Biometric magnetic resonance imaging analysis of fetal brain development in Down syndrome.

OBJECTIVES: To assess brain development in living fetuses with Down syndrome (DS) by biometric measurements on fetal brain magnetic resonance images (MRI). METHODS: We scanned 10 MRIs of fetuses with confirmed trisomy 21 at birth and 12 control fetal MRIs without any detected anomalies. Fetal brain MRIs were analyzed using 14 fetal brain and skull biometric parameters. We compared measures between DS and controls in both raw MRIs and motion-corrected and anterior-posterior commissure-aligned images. RESULTS: In the reconstructed images, the measured values of the height of the cerebellar vermis (HV) and anteroposterior diameter of the cerebellar vermis (APDV) were significantly smaller, and the anteroposterior diameter of the fourth ventricle (APDF) was significantly larger in fetuses with DS than controls. In the raw MRIs, the measured values of the right lateral ventricle were significantly larger in fetuses with DS than in controls. Logistic regression analyses revealed that a new parameter, the cerebellar-to-fourth-ventricle ratio (i.e., (APDV * Height of the vermis)/APDF), was significantly smaller in fetuses with DS than controls and was the most predictive to distinguish between fetuses with DS and controls. CONCLUSIONS: The study revealed that fetuses with DS have smaller cerebellums and larger fourth ventricles compared to the controls.

Safety and outcomes of penicillin allergy evaluation in pregnant women.

BACKGROUND: Penicillin allergy in pregnancy is associated with increased morbidity and the use of less effective antibiotics. Penicillin allergy evaluation in pregnancy is now recommended as per obstetrical guidelines but remains infrequent. OBJECTIVE: We studied pregnant women who underwent penicillin allergy evaluation in an allergy clinic to assess the effectiveness and safety of penicillin skin testing (PST) and incremental drug challenge (IDC) in pregnancy. METHODS: Index drug reactions, PST, and IDC results were reviewed. Antibiotic use, pregnancy outcomes, and pregnancy complications were compared with a control cohort of pregnant women with penicillin allergy who did not undergo allergy evaluation before delivery. RESULTS: Penicillin allergy was evaluated in 136 women. Culprit drugs included penicillin (37%), amoxicillin (30%), and unknown (20%). Index reactions occurred greater than 5 years ago in 91%, and these reactions were cutaneous or unknown in 92%. Of the 133 patients who underwent skin testing, 131 (99%) had negative or equivocal results and proceeded to incremental challenge. All 131 women passed penicillin IDC. Of the 69 women who ultimately used intrapartum beta-lactam antibiotics, all but 1 patient tolerated them. Women who underwent penicillin allergy evaluation did not have an increased risk of cesarean delivery or other pregnancy complications when compared with women without penicillin allergy evaluation. CONCLUSION: PST and IDC can be safely conducted in pregnant women. When evaluated as low risk, most women tolerate IDC and can receive penicillin intrapartum without adverse reactions or negative pregnancy outcomes.

Society for Maternal-Fetal Medicine Consult Series #59: The use of analgesia and anesthesia for maternal-fetal procedures.

Pain is a complex phenomenon that involves more than a simple physical response to external stimuli. In maternal-fetal surgical procedures, fetal analgesia is used primarily to blunt fetal autonomic responses and minimize fetal movement. The purpose of this Consult is to review the literature on what is known about the potential for fetal awareness of pain and to discuss the indications for and the risk-benefit calculus involved in the use of fetal anesthesia and analgesia. The recommendations by the Society for Maternal-Fetal Medicine are as follows: (1) we suggest that fetal paralytic agents be considered in the setting of intrauterine transfusion, if needed, for the purpose of decreasing fetal movement (GRADE 2C); (2) although the fetus is unable to experience pain at the gestational age when procedures are typically performed, we suggest that opioid analgesia should be administered to the fetus during invasive fetal surgical procedures to attenuate acute autonomic responses that may be deleterious, avoid long-term consequences of nociception and physiological stress on the fetus, and decrease fetal movement to enable the safe execution of procedures (GRADE 2C); and (3) due to maternal risk and a lack of evidence supporting benefit to the fetus, we recommend against the administration of fetal analgesia at the time of pregnancy termination (GRADE 1C).

