In utero treatment of congenital cytomegalovirus infection with valganciclovir: an observational study on safety and effectiveness.

BACKGROUND: The treatment of congenital cytomegalovirus (CMV) infection is usually administered to neonates after birth; however, it can be anticipated during the prenatal period by treating pregnant women in order to reduce the severity of the congenital disease. The most commonly used treatment for CMV during pregnancy is valaciclovir; however, valganciclovir has a higher potency against CMV and is the first choice for neonates with congenital CMV disease. OBJECTIVES: We investigated neonatal and maternal safety of tertiary prevention in infected fetuses showing ultrasound features of infection using valganciclovir. METHODS: Retrospective cohort study of pregnant women and their symptomatic infected fetuses taking valganciclovir, 3 × 450 mg per day. All fetuses presented at least one prenatal feature on ultrasound. We assessed fetal/neonatal and maternal safety, as well as neonatal efficacy of treatment. The main outcome was neutropenia. Secondary outcomes included other haematological side effects, symptoms at birth and neonatal CMV-PCR was positive. RESULTS: Seventeen women with singleton pregnancies received valganciclovir from a median (IQR) of 27.1 (26.0-30.3) to 11.6 (6.5-12.9) weeks of gestation. No neonatal neutropenia was reported. One pregnancy was terminated for severe features. Three newborns (18%) were asymptomatic at birth, including one with negative CMV-PCR from blood and saliva. CMV-PCR was positive for 12/13 symptomatic newborns, with a median (IQR) log10 viral load of 3.36 (3.30-4.20), 4.03 (1.75-4.27) and 3.04 (0.00-3.40) log10 copies/mL in blood, urine and saliva, respectively. CONCLUSIONS: Tertiary prevention by valganciclovir appears to be well tolerated for both fetus and mother. However, more extensive trials accompanied by long-term follow-up are needed.

Clinical Value of Serial Quantitative Analysis of Cytomegalovirus DNA in Blood and Saliva Over the First 24 Months of Life in Congenital Infection: The French Cymepedia Cohort.

OBJECTIVE: To evaluate cytomegalovirus (CMV) viral load dynamics in blood and saliva during the first 2 years of life in symptomatic and asymptomatic infected infants and to identify whether these kinetics could have practical clinical implications. STUDY DESIGN: The Cymepedia cohort prospectively included 256 congenitally infected neonates followed for 2 years. Whole blood and saliva were collected at inclusion and months 4 and 12, and saliva at months 18 and 24. Real-time CMV polymerase chain reaction (PCR) was performed, results expressed as log10 IU/mL in blood and in copies per milliliter in saliva. RESULTS: Viral load in saliva progressively decreased from 7.5 log10 at birth to 3.3 log10 at month 24. CMV PCR in saliva was positive in 100% and 96% of infants at 6 and 12 months, respectively. In the first month of life, neonatal saliva viral load of less than 5 log10 was related to a late CMV transplacental passage. Detection in blood was positive in 92% of neonates (147/159) in the first month of life. No viral load threshold values in blood or saliva could be associated with a high risk of sequelae. Neonatal blood viral load of less than 3 log10 IU/mL had a 100% negative predictive value for long-term sequelae. CONCLUSIONS: Viral loads in blood and saliva by CMV PCR testing in congenital infection fall over the first 24 months. In this study of infants affected mainly after primary maternal infection during pregnancy, all salivary samples were positive in the first 6 months of life and sequelae were not seen in infants with neonatal blood viral load of less than 3 log10 IU/mL.

Operative Hysteroscopy vs Vacuum Aspiration for Incomplete Spontaneous Abortion: A Randomized Clinical Trial.

