Vasa previa in singleton pregnancies: diagnosis and clinical management based on an international expert consensus.

BACKGROUND: There are limited data to guide the diagnosis and management of vasa previa. Currently, what is known is largely based on case reports or series and cohort studies. OBJECTIVE: This study aimed to systematically collect and classify expert opinions and achieve consensus on the diagnosis and clinical management of vasa previa using focus group discussions and a Delphi technique. STUDY DESIGN: A 4-round focus group discussion and a 3-round Delphi survey of an international panel of experts on vasa previa were conducted. Experts were selected on the basis of their publication record on vasa previa. First, we convened a focus group discussion panel of 20 experts and agreed on which issues were unresolved in the diagnosis and management of vasa previa. A 3-round anonymous electronic survey was then sent to the full expert panel. Survey questions were presented on the diagnosis and management of vasa previa, which the experts were asked to rate on a 5-point Likert scale (from "strongly disagree"=1 to "strongly agree"=5). Consensus was defined as a median score of 5. Following responses to each round, any statements that had median scores of ≤3 were deemed to have had no consensus and were excluded. Statements with a median score of 4 were revised and re-presented to the experts in the next round. Consensus and nonconsensus statements were then aggregated. RESULTS: A total of 68 international experts were invited to participate in the study, of which 57 participated. Experts were from 13 countries on 5 continents and have contributed to >80% of published cohort studies on vasa previa, as well as national and international society guidelines. Completion rates were 84%, 93%, and 91% for the first, second, and third rounds, respectively, and 71% completed all 3 rounds. The panel reached a consensus on 26 statements regarding the diagnosis and key points of management of vasa previa, including the following: (1) although there is no agreement on the distance between the fetal vessels and the cervical internal os to define vasa previa, the definition should not be limited to a 2-cm distance; (2) all pregnancies should be screened for vasa previa with routine examination for placental cord insertion and a color Doppler sweep of the region over the cervix at the second-trimester anatomy scan; (3) when a low-lying placenta or placenta previa is found in the second trimester, a transvaginal ultrasound with Doppler should be performed at approximately 32 weeks to rule out vasa previa; (4) outpatient management of asymptomatic patients without risk factors for preterm birth is reasonable; (5) asymptomatic patients with vasa previa should be delivered by scheduled cesarean delivery between 35 and 37 weeks of gestation; and (6) there was no agreement on routine hospitalization, avoidance of intercourse, or use of 3-dimensional ultrasound for diagnosis of vasa previa. CONCLUSION: Through focus group discussion and a Delphi process, an international expert panel reached consensus on the definition, screening, clinical management, and timing of delivery in vasa previa, which could inform the development of new clinical guidelines.

Late termination of pregnancy at a major Queensland tertiary hospital, 2010-2020.

OBJECTIVE: To review rates of and indications for late pregnancy feticide at a major Queensland tertiary perinatal centre over the past decade. DESIGN: Retrospective cohort study. SETTING, PARTICIPANTS: The Centre for Advanced Prenatal Care at the Royal Brisbane and Women's Hospital, a tertiary perinatal centre; feticides of singleton pregnancies of at least 22 weeks' gestation, 1 January 2010 - 31 December 2020. MAIN OUTCOME MEASURES: Indications for feticide; median gestational age at feticide; referral source; time between referral, maternal-fetal medicine review, and feticide. RESULTS: During 2010-2020, 305 feticides were undertaken at 22 weeks' gestation or later. The annual number of feticides increased from 20 in 2010 to 54 in 2020. The median gestational age at feticide was consistent across the decade (24+6 weeks; range, 17+0 to 37+1 weeks). The most frequent fetal indications for feticide were neurological abnormalities (110 of 305, 36%), aneuploidy or genetic syndromes (67, 22%), and cardiac malformations (59, 19%). Most women were seen for review within seven days of referral for feticide (154 of 197 for whom this information was available, 78%; median, five days; range, 0-34 days), and 136 of 197 feticides (69%) were undertaken within seven days of the initial maternal-fetal medicine review. CONCLUSIONS: Most late pregnancy feticides were performed because of fetal indications, primarily structural malformations or genetic abnormalities. Despite advances in prenatal imaging and diagnosis, late termination of pregnancy remains a necessary option in some pregnancies with maternal or fetal indications, and equitable access to late termination of pregnancy services is a vital component of reproductive health care.

