Steven J. Ralston

Clinical report - Maternal-fetal intervention and fetal care centers

The past 2 decades have yielded profound advances in the fields of prenatal diagnosis and fetal intervention. Although fetal interventions are driven by a beneficence-based motivation to improve fetal and neonatal outcomes, advancement in fetal therapies raises ethical issues surrounding maternal autonomy and decision-making, concepts of innovation versus research, and organizational aspects within institutions in the development of fetal care centers. To safeguard the interests of both the pregnant woman and the fetus, the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics make recommendations regarding informed consent, the role of research subject advocates and other independent advocates, the availability of support services, the multidisciplinary nature of fetal intervention teams, the oversight of centers, and the need to accumulate maternal and fetal outcome data.

Plasma Concentrations of Soluble Endoglin versus Standard Evaluation in Patients with Suspected Preeclampsia

Background The purpose of this study was to compare plasma soluble endoglin (sEng) levels with standard clinical evaluation or plasma levels of other angiogenic proteins [soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF)] in predicting short-term adverse maternal and perinatal outcomes in women with suspected preeclampsia presenting prior to 34 weeks. Methods and Findings Data from all women presenting at <34 weeks for evaluation of preeclampsia with singleton pregnancies (July 2009−October 2010) were included in this analysis and sEng levels were measured at presentation. Data was analyzed for 170 triage encounters and presented as median {25−75th centile}. Thirty-three percent of patients (56 of 170) experienced an adverse outcome. sEng levels (ng/ml) were significantly elevated in patients who subsequently experienced adverse outcomes compared to those who did not (32.3 {18.1, 55.8} vs 4.8 {3.2, 8.6}, p<0.0001). At a 10% false positive rate, sEng had higher detection rates of adverse outcomes than the combination of highest systolic blood pressure, proteinuria and abnormal laboratory tests (80.4 {70.0, 90.8} vs 63.8 {51.4, 76.2}, respectively). Subjects in the highest quartile of sEng were more likely to deliver early compared to those in the lowest quartile (HR: 14.96 95% CI: 8.73−25.62, p<0.0001). Natural log transformed sEng correlated positively with log sFlt1 levels (r = 0.87) and inversely with log PlGF levels (r = −0.79) (p<0.0001 for both). Plasma sEng had comparable area under the curve for prediction of adverse outcomes as measurement of sFlt1/PlGF ratio (0.88 {0.81, 0.95} for sEng versus 0.89 {0.83, 0.95} for sFlt1/PlGF ratio, p = 0.74). Conclusions In women with suspected preeclampsia presenting prior to 34 weeks of gestation, sEng performs better than standard clinical evaluation in detecting adverse maternal and fetal outcomes occurring within two weeks of presentation. Soluble endoglin was strongly correlated with sFlt1 and PlGF levels, suggesting common pathogenic pathways leading to preeclampsia.

Aberrant cell adhesion molecule expression in human bronchopulmonary sequestration and congenital cystic adenomatoid malformation

In many organs, integrins and cadherins are partly regulated by Hox genes, but their interactions in airway morphogenesis and congenital lung diseases are unknown. We previously showed that the Hox protein HoxB5 is abnormally increased in bronchopulmonary sequestration (BPS) and congenital cystic adenomatoid malformation (CCAM), congenital lung lesions with abnormal airway branching. We now report on alpha(2)-, alpha(3)-, and beta(1)-integrin and E-cadherin expression in normal human lung and in BPS and CCAM tissue previously shown to have abnormal HoxB5 expression and on the relationship of cell adhesion molecule expression to Hoxb5 regulation. alpha(2)-, alpha(3)-, and beta(1)-integrins and E-cadherin expression in normal human lung and BPS and CCAM were evaluated using Western blot and immunohistochemistry. Fetal mouse lung fibroblasts with Hoxb5-specific siRNA downregulation were evaluated for alpha(2)-integrin protein levels by Western blot. Compared with normal human lung, a previously undetected alpha(2)-integrin isoform potentially lacking essential cytoplasmic sequences was significantly increased in BPS and CCAM, and alpha(2)-integrin spatial and cellular expression was more intense. E-cadherin protein levels were also significantly increased, whereas alpha(3) increased in CCAM compared with canalicular, but not with alveolar, stage lung. beta(1)-integrin levels were unchanged. We conclude that in BPS and CCAM, altered alpha(2)-integrin cytoplasmic signaling contributes to abnormal cellular behavior in these lung lesions. Aberrant cell adhesion molecule and Hox protein regulation are likely part of the mechanism involved in the development of BPS and CCAM.