Importance: Vacuum aspiration is commonly used to remove retained products of conception in patients with incomplete spontaneous abortion. Scarring of the uterine cavity may occur, potentially impairing future fertility. A procedural alternative, operative hysteroscopy, has gained popularity with a presumption of better future fertility. Objective: To assess the superiority of hysteroscopy to vacuum aspiration for subsequent pregnancy in patients with incomplete spontaneous abortion who intend to have future pregnancy. Design, Setting, and Participants: The HY-PER randomized, controlled, single-blind trial included 574 patients between November 6, 2014, and May 3, 2017, with a 2-year duration of follow-up. This multicenter trial recruited patients in 15 French hospitals. Individuals aged 18 to 44 years and planned for surgery for an incomplete spontaneous abortion with plans to subsequently conceive were randomized in a 1:1 ratio. Interventions: Surgical treatment by hysteroscopy (n = 288) or vacuum aspiration (n = 286). Main Outcomes and Measures: The primary outcome was a pregnancy of at least 22 weeks' duration during 2-year follow-up. Results: The intention-to-treat analyses included 563 women (mean [SD] age, 32.6 [5.4] years). All aspiration procedures were completed. The hysteroscopic procedure could not be completed for 19 patients (7%), 18 of which were converted to vacuum aspiration (8 with inability to completely resect, 7 with insufficient visualization, 2 with anesthetic complications that required a shortened procedure, 1 with equipment failure). One hysteroscopy failed due to a false passage during cervical dilatation. During the 2-year follow-up, 177 patients (62.8%) in the hysteroscopy group and 190 (67.6%) in the vacuum aspiration (control) group achieved the primary outcome (difference, -4.8% [95% CI, -13% to 3.0%]; P = .23). The time-to-event analyses showed no statistically significant difference between groups for the primary outcome (hazard ratio, 0.87 [95% CI, 0.71 to 1.07]). Duration of surgery and hospitalization were significantly longer for hysteroscopy. Rates of new miscarriages, ectopic pregnancies, Clavien-Dindo surgical complications of grade 3 or above (requiring surgical, endoscopic, or radiological intervention or life-threatening event or death), and reinterventions to remove remaining products of conception did not differ between groups. Conclusions and Relevance: Surgical management by hysteroscopy of incomplete spontaneous abortions in patients intending to conceive again was not associated with more subsequent births or a better safety profile than vacuum aspiration. Moreover, operative hysteroscopy was not feasible in all cases. Trial Registration: ClinicalTrials.gov Identifier: NCT02201732.

Laparotomy-Assisted 2-Port Fetoscopic Repair of Spina Bifida Aperta: Report of a Single-Center Experience in Paris, France.

BACKGROUND: Given the maternal morbidity of open fetal surgery, the development of prenatal fetoscopic repair for spina bifida aperta (SBA) is encouraged. OBJECTIVE: We hereby report the early results from our center, using a laparotomy-assisted CO2-fetoscopic approach. METHODS: This study was conducted in patients with an SBA < T1 and >S1, <26 weeks of gestation, with Chiari II. Fetoscopic repair was performed using 2 operating trocars in the uterus exteriorized through a transverse laparotomy. Endoscopy was performed under humidified and heated CO2 insufflation. Following dissection of the lesion, a 1-layer approach was performed with a muscle/skin flap sutured over a patch of Duragen. Main outcomes were watertight repair at birth and the need for postnatal neurosurgical surgery including shunting within 6 months. RESULTS: Of 87 women assessed for prenatal therapy, 7 were included. Surgery was performed at 24 (23-26) weeks' gestation. There was no fetal demise. Conversion to hysterotomy was not performed, although surgery could not be performed in 1 case because of fetal position. Severe preeclampsia developed postoperatively in 1 case. In the other 6 cases, follow-up was uneventful except for premature rupture membranes which occurred in 3/6 cases at 30, 34, and 36+5 weeks' gestation. Gestational age at delivery was 32 + 5 (31-36 + 5) weeks' gestation. Repair was watertight at birth except in 2 cases which required complementary postnatal surgical repair. Reverse hindbrain herniation during pregnancy was observed in 4/6 cases. In 3/6 cases, shunting was necessary within 6 months after birth. At 12 months, a functional gain of ≥2 metameric levels was observed in 3 cases of the 6 survivors. CONCLUSION: Laparotomy-assisted fetoscopic repair is a reasonable option for women who choose and are eligible for antenatal surgery, both in terms of maternal and perinatal morbidity.

Intrauterine fetoscopic laser surgery versus expectant management in stage 1 twin-to-twin transfusion syndrome: an international randomized trial.