Extracellular vesicle-associated miRNAs are an adaptive response to gestational diabetes mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) is a serious public health issue affecting 9-15% of all pregnancies worldwide. Recently, it has been suggested that extracellular vesicles (EVs) play a role throughout gestation, including mediating a placental response to hyperglycaemia. Here, we investigated the EV-associated miRNA profile across gestation in GDM, assessed their utility in developing accurate, multivariate classification models, and determined the signaling pathways in skeletal muscle proteome associated with the changes in the EV miRNA profile. METHODS: Discovery: A retrospective, case-control study design was used to identify EV-associated miRNAs that vary across pregnancy and clinical status (i.e. GDM or Normal Glucose Tolerance, NGT). EVs were isolated from maternal plasma obtained at early, mid and late gestation (n = 29) and small RNA sequencing was performed. Validation: A longitudinal study design was used to quantify expression of selected miRNAs. EV miRNAs were quantified by real-time PCR (cases = 8, control = 14, samples at three times during pregnancy) and their individual and combined classification efficiencies were evaluated. Quantitative, data-independent acquisition mass spectrometry was use to establish the protein profile in skeletal muscle biopsies from normal and GDM. RESULTS: A total of 2822 miRNAs were analyzed using a small RNA library, and a total of 563 miRNAs that significantly changed (p < 0.05) across gestation and 101 miRNAs were significantly changed between NGT and GDM. Analysis of the miRNA changes in NGT and GDM separately identified a total of 256 (NGT-group), and 302 (GDM-group) miRNAs that change across gestation. A multivariate classification model was developed, based on the quantitative expression of EV-associated miRNAs, and the accuracy to correctly assign samples was > 90%. We identified a set of proteins in skeletal muscle biopsies from women with GDM associated with JAK-STAT signaling which could be targeted by the miRNA-92a-3p within circulating EVs. Interestingly, overexpression of miRNA-92a-3p in primary skeletal muscle cells increase insulin-stimulated glucose uptake. CONCLUSIONS: During early pregnancy, differently-expressed, EV-associated miRNAs may be of clinical utility in identifying presymptomatic women who will subsequently develop GDM later in gestation. We suggest that miRNA-92a-3p within EVs might be a protected mechanism to increase skeletal muscle insulin sensitivity in GDM.

Extracellular Vesicles and Preeclampsia: Current Knowledge and Future Research Directions.

Preeclampsia (PE) is associated with long-term morbidity in mothers and lifelong morbidities for their children, ranging from cerebral palsy and cognitive delay in preterm infants, to hypertension, diabetes and obesity in adolescents and young adults. There are several processes that are critical for development of materno-fetal exchange, including establishing adequate perfusion of the placenta by maternal blood, and the formation of the placental villous vascular tree. Recent studies provide persuasive evidence that placenta-derived extracellular vesicles (EVs) represent a significant intercellular communication pathway, and that they may play an important role in placental and endothelial cell (both fetal and maternal) function. These functions are known to be altered in PE. EVs can carry and transport a wide range of bioactive molescules that have potential to be used as biomarkers and therapeutic delivery tools for PE. EV content is often parent cell specific, thus providing an insight or "thumbprint" of the intracellular environment of the originating cell (e.g., human placenta). EV have been identified in plasma under both normal and pathological conditions, including PE. The concentration of EVs and their content in plasma has been reported to increase in association with disease severity and/or progression. Placenta-derived EVs have been identified in maternal plasma during normal pregnancy and PE pregnancies. They contain placenta-specific proteins and miRNAs and, as such, may be differentiated from maternally-derived EVs. The aim of this review, thus, is to describe the potential roles of EVs in preecmpatic pregnancies, focussing on EVs secreted from placental cells. The biogenesis, specificity of placental EVs, and methods used to characterise EVs in the context of PE pregnancies will be also discussed.

Human placental exosomes in gestational diabetes mellitus carry a specific set of miRNAs associated with skeletal muscle insulin sensitivity.

