Improved technical success, postnatal outcome and refined predictors of outcome for fetal aortic valvuloplasty.

OBJECTIVES: Fetal aortic valvuloplasty (FAV) may prevent progression of mid-gestation aortic stenosis to hypoplastic left heart syndrome (HLHS). The aim of this study was to evaluate whether technical success and biventricular (Biv) outcome after FAV have changed from an earlier (2000-2008) to a more recent (2009-2015) era and identify pre-FAV predictors of Biv outcome. METHODS: We evaluated procedural and postnatal outcomes in 123 fetuses that underwent FAV for evolving HLHS at Boston Children's Hospital between 2000 and 2015. The primary outcome measure was circulation type (Biv vs single ventricle) at the time of neonatal hospital discharge. Classification and regression tree (CART) analysis was performed to construct a stratification algorithm to predict Biv circulation based on pre-FAV fetal variables. RESULTS: The FAV procedure was technically successful in 101/123 (82%) fetuses, with a higher technical success rate in the more recent era than in the earlier one (49/52 (94%) vs 52/71 (73%); P = 0.003). In liveborn patients, the incidence of Biv outcome was higher in the recent than in the earlier era, both in the entire liveborn cohort (29/49 (59%) vs 16/62 (26%); P = 0.001) and in those in whom the procedure was technically successful (27/46 (59%) vs 15/47 (32%); P = 0.007). Independent predictors of Biv outcome were higher left ventricular (LV) pressure, larger ascending aorta, better LV diastolic function and higher LV long-axis Z-score. On CART analysis, fetuses with LV pressure > 47 mmHg and ascending aorta Z-score ≥ 0.57 had a 92% probability of Biv outcome (n = 24). Those with a lower LV pressure, or mitral dimension Z-score < 0.1 and mitral valve inflow time Z-score < -2 (n = 34) were unlikely to have Biv (probability of 9%). The remainder of the patients had an intermediate (∼40-60%) likelihood of Biv circulation. CONCLUSIONS: The proportion of patients achieving Biv outcome after FAV has increased, probably owing to an improved technical success rate and modified selection criteria. Fetal factors, including LV pressure, size of the ascending aorta and diastolic function, are associated with likelihood of Biv circulation after FAV. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Should embryos with autosomal monosomy by preimplantation genetic testing for aneuploidy be transferred?: Implications for embryo selection from a systematic literature review of autosomal monosomy survivors.

OBJECTIVE: To review the literature for survival and phenotypes of liveborns with autosomal monosomy to inform decisions regarding transfer of in vitro fertilization-derived embryos reported as monosomic on preimplantation genetic testing for aneuploidy (PGT-A). METHOD: Ovid-Medline and EMBASE were systematically searched to identify published case reports of liveborn individuals with autosomal monosomy, full or mosaic, for a whole chromosome. RESULTS: Fifty-three reports describing 56 individuals with autosomal monosomy met the selection criteria: 1 case each of monosomy 14 and 16, 3 each for monosomy 15 and 18, 1 for group "E", 5 for monosomy 20, 24 for monosomy 21, 7 for monosomy 22, and eleven for a "G" group chromosome. There were no reports with monosomy for the larger chromosomes 1 through 13, nor for chromosomes 17 or 19, autosomes with highest gene density. Most reported individuals had severe handicaps and died in infancy with some surviving longer. CONCLUSION: Given potential for survival of handicapped individuals with autosomal monosomy for chromosomes 14, 15, 16, 18, 20, 21, and 22, low priority should be given to transfer of embryos apparently monosomic for these chromosomes. Couples electing transfer of monosomic embryos should consider amniocentesis for ongoing pregnancies but should be informed of its limitations.

Confined placental mosaicism for 22q11.2 deletion as the etiology for discordant positive NIPT results.