BACKGROUND: Selective fetoscopic laser coagulation of the intertwin anastomotic chorionic vessels is the first-line treatment for twin-twin transfusion syndrome. However, in stage 1 twin-twin transfusion syndrome, the risks of intrauterine surgery may be higher than those of the natural progression of the condition. OBJECTIVE: This study aimed to compare immediate surgery and expectant follow-up in stage 1 twin-twin transfusion syndrome. STUDY DESIGN: We conducted a multicentric randomized trial, which recruited from 2011 to 2018 with a 6-month postnatal follow-up. The study was conducted in 9 fetal medicine centers in Europe and the Unites States. Asymptomatic women with stage 1 twin-twin transfusion syndrome between 16 and 26 weeks' gestation, a cervix of >15 mm, and access to a surgical center within 48 hours of diagnosis were randomized between expectant management and immediate surgery. In patients allocated to immediate laser treatment, percutaneous laser coagulation of anastomotic vessels was performed within 72 hours. In patients allocated to expectant management, a weekly ultrasound follow-up was planned. Rescue fetoscopic coagulation of anastomoses was offered if the syndrome worsened as seen during a follow-up, either because of progression to a higher Quintero stage or because of the maternal complications of polyhydramnios. The primary outcome was survival at 6 months without severe neurologic morbidity. Severe complications of prematurity and maternal morbidity were secondary outcomes. RESULTS: The trial was stopped at 117 of 200 planned inclusions for slow accrual rate over 7 years: 58 women were allocated to expectant management and 59 to immediate laser treatment. Intact survival was seen in 84 of 109 (77%) expectant cases and in 89 of 114 (78%) (P=.88) immediate surgery cases, and severe neurologic morbidity occurred in 5 of 109 (4.6%) and 3 of 114 (2.6%) (P=.49) cases in the expectant and immediate surgery groups, respectively. In patients followed expectantly, 24 of 58 (41%) cases remained stable with dual intact survival in 36 of 44 (86%) cases at 6 months. Intact survival was lower following surgery than for the nonprogressive cases, although nonsignificantly (78% and 71% following immediate and rescue surgery, respectively). CONCLUSION: It is unlikely that early fetal surgery is of benefit for stage 1 twin-twin transfusion syndrome in asymptomatic pregnant women with a long cervix. Although expectant management is reasonable for these cases, 60% of the cases will progress and require rapid transfer to a surgical center.

Sequelae of Congenital Cytomegalovirus Following Maternal Primary Infections Are Limited to Those Acquired in the First Trimester of Pregnancy.

BACKGROUND: The known relationship between the gestational age at maternal primary infection an the outcome of congenital CMV is based on small, retrospective studies conducted between 1980 and 2011. They reported that 32% and 15% of cases had sequelae following a maternal primary infection in the first and second or the third trimester, respectively. We aimed to revisit this relationship prospectively between 2011 and 2017, using accurate virological tools. METHODS: We collected data on women with a primary infection and an infected child aged at least 1 year at the time of analysis. An accurate determination of the timing of the primary infection was based upon serial measurements of immunoglobulin (Ig) M and IgG and on IgG avidity in sera collected at each trimester. The case outcome was assessed according to a structured follow-up between birth and 48 months. RESULTS: We included 255 women and their 260 fetuses/neonates. The dating of the maternal infection was prospective in 86% of cases and retrospective in 14%. At a median follow-up of 24 months, the proportion of sensorineural hearing loss and/or neurologic sequelae were 32.4% (95% confidence interval [CI] 23.72-42.09) after a maternal primary infection in the first trimester, 0 (95% CI 0-6.49) after an infection in the second trimester, and 0 (95% CI 0-11.95) after an infection in the third trimester (P < .0001). CONCLUSIONS: These results suggest that a cytomegalovirus infection can be severe only when the virus hits the fetus in the embryonic or early fetal period. Recent guidelines recommend auditory follow-ups for at least 5 years for all infected children. This raises parental anxiety and generates significant costs. We suggest that auditory and specialized neurologic follow-ups may be recommended only in cases of a maternal infection in the first trimester.

Impact of laser therapy for twin-to-twin transfusion syndrome on subsequent pregnancy.

OBJECTIVES: The objective of our study was to determine the impact of laser therapy for twin-to-twin transfusion syndrome (TTTs) on subsequent pregnancies. METHODS: This was a monocentric retrospective observational study. Women treated by laser fetoscopy for TTTs were asked to answer a postal questionnaire about subsequent pregnancies. The primary outcome was fecundity (number of pregnancies and time to pregnancy). We also assessed pregnancy complications, birth weight, and gestational age at delivery. Pregnancy complications included the following: threatened preterm labor, preeclampsia, placenta accreta, postpartum hemorrhage, and psychological disorders. Our study population was compared with an external control group made up of mothers of monochorionic twins without TTTs. RESULTS: We included 122 cases managed at the Necker Hospital between 2008 and 2012 and 39 controls. The median conception time was longer in the TTTs group (6.4 ± 11.1 versus 2 ± 1.6 months, P = .03). The numbers of live childbirths at the end of those pregnancies were equivalent (77.6% versus 66.7%, P = .56). Birth weight (3317 ± 726 versus 3240 ± 382 g, P = .81) and gestational age at delivery (38.2 ± 6.8 WG versus 39.5 ± 1.2 WG, P = .64) were similar, with no increase of obstetrical complications compared with the control group. DISCUSSION: Twin-to-twin transfusion syndrome and its treatment do not seem to impact subsequent pregnancies.

Effect of Cell-Free DNA Screening vs Direct Invasive Diagnosis on Miscarriage Rates in Women With Pregnancies at High Risk of Trisomy 21: A Randomized Clinical Trial.