Cost and resource implications with serum angiogenic factor estimation in the triage of pre-eclampsia

To analyse the economic and resource implications of using plasma soluble fms‐like tyrosine kinase‐1 s(Flt1) and placenta growth factor (PlGF) measurements in pre‐eclampsia evaluation and management.

Liver hematoma and rupture in pregnancy.

Liver hematoma and rupture is a rare but devastating complication of pregnancy. The majority of cases have been associated with severe preeclampsia, but unlike typical preeclampsia, it is a disease of older, multiparous patients. Although there are predictable findings on liver pathology, the underlying pathophysiology is poorly understood. Early recognition and prompt surgical intervention are crucial to reduce the high fetal and maternal mortality rate associated with this disease.

Limited Prognostic Value of a Staging System for Twin-to-Twin Transfusion Syndrome

Objective: Severe twin-to-twin transfusion syndrome (TTTS) is usually classified according to a staging system (I–V) based on ultrasonographic findings of polyhydramnios in the recipient, oligohydramnios in the donor, the presence or absence of the donor’s bladder, Doppler waveform changes and (impending) hydrops. Stage correlates with the severity of disease, and it is assumed that, without intervention, severe TTTS will evolve in succession from stage I to stage V (fetal demise). However, this progression has not been validated in longitudinal studies. Herein, we report on the natural progression of severe TTTS in a cohort of patients from a regional Fetal Treatment Program. Methods: Eighteen patients with severe TTTS, diagnosed between 15 and 25 weeks of gestation, were managed over a 28-month period. Data were collected until delivery, endoscopic surgical intervention or dual fetal demise. Patients were evaluated at least once a week. Stage, estimated fetal weight, percent recipient/donor body weight discordance and survival were recorded. Results: The present study represents a total follow-up of 108 patient-weeks. Of 90 week-to-week evaluations, 65 showed no change in stage; 11 showed downstaging (by more than 1 stage in 3, or 27%), and 13 showed upstaging (by more than 1 stage in 8, or 62%). Nine patients (all stage II or above) underwent endoscopic laser ablation. Overall survival was 67%, and survival of at least 1 twin occurred in 78% of pregnancies. Weight discordance between the donor and recipient did not predict outcome. Conclusion: The current staging system for severe TTTS may not be helpful in predicting the direction, degree or speed of progression of the condition. Indications for intervention should remain stage-related, and not based on projected progression.

Circulating cell-free DNA levels increase variably following chorionic villus sampling.

Cell‐free fetal DNA (cffDNA) in maternal plasma results from degradation of fetal and/or placental cells. Our objective was to determine if chorionic villus sampling (CVS) causes increased release of fetal and/or maternal DNA.

