Perinatal Lethal Gaucher Disease due to RecNcil Recombinant Mutation in the GBA Gene Presenting with Hydrops Fetalis and Severe Congenital Anemia.

A 35-year-old woman presented at 27-week gestation with hypertension and pedal edema. Antenatal scan showed hydrops fetalis and growth restriction. Cordocentesis showed severe fetal anemia. This was treated with multiple in utero blood transfusions with no clinically significant improvement and intrauterine death occurred at 28 weeks. Perinatal autopsy confirmed severe hydrops with hepatosplenomegaly and visceral effusions. Microscopic examination of the reticuloendothelial organs showed widespread infiltration by large mono- and multinucleate histiocytic cells with fibrillary appearance ("Gaucher cells"). DNA extracted from fetal tissue was submitted for analysis by next generation sequencing which revealed homozygosity for the RecNcil mutation in the GBA gene. Both parents were found to be heterozygous for the variant. The case report highlights a severe form of Gaucher disease with histopathological and molecular confirmation that presents with hydrops fetalis and severe refractory anemia. It also emphasizes the importance of perinatal autopsy coupled with exome sequencing in confirming syndromic diagnosis in the modern area.

Utility of ßhCG monitoring in the follow-up of medical management of miscarriage.

OBJECTIVE: To evaluate the percentage change in total ßeta-unit human chorionic gonadotropin (ßhCG) levels (%ΔßhCG) in the prediction of treatment outcomes following intravaginal misoprostol for missed miscarriage before 13 weeks. METHODS: A secondary analysis of a randomised controlled study of medical management of miscarriage was performed. Total ßhCG levels were collected before misoprostol (baseline) and after a planned seven day interval (follow-up), when a transvaginal ultrasound (TVUS) reported a gestational sac as present or not. If no sac at TVUS, surgery was indicated on clinical criteria. %ΔßhCG ((baseline ßhCG - follow-up ßhCG)/baseline ßhCG × 100) was evaluated in the prediction of a sac at TVUS and surgery on clinical criteria. RESULTS: %ΔßhCG was calculated for cases with ßhCG levels within two days of misoprostol and TVUS; calculation interval determined case number. The median %ΔßhCG for 24 cases with a persistent sac (6-9 day interval) was significantly lower than for 145 with no sac (58.75% (interquartile range (IQR): 37.59-76.69; maximum 86.54) vs 97.65% (IQR: 95.44-98.43); P < 0.0001). The median %ΔßhCG for eight cases needing surgery on clinical criteria (5-9 day interval) was significantly lower than for 140 cases with no sac not needing surgery (79.68% (IQR: 64.63-91.15; maximum 94.06) vs 97.68% (IQR: 95.61-98.50); P < 0.0001). The area under the receiver-operator curve was 0.975 for prediction of a persistent sac and 0.944 for prediction of surgery on clinical criteria, respectively. %ΔßhCG > 87% predicted no sac at TVUS. %ΔßhCG > 94.5% predicted no surgery on clinical criteria. CONCLUSION: %ΔßhCG calculation over one week reliably predicted treatment outcomes after medical management of missed miscarriage.

The Impact of Entry Technique and Access Diameter on Prelabour Rupture of Membranes Following Primary Fetoscopic Laser Treatment for Twin-Twin Transfusion Syndrome.

OBJECTIVE: To evaluate the impact of entry method and access diameter at fetoscopic surgery for twin-twin transfusion syndrome in twin pregnancies with at least one survivor. The outcomes evaluated were prelabour rupture of membranes (PROM) and birth <4 weeks, preterm birth (PTB) <28 weeks, and latency to birth. METHODS: A retrospective analysis of prospectively collected data of consecutive laser procedures from 6 centers was performed. Three entry methods (sheath + trocar; cannula + trocar; cannula + Seldinger) and 6 access diameters (2.3, 3.0, 3.3, 3.5, 3.8, 4.0 mm) were used. Exclusion criteria were subsequent invasive interventions, termination of pregnancy or double fetal death after laser. Multivariate analysis was performed to determine risk factors for the study outcomes. RESULTS: Six hundred seventy three fetoscopic laser cases were analyzed. The use of different entry methods and access diameters did not affect PROM or birth <4 weeks, or latency from laser to birth. Access diameter was associated with PTB <28 weeks. Cervical length was associated with PROM and birth <4 weeks, and latency from laser to birth. CONCLUSION: Instrument choice at fetoscopic laser procedures did not affect outcomes <4 weeks. Access diameter may affect the likelihood for PTB <28 weeks. Cervical length is critically associated with obstetrical outcomes following laser surgery.

