Association between Human Papillomavirus 16 Viral Load in Pregnancy and Preterm Birth.

Recent evidence shows increased preterm birth risk with human papillomavirus-16 (HPV16) infection during pregnancy. This study aimed to measure the association between HPV16 viral load during pregnancy and preterm birth. We used data from participants in the HERITAGE study. The Linear Array assay was used for HPV DNA testing on vaginal samples collected during the first and third trimesters of pregnancy. The HPV16 viral load was measured with a real-time polymerase chain reaction. We used logistic regression to measure the associations between HPV16 viral load during pregnancy and preterm birth (defined as birth before 37 weeks of gestation). The adjusted odd ratios (aORs) and the 95% confidence intervals [CIs] were estimated with inverse probability treatment weighting of the propensity score. This study included 48 participants who tested positive for HPV16 during the first trimester of pregnancy. The aOR for the association between first-trimester HPV16 viral load (higher viral load categorized with a cutoff of 0.5 copy/cell) was 13.04 [95% CI: 1.58-107.57]). Similar associations were found using different cutoffs for the categorization of viral load during the first and third trimesters. Our findings suggest a strong association between a high HPV16 viral load during pregnancy and preterm birth, demonstrating a biological gradient that reinforces the biological plausibility of a causal association.

Association between the Mode of Delivery and Vertical Transmission of Human Papillomavirus.

Human papillomavirus (HPV) can be vertically transmitted. Our objective was to measure the association between the mode of delivery and the detection of HPV in infants. We used data collected from pregnant women during the HERITAGE study. Self-collected vaginal samples from the first and third trimester were obtained for HPV testing. Specimens from oral, pharyngeal, conjunctival and anogenital mucosa were collected from infants 36-48 h after delivery and at 3 months of age. All samples were tested for HPV DNA by the Linear Array assay. Adjusted odd ratios (aOR) and 95% confidence interval (CI) were estimated using multivariate logistic regressions. From the 282 women revealed to be HPV-positive in both the first and third trimesters, 25 infants were born HPV-positive. The overall probability of transmission was 8.9% (25/282); 3.7% (3/81) in participants with a caesarean section and 10.9% (22/201) for those who delivered vaginally. Vaginal delivery increased the risk of HPV in infants compared to caesarean (aOR: 3.63, 95%CI: 1.03-12.82). Infants born after a caesarean with ruptured membranes were not at increased risk of HPV compared to infants born after an elective caesarean section with intact membranes (aOR: 1.31, 95%CI: 0.10-17.76). Our results support the hypothesis that transmission occurs mostly during the passage in the vaginal canal.

Human Papillomavirus Transmission and Persistence in Pregnant Women and Neonates.

Importance: The prevalence of human papillomavirus (HPV) infection during pregnancy and its risk of transmission to newborns are not well documented. Objective: To ascertain the prevalence of HPV in pregnant women, the risk of HPV detection in the placenta and in children at birth, and the probability that HPV detected at birth may persist in newborns. Design, Setting, and Participants: The Human Papillomavirus Perinatal Transmission and Risk of HPV Persistence Among Children (HERITAGE) study was a prospective cohort study that recruited participants between November 8, 2010, and October 16, 2016. Participant follow-up visits were completed on June 15, 2017. Participants, which included pregnant women of at least 18 years of age and at 14 weeks or earlier of gestation, were recruited from 3 academic hospitals in Montreal, Québec, Canada. Laboratory and statistical analysis were completed on November 15, 2022. Exposures: HPV DNA testing on self-collected vaginal and placental samples. Among children of mothers positive for HPV, conjunctival, oral, pharyngeal, and genital samples were collected for HPV DNA testing. Main Outcomes and Measures: Vaginal HPV DNA testing was done on self-collected vaginal samples obtained among pregnant women recruited during their first trimester of pregnancy and in the third trimester for those who had HPV-positive samples in the first trimester. HPV DNA testing was also done on placental samples (swabs and biopsies) collected after birth in all participants. HPV DNA testing among children included conjunctival, oral, pharyngeal, and genital samples collected in children of HPV-positive mothers at birth, 3 months, and 6 months of age. Results: A total of 1050 pregnant women (mean [SD] age, 31.3 [4.7] years) were included in this study. Prevalence of HPV in pregnant women at recruitment was 40.3% (95% CI, 37.3%-43.3%). Among the 422 HPV-positive women, 280 (66.4%) harbored at least 1 high-risk genotype, and 190 (45.0%) were coinfected with multiple genotypes. HPV was detected in 10.7% of placentas (92 of 860; 95% CI, 8.8%-12.9%) overall, but only 3.9% of biopsies (14 of 361) on the fetal side under the amniotic membrane were positive. Neonatal HPV detection (at birth and/or at 3 months) was 7.2% (95% CI, 5.0%-10.3%) overall, with the most frequent site of infection being the conjunctiva (3.2%; 95% CI, 1.8%-5.6%), followed by the mouth (2.9%; 95% CI, 1.6%-5.2%), the genital area (2.7%; 95% CI, 1.4%-4.9%), and the pharynx (0.8%; 95% CI, 0.2%-2.5%). Importantly, all HPV detected in children at birth cleared before the age of 6 months. Conclusions and relevance: In this cohort study, vaginal HPV was frequently detected in pregnant women. Perinatal transmission was infrequent, and in this cohort, no infection detected at birth persisted at 6 months. Although HPV was detected in placentas, it remains difficult to differentiate contamination vs true infection.

