Arabin pessary to prevent adverse perinatal outcomes in twin pregnancies with a short cervix: a multicenter randomized controlled trial (PESSARONE).

BACKGROUND: The number of twin pregnancies continues to increase worldwide as both the number of pregnancies obtained by medically assisted reproduction and age at first pregnancy keep rising. Preterm delivery is the major complication associated with twin pregnancies. The effectiveness of preventive treatments such as progesterone or cervical cerclage for women with a short cervix is doubtful in twin pregnancies. The effectivity of cervical pessaries in preventing preterm birth and its associated morbidity and mortality is also controversial. OBJECTIVE: We sought to investigate if the Arabin pessary reduces adverse neonatal outcomes in twin pregnancies with a short cervix. STUDY DESIGN: This open-label, multicenter, randomized controlled trial on twin pregnancies with a cervical length of <35 mm compared pessary placement at 16+0 to 24+0 weeks' gestation with standard care alone. The primary endpoint was a composite of adverse neonatal outcomes, namely peripartum or neonatal death or significant neonatal morbidity before hospital discharge, defined as at least 1 of the following complications: bronchopulmonary dysplasia, intraventricular hemorrhage grade III to IV, periventricular leukomalacia, necrotizing enterocolitis grade II or higher, culture-proven sepsis, and retinopathy requiring treatment. A sample size of 308 pregnancies was planned to ensure 80% power to compare the proportions of women with at least 1 infant with an adverse neonatal outcome. The intention-to-treat analysis after multiple imputation of missing data, was supplemented with a secondary analysis that controlled for gestational age and cervical length, both at inclusion. The primary endpoint was also compared between randomization groups in the per-protocol population, which excluded patients with prespecified major protocol violations (mostly cervical cerclage and/or progesterone after inclusion). Secondary endpoints included preterm birth, spontaneous preterm birth, and pessary side effects. RESULTS: In total, 315 women were randomized to either receive a pessary (n=157) or standard management (n=158). Overall, 10.8% (34 women) of participants had a missing value for the primary endpoint, mostly (79%) because of the lack of paternal consent for neonatal data collection. In the intention-to-treat analysis, the adverse neonatal outcome occurred in 16.8% of the pessary group vs in 22.5% of the control group (risk ratio, 0.69; 95% confidence interval, 0.39-1.23; P=.210). The per-protocol analysis did not show any significant difference between groups (risk ratio, 0.78; 95% confidence interval, 0.47-1.28; P=.320). The occurrence of preterm birth or spontaneous preterm birth did not differ significantly between groups. No serious side effects were associated with pessary use. CONCLUSION: Pessary use in our study did not significantly reduce adverse neonatal outcomes in twin pregnancies with a short cervix.

Should prenatal chromosomal microarray analysis be offered for isolated fetal growth restriction? A French multicenter study.

BACKGROUND: Compared with standard karyotype, chromosomal microarray analysis improves the detection of genetic anomalies and is thus recommended in many prenatal indications. However, evidence is still lacking on the clinical utility of chromosomal microarray analysis in cases of isolated fetal growth restriction. OBJECTIVE: This study aimed to estimate the proportion of copy number variants detected by chromosomal microarray analysis and the incremental yield of chromosomal microarray analysis compared with karyotype in the detection of genetic abnormalities in fetuses with isolated fetal growth restriction. STUDY DESIGN: This retrospective study included all singleton fetuses diagnosed with fetal growth restriction and no structural ultrasound anomalies and referred to 13 French fetal medicine centers over 1 year in 2016. Fetal growth restriction was defined as an estimated fetal weight of

Exome sequencing identifies the first genetic determinants of sirenomelia in humans.

Sirenomelia is a rare severe malformation sequence of unknown cause characterized by fused legs and severe visceral abnormalities. We present a series of nine families including two rare familial aggregations of sirenomelia investigated by a trio-based exome sequencing strategy. This approach identified CDX2 variants in the two familial aggregations, both fitting an autosomal dominant pattern of inheritance with variable expressivity. CDX2 is a major regulator of caudal development in vertebrate and mouse heterozygotes are a previously described model of sirenomelia. Remarkably, the p.(Arg237His) variant has already been reported in a patient with persistent cloaca. Analysis of the sporadic cases revealed six additional candidate variants including a de novo frameshift variant in the genetically constrained NKD1 gene, encoding a known interactor of CDX2. We provide the first insights for a genetic contribution in human sirenomelia and highlight the role of Cdx and Wnt signaling pathways in the development of this disorder.

Ultrasound features of fetal toxoplasmosis: A contemporary multicenter survey in 88 fetuses.