Importance: Cell-free DNA (cfDNA) tests are increasingly being offered to women in the first trimester of pregnancies at a high risk of trisomy 21 to decrease the number of required invasive fetal karyotyping procedures and their associated miscarriages. The effect of this strategy has not been evaluated. Objective: To compare the rates of miscarriage following invasive procedures only in the case of positive cfDNA test results vs immediate invasive testing procedures (amniocentesis or chorionic villus sampling) in women with pregnancies at high risk of trisomy 21 as identified by first-trimester combined screening. Design, Setting, and Participants: Randomized clinical trial conducted from April 8, 2014, to April 7, 2016, in 57 centers in France among 2111 women with pregnancies with a risk of trisomy 21 between 1 in 5 and 1 in 250 following combined first-trimester screening. Interventions: Patients were randomized to receive either cfDNA testing followed by invasive testing procedures only when cfDNA tests results were positive (n = 1034) or to receive immediate invasive testing procedures (n = 1017). The cfDNA testing was performed using an in-house validated method based on next-generation sequencing. Main Outcomes and Measures: The primary outcome was number of miscarriages before 24 weeks' gestation. Secondary outcomes included cfDNA testing detection rate for trisomy 21. The primary outcome underwent 1-sided testing; secondary outcomes underwent 2-sided testing. Results: Among 2051 women who were randomized and analyzed (mean age, 36.3 [SD, 5.0] years), 1997 (97.4%) completed the trial. The miscarriage rate was not significantly different between groups at 8 (0.8%) vs 8 (0.8%), for a risk difference of -0.03% (1-sided 95% CI, -0.68% to ∞; P = .47). The cfDNA detection rate for trisomy 21 was 100% (95% CI, 87.2%-100%). Conclusions and Relevance: Among women with pregnancies at high risk of trisomy 21, offering cfDNA screening, followed by invasive testing if cfDNA test results were positive, compared with invasive testing procedures alone, did not result in a significant reduction in miscarriage before 24 weeks. The study may have been underpowered to detect clinically important differences in miscarriage rates. Trial Registration: ClinicalTrials.gov Identifier: NCT02127515.

Risk Factors for Congenital Cytomegalovirus Infection Following Primary and Nonprimary Maternal Infection: A Prospective Neonatal Screening Study Using Polymerase Chain Reaction in Saliva.

BACKGROUND: The design of diagnostic and preventive strategies have been prevented by gaps in knowledge of the epidemiology of congenital cytomegalovirus (cCMV) with the type of maternal infection as well as the lack of large-scale neonatal screening tools. METHODS: In sum, 11715 consecutive newborns were screened for cCMV by polymerase chain reaction (PCR) in saliva. Prevalence, type of maternal infection, sociodemographic, obstetrical, and serological data were analyzed. RESULTS: Positive predictive value of CMV PCR in saliva was 59%; false positive results were associated with lower viral loads (P < .001). Maternal seroprevalence was 61%, birth prevalence was 0.37%, resulting from primary and nonprimary infections in 52% and 47.7% of cases, respectively. The risk to deliver an infected baby after primary infection was increased in younger (OD = 7.9), parous (OD = 4.1) women born in high resources countries (OD = 5.2) and from higher income groups (P = .019). The only 2 risk factors to deliver an infected baby after nonprimary infection were to be young (OD = 4.6) and unemployed (OD = 5.8). The risk to deliver an infected baby was 4-fold higher in women seronegative before their pregnancy (P = .021). CONCLUSIONS: A positive CMV PCR in newborns' saliva should always be confirmed in a repeat-sample. Sociodemographic characteristics of women giving birth to an infected baby after primary and nonprimary infection are different. Seronegative, parous women represent the highest risk population for cCMV in countries with low to intermediate seroprevalence. Urgent action is needed to stop the cCMV's epidemic, particularly in this population easily identifiable by maternal serology and amenable to prevention messages. CLINICAL TRIALS REGISTRATION: NCT01923636.

In utero treatment of congenital cytomegalovirus infection with valacyclovir in a multicenter, open-label, phase II study.