Quantitative MRI Analyses of Regional Brain Growth in Living Fetuses with Down Syndrome.

Down syndrome (DS) is the most common liveborn autosomal chromosomal anomaly and is a major cause of developmental disability. Atypical brain development and the resulting intellectual disability originate during the fetal period. Perinatal interventions to correct such aberrant development are on the horizon in preclinical studies. However, we lack tools to sensitively measure aberrant structural brain development in living human fetuses with DS. In this study, we aimed to develop safe and precise neuroimaging measures to monitor fetal brain development in DS. We measured growth patterns of regional brain structures in 10 fetal brains with DS (29.1 ± 4.2, weeks of gestation, mean ± SD, range 21.7~35.1) and 12 control fetuses (25.2 ± 5.0, range 18.6~33.3) using regional volumetric analysis of fetal brain MRI. All cases with DS had confirmed karyotypes. We performed non-linear regression models to compare fitted regional growth curves between DS and controls. We found decreased growth trajectories of the cortical plate (P = 0.033), the subcortical parenchyma (P = 0.010), and the cerebellar hemispheres (P < 0.0001) in DS compared to controls. This study provides proof of principle that regional volumetric analysis of fetal brain MRI facilitates successful evaluation of brain development in living fetuses with DS.

The Conscience of an MFM.

Much has been written about conscience-based objections to the provision of reproductive abortion services. Nevertheless, conscience may drive providers in the other direction as well: OB/GYNs may, in fact, decide to provide these services because of their well-considered moral, ethical, and religious convictions.

Counselling, Research Gaps, and Ethical Considerations Surrounding Pregnancy in Solid Organ Transplant Recipients.

Survival after solid-organ transplantation has improved significantly, and many contemporary transplant recipients are of childbearing potential. There are limited data to guide decision-making surrounding pregnancy after transplantation, variations in clinical practice, and significant knowledge gaps, all of which raise significant ethical issues. Post-transplant pregnancy is associated with an increased risk of maternal and fetal complications. Shared decision-making is a central aspect of patient counselling but is complicated by significant knowledge gaps. Stakeholder interests can be in conflict; exploring these tensions can help patients to evaluate their options and inform their deliberations. We argue that uniform, evidence-based recommendations for pregnancy after solid organ transplantation are needed. Conducting research, including patient-engaged studies, in this area should be priority for the transplant community.

Uterine transplantation: A maternal-fetal medicine perspective.

Uterine transplantation is a novel approach to solving a clinical problem faced by women with uterine factor infertility whose desire to parent includes a desire to give birth. The ethical precepts used for other solid organ transplants are helpful in developing normative frameworks for understanding this experimental therapy. Nevertheless, both fetal and neonatal risks complicate this calculus and therefore it is useful to incorporate analyses used in other realms of maternal-fetal medicine to understand and justify this research. Preliminary data on maternal and neonatal outcomes from the many centers exploring this technique are encouraging, but as these techniques move into mainstream care, ongoing vigilance will be necessary to ensure that women and their families are afforded similar protections required of research protocols. Uterine transplantation is a captivating topic for the myriad ethical issues it raises. Many of these issues have been analyzed extensively in the literature since the marvel of solid organ transplantation was first realized in the 1950s. But we have now been collecting data on uterine transplantation since the first successful birth in 20151 and the questions raised have morphed very quickly from "Can we do this?" to "Should we do this?" and "How should we do this?" The good news for patients and the public is that bioethicists have been front and center in participating in and helping to inform the rolling out of this innovative treatment for rare forms of infertility. The model for such an integrative role of ethics in uterine transplantation programs grew out of similar programs in high risk obstetrical procedures such as the repair of fetal meningomyelocele trials.2 The goal of this review is to outline some of the key issues these transplantations raise from the perspective of maternal-fetal medicine, a field well acquainted with the dilemmas that may arise in maximizing outcomes for both pregnant women and their fetuses.