OBJECTIVE: To describe the lesions detected by prenatal ultrasound examination in congenital toxoplasmosis (CT). METHODS: We retrospectively analyzed all cases of fetal infection with Toxoplasma gondii with ultrasound anomalies described by fetal medicine experts in 2009 to 2019 in 30 French centers. RESULTS: Eighty-eight cases of CT were included. Forty-five (51.1%) had one or more cerebral signs only, 35 (39.8%) had cerebral plus extracerebral signs and 8 (9.1%) had extracerebral signs only. The main cerebral signs were intracranial hyperechogenic nodular foci (n = 60) of which 20 were isolated, ventriculomegalies (n = 44) which generally increased during follow-up, and periventricular abscesses (n = 12). The main extracerebral signs were hepatomegaly and/or splenomegaly (n = 14), small for gestational age (n = 14), ascites (n = 14, including 2 with hydrops), and hyperechogenic bowel (n = 11). Maternal infection occurred mostly in the first or second trimester (81 cases), periconceptionally in one and in the third trimester in six cases. The first ultrasound signs were detected after a median of 7 weeks (range: 1.4; 24.0) following maternal toxoplasmosis seroconversion. CONCLUSION: While no sign was specific of CT, there were typical associations of cerebral signs with or without extracerebral signs. Detailed ultrasound examination could improve prognostic evaluation, as well as diagnosis of CT in settings lacking serological screening.

Is laterality of congenital diaphragmatic hernia a reliable prognostic factor? French national cohort study.

OBJECTIVES: The objective of this study was to assess whether the laterality of congenital diaphragmatic hernia (CDH) was a prognostic factor for neonatal survival. METHODS: This was a cohort study using the French national database of the Reference Center for Diaphragmatic Hernias. The principal endpoint was survival after hospitalization in intensive care. We made a comparative study between right CDH and left CDH by univariate and multivariate analysis. Terminations and stillbirths were excluded from analyses of neonatal outcomes. RESULTS: A total of 506 CDH were included with 67 (13%) right CDH and 439 left CDH (87%). Rate of survival was 49% for right CDH and 74% for left CDH (P < .01). Multivariate analysis showed two factors significantly associated with mortality: thoracic herniation of liver (OR 2.27; IC 95% [1.07-4.76]; P = .03) and lung-to-head-ratio over under expected (OR 2.99; IC 95% [1.41-6.36]; P < .01). Side of CDH was not significantly associated with mortality (OR 1.87; IC 95% [0.61-5.51], P = .26). CONCLUSION: Rate of right CDH mortality is more important than left CDH. Nevertheless after adjusting for lung-to-head-ratio and thoracic herniation of liver, right CDH does not have a higher risk of mortality than left CDH.

[Characteristics and challenges of the antenatal diagnosis]. / Caractéristiques et enjeux du diagnostic anténatal.

The period of antenatal diagnostic testing is fraught with emotions for the parents. Screening ultrasound scans often constitute the indication of an antenatal diagnostic consultation in a multidisciplinary centre. There then follows a period of diagnosis, prognosis and decisions. Parents must be given specific support throughout this time.

A case of prenatally diagnosed limited dorsal myeloschisis with good prognosis.

Diagnosis of fetal spinal dysraphism is a challenge. It is difficult to distinguish between a meningocele, myelomeningocele, and a recently described entity called limited dorsal myeloschisis (LDM). Although myelomeningocele is associated with a poor prognosis, LDM can have a good outcome. We present a case of prenatally diagnosed LDM. Because sonographic examination revealed a round, cystic, septated cervical mass without associated cerebral anomalies, the lesion was initially considered an isolated meningocele. Fetal MRI contributed to correct the diagnosis. A diagnostic error can lead to the wrong surgical support or even the termination of pregnancy. Therefore, we highlight the importance of fetal MRI in such cases, particularly when no cerebral abnormalities are observed on sonographic examination.

Pseudoamniotic Band Syndrome After Fetoscopic Laser Ablation of Placental Anastomoses for Twin-Twin Transfusion Syndrome: Two Case Reports and Systematic Review.

Pseudoamniotic band syndrome is a rare complication that occurs after invasive procedures for complicated monochorionic twins. We report 2 cases of intrauterine recipient fetal death after laser therapy for twin-twin transfusion syndrome due to umbilical cord constriction by the amniotic band.

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.

Prenatal diagnosis of clubfoot: Chromosomal abnormalities associated with fetal defects and outcome in a tertiary center.