The influence of mode of birth on neonatal survival and maternal outcomes at extreme prematurity: A retrospective cohort study.

BACKGROUND: There is a paucity of published clinical data to guide obstetric decision-making regarding mode of birth at extreme prematurity. AIMS: To evaluate whether neonatal survival or maternal outcomes were affected by the decision to perform a caesarean section (CS) between 23 + 0 and 26 + 6 weeks' gestation. MATERIALS AND METHODS: A single-centre retrospective cohort study of all liveborn infants born with a plan for active resuscitation at 23-26 weeks' gestation was performed. Descriptive and multivariate logistic regression analyses compared outcomes after vaginal birth and CS. Subgroup analyses of nonfootling breech presentations, multiple pregnancies and singleton pregnancies in spontaneous preterm labour were performed. RESULTS: Outcomes for 625 neonates delivered by 540 mothers were analysed. A total of 300 (48%) neonates were born vaginally and 325 (52%) by CS. Mode of birth was not associated independently with survival for any multivariate analysis; gestational age at birth was an independent predictor across all analyses. Adverse maternal outcomes were documented in 112 (21%) pregnancies; the rate of severe maternal complications was low. Maternal morbidity was not affected by mode of birth. CONCLUSIONS: Mode of birth did not affect neonatal survival or the rate of maternal morbidity for deliveries at 23-26 completed weeks' gestation.

Surgical management of abnormally invasive placenta: a retrospective cohort study demonstrating the benefits of a standardized operative approach.

INTRODUCTION: Abnormally invasive placenta is a major cause of maternal morbidity and mortality. The aim of this study was to assess the effectiveness of a standardized operative approach performed by gynecological oncologists in the surgical management of abnormally invasive placenta. MATERIALS AND METHODS: We performed a retrospective analysis of all cases of morbid placental adherence managed at the Mater Mothers' Hospitals, Brisbane, Australia between January 2000 and June 2013. A standard operative approach involving extensive retro-peritoneal and bladder dissection before delivery of the fetus, was undertaken when a gynecological oncologist was present at the start of the procedure. Main outcome measures were estimated blood loss, transfusion requirements, and maternal and neonatal morbidity. RESULTS: The study includes 98 cases of histologically confirmed abnormally invasive placenta. Median estimated blood loss for the entire cohort was 2150 mL (range 300-11 500 mL). Women were divided into three groups, (1) those who had a gynecological oncologist present at the start of the procedure (group 1; n = 43), (2) those who had a gynecological oncologist called in during the procedure (group 2; n = 23), and (3) those who had no gynecological oncologist involved (group 3; n = 32). Group 2 had a significantly higher blood loss than the other groups (p = 0.001) (median 4400 mL). Transfusion requirements were higher in groups 2 and 3 compared with group 1 (p = 0.004). Other maternal and neonatal morbidity was similar across all three groups. CONCLUSION: This study supports the early presence of a gynecological oncologist at delivery when abnormally invasive placenta is suspected and demonstrates that a "call if needed" approach is not acceptable for these complex cases.

Is the third trimester repeat ultrasound scan for placental localisation needed if the placenta is low lying but clear of the os at the mid-trimester morphology scan?

INTRODUCTION: It is unclear whether women with a low-lying placenta (not overlapping the internal cervical os) at the mid-trimester scan need follow-up. The aim of the study was to determine the rate of placenta praevia, vasa praevia and cord prolapse in the third trimester in this cohort of women. METHODS: A retrospective cohort study of women with a documented low-lying placenta (<30 mm from the internal cervical os) at the mid-trimester morphology ultrasound scan was done. A composite outcome of rate of placenta praevia, vasa praevia or cord prolapse at term was evaluated. Multivariate analysis was performed to investigate the variables influencing the composite outcome. In addition, a meta-analysis of methodologically similar studies was performed to investigate the effect of the placenta to os distance at the mid-trimester scan on the rate of placenta praevia at term. RESULTS: One hundred and eighty-one women with a low-lying placenta not overlapping the os at mid-trimester scan were identified. The composite outcome was documented in 20 (11.0%) women, including placenta praevia in 15 (8.3%). Based on multivariate analysis, multiparity, distance from os < 10 mm and antenatal bleeding were independently associated with the composite outcome. Meta-analysis demonstrated significant reduction in rate of placenta praevia for every 10-mm increase in placenta-os distance at mid-trimester. CONCLUSION: Our study supports the recommendation to follow up all women with a placenta lying <20 mm from the cervical os at mid-trimester.

