Kelly Bennett

Pregnancy and multiple sclerosis.

Introduction Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system (CNS). Two-thirds of patients with MS are women of childbearing age, and approximately 10% have disease onset during pregnancy. The pathogenesis of MS involves a combination of inflammation and demyelination in the brain and spinal cord. Increased helper-suppressor T-cell ratios are associated with MS disease activity. Available immune-modulating drugs with proven benefit in the treatment of relapsing remitting MS have aimed to reduce proinflammatory or increase anti-inflammatory cytokines. Although both genetic predisposition and environment contribute to causation, there is no clear understanding of etiology, severity of disability, or variations in the natural history of MS. Observation of a reduction in the serum levels of helper T lymphocytes during pregnancy with a consequent lowering of the helper-suppressor T-cell ratio theoretically has a mediating effect on the course of MS. A number of pregnancy-associated proteins, such as estriol, a-fetoprotein, and pregnancy-associated plasma protein A, have immunosuppressive properties that may be important in pregnancy-related immune suppression. Estriol, an estrogen made by the fetal placental unit, is not present in appreciable amounts during the nonpregnant state and has been identified by Sicotte et al to be the hormone most likely to be responsible for the mediating effects of pregnancy upon MS. Clinical manifestations of MS may be chronic and progressive or, more commonly, may present with relapses followed by remissions. Approximately 85% of patients exhibit a relapsing-remitting course at onset. The remaining 15% will present with a progressive course from onset. Clinically isolated syndromes such as optic neuritis often herald relapsing-remitting MS. Common presenting symptoms include visual loss, diplopia, paresthesias, spasticity, tremors, poor coordination, or paresis. Magnetic resonance imaging (MRI) is one of the more useful tests to detect lesions compatible with Correspondence: Kelly A. Bennett, MD, FRCSC, Division of Maternal Fetal Medicine, Vanderbilt University Medical Center, B-1100 MCN, Nashville, TN 37232. E-mail: kelly.a.bennett@vanderbilt.edu

The Management of Myelomeningocele Study: Obstetrical Outcomes and Risk Factors for Obstetrical Complications Following Prenatal Surgery

BACKGROUND The Management of Myelomeningocele Study was a multicenter randomized trial to compare prenatal and standard postnatal closure of myelomeningocele. The trial was stopped early at recommendation of the data and safety monitoring committee and outcome data for 158 of the 183 randomized women published. OBJECTIVE In this report, pregnancy outcomes for the complete trial cohort are presented. We also sought to analyze risk factors for adverse pregnancy outcome among those women who underwent prenatal myelomeningocele repair. STUDY DESIGN Pregnancy outcomes were compared between the 2 surgery groups. For women who underwent prenatal surgery, antecedent demographic, surgical, and pregnancy complication risk factors were evaluated for the following outcomes: premature spontaneous membrane rupture ≤34 weeks 0 days (preterm premature rupture of membranes), spontaneous membrane rupture at any gestational age, preterm delivery at ≤34 weeks 0 days, nonintact hysterotomy (minimal uterine wall tissue between fetal membranes and uterine serosa, or partial or complete dehiscence at delivery), and chorioamniotic membrane separation. Risk factors were evaluated using χ2 and Wilcoxon tests and multivariable logistic regression. RESULTS A total of 183 women were randomized: 91 to prenatal and 92 to postnatal surgery groups. Analysis of the complete cohort confirmed initial findings: that prenatal surgery was associated with an increased risk for membrane separation, oligohydramnios, spontaneous membrane rupture, spontaneous onset of labor, and earlier gestational age at birth. In multivariable logistic regression of the prenatal surgery group adjusting for clinical center, earlier gestational age at surgery and chorioamniotic membrane separation were associated with increased risk of spontaneous membrane rupture (odds ratio, 1.49; 95% confidence interval, 1.01-2.22; and odds ratio, 2.96, 95% confidence interval, 1.05-8.35, respectively). Oligohydramnios was associated with an increased risk of subsequent preterm delivery (odds ratio, 9.21; 95% confidence interval, 2.19-38.78). Nulliparity was a risk factor for nonintact hysterotomy (odds ratio, 3.68; 95% confidence interval, 1.35-10.05). CONCLUSION Despite the confirmed benefits of prenatal surgery, considerable maternal and fetal risk exists compared with postnatal repair. Early gestational age at surgery and development of chorioamniotic membrane separation are risk factors for ruptured membranes. Oligohydramnios is a risk factor for preterm delivery and nulliparity is a risk factor for nonintact hysterotomy at delivery.