BACKGROUND: Congenital infection with human cytomegalovirus is a major cause of morbidity and mortality. A randomized controlled trial showed that high-dosage valacyclovir prevents cytomegalovirus disease in transplant recipients. Fetuses showing ultrasound features of infection are at high risk of being symptomatic at or before birth. In a pilot study, oral administration of high-dosage valacyclovir to mothers significantly decreased viral load and produced therapeutic concentrations in the blood of infected fetuses. A randomized controlled trial comparing prenatal treatment with valacyclovir against placebo in infected fetuses failed to recruit because women declined randomization. Randomized controlled trials in fetal medicine have often proven unacceptable by women who decline termination of pregnancy and are not prepared to resign themselves to the odds of the natural history of the disease. OBJECTIVE: We evaluated the efficacy of oral valacyclovir, 8 g daily, for pregnant women carrying a symptomatic cytomegalovirus-infected fetus, targeting a high-risk group for developing both neurosensory and neurological impairment. STUDY DESIGN: We designed a multicenter, open-label, phase II study with 1 arm, using one of Simon's optimal 2-stage designs. Symptomatic fetuses were defined by the presence of measurable extracerebral or mild cerebral ultrasound symptoms. They were treated in utero from prenatal diagnosis at a median of 25.9 weeks' gestation until delivery or termination of pregnancy. Fetuses with severe brain anomalies on ultrasound were not included as were cases completely asymptomatic at presentation, because treatment was unlikely to modify either outcome. The primary endpoint was the proportion of asymptomatic neonates born to treated mothers. RESULTS: At the interim analysis, 8 of 11 women delivered an asymptomatic neonate (required: ≥7). In step 2, 32 additional cases were included for a total of 43; the final number of asymptomatic neonates was 34, more than the 31 required to indicate efficacy according to the Simon 2-stage design. They remained asymptomatic at 12 months. High-dosage valacyclovir given for a median of 89 days to pregnant women carrying a moderately infected fetus was efficient at giving birth to asymptomatic neonates. Fetal blood viral loads decreased and platelet counts increased, both significantly (P = .01 and P < .001, respectively), between treatment initiation and birth after treatment completion, regardless of duration of fetal infection. Compared with a historical cohort obtained by a metaanalysis of the literature, the use of valacyclovir (8 g daily) significantly increased the proportion of asymptomatic neonates from 43% without treatment to 82% with treatment. Although the pill burden was high (16 pills a day) adherence to treatment was >90%. Finally, valacyclovir at this high dosage was extremely well tolerated. CONCLUSION: Our results indicate that high-dosage valacyclovir given in pregnancy is effective for improving the outcome of moderately symptomatic infected fetuses. Although this study is not a randomized controlled trial, this is the first study reporting the efficacy of an antiviral drug to treat cytomegalovirus-infected fetuses. Moreover, this first study will allow new trials to be conducted, using valacyclovir as a baseline safe and effective treatment in pregnancy, to be compared to the new emerging and more potent anticytomegalovirus drugs that have not currently been tested in pregnancy.

Are Meteorological Conditions within the First Trimester of Pregnancy Associated with the Risk of Severe Pre-Eclampsia?

BACKGROUND: Severe pre-eclampsia (SPE) is the second cause of maternal death in developed countries. The literature suggests different risk factors for early- and late-onset pre-eclampsia. SPE is usually related to the early-onset type. Pre-eclampsia rate exhibits seasonal variation. However, the weather-SPE association is still unknown. We examined the associations between maternal exposure to meteorological parameters after conception and SPE. METHODS: From 2008 to 2011, all deliveries of women living in the Yvelines area, France, have been prospectively registered. Meteorological measurements from weather stations scattered inside Yvelines were averaged on two exposure windows: early-pregnancy (30 days after conception) and first-trimester (90 days after conception). The relationship between SPE and season of conception was also examined. Hierarchical complementary log-log regression models were used to estimate the weather-SPE association. RESULTS: SPE was diagnosed in 526 (0.8%) out of 63,633 singleton pregnancies. Increasing temperature or sunshine across both windows was associated with increased SPE risk. Early-pregnancy minimum temperature showed the strongest effect with adjusted odds ratio (OR) per 1 degree Celsius: 1.03 [95% confidence interval (CI) 1.01, 1.04]. The risk of SPE was higher when conception was in summer as compared to winter (OR 1.53, 95% CI 1.27, 1.85). Effect estimates showed only small variations in sensitivity analyses. CONCLUSIONS: Our findings of a weather impact during early pregnancy on SPE may provide a new clue for understanding the causes of pre-eclampsia. Further investigation into the biologic mechanisms for this finding is required.

Predictors of the Outcome at 2 Years in Neonates With Congenital Cytomegalovirus Infection.