There is increasing evidence that miRNAs, which are enriched in nanovesicles called exosomes, are important regulators of gene expression. When compared with normal pregnancies, pregnancies with gestational diabetes mellitus (GDM) are associated with skeletal muscle insulin resistance as well as increased levels of circulating placental exosomes. Here we investigated whether placental exosomes in GDM carry a specific set of miRNAs associated with skeletal muscle insulin sensitivity. Exosomes were isolated from chorionic villous (CV) explants from both women with Normal Glucose Tolerant (NGT) and GDM pregnancies. Using miRNA sequencing, we identified a specific set of miRNAs selectively enriched with exosomes and compared with their cells of origin indicating a specific packaging of miRNAs into exosomes. Gene target and ontology analysis of miRNA differentially expressed in exosomes secreted in GDM compared with NGT are associated with pathways regulating cell migration and carbohydrate metabolism. We determined the expression of a selected set of miRNAs in placenta, plasma, and skeletal muscle biopsies from NGT and GDM. Interestingly, the expression of these miRNAs varied in a consistent pattern in the placenta, in circulating exosomes, and in skeletal muscle in GDM. Placental exosomes from GDM pregnancies decreased insulin-stimulated migration and glucose uptake in primary skeletal muscle cells obtained from patients with normal insulin sensitivity. Interestingly, placental exosomes from NGT increase migration and glucose uptake in response to insulin in skeletal muscle from diabetic subjects. These findings suggest that placental exosomes might have a role in the changes on insulin sensitivity in normal and GDM pregnancies.

Hysterosalpingo-foam sonography (HyFoSy): Tolerability, safety and the occurrence of pregnancy post-procedure.

BACKGROUND: Fallopian tube patency testing is an essential part of infertility evaluation. Hysterosalpingo-contrast sonography (HyCoSy) has been described as reliable, well tolerated and safe compared to other modalities such as laparoscopy and a dye test or hysterosalpingography. Limited availability of the previously used contrast has led to the introduction of a foam contrast agent as an alternative. AIMS: To assess the tolerability, safety and occurrence of pregnancy post-procedure of hysterosalpingo-foam sonography (HyFoSy). MATERIALS AND METHODS: A retrospective cohort study of women who had a HyFoSy at Queensland Ultrasound for Women from March 2013 to February 2015. A questionnaire was sent to their referring doctor to identify any complications or subsequent pregnancies with or without artificial reproductive technology (ART) within six months of the HyFoSy. RESULTS: Of 200 women, four cases were abandoned due to difficulty introducing the intracervical catheter, severe discomfort or a vasovagal episode. Response from referring doctors for 155 women reported no post-procedural complication. One hundred and eleven women were followed up for at least six months. Twenty-four out of 59 women (40.7%) who had ART and 24 out of 52 women (46.2%) who did not have ART conceived. Fifty percent of women who were nulligravida at the time of investigation, found to have at least one patent fallopian tube, whose partner had a normal semen analysis, spontaneously conceived within the time of follow up. CONCLUSIONS: HyFoSy is well tolerated and safe. A preponderance of pregnancies in the first month after HyFoSy suggests that a therapeutic effect may exist.

Vasa Previa Diagnosis, Clinical Practice, and Outcomes in Australia.

OBJECTIVE: To estimate the incidence of women with vasa previa in Australia and to describe risk factors, timing of diagnosis, clinical practice, and perinatal outcomes. METHODS: A prospective population-based cohort study was undertaken using the Australasian Maternity Outcomes Surveillance System between May 1, 2013, and April 30, 2014, in hospitals in Australia with greater than 50 births per year. Women were included if they were diagnosed with vasa previa during pregnancy or childbirth, confirmed by clinical examination or placental pathology. The main outcome measures included stillbirth, neonatal death, cesarean delivery, and preterm birth. RESULTS: Sixty-three women had a confirmed diagnosis of vasa previa. The estimated incidence was 2.1 per 10,000 women giving birth (95% CI 1.7-2.7). Fifty-eight women were diagnosed prenatally and all had a cesarean delivery. Fifty-five (95%) of the 58 women had at least one risk factor for vasa previa with velamentous cord insertion (62%) and low-lying placenta (60%) the most prevalent. There were no perinatal deaths in women diagnosed prenatally. For the five women with vasa previa not diagnosed prenatally, there were two perinatal deaths with a case fatality rate of 40%. One woman had an antepartum stillbirth and delivered vaginally and the other four women had cesarean deliveries categorized as urgent threat to the life of a fetus with one neonatal death. The overall perinatal case fatality rate was 3.1% (95% CI 0.8-10.5). Two thirds (68%) of the 65 neonates were preterm and 29% were low birth weight. CONCLUSION: The outcomes for neonates in which vasa previa was not diagnosed prenatally were inferior with higher rates of perinatal morbidity and mortality. Our study shows a high rate of prenatal diagnosis of vasa previa in Australia and associated good outcomes.