First-trimester screening for Down syndrome using quadruple maternal biochemical markers.

OBJECTIVES: Placental growth factor (PlGF) is used for first-trimester preeclampsia screening and could be combined with other biochemical markers for Down syndrome screening. We aim to estimate the predictive value of the combination of pregnancy-associated plasma protein (PAPP-A), free ß-human chorionic gonadotropin (free ß-hCG), placental growth factor (PlGF) and α-fetoprotein (AFP) with and without nuchal translucency. METHODS: Singleton pregnancies recruited at 11-14 weeks and followed until delivery. The four maternal markers were measured using Kryptor (ThermoFisher-BRAHMS) and adjusted for gestational age and maternal characteristics. The risk of Down syndrome was calculated using the Fetal Medicine Foundation algorithm and multivariate linear regression analyses in all cases and in 2,200 controls. Receiver-operator characteristic (ROC) curves were used to calculate the detection and false-positive rates. RESULTS: Twenty-six (0.2%) cases of Down syndrome were diagnosed among 13,386 participants. The combination of the four biomarkers could have detected 88% (95% CI: 72-97%) of the cases at a false-positive rate of 13% (95% CI: 12-15%). The addition of nuchal translucency would have increased the detection rate to 96% (95% CI: 82-99%) at a false-positive rate of 4% (95% CI: 4-5%) using a 1:300 cut-off and to 100% (95% CI: 89-100%) at a false-positive rate of 6% (95% CI: 5-8%) using a 1:500 cut-off. CONCLUSIONS: First-trimester screening using biochemical markers allows the identification of approximately 88% of Down syndrome cases for a false-positive rate of 13%. The addition of nuchal translucency raises the detection rate above 95% with a false-positive rate below 5%.

Impact of Selective Fetal Growth Restriction on Laser Therapy Outcomes in Twin-Twin Transfusion Syndrome.

INTRODUCTION: The aim of this study was to determine if outcomes of fetoscopic laser photocoagulation in isolated twin-twin transfusion syndrome (TTTS) differ from TTTS with concomitant selective fetal growth restriction (sFGR). METHODS: This is a retrospective cohort study of all cases of TTTS treated at the CHU Sainte-Justine between February 2006 and January 2020. Data were collected from maternal, obstetrical, and neonatal chart review. RESULTS: A total of 149 patients were included in our study. Forty-seven patients (31.5%) had a pregnancy complicated by TTTS and sFGR. Mean gestational age at diagnosis and at treatment was 20+4 weeks and 20+6 weeks for TTTS alone, and 20+5 weeks and 21+2 weeks with concomitant sFGR. The presence of concomitant sFGR negatively impacted survival. Double survival in the TTTS + sFGR was 48.9% (23/47) versus 68.6% (70/102) in the TTTS-only group (p = 0.021). Fetal donor survival was 59.6% (28/47) in the TTTS + sFGR group and 84.3% (86/102) in the TTTS-only group (p = 0.001). However, the survival of at least one twin did not differ between the two groups: 93.6% (44/47) in the TTTS + sFGR group versus 92.2% (94/102) in the TTTS-only group (p = 0.751). The presence of type 2-3 sFGR (OR = 0.56; 95% CI 0.32-0.96, p = 0.033) and gestational age at laser therapy (OR = 1.17; 95% CI 1.01 = 1.36, p = 0.036) were independently associated with dual survival. CONCLUSION: sFGR is independently associated with decreased double survivorship at the expense of the donor in TTTS undergoing laser therapy. Type 2 or 3 sFGR and early gestational age at treatment are especially at risk. A larger cohort is needed to validate our results.

Risk factors for placental human papillomavirus infection.