22q11.2 deletion, the most common microdeletion syndrome within the general population, is estimated to have a prevalence of 1 in 3000 to 6000. Non-invasive prenatal testing has recently expanded to include screening for several microdeletions including 22q11.2. Given the expansion of prenatal screening options to include microdeletions, it is important to understand the limits of this technology and the variety of reasons that a discordant positive result can occur. Here, we describe a case of a pregnant woman who received a positive non-invasive prenatal maternal plasma screen for 22q11.2 deletion. Maternal and postnatal neonatal peripheral blood cytogenetic, PCR, and fluorescence in situ hybridization studies were normal, but the placenta was mosaic for 22q11.2 deletion in two of three biopsy sites. This case illustrates both the complexities of pre- and post-test counseling for microdeletion screening and the potential for a discordant positive microdeletion result because of confined placental mosaicism. © 2017 John Wiley & Sons, Ltd.

Review: cell-free fetal DNA in the maternal circulation as an indication of placental health and disease.

In human pregnancy, the constant turnover of villous trophoblast results in extrusion of apoptotic material into the maternal circulation. This material includes cell-free (cf) DNA, which is commonly referred to as "fetal", but is actually derived from the placenta. As the release of cf DNA is closely tied to placental morphogenesis, conditions associated with abnormal placentation, such as preeclampsia, are associated with high DNA levels in the blood of pregnant women. Over the past five years, the development and commercial availability of techniques of massively parallel DNA sequencing have facilitated noninvasive prenatal testing (NIPT) for fetal trisomies 13, 18, and 21. Clinical experience accrued over the past two years has highlighted the importance of the fetal fraction (ff) in cf DNA analysis. The ff is the amount of cell-free fetal DNA in a given sample divided by the total amount of cell-free DNA. At any gestational age, ff has a bell-shaped distribution that peaks between 10 and 20% at 10-21 weeks. ff is affected by maternal body mass index, gestational age, fetal aneuploidy, and whether the gestation is a singleton or multiple. In approximately 0.1% of clinical cases, the NIPT result and a subsequent diagnostic karyotype are discordant; confined placental mosaicism has been increasingly reported as an underlying biologic explanation. Cell-free fetal DNA is a new biomarker that can provide information about the placenta and potentially be used to predict clinical problems. Knowledge gaps still exist with regard to what affects production, metabolism, and clearance of feto-placental DNA.

The effect of obstetric practice change to reduce early term delivery on perinatal outcome.

OBJECTIVE: To investigate whether the national emphasis on attaining 39 weeks gestation has altered obstetric practice, and if so whether this has affected perinatal morbidity. STUDY DESIGN: We examined trends in gestational age, neonatal morbidity, maternal complications and stillbirth for a retrospective cohort of singleton, live births between 37+0 and 39+6 weeks of gestation over a 5-year period at a single tertiary care center. RESULT: There were 21 343 eligible deliveries. The proportion of deliveries in the early term (<39 weeks) decreased from 47.8 to 40.2% (P<0.01). The reduction was most pronounced for elective inductions (27.5 to 8.0%; P<0.01) and scheduled cesareans (56.9 to 24.9%; P<0.01), although a similar trend was seen for nonelective inductions (51.2 to 47.9%; P=0.03). In multivariable analysis, there was a 10% decreased odds of early term delivery per year (P<0.01). There were no changes in the rates of neonatal intensive care unit (NICU) evaluation (29.8 to 28.1%; P=0.11), pre-eclampsia (7.6 to 8.5%; P=0.06) or stillbirth (11.5 to 14.4 per 10 000; P=0.55). CONCLUSION: A 10% annual decline in the odds of early term delivery was not accompanied by significant changes in perinatal morbidity.

Changes in left heart hemodynamics after technically successful in-utero aortic valvuloplasty.