Reducing perinatal complications and preterm delivery for patients undergoing in utero closure of fetal myelomeningocele: further modifications to the multidisciplinary surgical technique

UNLABELLED OBJECT.: As more pediatric neurosurgeons become involved with fetal myelomeningocele closure efforts, examining refined techniques in the overall surgical approach that could maximize beneficial outcomes becomes critical. The authors compared outcomes for patients who had undergone a modified technique with those for patients who had undergone fetal repair as part of the earlier Management of Myelomeningocele Study (MOMS). METHODS Demographic and outcomes data were collected for a series of 43 delivered patients who had undergone in utero myelomeningocele closure at the Fetal Center at Vanderbilt from March 2011 through January 2013 (the study cohort) and were compared with data for 78 patients who had undergone fetal repair as part of MOMS (the MOMS cohort). For the study cohort, no uterine trocar was used, and uterine entry, manipulation, and closure were modified to minimize separation of the amniotic membrane. Weekly ultrasound reports were obtained from primary maternal-fetal medicine providers and reviewed. A test for normality revealed that distribution for the study cohort was normal; therefore, parametric statistics were used for comparisons. RESULTS The incidence of premature rupture of membranes (22% vs 46%, p = 0.011) and chorioamnion separation (0% vs 26%, p < 0.001) were lower for the study cohort than for the MOMS cohort. Incidence of oligohydramnios did not differ between the cohorts. The mean (± SD) gestational age of 34.4 (± 6.6) weeks for the study cohort was similar to that for the MOMS cohort (34.1 ± 3.1 weeks). However, the proportion of infants born at term (37 weeks or greater) was significantly higher for the study cohort (16 of 41; 39%) than for the MOMS cohort (16 of 78; 21%) (p = 0.030). Compared with 10 (13%) of 78 patients in the MOMS cohort, only 2 (4%) of 41 infants in the study cohort were delivered earlier than 30 weeks of gestation (p = 0.084, approaching significance). For the study cohort, 2 fetal deaths were attributed to the intervention, and both were believed to be associated with placental disruption; one of these mothers had previously unidentified thrombophilia. Mortality rates did not statistically differ between the cohorts. CONCLUSIONS These early results suggest that careful attention to uterine entry, manipulation, and closure by the surgical team can result in a decreased rate of premature rupture of membranes and chorioamnion separation and can reduce early preterm delivery. Although these results are promising, their confirmation will require further study of a larger series of patients.

Is preterm delivery indicated in fetuses with gastroschisis and antenatally detected bowel dilation

Introduction: Due to the controversy surrounding diagnostic ultrasound evaluations and elective preterm delivery of fetuses with gastroschisis, we sought to calculate the predictive value of bowel dilation in fetuses with gastroschisis and evaluate the effect of preterm delivery on neonatal outcomes. Materials and Methods: Ultrasounds and medical records of 103 mother-infant pairs with fetal gastroschisis were reviewed. Eighty-nine pairs met the criteria. Intestinal complications, gestational age at delivery, birth weight, and number of abdominal surgeries were documented. Results: Forty-eight fetuses (54%) had bowel dilation and 41 (46%) did not. The positive predictive value of bowel dilation for complicated gastroschisis was 21%. There were 50 (56%) preterm and 39 (44%) term deliveries. The mean birth weight was 2,114 g (SD = 507) and 2,659 g (SD = 687), p = 0.001. For infants delivered preterm, the mean number of postnatal abdominal surgeries was 2.1 (SD = 1.1) as compared to 1.3 (SD = 0.5) surgical procedures for those infants delivered at term gestation. This was not statistically significant. With respect to hospital stay for each group, the mean length of neonatal intensive care unit admission was 48 days (SD = 33) in the preterm group and 35 days (SD = 50) in the term group, which was not statistically significant. Discussion: Ultrasound-detected bowel dilation was not predictive of important intestinal complications. Our data did not substantiate any benefit for elective preterm delivery of neonates with gastroschisis.