Role of Extracellular Vesicles and microRNAs on Dysfunctional Angiogenesis during Preeclamptic Pregnancies.

Preeclampsia is a syndrome characterized by hypertension during pregnancy, which is a leading cause of morbidity and mortality in both mother and newborn in developing countries. Some advances have increased the understanding of pathophysiology of this disease. For example, reduced utero-placental blood flow associated with impaired trophoblast invasion may lead to a hypoxic placenta that releases harmful materials into the maternal and feto-placental circulation and impairs endothelial function. Identification of these harmful materials is one of the hot topics in the literature, since these provide potential biomarkers. Certainty, such knowledge will help us to understand the miscommunication between mother and fetus. In this review we highlight how placental extracellular vesicles and their cargo, such as small RNAs (i.e., microRNAs), might be involved in endothelial dysfunction, and then in the angiogenesis process, during preeclampsia. Currently only a few reports have addressed the potential role of endothelial regulatory miRNA in the impaired angiogenesis in preeclampsia. One of the main limitations in this area is the variability of the analyses performed in the current literature. This includes variability in the size of the particles analyzed, and broad variation in the exosomes considered. The quantity of microRNA targets genes suggest that practically all endothelial cell metabolic functions might be impaired. More studies are required to investigate mechanisms underlying miRNA released from placenta upon endothelial function involved in the angiogenenic process.

Gestational Diabetes Mellitus Is Associated With Changes in the Concentration and Bioactivity of Placenta-Derived Exosomes in Maternal Circulation Across Gestation.

Although there is significant interest in elucidating the role of placenta-derived exosomes (PdEs) during pregnancy, the exosomal profile in pregnancies complicated by gestational diabetes mellitus (GDM) remains to be established. The aim of this study was to compare the gestational-age profile of PdEs in maternal plasma of GDM with normal pregnancies and to determine the effect of exosomes on cytokine release from human umbilical vein endothelial cells. A prospective cohort of patients was sampled at three time points during pregnancy for each patient (i.e., 11-14, 22-24, and 32-36 weeks' gestation). A retrospective stratified study design was used to quantify exosomes present in maternal plasma of normal (n = 13) and GDM (n = 7) pregnancies. Gestational age and pregnancy status were identified as significant factors contributing to variation in plasma exosome concentration (ANOVA, P < 0.05). Post hoc analyses established that PdE concentration increased during gestation in both normal and GDM pregnancies; however, the increase was significantly greater in GDM (∼2.2-fold, ∼1.5-fold, and ∼1.8-fold greater at each gestational age compared with normal pregnancies). Exosomes isolated from GDM pregnancies significantly increased the release of proinflammatory cytokines from endothelial cells. Although the role of exosomes during GDM remains to be fully elucidated, exosome profiles may be of diagnostic utility for screening asymptomatic populations.

A prospective pilot study in assessing the accuracy of ultrasound estimated fetal weight prior to delivery.

BACKGROUND: Perinatal mortality and morbidity related to growth restriction and macrosomia are predicted by birthweight. Estimated fetal weight is a surrogate measure for neonatal weight, and accurate measurement of this is central to providing counselling and managing preterm birth. AIMS: To assess the accuracy of estimated fetal weight (EFW) measured by two sonographers within 1 week of delivery using Hadlock formula. MATERIALS AND METHODS: Two sonographers independently scanned 150 women with singleton pregnancies, who were booked for elective delivery. The sonographers measured four biometric measurements in estimating fetal weight. The accuracy of EFW compared to the birthweight was examined. We also assessed the sensitivity and specificity for diagnosis of small-for-gestational age (SGA) and large-for-gestational age (LGA) according to the EFW. RESULTS: Estimated fetal weight was similar to actual birthweight, with a mean percentage difference (SD) of 1.4(7.0) (P = 0.44). The reliability coefficient of EFW compared to actual birthweight was 0.97 (95% CI (0.96, 0.98)). There was no significant difference between the sonographers for EFWs and among the sonographers from the ultrasound scan to delivery interval. The sensitivity and specificity for detection of SGA and LGA were 93.3% and 99.3%, 60% and 95.6%, respectively. CONCLUSIONS: There is high reproducibility with minimum discrepancy from actual birthweight among sonographers 1 week prior to delivery using Hadlock formula with better prediction of SGA neonates.