OBJECTIVE: Severe aortic stenosis in the mid-gestation fetus can progress to hypoplastic left heart syndrome (HLHS). @ In-utero aortic valvuloplasty is an innovative therapy to promote left ventricular growth and function and potentially to prevent HLHS. This study evaluated the effects of mid-gestation fetal balloon aortic valvuloplasty on subsequent fetal left ventricular function and left heart Doppler characteristics. METHODS: We reviewed fetuses with aortic stenosis that underwent attempted in-utero aortic valvuloplasty between 2000 and 2006. Pre-intervention and the latest post-intervention fetal echocardiograms were analyzed to characterize changes in left heart function and Doppler characteristics in utero. RESULTS: Forty-two fetuses underwent attempted aortic valvuloplasty during the study period, 12 of which were excluded from analysis secondary to inadequate follow-up data, termination or fetal demise. Study fetuses (n = 30) underwent pre-intervention echocardiography at a median gestational age of 23 weeks, and were followed for a median of 66 +/- 23 days post-intervention. In 26 fetuses, aortic valvuloplasty was technically successful. Among these 26, left heart physiology was abnormal pre-intervention and improved or normalized after intervention in most cases: biphasic mitral inflow was present in 5/25 (20%) cases pre-intervention and in 21/23 (91%) post-intervention (P < 0.001); moderate or severe mitral regurgitation was present in 14/26 (54%) cases pre-intervention and in 5/23 (22%) post-intervention (P = 0.02); bidirectional flow across the patent foramen ovale was present in 0/26 cases pre-intervention and in 6/25 (24%) post-intervention (P = 0.01); antegrade flow in the transverse arch was present in 0/25 cases pre-intervention and in 17/26 (65%) post-intervention (P < 0.001). The left ventricular ejection fraction increased from 19 +/- 10% pre-intervention to 39 +/- 14% post-intervention (P < 0.001). These changes were not observed in control fetuses (n = 18). CONCLUSION: Fetal aortic valvuloplasty, when technically successful, improves left ventricular systolic function and left heart Doppler characteristics.

Factors affecting technical success of fetal aortic valve dilation.

OBJECTIVE: We have reported previously that valve dilation enhances growth of cardiac structures and may prevent hypoplastic left heart syndrome (HLHS) in fetuses with critical aortic stenosis. We aimed to investigate maternal/fetal factors which may affect the technical success of fetal valvuloplasty, and to describe perinatal complications of the procedure. METHODS: This was a descriptive series of 22 fetuses diagnosed with critical aortic stenosis developing into HLHS which underwent intervention by valvuloplasty. Initially this was attempted using a percutaneous approach; reassessment after our first five attempts, only one of which was successful, led to the introduction of the option of laparotomy. Technical success was defined as balloon inflation across the aortic annulus and a broader jet through the aortic valve as assessed by Doppler. Data collected included body mass index, demographic variables, ultrasound findings and postprocedure interventions. RESULTS: Technical success increased significantly if maternal laparotomy was an option (83.3% vs. 20.0%, P = 0.017). Laparotomy was performed in 66.6% (12/18) of cases. There was a learning curve that showed an increase in success rate and decrease in need for laparotomy over the 3-year study period. Neither the need for laparotomy nor the chances of technical success were predictable by gestational age, body mass index or placental location. Tocolysis was limited to perioperative prophylaxis; one woman experienced wound infection and fluid overload. Postoperatively, three fetuses died and two delivered prematurely, 2 and 7 weeks after intervention. CONCLUSION: Fetal aortic valvuloplasty can be performed with technical success, with low fetal loss rate and few maternal complications. While the need for laparotomy cannot be predicted, having it available as an option improves the technical success rate.

Chemotherapy for a patient with advanced non-small-cell lung cancer during pregnancy: a case report and a review of chemotherapy treatment during pregnancy.

BACKGROUND: Lung cancer is the most common cause of cancer death in women in the USA. Lung cancer arising during pregnancy is rare and has been reported only 15 times since the 1950s. However, the use of chemotherapy for lung cancer during pregnancy has not previously been reported. METHODS: The history, treatment and outcome of a patient with stage IV non-small-cell lung carcinoma (NSCLC) diagnosed during pregnancy is presented. Previous published reports on lung cancer were retrieved by a literature search of Medline and Cancerlit. RESULTS: A 31-year-old woman was diagnosed as having stage IV NSCLC with bilateral pulmonary involvement when 26 weeks pregnant. Her shortness of breath progressed to dyspnea at rest on 100% inspired oxygen. Therefore, she was treated with systemic chemotherapy using cisplatin and vinorelbine. Despite this treatment, her oxygenation declined further over the next 4 days and thus the baby was delivered via cesarean section after 27 weeks of gestation. Four cycles of vinorelbine and cisplatin have now been administered. Following this treatment, the patient has experienced a significant clinical improvement and no longer requires supplemental oxygen. No chemotherapy-related adverse effects have been noted in the baby. In the 15 previously reported patients with concurrent lung cancer and pregnancy, chemotherapy administration during pregnancy has not been described. CONCLUSIONS: Treatment of lung cancer with chemotherapy during pregnancy should be considered on an individual basis with regard to the stage of the cancer and the maturity of the fetus. To our knowledge, the case presented here is the first report of a woman receiving chemotherapy for lung cancer while pregnant.