Society for Maternal-Fetal Medicine Consult Series #59: The use of analgesia and anesthesia for maternal-fetal procedures.

Pain is a complex phenomenon that involves more than a simple physical response to external stimuli. In maternal-fetal surgical procedures, fetal analgesia is used primarily to blunt fetal autonomic responses and minimize fetal movement. The purpose of this Consult is to review the literature on what is known about the potential for fetal awareness of pain and to discuss the indications for and the risk-benefit calculus involved in the use of fetal anesthesia and analgesia. The recommendations by the Society for Maternal-Fetal Medicine are as follows: (1) we suggest that fetal paralytic agents be considered in the setting of intrauterine transfusion, if needed, for the purpose of decreasing fetal movement (GRADE 2C); (2) although the fetus is unable to experience pain at the gestational age when procedures are typically performed, we suggest that opioid analgesia should be administered to the fetus during invasive fetal surgical procedures to attenuate acute autonomic responses that may be deleterious, avoid long-term consequences of nociception and physiological stress on the fetus, and decrease fetal movement to enable the safe execution of procedures (GRADE 2C); and (3) due to maternal risk and a lack of evidence supporting benefit to the fetus, we recommend against the administration of fetal analgesia at the time of pregnancy termination (GRADE 1C).

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

OBJECTIVE: 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. METHODS: Fifty-two pregnant women were recruited prior to CVS, performed for clinical indications, at 10 5/7 to 13 2/7 weeks. Maternal blood was collected before and within 15 min after CVS. cffDNA was extracted from plasma. Real-time polymerase chain reaction (PCR) amplification of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the Y chromosome sequence DYS1 were used as measures of total and fetal DNA, respectively. All samples were analyzed in triplicate without knowledge of fetal gender. RESULTS: Sensitivity of DYS1 detection in male fetuses was 100% (n = 30); specificity in female fetuses was 100% (n = 22). While a majority of women had > 50% post-procedure increases in both fetal and total DNA, some showed post-procedure decreases. However, overall median proportional increases were not statistically significant. Gestational age (GA), placental location, and individual CVS operator did not correlate with changes in DNA levels. CONCLUSIONS: While there were no statistically significant overall changes in DNA levels after CVS, as-yet undiscovered variables may influence the extent of post-procedure release of cell-free DNA in the circulation of pregnant women.

Pregnancy-associated changes in cervical noncoding RNA.

Aim: To identify pregnancy-associated changes in cervical noncoding RNA (ncRNA), including miRNA and long noncoding RNA (lncRNA), and their potential effects on biologic processes. Materials & methods: We enrolled 21 pregnant women with term deliveries (≥37 weeks' gestation) in a prospective cohort and collected cervical swabs before 28 weeks' gestation. We enrolled 21 nonpregnant controls. We analyzed miRNA, lncRNA and mRNA expression, applying a Bonferroni correction. Results: Five miRNA and three lncRNA were significantly differentially (>twofold change) expressed. Putative miRNA targets are enriched in genes mediating organogenesis, glucocorticoid signaling, cell adhesion and ncRNA machinery. Conclusion: Differential cervical ncRNA expression occurs in the setting of pregnancy. Gene ontology classification reveals biological pathways through which miRNA may play a biologic role in normal pregnancy physiology.

Long noncoding RNA expression in the cervix mid-pregnancy is associated with the length of gestation at delivery.