OBJECTIVE: Human papillomavirus (HPV) has been associated with adverse pregnancy outcomes but placental HPV infection has been rarely studied. The objective was to determine the proportion of HPV-positive placentas and the associated risk factors among HPV-positive women during pregnancy. METHODS: We analysed data from pregnant women enrolled in HERITAGE cohort study between 2010 and 2016 with positive vaginal HPV infection during the first trimester of pregnancy (n=354). Placental swabs and biopsies were collected. HPV genotyping was performed using Linear Array. The predictors of placental HPV detection were identified by generalised estimating equations models. RESULTS: HPV was detected in 78 placentas (22.0%) (one among 96 caesarean sections and 77 among 258 vaginal deliveries). Overall, 91% of HPV-positive placentas were positive for a genotype that was detected in vaginal samples during pregnancy. Among women who delivered vaginally, abnormal cytology (adjusted OR (aOR) 1.78 (95% CI 1.02 to 3.10)), other genitourinary infection (aOR 2.41 (95% CI 1.31 to 4.44)), presence of multiple HPV genotypes in the first trimester (aOR 2.69 (95% CI 1.76 to 4.12)) and persistence of high-risk HPV infections during pregnancy (HPV-16/18: aOR 3.94 (95% CI 2.06 to 7.55) and other than HPV-16/18: aOR 2.06 (95% CI 1.05 to 4.02)) were independently associated with placental HPV. CONCLUSIONS: HPV was frequently detected in the placenta of women who delivered vaginally and may be associated with host immune response characteristics.

Association Between Human Papillomavirus Infection Among Pregnant Women and Preterm Birth.

Importance: Preterm birth remains a leading cause of perinatal mortality and lifelong morbidity worldwide. The cause of most preterm births is unknown, although several infectious processes have been implicated. Objective: To assess whether human papillomavirus (HPV) infection, a frequent infection among women of childbearing age, is associated with preterm birth. Design, Setting, and Participants: The prospective HERITAGE cohort study was conducted at 3 academic hospitals in Montreal, Québec, Canada, among 899 pregnant women recruited between November 8, 2010, and October 16, 2016. Follow-up was completed on June 15, 2017. Statistical analysis was conducted from February 6, 2020, to January 21, 2021. Exposures: Vaginal HPV DNA detection in the first and third trimesters of pregnancy and placental HPV infection. Main Outcomes and Measures: The main outcome was preterm birth (defined as a live birth or stillbirth between 20 weeks and 0 days and 36 weeks and 6 days of gestation). The association between HPV DNA detection and preterm birth was measured using logistic regression. Odds ratios (ORs) and 95% CIs were adjusted by inverse probability of treatment weights of the propensity score. Results: The study included 899 women (mean [SD] age, 31.3 [4.6] years [range, 19-47 years]) with singleton pregnancies. A total of 378 women (42.0%) had HPV DNA detected in vaginal samples collected during the first trimester, and it was detected in 91 of 819 placentas (11.1%) at delivery. Fifty-five participants experienced preterm birth (38 spontaneous and 17 medically indicated). Persistent vaginal HPV-16/18 detection was significantly associated with all preterm births (adjusted OR [aOR], 3.72; 95% CI, 1.47-9.39) and spontaneous preterm births (aOR, 3.32; 95% CI, 1.13-9.80), as was placental HPV infection (all preterm births: aOR, 2.53; 95% CI, 1.06-6.03; spontaneous preterm births: aOR, 2.92; 95% CI, 1.09-7.81). Results were similar when restricting the analysis to participants without a history of cervical intraepithelial neoplasia treatment. Conclusions and Relevance: The study's results suggest that persistent HPV-16/18 infection is associated with an increased risk of preterm birth, independent of cervical treatment. Future studies should investigate the association of HPV vaccination and vaccination programs with the risk of preterm birth.

The plasma antioxidant vitamin status of the INTAPP cohort examined: The unsuspected importance of ß-carotene and γ-tocopherol in preeclampsia.

OBJECTIVE: Examine the levels of plasma antioxidant vitamins before and during a treatment with placebo or vitamin E + C supplement to prevent preeclampsia (PE). STUDY DESIGN: Per-protocol analysis of a subset group of pregnant women (n = 295) from the International Trial of Antioxidants for the Prevention of PE (INTAPP) randomized case-control study. Normotensive receiving placebo or vitamins (n = 115 and 87 respectively) were compared to gestational hypertension (GH) without proteinuria (n = 30 and 27) and PE (n = 21 and 15). Vitamin quantification was performed at 12-18, 24-26 and 32-34 weeks of gestation. MAIN OUTCOME MEASURES: Coenzyme (Co) Q10, ß-carotene and vitamins E (α and γ forms) plasma levels. RESULTS: Vitamin E + C supplementation was found to increase the α-tocopherol levels by 40% but was associated with a 57% decrease in the γ-tocopherol isoform for all study groups (p < 0.001). The ß -carotene was lower in the PE than in the normotensive and GH groups (p < 0.001) while the level of CoQ10 remained unaffected. CONCLUSIONS: A more personalized approach that target the suboptimal levels of specific antioxidants without disturbing the α/γ-tocopherol ratio could be a more successful approach to counteract oxidative stress in PE.