Current Selection Criteria and Perioperative Therapy Used for Fetal Myelomeningocele Surgery

OBJECTIVE: To determine the current maternal and fetal selection criteria and operative approaches used at centers performing fetal myelomeningocele surgery. METHODS: The 17 principal investigators participating in the Fetal Myelomeningocele Consortium were asked to participate in an anonymous online survey regarding the current practice of maternal–fetal surgery for neural tube defect repair and results were tabulated. The 35-question survey related to diagnostic testing, inclusion and exclusion criteria, and clinical management. RESULTS: Sixty-five percent (11/17) of principal investigators responded to the survey and not all centers responded to all 35 questions. All centers continue to use magnetic resonance imaging in their preoperative evaluation. Diagnostic testing from amniocentesis is varied: 5 of 11 (45%) require amniotic fluid &agr;-fetoprotein, 4 of 10 (40%) amniotic fluid acetylcholinesterase, and 8 of 11 (73%) DNA microarray. There is also variation from the Management of Myelomeningocele Study with regard to body mass index (BMI) (1/11; 9% would offer surgery with BMIs higher than 35), maternal medical risk factors (surgery would be offered for controlled pregestational diabetes [3/10 (30%)]), hepatitis C with negative viral load (4/11 [36%]), and human immunodeficiency virus with an undetectable viral load (1/10 [10%] or an obstetric history [3/11 (27%)] would offer surgery with a history of preterm delivery on progesterone). Ten of 11 (91%) centers did not consider ventriculomegaly of 18 mm and 9 of 11 (82%) centers did not consider lack of leg movement as an exclusion criteria. Nuances in the perioperative and intraoperative management were also reported, including 5 of 11 (45%) use intraoperative echocardiography and alterations in postoperative tocolytics. CONCLUSION: Variation in practice patterns for offering and performing maternal–fetal surgery for myelomeningocele repair exists among centers. Ongoing evaluation of inclusion and exclusion criteria as well as operative techniques is warranted to ensure continued safety, effectiveness, and beneficence.

Raman spectroscopy provides a noninvasive approach for determining biochemical composition of the pregnant cervix in vivo

The molecular changes that occur with cervical remodelling during pregnancy are not completely understood. This study reviews Raman spectroscopy, an optical technique for detecting changes in the pregnant cervix, and reports preliminary studies on cervical remodelling in mice that suggest that the technique provides advantages over other methods.

Detecting changes during pregnancy with Raman spectroscopy

Preterm labor is the second leading cause of neonatal mortality and leads to a myriad of complications like delayed development and cerebral palsy. Currently, there is no way to accurately predict preterm labor, making its prevention and treatment virtually impossible. While there are some at-risk patients, over half of all preterm births do not fall into any high-risk category. This study seeks to predict and prevent preterm labor by using Raman spectroscopy to detect changes in the cervix during pregnancy. Since Raman spectroscopy has been used to detect cancers in vivo in organs like the cervix and skin, it follows that spectra will change over the course of pregnancy. Previous studies have shown that fluorescence decreased during pregnancy and increased during post-partum exams to pre-pregnancy levels. We believe significant changes will occur in the Raman spectra obtained during the course of pregnancy. In this study, Raman spectra from the cervix of pregnant mice will be acquired. Specific changes that occur due to cervical softening or changes in hormonal levels will be observed to understand the changes that occur before and after labor in the cervix.

In Vivo Raman Spectroscopy for Biochemical Monitoring of the Human Cervix Throughout Pregnancy