PURPOSE: Our aim was to evaluate the rate of occurrence of chromosomal abnormalities, associated findings, and outcome in a series of cases of prenatally diagnosed clubfoot. METHODS: We conducted a retrospective study of all cases of clubfoot diagnosed prenatally in the ultrasound unit of a French tertiary center from January 2004 through December 2011. Clubfoot was scored as complex or isolated depending on the presence or absence of another structural abnormality observed on sonographic examination. RESULTS: Data from 90 fetuses prenatally diagnosed with clubfoot were included in this study. Thirty-four cases were considered complex (38%) and 56 were considered isolated (62%). A chromosomal abnormality was identified in 10 of 33 of the fetuses with complex clubfoot and in 1 of 45 of those with isolated clubfoot (p < 0.001). Clubfoot was associated with a poor outcome in 5 of 52 cases of isolated clubfoot and in 31 of 34 cases associated with other structural defects (p < 0.001). The deformity was bilateral in 62 cases (69%) and unilateral in 28 (31%). No statistically significantly higher rate of poor outcome was identified when the deformity occurred bilaterally nor was a significantly higher rate of chromosomal abnormality noted in this condition. CONCLUSIONS: Aneuploidy and adverse pregnancy outcomes occur more commonly in prenatally diagnosed cases of complex clubfoot than in those of isolated clubfoot. Fetal karyotyping is required in cases of complex clubfoot, but the need for that procedure in isolated clubfoot remains controversial.

Impact of prolonged dinoprostone cervical ripening on the rate of artificial induction of labor: a prospective study of 330 patients.

AIM: The aim of this study was to evaluate two regimens of administration of sustained-release dinoprostone on the need for oxytocin induction of labor. MATERIAL AND METHODS: We carried out an open prospective study comparing labor, maternal and neonatal outcomes after 12 h of prostaglandin cervical ripening insert versus 24 h of prostaglandin cervical ripening insert in 284 patients (142 ripenings at 12 h [P12 group] and 142 ripenings at 24 h [P24 group]). RESULTS: The two groups were demographically similar. There was a significant difference in the need for artificial rupture of membranes/oxytocin induction of labor between the groups (49.3% for the P12 group vs 38% for the P24 group, P = 0.03). The delay between the beginning of ripening and delivery was significantly decreased in the P12 group, but the duration of active labor (6.6 h), the dose of oxytocics used (1326 UI), the rate of cesarean section, the rate of uterine hyperstimulation, the rates of hemorrhaging from delivery, the neonatal state and the experience of induction were similar in the two groups. CONCLUSION: This study allows us to show for the first time that sustained-release of dinoprostone leads to spontaneous induction of labor without increasing the obstetrical risk in a majority of patients.

Pai syndrome: challenging prenatal diagnosis and management.

Pai syndrome is a rare disorder that includes midline cleft lip, pericallosal lipoma and cutaneous polyp of the face. We report a case of prenatal diagnosis using sonography and MRI. We emphasize the importance of facial examination with prenatal association of midline cleft lip and pericallosal lipoma in making the diagnosis of Pai syndrome.

Management of pregnancies with confirmed cytomegalovirus fetal infection.

Systematic screening for cytomegalovirus (CMV) maternal infection is not recommended in most countries. Nevertheless, primary CMV infection will occur in around 1% of women. The vertical transmission rate is estimated to be around 30-50%. Newborns with congenital CMV infection remain asymptomatic in the majority of cases and around 10% will present with a wide range of abnormalities. Fetal infection can be diagnosed by amniocentesis with amplification of the viral genome in the amniotic fluid by polymerase chain reaction. This prenatal diagnosis is mainly performed when ultrasound abnormalities are observed. The purpose of this mini-review is to describe the management options when a fetus is known to be infected.

Array CGH analysis in high-risk pregnancies: comparing DNA from cultured cells and cell-free fetal DNA.

OBJECTIVE: To compare results of array comparative genomic hybridization (CGH) on cell-free fetal (cff) DNA from amniotic fluid supernatant and DNA from cultured amniocytes in high-risk pregnancies. METHOD: We selected 48 cases of high-risk pregnancies (in utero growth retardation [IUGR] and/or at least two fetal malformations [polymalformation]). Bacterial artificial chromosome array CGH (BlueGnome) was performed on 38 fetal samples (frozen cff DNA and DNA from cultured cells) with previously normal karyotypes. RESULTS: From the 38 specimens, we obtained an adequate amount of sufficient quality DNA with a better quality profile using cff DNA compared to cellular DNA. Aberrations of clinical relevance were detected in three fetuses, and copy number variations considered as benign polymorphism were detected in one case using both sources of DNA. This results in an 8% detection rate of significant abnormalities in high-risk pregnancies with a normal karyotype using array CGH (two cases with IUGR, one with polymalformation). CONCLUSION: These findings indicate the possibility of using cff DNA from amniotic fluid supernatant for array CGH with excellent results, even in late pregnancy when culture is no longer available. In this small series, pathogenic copy number variations are detected more often in the presence of IUGR than with polymalformation.