BACKGROUND: Approximately 20% of neonates with congenital cytomegalovirus (cCMV) develop long-term sequelae. The ability to accurately predict long-term outcomes as early as the neonatal period would help to provide for appropriate parental counseling and treatment indications. With this study, we aimed to identify neonatal predictive markers of cCMV long-term outcomes. METHODS: As this study's subjects, we chose neonates diagnosed with cCMV in 13 hospitals throughout France recruited from 2013 to 2017 and evaluated for at least 2 years with thorough clinical, audiology, and imaging evaluations and psychomotor development tests. RESULTS: A total of 253 neonates were included, and 3 were later excluded because of the identification of a genetic disorder. A total of 227 were followed up for 2 years: 187/227 (82%) and 34/227 (15%) were infected after a maternal primary or nonprimary infection, respectively, 91/227 (40%) were symptomatic at birth, and 44/227 (19%) had cCMV sequelae. Maternal primary infection in the first trimester was the strongest prognosis factor (odds ratio = 38.34 [95% confidence interval, 5.02-293], P < .001). A predictive model of no risk of sequelae at 2 years of age according to normal hearing loss at birth, normal cerebral ultrasound, and normal platelet count had 98% specificity, 69% sensitivity, and 0.89 area under the curve (95% confidence interval, 0.83-0.96). CONCLUSIONS: In the studied population, children with normal hearing at birth, normal platelet count at birth, and a normal cranial ultrasound had no risk of neurologic sequelae and a low risk of delayed unilateral sensorineural hearing loss. The use of this model based on readily available neonatal markers should help clinicians establish a personalized care pathway for each cCMV neonate.

Circulating trophoblastic cells provide genetic diagnosis in 63 fetuses at risk for cystic fibrosis or spinal muscular atrophy.

This study sought to determine whether a reliable non-invasive prenatal diagnosis (NI-PND) of cystic fibrosis (CF) or spinal muscular atrophy (SMA) can be achieved through analysis of circulating fetal trophoblastic cells (CFTC). The kinetics of CFTC circulation were also studied. CFTC were isolated by isolation by size of epithelial tumour/trophoblastic cells at 9-11 weeks of gestation, before chorionic villus sampling (CVS), from the blood of 63 pregnant women at 25% risk for having a child affected by either CF (n=32) or SMA (n=31). Collected cells were laser-microdissected, short tandem repeat-genotyped to determine fetal origin and blindly assessed for mutation analysis. CFTC were independently analysed weekly (4-12 weeks of gestation) in 14 women who achieved pregnancy following IVF. Diagnostic results were compared with those obtained by CVS. All seven CF and seven SMA pregnancies carrying an affected fetus were correctly identified as well as non-affected pregnancies. CFTC provided 100% diagnostic sensitivity (95% CI 76.8-100%) and specificity (95% CI 92.7-100%) in these 63 consecutive pregnancies at risk for CF or SMA. CFTC were found to circulate from 5 weeks of gestation and can be used to develop an early and reliable approach for NI-PND. We sought to determine whether a reliable non-invasive prenatal diagnosis (NI-PND) of two rare genetic diseases - cystic fibrosis (CF) and spinal muscular atrophy (SMA) - can be achieved through analysis of circulating fetal trophoblastic cells (CFTC) in blood of pregnant women. We also studied the time of appearance and circulation of CFTC in maternal blood. CFTC were isolated from maternal blood by isolation by size of epithelial tumour/trophoblastic cells (ISET; an approach for cell isolation from blood) at 9-11 weeks of gestation before chorionic villus sampling (CVS) from the blood of 63 pregnant women at 25% risk for having a child affected by either CF (n=32) or SMA (n=31). Collected cells were analysed by genetic test to determine fetal origin and blindly assessed for mutation analysis. We independently analysed CFTC in maternal blood samples taken weekly (4-12 weeks of gestation) from 14 women who achieved pregnancy following IVF. Diagnostic results were compared with those obtained by CVS. All seven CF and seven SMA pregnancies carrying an affected fetus were correctly identified as well as non-affected pregnancies. CFTC provided 100% diagnostic sensitivity and specificity in these 63 consecutive pregnancies at risk for CF or SMA. CFTC were found to circulate from 5 weeks of gestation and can be used to develop an early and reliable approach for NI-PND.

Immediate versus delayed medical treatment for first-trimester miscarriage: a randomized trial.

OBJECTIVE: To compare immediate vs delayed medical treatment for first-trimester miscarriage. STUDY DESIGN: Randomized open-label trial in a university hospital gynecologic emergency department. Between April 2003 and April 2006, 182 women diagnosed with spontaneous abortion before 14 weeks' gestation were assigned to immediate medical treatment (oral mifepristone, followed 48 hours later by vaginal misoprostol, n = 91) or sequential management (1 week of watchful waiting followed, if necessary, by the above-described medical treatment, n = 91). Vacuum aspiration was performed in case of treatment failure, hemorrhage, pain, infection, or patient request. RESULTS: Compared with immediate medical treatment, sequential management resulted in twice as many vacuum aspirations overall (43.5% vs 19.1%; P < .001), 4 times as many emergent vacuum aspirations (20% vs 4.5%; P = .001), and twice as many unplanned visits to the emergency department (34.1% vs 16.9%; P = .009). CONCLUSION: Delaying medical treatment of first-trimester miscarriage increases the rate of unplanned surgical uterine evacuation.