Placental exosomes in normal and complicated pregnancy.

While there is considerable contemporary interest in elucidating the role of placenta-derived extracellular vesicles in normal and complicated pregnancies and their utility as biomarkers and therapeutic interventions, progress in the field is hindered by a lack of standardized extracellular vesicle taxonomy and isolation protocols. The term "extracellular vesicle" is nonspecific and refers to all membrane-bound vesicles from nanometer to micrometer diameters and of different biogenic origins. To meaningfully ascribe biological function and/or diagnostic and therapeutic utility to extracellular vesicles, and in particular exosomes, greater specificity and vesicle characterization is required. The current literature relating to exosome biology must be interpreted in this context. Exosomes are a subtype of extracellular vesicle that are specifically defined by an endosomal biogenesis and particle size (40-120 nm) and density (1.13-1.19 g/mL(-1)). Exosomes are specifically package with signaling molecules (including protein, messenger RNA, microRNA, and noncoding RNA) and are released by exocytosis into biofluid compartments. Exosomes regulate the activity of both proximal and distal target cells, including translational activity, angiogenesis, proliferation, metabolism, and apoptosis. As such, exosomal signaling represents an integral pathway mediating intercellular communication. During pregnancy, the placenta releases exosomes into the maternal circulation from as early as 6 weeks of gestation. Release is regulated by factors that include both oxygen tension and glucose concentration and correlates with placental mass and perfusion. The concentration of placenta-derived exosomes in maternal plasma increases progressively during gestation. Exosomes isolated from maternal plasma are bioactive in vitro and are incorporated into target cells by endocytosis. While the functional significance of placental exosomes in pregnancy remains to be fully elucidated, available data support a role in normal placental development and maternal immunotolerance. Similarly, the role of exosomes in the etiology and progression of complications of pregnancy remains in a formative stage. Changes in the release of placenta- and nonplacenta-derived exosomes, their concentration in maternal plasma, composition, and bioactivity have been reported in association with pregnancies complicated by gestational diabetes and preeclampsia. The data, however, are confounded by the use of different isolation methodologies and vesicle subpopulations. The application of specific and well-characterized isolation methodologies is requisite to resolving the precise role of exosomes in complications of pregnancies and their ultimate clinical utility.

The Effect of Glucose on the Release and Bioactivity of Exosomes From First Trimester Trophoblast Cells.

CONTEXT: Hyperglycemia and hypoxia are risk factors of metabolic complication during pregnancy. The interactions between oxygen and glucose-sensing pathways that regulate exosome bioactivity from placental cells, however, have not been established. OBJECTIVE: The aim of this study was to test the hypothesis that exosomal signaling by placental cells (defined as the number of exosomes released per unit time and their bioactivity) is responsive to extracellular glucose concentration. METHODS: First-trimester primary trophoblast cells were incubated with D-glucose (5 mM or 25 mM) under 1%, 3%, or 8% O2 for 48 hours. Exosomes were isolated from cell-conditioned media by differential and buoyant density centrifugation. The total number of exosome vesicles was determined by quantifying immunoreactive exosomal CD63. The effect of exosomes on cytokine (granulocyte macrophage colony-stimulating factor, IL-2, IL-4, IL-6. IL-8, IL-10, interferon-γ, and TNF-α) release from endothelial cells was established by a protein solution array analysis. RESULTS: Glucose (25 mM) significantly increased the release of exosomes from trophoblast cells at all oxygen tensions tested (by approximately 2-fold when compared with controls, P < .001). Exosomes (100 µg/mL exosomal protein) released from trophoblast cells significantly increased (P < .05) the release of all cytokines from human umbilical vein endothelial cells when compared with the control (ie, cells without exosomes), with the exception of IL-2 and IL-10 (P > .05). CONCLUSIONS: The effects of high glucose on exosomes bioactivity may be recapitulated in vivo and is of clinical relevance in association with maternal insulin resistance (resulting in hyperglycemia) and preeclampsia (associated with placental insufficiency and hypoxia).