Prominent cervical mucous and its impact on cervical length measurement: findings of a national survey.

INTRODUCTION: Cervical length measurement by transvaginal scanning (TVS) has been proposed by some as a universal screening test for preterm labour. The presence of prominent cervical mucous may affect assessment of the cervix; however, the exact technique to measure the cervix when there is prominent mucous or funnelling has not been described. We evaluated the level of agreement in cervical length measurements amongst Australian specialists and sonographers reporting on cervical assessment using an online survey. METHODS: We conducted an online survey with 11 images of the cervix to assess how obstetric sonographers and sonologists report on the cervix when there is prominent mucous or funnelling. They were asked five questions about the image of the cervix. A kappa coefficient was calculated from the responses. RESULTS: We had 151 complete responses to the online survey. For the images which showed funnelling or prominent cervical mucous, there was little agreement regarding the cervix being open or closed and regards the location of the internal os. The Kappa coefficient was 0.22 indicating a low level of agreement for the location of the internal os. CONCLUSION: There is lack of agreement amongst Australian specialists and sonographers reporting on cervical assessment when there is prominent mucous or funnelling seen in the cervix. We propose a method to standardise reporting on the cervix incorporating the chorioamniotic membrane for the identification of the inner cervical os when there is prominent mucous or funnelling.

The medical management of missed miscarriage: outcomes from a prospective, single-centre, Australian cohort.

OBJECTIVE: To report the prospective outcomes of medical management of missed miscarriage before 13 weeks' gestation from an Australian cohort. DESIGN: Descriptive study of a cohort selected out of a randomised controlled trial. SETTING: Outpatient management at a maternity hospital between 1 May 2007 and 28 July 2010. PARTICIPANTS: 264 women requesting medical management of missed miscarriage. MAIN OUTCOME MEASURES: Number of doses of misoprostol required, unscheduled visits for care, findings at ultrasound follow-up, requirement for surgical management, number of cases of gestational trophoblastic disease (GTD), and self-reported patient experience. RESULTS: 107 women (40.5%) received a repeat dose of misoprostol, and 79 women (29.9%) made unscheduled visits for care. Among the 241 women with Day 7 ultrasound follow-up, a gestational sac was found in 32 women (13.3%), indicating failure of medical management. Complete miscarriage was induced without the need for surgery in 206 women (78.0%). Surgery was performed as an emergency in 13 women (4.9%). Twelve women (4.5%) had surgery for ongoing bleeding after medical management, and four of these did not have chorionic villi on histopathological examination. Five women (1.9%) had GTD, which was managed incidentally under the protocol. Among those who returned patient questionnaires, 73.0% participants (116/159) indicated that they would recommend medical management of miscarriage to other women, while 18.2% (29/159) indicated that they would undergo surgery next time. CONCLUSION: The medical management of missed miscarriage on an outpatient basis is safe and effective. TRIAL REGISTRATION: ACTRN12612000150842.

Can we use a lower intravaginal dose of misoprostol in the medical management of miscarriage? A randomised controlled study.

BACKGROUND: The optimal dose of misoprostol to be used in the medical management of miscarriage before 13 weeks has not been resolved. AIM: To evaluate the effectiveness and side effect profile of two different dosages of misoprostol. METHODS: A randomised controlled, equivalence study comparing 400 vs 800 µg misoprostol per vaginum (PV) on an outpatient basis. The allocated dose was repeated the next day if clinically the products of conception had not been passed. Complete miscarriage was evaluated using two methods: ultrasound criteria on Day 7 and the need for surgical management (clinical criteria). Equivalence was demonstrated if the 95% confidence interval [CI] of the observed risk difference between the two doses for complete miscarriage lay between -15.0 and 15.0%. Differences in side effects and patient satisfaction were evaluated using patient-completed questionnaires. RESULTS: One hundred and fifty-eight women were allocated to receive 400 µg and 152 women to 800 µg misoprostol for the management of missed (91.3%) or incomplete (8.7%) miscarriage. The rate of induced complete miscarriage was equivalent using both ultrasound criteria (observed risk difference (ORD) -4.6%, 95% CI -12.8 to 3.7%; P = 0.313) and clinical criteria (ORD -5.6%, 95% CI -14.8 to 3.6%; P = 0.273). Following the 400 µg dose, the reported rate of fever/rigors was lower (ORD -15.6%, 95% CI -28.1 to -3.0%; P = 0.015), and more women reported their decision to undergo medical management as a good decision (ORD 15.2%, 95% CI 2.8 to 27.7%; P = 0.018). CONCLUSION: Four hundred-microgram misoprostol PV can be recommended for the medical management of miscarriage on an outpatient basis.