GPC3 mutation analysis in a spectrum of patients with overgrowth expands the phenotype of Simpson-Golabi-Behmel syndrome.

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked overgrowth syndrome caused by deletions in glypican 3 (GPC3). SGBS is characterized by pre- and postnatal overgrowth, a characteristic facial appearance, and a spectrum of congenital malformations which overlaps that of other overgrowth syndromes. We performed GPC3 deletion screening on 80 male patients with somatic overgrowth in the following categories: SGBS (n = 19), possible SGBS (n = 26), including families in which individuals had previously been diagnosed with other overgrowth syndromes, and Wiedemann-Beckwith syndrome (WBS) (n = 35). Using exon-specific PCR and Southern blot analysis, we identified seven GPC3 deletions. In most cases a clear X-linked family history was not present. In two cases, GPC3 deletions were identified in patients belonging to pedigrees published previously as other overgrowth syndromes: one with a diagnosis of Sotos syndrome and the other Perlman syndrome with nephroblastomatosis. A third patient developed hepatoblastoma, a tumor type not previously described in SGBS. No GPC3 deletions were identified among the WBS patients. Direct sequencing of all GPC3 exons in the remaining 13 SGBS patients without GPC3 deletions did not identify any further mutations, raising the possibility of alternative silencing mechanisms and/or other genes in the pathogenesis of SGBS. Our results validate the clinical specificity of the facial appearance, skeletal/hand anomalies, and supernumerary nipples in patients with GPC3 deletions. Our data also suggest that nephroblastomatosis and hepatoblastoma are included in the phenotypic spectrum of GPC3 deletions and SGBS, underscoring the importance of tumor surveillance in these children.

Obstetrician-gynecologists' opinions and attitudes on the role of genetics in women's health.

Our objective was to describe gynecologists' current practice patterns and opinions on genetic screening and their perceived importance of genetic screening within individual practices. A questionnaire survey was sent to 1248 American College of Obstetrics and Gynecology (ACOG) Fellows, of whom 564 (45%) responded. Results from the 428 respondents providing genetic screening for heritable diseases or disorders are reported. Forty-four percent of respondents believe advances in the treatment of genetic diseases are likely in the next 10 years. Currently, however, genetics in gynecological practice receives infrequent attention. Twenty-four percent of respondents do not routinely review family histories at gynecological visits, 39% rate genetic issues as last among priorities in the office, and only 14% obtain consent for the DNA tests that they initiate. Although 21.3% identified themselves as sole providers of genetic information and counseling to their patients, most (65.4%) note they are not confident of their knowledge of genetics, particularly concerning breast and ovarian cancer. For obstetrician-gynecologists to keep pace with the rapid changes in genetics, further education and assimilation of genetics into the routine office practice will need to occur. Not currently viewed as a priority among practitioners, issues of genetic knowledge, ethics, and test interpretation will soon need attention. National organizations, continuing medical education, and existing genetic centers will need to meet these recognized demands.

A brief intervention for prenatal alcohol use: an in-depth look.