Infants born preterm are at increased risk of multiple morbidities and mortality. Why some women deliver preterm remains poorly understood. Prior studies have shown that cervical microRNA expression and DNA methylation are associated with the length of gestation. However, no study has examined the role of long noncoding RNAs (lncRNAs) in the cervix during pregnancy. To determine whether expression of lncRNAs is associated with length of gestation at delivery, we analyzed RNA from cervical swabs obtained from 78 women during pregnancy (mean 15.5, SD 5.0, weeks of gestation) who were participating in the Spontaneous Prematurity and Epigenetics of the Cervix (SPEC) Study in Boston, MA, USA. We used a PCR-based platform and found that 9 lncRNAs were expressed in at least 50% of the participants. Of these, a doubling of the expression of TUG1, TINCR, and FALEC was associated with shorter lengths of gestation at delivery [2.8 (95% CI: 0.31, 5.2); 3.3 (0.22, 6.3); and 4.5 (7.3, 1.6) days shorter respectively]. Of the lncRNAs analyzed, none was statistically associated with preterm birth, but expression of FALEC was 2.6-fold higher in women who delivered preterm vs. term (P = 0.051). These findings demonstrate that lncRNAs can be measured in cervical samples obtained during pregnancy and are associated with subsequent length of gestation at delivery. Further, this study supports future work to replicate these findings in other cohorts and perform mechanistic studies to determine the role of lncRNAs in the cervix during pregnancy.

Ethical Considerations Concerning Amnioinfusions for Treating Fetal Bilateral Renal Agenesis.

Congenital bilateral renal agenesis has been considered a uniformly fatal condition. However, the report of using serial amnioinfusions followed by the live birth in 2012 and ongoing survival of a child with bilateral renal agenesis has generated hope, but also considerable controversy over an array of complex clinical and ethical concerns. To assess the ethical concerns associated with using serial amnioinfusions for bilateral renal agenesis, we assembled a multidisciplinary group to map the ethical issues relevant to this novel intervention. The key ethical issues identified were related to 1) potential risks and benefits, 2) clinical care compared with innovation compared with research, 3) counseling of expectant parents, 4) consent, 5) outcome measures, 6) access and justice, 7) conflicts of interest, 8) effects on clinicians, 9) effects on institutions, and 10) long-term societal implications. These ethical issues should be addressed in conjunction with systematic efforts to examine whether this intervention is safe and effective. Future work should capture the experiences of expectant parents, women who undergo serial amnioinfusions, those born with bilateral renal agenesis and their families as well as clinicians confronted with making difficult choices related to it.

Complexity analysis of fetal heart rate preceding intrauterine demise.

BACKGROUND: Visual non-stress test interpretation lacks the optimal specificity and observer-agreement of an ideal screening tool for intrauterine fetal demise (IUFD) syndrome prevention. Computational methods based on traditional heart rate variability have also been of limited value. Complexity analysis probes properties of the dynamics of physiologic signals that are otherwise not accessible and, therefore, might be useful in this context. OBJECTIVE: To explore the association between fetal heart rate (FHR) complexity analysis and subsequent IUFD. Our specific hypothesis is that the complexity of the fetal heart rate dynamics is lower in the IUFD group compared with controls. STUDY DESIGN: This case-control study utilized cases of IUFD at a single tertiary-care center among singleton pregnancies with at least 10min of continuous electronic FHR monitoring on at least 2 weekly occasions in the 3 weeks immediately prior to fetal demise. Controls delivered a live singleton beyond 35 weeks' gestation and were matched to cases by gestational age, testing indication, and maternal age in a 3:1 ratio. FHR data was analyzed using the multiscale entropy (MSE) method to derive their complexity index. In addition, pNNx, a measure of short-term heart rate variability, which in adults is ascribable primarily to cardiac vagal tone modulation, was also computed. RESULTS: 211 IUFDs occurred during the 9-year period of review, but only 6 met inclusion criteria. The median gestational age at the time of IUFD was 35.5 weeks. Three controls were matched to each case for a total of 24 subjects, and 87 FHR tracings were included for analysis. The median gestational age at the first fetal heart rate tracing was similar between groups (median [1st-3rd quartiles] weeks: IUFD cases: 34.7 (34.4-36.2); controls: 35.3 (34.4-36.1); p=.94). The median complexity of the cases' tracings was significantly less than the controls' (12.44 [8.9-16.77] vs. 17.82 [15.21-22.17]; p<.0001). Furthermore, the cases' median complexity decreased as gestation advanced whereas the controls' median complexity increased over time. However, this difference was not statistically significant [-0.83 (-2.03 to 0.47) vs. 0.14 (-1.25 to 0.94); p=.62]. The degree of short-term variability of FHR tracings, as measured by the pNN metric, was significantly lower (p<.005) for the controls (1.1 [0.8-1.3]) than the IUFD cases (1.3 [1.1-1.6]). CONCLUSIONS: FHR complexity analysis using multiscale entropy analysis may add value to other measures in detecting and monitoring pregnancies at the highest risk for IUFD. The decrease in complexity and short-term variability seen in the IUFD cases may reflect perturbations in neuroautonomic control due to multiple maternal-fetal factors.