Timing of delivery following selective laser photocoagulation for twin-to-twin transfusion syndrome.

OBJECTIVE: We sought to compare intrauterine risks with postnatal outcome in monochorionic pregnancies operated by fetoscopic laser surgery for twin-to-twin transfusion syndrome. STUDY DESIGN: A cohort of 602 consecutive cases was analyzed. Unexpected prenatal adverse events were identified when a fatal or potentially fatal event occurred that could have been avoided by timely delivery. RESULTS: The prospective risk of an unexpected adverse event dropped from 16.8% (95% confidence interval [CI], 13.6-20.5%) to 0% (95% CI, 0-11%) between 26-36 weeks. At 32 weeks, the residual risk was 1 in 17 (95% CI, 1/28-1/11). The perinatal rate of death or severe brain lesions dropped from 35% (25-47%) in infants delivered at 26-28 weeks down to 3% (1-6%) at 34-36 weeks. CONCLUSION: Our results did not identify an optimal cut-off for elective preterm delivery in laser-operated twin-to-twin transfusion syndrome. Perinatal morbidity appears low from ≥32 weeks and the decision for elective delivery should be based upon medical history, parental demand, and expert assessment.

Myiasis of the exenterated orbital cavity: Case report and video.

PURPOSE: We present an unusual case of myiasis involving the orbital cavity. OBSERVATIONS: Our patient had undergone orbital exenteration one month prior to presentation. Post-operatively, he presented with multiple, highly mobile larvae in the orbital cavity. The species was identified to be Lucilia sericata, known commonly as the blowfly. The maggots were removed mechanically. CONCLUSION AND IMPORTANCE: The orbital cavity subsequently healed rapidly without sequalae. This raised the question as to whether L. sericata maggots may have had beneficial effects to the healing process.

Performance of Targeted Congenital Cytomegalovirus Screening in Newborns Failing Universal Hearing Screening: A Multicenter Study.

BACKGROUND: Cytomegalovirus (CMV) is the most frequent cause of congenital infection and ≈20% of all infected neonates present or will develop sensorineural hearing loss. Targeted congenital CMV (cCMV) screening in newborns who failed universal newborn hearing screening has been proposed as a strategy to identify neonates with both hearing loss and cCMV infection who could benefit from antiviral treatment implemented within the first month of life. OBJECTIVES: To evaluate the feasibility and performance of cCMV targeted screening in a French setting. METHODS: Neonates were recruited in 5 maternity centers in greater Paris. A saliva sample for CMV polymerase chain reaction (PCR) testing was collected in neonates who failed newborn hearing screening. Outcomes including CMV PCR result and confirmation of hearing loss by an otorhinolaryngologist specialist were documented. RESULTS: Two-hundred thirty-six newborns were included and a saliva sample was collected in 98% (231/236) of them. The result of CMV PCR was available at a median of 9 days (7-10 days) of life and in 96% of cases within the first month of life. Two neonates were infected with CMV. The result of the otorhinolaryngologist assessment was available in 75% (178/236) of cases at a median of 16 days (9-26 days). Hearing loss was confirmed in 2.8% (5/178). The 2 infected neonates had hearing loss confirmed at 5 and 8 days of life and were treated with valganciclovir at days 9 and 16, respectively. CONCLUSIONS: The result of this study confirms that targeted cCMV screening is feasible in these French settings.

Impact of COVID-19-Related Lockdown on Delivery and Perinatal Outcomes: A Retrospective Cohort Study.