Vasa praevia: ultrasound diagnosis at the mid-trimester scan.

Background: Vasa praevia is a condition in which fetal vessels, unsupported by the umbilical cord or placenta, run on the fetal membranes in the lower uterine segment near the cervix. Rupture of these vessels prior to or at the time of delivery is associated with a very high perinatal mortality rate. Antenatal diagnosis of this condition with ultrasound is readily available, alters management and significantly decreases the risk of fetal loss. Materials and methods: We describe our experience of diagnosing vasa praevia at a tertiary referral ultrasound centre. The ultrasound characteristics that led to the diagnosis of vasa praevia and associated risk factors will be discussed. A guide to aid sonographers when performing an obstetric examination to help screen for this condition has been included. Conclusions: Where suspicion of vasa praevia is raised, and cannot be ruled out on transvaginal ultrasound, a third trimester scan is required.

Uptake of invasive prenatal tests in pregnancies conceived via assisted reproductive technologies: the experience in Queensland, Australia.

OBJECTIVE: Prenatal diagnosis of a chromosomal abnormality currently involves the use of an invasive procedure, which has a risk of fetal loss. The aim of this study was to identify whether pregnancies conceived via assisted reproductive technologies were more or less likely to be subjected to an invasive procedure compared with pregnancies that were conceived spontaneously. METHOD: Population data were collated from three private ultrasound clinics across southeast Queensland, Australia. RESULTS: Of the 15,032 spontaneously conceived pregnancies, 775 (5.2%) had invasive testing, while 95 (6.0%) of the 1581 pregnancies conceived through assisted reproductive technologies had invasive testing. When the uptake of testing is adjusted by the maternal age the assisted reproductive population was significantly less likely to pursue invasive testing (p = 0.003). Similarly when adjusted for the combined first trimester screen risk estimate, the assisted reproduction population is significantly less likely to undergo invasive testing than the spontaneous population (p = 0.005). CONCLUSION: Pregnancies conceived using assisted reproductive technologies are significantly less likely to be subjected to invasive testing than pregnancies conceived spontaneously in women of the same age and combined first trimester screen risk.

The long term neurologic outcome of children from pregnancies complicated by twin-to-twin transfusion syndrome.

OBJECTIVE: To assess long term outcomes of children from pregnancies complicated by twin-to-twin transfusion syndrome. DESIGN: Comparison of children from pregnancies with twin-to-twin transfusion syndrome in Western Australia with a contemporaneous regional comparison cohort of preterm and term infants studied using an identical assessment procedure. POPULATION AND SETTING: All infants aged > or =18 months were identified from a geographically based longitudinal cohort of monochorionic twin pregnancies with an antenatal diagnosis of twin-to-twin transfusion syndrome conducted prospectively since 1992. METHODS: Children were evaluated using age-specific developmental and behavioural assessments. Cerebral palsy was diagnosed clinically and ascertainment confirmed through the Western Australian Cerebral Palsy Register. MAIN OUTCOME MEASURES: Intellectual disability, cerebral palsy, behavioural and cognitive function. RESULTS: Fifty-two children were identified as eligible for study and assessments were performed on 49 (94%). Three surviving children had a diagnosis of cerebral palsy (5.8%). The mean IQ score was 8 points lower in twin-to-twin transfusion syndrome children compared with the comparison cohort although this was mainly due to a decrement of 13 points in those born before 33 weeks of gestation. There was no difference between the donor and the recipient twin in terms of IQ scores (median difference -3, 95% CI -9 to 6). There was no relationship of IQ score to the worst stage of the twin-to-twin transfusion syndrome. Child Behavior Check List and Vineland Adaptive Behavior Scale scores did not differ between twin-to-twin transfusion syndrome children and the comparison group. CONCLUSIONS: Twin-to-twin transfusion syndrome is associated with a significant reduction in IQ score in very preterm survivors. There seems to be no increase in the prevalence of cerebral palsy. Overall behaviour and adaptive behaviour scale scores are similar to a comparison group.

Perinatal characteristics and outcomes of pregnancies complicated by twin-twin transfusion syndrome.

