hour of interpretable electronic fetal monitoring (EFM) was obtained in active labor. Fall to rise (F:R) ratio was calculated by measuring the time for a contraction to return to its baseline from its peak ("fall") and the time for a contraction to rise to its peak ("rise"). The F:Rs were then averaged over the number of contractions. Data were analyzed using Student t test, Chi-square, and Fisher exact tests where appropriate. RESULTS: Maternal demographics are listed in Table I. The average F:R ratio was 1.55 for SVD versus 1.77 for C/S, a statistically significant difference (P = .00003). Analysis of variance revealed this difference persists when controlled for the potentially confounding factors shown. At F:R >1.76, moreover, there was a trend towards larger birth weight (P = .06). CONCLUSION: Our study demonstrates there is a difference in uterine contraction configuration that is more common in those labors destined for C/S due to CPD. This may indicate the presence of a heretofore unknown feedback mechanism as the uterus adapts to the dysfunctional labor.

Intracranial hemorrhage as the initial manifestation of a congenital disorder of glycosylation.

Intracranial hemorrhage in a term neonate is a rare event in the absence of an identifiable precipitating factor such as severe thrombocytopenia, mechanical trauma, asphyxia, infections, or congenital vascular malformations. Congenital disorders of glycosylation are a genetically and clinically heterogeneous group of multisystem disorders characterized by the abnormal glycosylation of a number of glycoproteins. Although bleeding caused by abnormal glycosylation of various coagulation factors is a well-known clinical complication of several types of congenital disorders of glycosylation, intracranial hemorrhage has not been reported as an initial manifestation of this entity. Here we report the detailed history of a family with 2 consecutive male infants, both born at term with intracranial hemorrhage diagnosed within the first 24 hours of life. The diagnosis of a congenital disorder of glycosylation was established in the second infant by an abnormal glycosylation of serum transferrin detected by electrospray-ionization mass spectrometry. Both infants showed significant neurologic deterioration during the first month of life, and both died at 5 months of age. Intracranial hemorrhage in a term neonate without a potential precipitating factor represents yet another clinical feature that should raise the suspicion for a congenital disorder of glycosylation.

Chronic villitis in untreated neonatal alloimmune thrombocytopenia: an etiology for severe early intrauterine growth restriction and the effect of intravenous immunoglobulin therapy.

OBJECTIVE: The objective of the study was to examine placental histopathology in intravenous immunoglobulin-treated and untreated neonatal alloimmune thrombocytopenia and correlate pathological findings with clinical outcomes. STUDY DESIGN: Placentas from 14 neonatal alloimmune thrombocytopenia-affected pregnancies were identified. Maternal antepartum treatment with intravenous immunoglobulin and pregnancy outcomes were abstracted from medical records. Placental histopathology and clinical outcomes were compared between intravenous immunoglobulin and no intravenous immunoglobulin treatment groups using Fisher's exact test. One subject, treated only after an intracranial hemorrhage (ICH) was diagnosed, was excluded from the analysis. P < .05 was considered significant. RESULTS: Untreated pregnancies demonstrated a lymphoplasmacytic chronic villitis not seen in the intravenous immunoglobulin-treated pregnancies (P = .005). Intrauterine growth restriction and intrauterine fetal demise occurred as frequently as ICH in the untreated group. No ICH, intrauterine growth restriction, or intrauterine fetal demises occurred in the treated group, although the P value was not significant. CONCLUSION: Chronic villitis is frequently manifest in neonatal alloimmune thrombocytopenia, with intravenous immunoglobulin alleviating this inflammatory immunologic response. We suspect a more universal role for the maternal antibody, such as fetal endothelial cell damage, in the sequelae of neonatal alloimmune thrombocytopenia.

Analgesia and anesthesia in labor.

Whether given as an epidural, spinal, or combination, regional anesthesia is an integral part of obstetrics in the United States. A variety of drugs and dosages are used in various combinations, with no one protocol exceeding others in terms of efficacy and safety. The availability of anesthesia and analgesia has had an extraordinary impact on the field of obstetrics in the twentieth century. Knowledge of the techniques and medications used, their potential toxicities, and effects on the labor process itself can only enhance obstetricians' management of the parturient in labor.

Can electronic fetal monitoring identify preterm neonates with cerebral white matter injury?

OBJECTIVE: Although preterm delivery occurs in only 10% of all births, these infants are at high risk for cerebral white matter injury and constitute a third of all cerebral palsy cases. Our objective was to estimate if electronic monitoring can identify preterm fetuses diagnosed with brain injury during the neonatal period. METHODS: In this case-control study, 150 consecutive neonates with ultrasonography-diagnosed cerebral white matter injury were matched by gestational age within 7 days to 150 controls with normal head ultrasonograms. Tracings were retrieved for 125 cases (83%) and 121 controls (81%) and reviewed by 3 perinatologists blinded to outcome. Vaginal (64 cases, 72 controls) and cesarean deliveries (61 cases, 49 controls) were analyzed separately. RESULTS: There was no difference in baseline heart rate, tachycardia, bradycardia, short-term variability, accelerations, reactivity, number or types of decelerations, or bradycardic episodes between cases and controls in either the vaginal or cesarean delivery groups. For the 6 neonates with metabolic acidosis severe enough to increase the risk for long-term neurologic morbidity, there was a significant increase in baseline amplitude range less than 5 beats per minute; however, its positive predictive value in predicting severe metabolic acidosis was only 7.7%. Increasing late decelerations were associated with decreasing umbilical arterial pH and base excess, but were not significantly different in the acidosis and control groups (1.0 +/- 1.8, 0.55 +/- 1.23 late decelerations per hour, P = .39). CONCLUSION: Although decreased short-term variability and increased late decelerations are associated with decreasing umbilical arterial pH and base excess, electronic fetal monitoring is unable to identify preterm neonates with cerebral white matter injury.