About 20% of pregnant women will drink alcohol, even though no universally safe level of prenatal alcohol consumption has been established. This study of 123 alcohol screen-positive pregnant women receiving a brief intervention in the 16th week of gestation examines the relationship of drinking goals, reasons for the goals, recognition of situations increasing risk of drinking, and subsequent antepartum consumption. While women who named abstinence as their antepartum drinking goal were more likely not to be consuming alcohol at the time of study enrollment (chi(2) = 16.80, df = 1, p =.001), current drinkers who named abstinence as their goal did reduce subsequent prenatal alcohol use (chi(2) = 10.04, df = 1, p =.002). All current drinkers who indicated fetal alcohol syndrome as a reason not to drink reduced their subsequent alcohol consumption (chi(2) = 11.04, df = 1, p =.001). Future efforts may include the partners and support systems of pregnant women in education or intervention programs to reduce prenatal alcohol consumption to enhance their effectiveness.

Gynecologists' training, knowledge, and experiences in genetics: a survey.

OBJECTIVE: To explore gynecologists' knowledge, training, and practice experience with genetic screening and DNA-based testing. METHODS: A questionnaire survey was sent to 1,248 ACOG Fellows, of whom 564 (45%) responded. One hundred thirty-four respondents (24%) reported that they do not order DNA-based tests or take family histories to screen for heritable diseases or disorders. Results from the 428 respondents who provide genetic screening services are reported. RESULTS: Most physicians (90%) knew that genetic tests are most informative when used in conjunction with family histories. Gynecologists gave more correct responses regarding genetic testing for breast and ovarian cancers than for colon cancer and other adult-onset diseases. Sixty-five percent of the respondents had not received formal training in DNA-based testing in gynecologic practice. Older physicians were less likely to have had training. Younger physicians generally gave more correct responses on the knowledge portion of the survey (r = -.165, P < .01). Physicians who had formal training in genetics gave more correct answers. Physicians who order DNA-based tests scored higher than those who do not and had no formal training, but not higher than those who had formal training and do not order DNA-based tests. CONCLUSION: Gynecologists were more knowledgeable about genetic issues pertaining to breast and ovarian cancer than to other cancers or certain adult-onset disorders. Training appeared to increase knowledge. Increased training and affiliation with genetic specialists and others could improve gynecologists' ability to use genetic screening in clinical practice.

Prenatal alcohol consumption. Self versus collateral report.

The reservations expressed about the accuracy of patient self-reports of drinking may be heightened when obtaining information about prenatal alcohol consumption, which may be subject to fears of social or medical disapproval. Thus, clinicians may seek collateral reports to confirm patients' reports during this critical time. The purpose of this study is to compare the self and collateral reports of antepartum alcohol consumption by 247 pregnant women, obtained shortly after the initiation of prenatal care, and again after delivery. Collateral reports of subjects were exceeded by the subjects' self-reports of alcohol consumption before pregnancy and in the antepartum.

Considerations for delivery of infants with congenital abnormalities.

The antepartum evaluation of fetuses with congenital anomalies includes consideration of peripartum variables, such as route of delivery, gestational age, and location of each, which may impact eventual outcomes. In this article, the controversies, risks, and benefits surrounding peripartum interventions for various fetal congenital anomalies are discussed.

The TWEAK: application in a prenatal setting.

OBJECTIVE: The TWEAK is a screening instrument used to identify women who are risk drinkers. Potential limitations of previous studies of the TWEAK in the prenatal setting include indirect administration of the instrument to minority, indigent pregnant women. The purpose of this study is to assess the efficacy of the TWEAK when it is given directly to a sample of pregnant women of different socioeconomic backgrounds. METHOD: The original TWEAK, with two different tolerance questions, was administered to a sample of 135 pregnant women enrolled in a study of alcohol use during pregnancy at the obstetrics practices of the Brigham and Women's Hospital in Boston, Massachusetts. RESULTS: The TWEAK, using the first tolerance question (number of drinks before feeling the first effects of alcohol) with the cut point set at more than two drinks, had the best predictive ability for lifetime alcohol diagnoses and risk drinking. The sensitivity of the TWEAK can be increased if the cut point for the first tolerance question is set at two drinks, with some loss of specificity and predictive ability. Medical record assessment was the least sensitive but most specific method of identifying alcohol use by pregnant women. CONCLUSIONS: The TWEAK has promise as a screening instrument for identifying risk drinking during pregnancy. Future work should include testing in other clinical populations.