BACKGROUND The cervix must undergo significant biochemical remodeling to allow for successful parturition. This process is not fully understood, especially in instances of spontaneous preterm birth. In vivo Raman spectroscopy is an optical technique that can be used to investigate the biochemical composition of tissue longitudinally and noninvasively in human beings, and has been utilized to measure physiology and disease states in a variety of medical applications. OBJECTIVE The purpose of this study is to measure in vivo Raman spectra of the cervix throughout pregnancy in women, and to identify biochemical markers that change with the preparation for delivery and postpartum repair. STUDY DESIGN In all, 68 healthy pregnant women were recruited. Raman spectra were measured from the cervix of each patient monthly in the first and second trimesters, weekly in the third trimester, and at the 6‐week postpartum visit. Raman spectra were measured using an in vivo Raman system with an optical fiber probe to excite the tissue with 785 nm light. A spectral model was developed to highlight spectral regions that undergo the most changes throughout pregnancy, which were subsequently used for identifying Raman peaks for further analysis. These peaks were analyzed longitudinally to determine if they underwent significant changes over the course of pregnancy (P < .05). Finally, 6 individual components that comprise key biochemical constituents of the human cervix were measured to extract their contributions in spectral changes throughout pregnancy using a linear combination method. Patient factors including body mass index and parity were included as variables in these analyses. RESULTS Raman peaks indicative of extracellular matrix proteins (1248 and 1254 cm−1) significantly decreased (P < .05), while peaks corresponding to blood (1233 and 1563 cm–1) significantly increased (P < .0005) in a linear manner throughout pregnancy. In the postpartum cervix, significant increases in peaks corresponding to actin (1003, 1339, and 1657 cm–1) and cholesterol (1447 cm–1) were observed when compared to late gestation, while signatures from blood significantly decreased. Postpartum actin signals were significantly higher than early pregnancy, whereas extracellular matrix proteins and water signals were significantly lower than early weeks of gestation. Parity had a significant effect on blood and extracellular matrix protein signals, with nulliparous patients having significant increases in blood signals throughout pregnancy, and higher extracellular matrix protein signals in early pregnancy compared to patients with prior pregnancies. Body mass index significantly affected actin signal contribution, with low body mass index patients showing decreasing actin contribution throughout pregnancy and high body mass index patients demonstrating increasing actin signals. CONCLUSION Raman spectroscopy was successfully used to biochemically monitor cervical remodeling in pregnant women during prenatal visits. This foundational study has demonstrated sensitivity to known biochemical dynamics that occur during cervical remodeling, and identified patient variables that have significant effects on Raman spectra throughout pregnancy. Raman spectroscopy has the potential to improve our understanding of cervical maturation, and be used as a noninvasive preterm birth risk assessment tool to reduce the incidence, morbidity, and mortality caused by preterm birth.

Characterization of human cervical remodeling throughout pregnancy using in vivo Raman spectroscopy

Globally, fifteen million babies are born preterm each year, affecting 1 in 8 pregnancies in the US alone. Cervical remodeling includes a biochemical cascade of changes that ultimately result in the thinning and dilation of the cervix for passage of a fetus. This process is poorly understood and is the focus of this study. Our group is utilizing Raman spectroscopy to evaluate biochemical changes occurring in the human cervix throughout pregnancy. This technique has high molecular specificity and can be performed in vivo, with the potential to unveil new molecular dynamics essential for cervical remodeling.

Prenatal ultrasound: A critical look

Prenatal ultrasonography: Implications for pediatric urology is a provocative review that raises a number of concerns about prenatal ultrasound performed for the purpose of detection of fetal anomalies. These concerns arise mainly due to the paucity of evidence supporting the appropriateness of subjecting pregnant women to extensive serial imaging for the purpose of monitoring fetal abnormalities of undetermined clinical significance. Indisputably, prenatal ultrasound has allowed early detection of both major and minor genitourinary anomalies with a high degree of sensitivity [1]. This has allowed pediatric urologists to offer parents prenatal counseling, and in some circumstances neonatal intervention capable of improving clinical outcomes. Unfortunately, as suggested in the accompanying article, this has also at times led to a considerable level of prenatal imaging and, in some children, unnecessary postnatal invasive diagnostic procedures. Over the past 20 years, multiple developments in ultrasound technology have opened the door to improved sensitivity in the prenatal diagnosis of major fetal abnormalities; sensitivity estimations determined in older studies necessarily reflect limitations of then-current technology, and may have limited validity today. Heterogeneity of study populations and inclusion criteria, such as low-risk patients only versus an unselected group, add to the difficulty of determining an estimate of the accuracy of diagnosis of specific fetal anomalies. It is a well-known and important characteristic of ultrasonography that sensitivity is user dependent, with studies using highly skilled providers reporting better results than those using providers with less training and expertise [2].