A longer tracheal occlusion period results in increased lung growth in the nitrofen rat model.

OBJECTIVE: Prenatal tracheal occlusion (TO) promotes lung growth and is applied clinically in fetuses with severe congenital diaphragmatic hernia. Limited data are available regarding the effect of duration of TO on lung development. Our objective was to evaluate the effects of long (2 and 2.5 days) versus short (1 day) TO on lung development in rats with nitrofen-induced diaphragmatic hernia. METHOD: Nitrofen was administered on embryonic day (ED) 9 and fetal TO performed either on ED18.5, 19 or 20 (term = 22 days). Sham-operated and untouched littermates served as controls. On ED21, lungs were harvested and only fetuses with a left-sided diaphragmatic defect were included in further analyses. RESULTS: Lung-body-weight ratio incrementally increased with the duration of TO. Increased proliferation following long TO was confirmed by immunohistochemistry and qRT-PCR for the proliferation marker Ki-67. Irrespective of duration, TO induced more complex airway architecture. Medial wall thickness of pulmonary arteries was thinner after long rather than short TO. CONCLUSION: In the nitrofen rat model of congenital diaphragmatic hernia, a longer period of TO leads to enhanced lung growth and less muscularized pulmonary arteries.

Early onset, severe fetal growth restriction with absent or reversed end-diastolic flow velocity waveform in the umbilical artery: perinatal and long-term outcomes.

OBJECTIVE: To assess perinatal and long-term outcomes for pregnancies complicated by early onset, severe fetal growth restriction with absent or reverse end-diastolic flow velocity waveform (AREDF) in the umbilical artery. METHODS: A retrospective cohort study of 36 singleton pregnancies with AREDF when the estimated fetal weight (EFW) is less than 501 g at presentation. RESULTS: At presentation, the median gestational age and EFW were 24 (18-29) weeks and 364 (167-496) g, respectively. The median interval between presentation and live birth or diagnosis of intrauterine fetal death (IUFD) was 13 (0-60) days. Delivery was for IUFD in 19 cases (53%), fetal indications in 13 cases (36%) and maternal indications in four cases (11%). Caesarean section (CS) was performed for the 17 live births of which 10 (59%) were by classical CS. Of the total cohort, five infants survived to hospital discharge giving an overall perinatal survival rate of 14%. All survivors had short-term morbidity. The cognitive function in four children was assessed as normal at two years of age. One survivor had developmental delay. None of the surviving children had any evidence of cerebral palsy. CONCLUSION: The overall perinatal survival rate for pregnancies complicated by early onset, severe growth restriction with an EFW of < 501 g and AREDF is low. When delivery occurs for fetal indications, the majority of these women require classical CS. Short-term neonatal morbidity is high though none of the survivors had cerebral palsy.

o-nitrobenzenesulfonamides in nucleoside synthesis: efficient 5'-aziridination of adenosine.

5'-Aziridinoadenylates of the form 1 and a related nitrogen mustard variant have been constructed using a novel variation of the Mitsunobu reaction. Such molecules allow conversion of biological methyltransferases into nucleoside transferases, thus providing powerful tools for investigating S-adenosyl-l-methionine (SAM)-dependent methylation. We present here a highly effective synthesis of such molecules that is amenable to aziridine diversification as well as elaboration of the base moiety so as to afford "bumped" cofactor mimics compatible with "hole"-bearing mutant proteins.

Conversion of aryl azides to O-alkyl imidates via modified Staudinger ligation.

[reaction: see text] o-Carboalkoxy triarylphosphines are shown to react with aryl azides to provide Staudinger ligation products bearing O-alkyl imidate linkages. This is in contrast to alkyl azides whose ligation to o-carboalkoxy triarylphosphines has been reported to yield amide-linked materials. This extension of the Staudinger ligation for coupling of abiotic reagents under biocompatible conditions highlights the utility of commercially available triarylphosphines through which suitable linkers can be attached via an ester moiety.