Pregnancy outcomes after prenatal diagnosis of aneuploidy

Objective To determine the benefits of antenatal diagnoses of fetal aneuploidy in women who continued their pregnancies. Methods A questionnaire was mailed to 51 mothers of children with aneuploidy. Women whose fetuses were diagnosed prenatally comprised the study group and those whose infants were diagnosed at birth were controls. Outcomes measured included an assessment of pregnancy management, neonatal outcome, subjective measures of depression and anxiety, and evaluation of womens emotional and physical experience of the pregnancy. For outcomes measured by nonparametric survey questions, 20 women were needed in each arm to achieve a power of 80% to detect a 2-point difference on a 6-point scale; for our neonatal outcomes, 100 women were needed in each arm to achieve 80% power to detect a difference in length of stay (less than 1 week versus greater than 1 week) or need for surgery. Results Thirty-eight women (75%) responded. Most (86%) had children with trisomy 21. Seventeen women (45%) received their childs diagnosis at birth; 21 (55%) had prenatal diagnoses. Demographic measures were similar except that women with prenatal diagnoses attended religious services more frequently (1–3 times per month versus once to several times per year, P = .04). Women with prenatal diagnosis had better perceptions of their physical experience of pregnancy (median score of 10 versus 6 on a 10-point visual analog scale, P = .005) and their emotional experience of the birth (median score of 7.5 versus 2, P = .001). Mental Health Inventory scores were similar between groups. Neonates without prenatal diagnoses were more likely to be transferred to tertiary centers after birth (70% versus 24%, P = .004); lengths of hospital stays and need for surgery were similar. Seventy-one percent (95% confidence interval [CI] 48, 89%) of women with prenatal diagnoses said they would have done nothing differently in the pregnancy compared with 29% (95% CI 10, 56%) of women with diagnoses at birth. Conclusion Early knowledge of fetal aneuploidy is beneficial to women who continue their pregnancies. These results might be useful when counseling women who do not intend to terminate abnormal pregnancies, but are considering prenatal diagnosis.

Ultrasound-guided procedures for prenatal diagnosis and therapy.

Ultrasonography has expanded the capabilities of perinatologists to examine,test, and treat the fetus. Amniocentesis and CVS are safe and widely available procedures, which can be used to diagnose a multitude of abnormalities through karyotype analysis and molecular studies. CVS allows earlier diagnosis, but both procedures can provide highly accurate results in the first half of pregnancy. Cordocentesis has fewer indications, but allows direct laboratory testing of fetal blood. Fetocentesis and fetal biopsy are reserved for limited indications, but can play a crucial role in the diagnosis of some conditions, which cannot be assessed less invasively. Fetal transfusion is an important tool in the treatment of isoimmunization, some other forms of fetal anemia, and alloimmune thrombocytopenia. Amnioreduction is a commonly used procedure for the treatment of polyhydramnios and TTTS. Multifetal reduction and selective termination offer previously unavailable options to patients carrying multiple gestations. Fetal shunts can reduce perinatal morbidity and mortality in cases of bladder outlet obstruction and hydrothorax. The limited experience with cord ligation procedures and balloon valvuloplasty suggests these relatively new procedures may serve a greater role in the future as techniques are improved. By providing guidance for all of these procedures, real-time ultrasonography has revolutionized prenatal diagnosis and therapy; it will continue to be a crucial component in evaluating and treating complicated pregnancies.

Surgical and ethical challenges in disorders of sexual development.

A resolution to the difficulties faced by parents, physicians, and pediatric patients in treating DSDs will only come with better communication and improved research methodologies. Advocacy groups and the Internet have allowed the intersex community to have a larger role in guiding the research and the ethical frameworks that are used in treating these disorders. These disorders are unusual and collaboration across medical centers should be the rule rather than the exception. When possible, treatments that are innovative or experimental should be subjected to rigorous research oversight [29,30]. Defined periods of family crisis in which counseling and education become important are at the time of diagnosis [30,31], at the time of any surgical procedure, and at the beginning of major developmental stages. Historically, children were often left uninformed until someone judged them old and mature enough to comprehend how they were different. These attempts to protect individual children from their condition may have left them vulnerable to a personal crisis at an age when sexual identity and identity with a peer group are important. Both the needs of the child and the adult the child will become should be considered in making treatment decisions for children and adolescents with DSDs. It is best to counsel parents and educate developing children in a way that parallels chronologic and conceptual growth. When possible, the child should be involved in an age-appropriate fashion in the decision-making process and accurate information about the childs history and body should be made available. In addition, parents and families need as much information as possible and support systems that will help them navigate these challenging situations.