OBJECTIVE: The magnitude and direction of effects on pregnancy outcomes of the lockdown imposed during COVID-19 have been uncertain and debated. Therefore, we aimed to quantify delivery and perinatal outcomes during the first nationwide lockdown due to the COVID-19 pandemic compared with the same durations of time for the pre- and post-lockdown periods. STUDY DESIGN: This was a retrospective cohort study of six university hospital maternity units distributed across France, each of which serves as the obstetric care referral unit within its respective perinatal network. Maternal and perinatal outcomes were compared between the lockdown period and same-duration (i.e., 55-day) periods before and after the 2020 lockdown (pre-lockdown: 22 January-16 March; lockdown: 17 March-10 May; post-lockdown: 11 May-4 July). We compared the overall rates of Caesarean delivery (CD), pre-labor CD, labor induction, operative vaginal delivery, severe postpartum hemorrhage (≥1 L), severe perineal tear, maternal transfusion, and neonatal mortality and morbidity (1- and 5-min Apgar scores < 7), hypoxia and anoxia (umbilical arterial pH < 7.20 or <7.10, respectively), and admission to a neonatal intensive care unit before discharge. Adjusted odds ratios were estimated using logistic regression, controlling for region of birth, maternal age category, multiparity, multiple pregnancies, diabetes, and hypertensive disorders. RESULTS: The study sample consisted of 11,929 women who delivered consecutively at one of the six maternity units studied (4093 pre-lockdown, 3829 during lockdown, and 4007 post-lockdown) and their 12,179 neonates (4169 pre-lockdown, 3905 during lockdown, and 4105 post-lockdown). The maternal and obstetric characteristics of the women delivering during the lockdown period were alike those delivering pre- and post-lockdown on maternal age, parity, body mass index, rate of complication by hypertensive disorders or insulin-treated diabetes, and gestational age at delivery. Overall CD rates were similar during the three periods (23.6%, 24.8%, and 24.3% pre-lockdown, lockdown, and post-lockdown, respectively) and no outcome differed significantly during lockdown compared to pre- and post-lockdown. These findings were consistent across maternity units. CONCLUSION: The maternal and perinatal outcomes are reassuring regarding the performance of the health-care system during the COVID-19 lockdown studied. Such information is crucial, because additional COVID-19-related lockdowns might still be needed. They are also instructive regarding potential future pandemics.

MRI based morphological examination of the placenta.

Ultrasound is widely used as the initial diagnostic imaging modality during pregnancy with both high spatial and temporal resolution. Although MRI in pregnancy has long focused on the fetus, its use in placental imaging has greatly increased over recent years. In addition to the possibilities of evaluating function, MRI with a wide field of view and high contrast resolution allows characterization of placental anatomy, particularly in situations that are difficult to specify with ultrasound, especially for suspected placenta accreta. MRI also appears to be a particularly useful examination for the anatomical evaluation of the placenta independent of maternal body habitus or fetal position. Indeed, surprisingly little attention is paid to the placenta in MRI when the indication for the examination is fetal. Thus, some aspects of the placenta seem to us to be important to be recognized by the radiologist and to be described on the MRI report. In this review, we will describe MRI sequences used for, and common features seen in, imaging of i) the normal placenta, ii) abnormal aspects of the placenta that should be identified on MRI performed for fetal reason, and iii) placental anomalies for which placental MRI may be indicated.

Impact of COVID-19 Lockdown on Preterm Births, Low Birthweights and Stillbirths: A Retrospective Cohort Study.

OBJECTIVE: The effect of lockdowns during the coronavirus (COVID-19) pandemic on pregnancy outcomes remains uncertain. We aimed to evaluate the association between the COVID-19-related lockdown and pregnancy outcomes in maternity hospitals in France. STUDY DESIGN: This was a retrospective cohort study from six tertiary referral hospitals in different regions of France. Three 55-day periods were compared: pre-lockdown from 22 January 2020, lockdown from 17 March 2020, and post-lockdown from 11 May 2020 to 4 July 2020. We included all women who delivered singleton or multiple pregnancies, who delivered at ≥24 weeks of gestation and with birthweights ≥500 g. We documented gestational ages at the delivery of liveborn and stillborn infants ('stillbirths'). These were categorized as having a very low birthweight (VLBW, <1500 g), or a low birthweight (LBW, <2500 g). Adjustments were made for place of birth, maternal age, parity and diabetes, and hypertensive disorders, as well as for multiple pregnancies. RESULTS: In total, 11,929 women delivered in the six selected centers. This figure is constituted of 4093, 3829, and 4007 deliveries in the pre-lockdown (1), peri-lockdown (2), and post-lockdown (3) periods, respectively. There were no differences in pregnancy outcomes between these three periods. Overall, birth rates <27+6 weeks, between weeks 28+0 and 31+6, and between 32+0 and weeks 36+6 were 1.0%, 1.9%, and 4.4%, respectively. After adjustment, these rates were stable between periods 1 and 2 (adjusted odds ratio, aOR 0.90; 95% confidence interval, CI 0.69-1.19) and between periods 2 and 3 (aOR 1.04; 95% CI 0.80-1.36). Although more VLBW neonates were born during lockdown (3.5% vs. 2.6%, p = 0.03), this difference did not persist after adjustment (aOR 0.84, CI 95% 0.64-1.10). The LBW rates were similar during the three periods at 12.5% overall. The stillbirth rate was unaffected by the lockdown. CONCLUSION: The pregnancy outcomes (preterm birth, LBW, VLBW, and stillbirth rates) were not modified by the COVID-19 lockdown in our cohort study in France. Considering the discrepancies in results and methodological issues in previous published studies, there is not sufficient evidence to conclude that such lockdowns have any impact on perinatal outcomes.