The Effect of a Universal Cervical Length Screening Program on Antepartum Management and Birth Outcomes.

Objective The objective of this study was to evaluate the effect of a universal cervical length screening program on the incidence of antepartum interventions. Study Design This retrospective cohort study included women delivering ≥ 20 weeks of gestation with singleton pregnancies before and after implementing universal cervical length screening. Antepartum interventions included admission for threatened preterm birth, ≥ 2 cervical length measurements, cervical cerclage, neonatology consultation, betamethasone, antibiotic administration for preterm premature rupture of membranes, and tocolysis. Results There were 1,131 women-506 before the screening program (unexposed) and 625 afterward (exposed). The screening program resulted in significantly more women screened (3.0 vs. 69.9%, p < 0.0001). The exposed group was more likely to undergo ≥ 1 intervention (20.0 vs. 9.5%, p < 0.0001); specifically, admission for threatened preterm birth (3.8 vs. 1.8%, p = 0.04) and ≥ 2 cervical measurements (11.2 vs. 2.0%, p < 0.001). Other interventions were similar between groups (all p ≥ 0.06). Median gestation length was significantly longer in the exposed (39.6 weeks [interquartile, IQR: 38.6-40.4] vs. 39.0 weeks [IQR: 38.0-40.0, p < 0.001]); however, preterm delivery incidence was unaffected (9.4 vs. 10.9%, p = 0.43). Remaining neonatal outcomes were similar (all p ≥ 0.14). Conclusion Implementing universal cervical length screening significantly increased the proportion of women undergoing ≥ 1 antepartum intervention. With the exception of a modestly prolonged gestation, other outcomes were unaffected.

The effect of adopting the IADPSG screening guidelines on the risk profile and outcomes of the gestational diabetes population.

OBJECTIVE: To compare characteristics and outcomes of women diagnosed with gestational diabetes mellitus (GDM) by the newer one-step glucose tolerance test and those diagnosed with the traditional two-step method. RESEARCH DESIGN AND METHODS: This was a retrospective cohort study of women with GDM who delivered in 2010-2011. Data are reported as proportion or median (interquartile range) and were compared using a Chi-square, Fisher's exact or Wilcoxon rank sum test based on data type. RESULTS: Of 235 women with GDM, 55.7% were diagnosed using the two-step method and 44.3% with the one-step method. The groups had similar demographics and GDM risk factors. The two-step method group was diagnosed with GDM one week later [27.0 (24.0-29.0) weeks versus 26.0 (24.0-28.0 weeks); p = 0.13]. The groups had similar median weight gain per week before diagnosis. After diagnosis, women in the one-step method group had significantly higher median weight gain per week [0.67 pounds/week (0.31-1.0) versus 0.56 pounds/week (0.15-0.89); p = 0.047]. In the one-step method group more women had suspected macrosomia (11.7% versus 5.3%, p = 0.07) and more neonates had a birth weight >4000 g (13.6% versus 7.5%, p = 0.13); however, these differences were not statistically significant. Other pregnancy and neonatal complications were similar. CONCLUSIONS: Women diagnosed with the one-step method gained more weight per week after GDM diagnosis and had a non-statistically significant increased risk for suspected macrosomia. Our data suggest the one-step method identifies women with at least equally high risk as the two-step method.