OBJECTIVE: To assess the outcome of a geographically based cohort of monochorionic twin pregnancies complicated by twin-twin transfusion syndrome managed in a single perinatal center over a 10-year period. METHODS: A prospective cohort design was established in 1992 within a single tertiary obstetric unit. RESULTS: Sixty-nine cases of twin-twin transfusion syndrome were identified during the study period. The median gestation at diagnosis was 22.1 weeks (interquartile range 19.7-25.4). Perinatal outcome was directly related to stage at diagnosis and gestation at delivery. The overall perinatal survival rate was 64.5%. For lesser disease severity (stages I and II) the perinatal survival rate was 76.4%, falling to 51.5% with increasing disease severity (stages III-V) (P =.004). The median gestation at delivery was 29.4 weeks (interquartile range 26.3-33.8). The perinatal survival for those born at less than 28 weeks' gestation was 27.1%, increasing to 84.4% for those born at more than 28 weeks' gestation (P =.001). The incidence of neonatal complications reflected the high preterm birth rate. Amnioreduction was the principal intervention employed in this series, but in 24.6% of cases no therapy was used because of the requirement for immediate delivery or fetal demise. CONCLUSION: Twin-twin transfusion syndrome is a heterogeneous disorder in its clinical manifestations and progress. There remain significant perinatal mortality and morbidity in pregnancies complicated by twin-twin transfusion syndrome, principally related to the high preterm birth rate that typifies this disorder. The severity of disease as assessed by stage and the gestation at delivery are the principal factors in determining perinatal outcome in this condition.

Low maternal nutrition during pregnancy reduces the number of Sertoli cells in the newborn lamb.

The nutritional status of females during pregnancy can play a critical role in the postnatal growth and development of the offspring, often leading to permanent changes ('fetal programming'). The Sertoli cells are a strong candidate for fetal programming of future performance because the number of Sertoli cells is highly correlated with adult testicular size and the maximum rate of sperm production. For Merino ewes, we imposed different levels of metabolizable energy (ME) intake (LowME: 70% of requirements for maintenance of ewe body mass and normal growth of conceptus (n = 13); HighME: 110% of those requirements (n = 12)) from Week 10 of pregnancy until parturition and then tested for effects on testicular histology in newborn males. Pregnant ewes were weighed weekly and lambs were weighed at birth and 2 days later. Blood was sampled at the same times. LowME ewes did not gain weight, whereas HighME ewes gained 17% over their pretreatment weight. Birthweights were higher in HighME lambs than in LowME lambs. Paired testes tended to be heavier in the HighME group than in the LowME group (P=0.08). The diameter of the testicular cords did not differ. The absolute volume of testicular cords (0.36 +/- 0.02 v. 0.30 +/- 0.02 mL for HighME v. LowME, respectively; P=0.03) and the number of Sertoli cells (43.0 +/- 2.5 v. 34.5 +/- 2.0 x 10(8) for HighME v. LowME, respectively; P=0.018) per testis were both greater in the HighME than in the LowME group. Plasma follicle-stimulating hormone concentrations were not significantly affected at birth or 2 days later. We conclude that undernutrition during pregnancy can reduce testicular development in the newborn. Depending on the ability of the Sertoli cell population to recover between birth and puberty, this may limit the ultimate number of Sertoli cells and, hence, the future capacity for sperm production and fertility.

Prenatal diagnosis and management of congenital cystic adenomatoid malformation of the lung.

OBJECTIVE: Our purpose was to review the management and outcome of pregnancies with a prenatal diagnosis of fetal congenital cystic adenomatoid malformation of the lung (CCAM). STUDY DESIGN: A retrospective review was performed of all cases since 1995 with a prenatal diagnosis of fetal CCAM from the sole tertiary perinatal referral center in Western Australia. RESULTS: Twenty-one pregnancies with CCAM were identified. The gestational age at diagnosis was <22 weeks in 86% of cases. Macrocysts were seen in 76% of cases during ultrasound examination. Seventeen pregnancies continued until term. Regression of the sonographic appearances was observed in 19% of cases. Fetal hydrops complicated two cases. One neonate died within 24 hours of delivery because of pulmonary hypoplasia. Twelve children have required pulmonary lobectomies. No adverse sequelae are evident in surviving children. CONCLUSION: Most cases of prenatally diagnosed CCAM have had a good outcome. This review has positively influenced the counseling of women with this diagnosis.