Obstetrical situations with a high risk of anal sphincter laceration in vacuum-assisted deliveries.

OBJECTIVE: To determine risk factors for anal sphincter laceration and define situations with a high risk for such trauma in vacuum-assisted deliveries. DESIGN: Retrospective observational study of 1961 vacuum-assisted deliveries over a period of 5 years. SETTING: French university hospital. POPULATION: All women who delivered with vacuum assistance. METHODS: Third- and fourth-degree perineal tears were reviewed. The factors studied through univariate and multivariate logistic regression were the mother's age, parity, history of assisted delivery, cesarean section, gestational age, uterine fundal height, duration of the second stage of labor, head position at expulsion, epidural anesthesia, episiotomy, biparietal diameter and birthweight. MAIN OUTCOME MEASURES: Third- and fourth-degree perineal tears. RESULTS: There were 1.9% third-degree and no fourth-degree perineal tears. Risk factors identified were occipito-posterior position (odds ratio 4.7, p < 0.001), biparietal diameter (odds ratio 2.0 for each 5 mm increase, p= 0.004), duration of second stage (only significant when parity was ≥ 1; odds ratio 1.3 for each 10 min increase, p= 0.004) and nulliparity (decreasing effect according to duration of the second stage). The patterns of the association between these factors and the risk of perineal tears were different for nulli- and multiparous women. CONCLUSIONS: In a targeted population of women having vacuum-assisted deliveries, the association of specific risk factors allows clinicians to identify women who are at high risk of anal sphincter laceration.

Toxoplasmosis screening during pregnancy in France: Opinion of an expert panel for the CNGOF.

Prenatal screening to prevent congenital toxoplasmosis as performed in France for several decades has been questioned in view of the decreasing incidence of this infection and the cost of testing. The French College of Obstetrics and Gynecology mandated a multidisciplinary panel of experts to perform a reassessment of the screening program in accordance with international good practice. In France, about 70% of pregnant women are not immune to T. gondii, and 0.2-0.25% become infected during pregnancy. The risk of maternal-fetal transmission of infection is on average 25-29% and depends greatly on the gestational age at seroconversion. In case of fetal transmission, the outcome is livebirth in 95% of cases, with latent congenital toxoplasmosis in 90% of cases and symptomatic forms in 10% of cases, of which 1/3 are severe and 2/3 moderate. Biological techniques have satisfactory performance regarding serologies for the diagnosis of maternal infections and PCR on amniotic fluid for the prenatal diagnosis of congenital toxoplasmosis. Primary prevention of toxoplasmosis is based on hygiene measures that are relatively simple, but poorly implemented. In case of maternal seroconversion, there is a strong case for prenatal prophylactic treatment as soon as possible (ideally within 3 weeks of seroconversion), spiramycin before 14 weeks of gestation (WG), and with a tendency to superiority of the pyrimethamine/sulfadiazine association over spiramycin beyond 14 W G, in order to reduce the risk of symptomatic congenital toxoplasmosis. In case of congenital toxoplasmosis, prompt initiation of treatment reduces the occurrence of cerebral signs and symptoms, as well as retinal lesions. Several medico-economic evaluations of the French toxoplasmosis screening program have been conducted including an individual cost-effectiveness approach with decision analysis which concluded on the profitability of prenatal screening as carried out in France (monthly surveillance of seronegative women, prenatal treatment in case of seroconversion, termination of pregnancy in severe forms). Though most international societies do not recommend systematic screening for mainly financial reasons, if congenital toxoplasmosis appears benign in France today, it is probably thanks to screening and the possibility of early treatment of fetuses and/or newborns. Thus, the panel recommends continuing for now the program in France for prevention of congenital toxoplasmosis.

Guidelines on CMV congenital infection.

Congenital cytomegalovirus (CMV) infection occurs in 0.6-0.7% of all newborns and is the most prevalent infection-related cause of congenital neurological handicap. Vertical transmission occurs in around 30% of cases, but the fetus is not always affected. Symptomatic newborns at birth have a much higher risk of suffering severe neurological sequelae. Detection of specific IgG and IgM and IgG avidity seem to be the most reliable tests to identify a primary infection but interpretation in a clinical context may be difficult. If a seroconversion is documented or a fetal infection is suspected by ultrasound markers, an amniocentesis should be performed to confirm a vertical transmission. In the absence of a confirmed fetal infection with fetal structural anomalies, a pregnancy termination should be discouraged. Fetal prognosis is mainly correlated to the presence of brain damage. Despite promising results with the use of antiviral drugs and CMV hyperimmune globulin (HIG), results have to be interpreted with caution. Pregnant women should not be systematically tested for CMV during pregnancy. Managing CMV screening should be restricted to pregnancies where a primary infection is suspected or among women at high risk. The magnitude of congenital CMV disease and the value of interventions to prevent its transmission or to decrease the sequelae need to be established before implementing public health interventions. In this paper, aspects of CMV infection in the pregnant woman and her infant are reviewed.

A case-control study about foetal trauma during caesarean delivery.

OBJECTIVE: The caesarean section rate is gradually increasing in most countries. The frequency of occurrence of foetal injury per birth is estimated to 1%. The majority of these injuries presents a low functional impact, but remains responsible for a significant neonatal morbidity. Even though the foetal risk factors are well documented in cases of vaginal birth, they have not been accurately identified for caesarean section. The aim of this study is to identify the risk factors for neonatal fracture during caesarean section. METHODS: We conducted a retrospective case-control study comparing complicated caesarean sections foetal fracture with uncomplicated caesarean sections in a tertiary teaching hospital. We collected all the caesarean sections carried out between 1st January 2003 and 1st September 2015 and selected those the medical files of which presented a foetal fracture diagnosis. RESULTS: We identified 10 fractures during the study period, including four skull fractures, three long bone fractures, three clavicle fractures. In all these cases there were no complications with a median perspective of six years (median=6, IQR=4). The push method, which is performed during a caesarean section at the second stage of labour, is identified as a risk factor for foetal trauma in our study (OR: 20.2 [2.8-116.85], p<0.01). A significant correlation was found between transverse lie and foetal trauma (OR: 16.67, CI [1.39; 123.18], p=0.0137). CONCLUSION: Foetal trauma during caesarean delivery is a rare event for which the prognosis is most often favourable. Data in the literature on the subject are minimal. This study highlighted transverse lie and the push method as risks factors for foetal fractures during caesarean sections. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Maternal-fetal transmission and adverse perinatal outcomes in pregnant women infected with Zika virus: prospective cohort study in French Guiana.

OBJECTIVES: To estimate the rates of maternal-fetal transmission of Zika virus, adverse fetal/neonatal outcomes, and subsequent rates of asymptomatic/symptomatic congenital Zika virus infections up to the first week of life. DESIGN: Cohort study with prospective data collection and subsequent review of fetal/neonatal outcomes. SETTINGS: Referral centre for prenatal diagnosis of the French Guiana Western Hospital. PARTICIPANTS: Pregnant women at any stage of pregnancy with a laboratory confirmed symptomatic or asymptomatic Zika virus infection during the epidemic period in western French Guiana. The cohort enrolled 300 participants and prospectively followed their 305 fetuses/newborns. MAIN OUTCOME MEASURES: Rate of maternal-fetal transmission of Zika virus (amniotic fluid, fetal and neonatal blood, urine, cerebrospinal fluid, and placentas); clinical, biological, and radiological outcomes (blindly reviewed); and adverse outcomes defined as moderate signs potentially related to congenital Zika syndrome (CZS), severe complications compatible with CZS, or fetal loss. Associations between a laboratory confirmed congenital Zika virus infection and adverse fetal/neonatal outcomes were evaluated. RESULTS: Maternal-fetal transmission was documented in 26% (76/291) of fetuses/newborns with complete data. Among the Zika virus positive fetuses/newborns, 45% (34/76) presented with no signs/complications at birth, 20% (15/76) with moderate signs potentially related to CZS, 21% (16/76) with severe complications compatible with CZS, and 14% (11/76) with fetal loss. Compared with the Zika virus positive fetuses/neonates, those that were identified as negative for Zika virus (215/291) were less likely to present with severe complications (5%; 10/215) or fetal loss (0.5%; 1/215; relative risk 6.9, 95% confidence interval 3.6 to 13.3). Association between a positive Zika virus test and any adverse fetal/neonatal outcome was also significant (relative risk 4.4, 2.9 to 6.6). The population attributable fraction estimates that a confirmed congenital Zika virus infection contributes to 47% of adverse outcomes and 61% of severe adverse outcomes observed. CONCLUSION: In cases of a known maternal Zika virus infection, approximately a quarter of fetuses will become congenitally infected, of which a third will have severe complications at birth or fetal loss. The burden of CZS might be lower than initially described in South America and may not differ from other congenital infections.