Validation and development of models using clinical, biochemical and ultrasound markers for predicting pre-eclampsia: an individual participant data meta-analysis.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management. OBJECTIVES: To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers. DESIGN: This was an individual participant data meta-analysis of cohort studies. SETTING: Source data from secondary and tertiary care. PREDICTORS: We identified predictors from systematic reviews, and prioritised for importance in an international survey. PRIMARY OUTCOMES: Early-onset (delivery at < 34 weeks' gestation), late-onset (delivery at ≥ 34 weeks' gestation) and any-onset pre-eclampsia. ANALYSIS: We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for C-statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using I2 and τ2. A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals. RESULTS: The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary C-statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia. LIMITATIONS: Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data. CONCLUSION: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings. FUTURE WORK: Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015029349. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 72. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Pre-eclampsia, a condition in pregnancy that results in raised blood pressure and protein in the urine, is a major cause of complications for the mother and baby. WHAT IS NEEDED?: A way of accurately identifying women at high risk of pre-eclampsia to allow clinicians to start preventative interventions such as administering aspirin or frequently monitoring women during pregnancy. WHERE ARE THE RESEARCH GAPS?: Although over 100 tools (models) have been reported worldwide to predict pre-eclampsia, to date their performance in women managed in the UK NHS is unknown. WHAT DID WE PLAN TO DO?: We planned to comprehensively identify all published models that predict the risk of pre-eclampsia occurring at any time during pregnancy and to assess if this prediction is accurate in the UK population. If the existing models did not perform satisfactorily, we aimed to develop new prediction models. WHAT DID WE FIND?: We formed the International Prediction of Pregnancy Complications network, which provided data from a large number of studies (78 studies, 25 countries, 125 researchers, 3,570,993 singleton pregnancies). We were able to assess the performance of 24 out of the 131 models published to predict pre-eclampsia in 11 UK data sets. The models did not accurately predict the risk of pre-eclampsia across all UK data sets, and their performance varied within individual data sets. We developed new prediction models that showed promising performance on average across all data sets, but their ability to correctly identify women who develop pre-eclampsia varied between populations. The models were more clinically useful when used in the care of first-time mothers pregnant with one child, compared to a strategy of treating them all as if they were at high-risk of pre-eclampsia. WHAT DOES THIS MEAN?: Before using the International Prediction of Pregnancy Complications models in various populations, they need to be adjusted for characteristics of the particular population and the setting of application.

Antibodies to human papillomavirus types 6, 11, 16 and 18: Vertical transmission and clearance in children up to two years of age.

Background: There is a paucity of data on the dynamics of human papillomavirus (HPV) antibodies in children. We aimed to describe the vertical transmission and clearance of antibodies against HPV6, 11, 16 and 18 in children. Methods: We used data from pregnant women recruited into the HERITAGE cohort study between 2009 and 2012 who were positive for HPV-DNA at baseline. Dried blood spots were collected during the first trimester in pregnant participants, and at birth, 6, 12, and 24 months of age in children. The level of total immunoglobulin G (IgG) against HPV6, 11, 16 and 18 were measured using Luminex immunoassays. Spearman's coefficients were used to correlate HPV antibody levels between newborns and mothers. Panel and Kaplan-Meier graphics described antibody dynamics in the first 24 months of life. Findings: Antibodies from newborns and mothers (n = 58 pairs) were moderately to highly correlated with coefficients of 0·81 (95% confidence intervals (CI):0·70-0·88), 0·68 (95% CI:0·5-0·80), 0·90 (95% CI:0·83-0·94) and 0·85 (95% CI:0·76-0·91) against HPV6, 11, 16 and 18, respectively. In newborns seropositive at birth, anti-HPV antibodies were cleared by 80% and 100% at 12 and 24 months, respectively. Only two children presented detectable HPV antibodies at 24 months. The first child had no detectable antibodies at birth and the second presented increasing levels after two undetected measures. Interpretation: Correlation between mother and newborn IgG antibodies against HPV suggests vertical transfer. Most children cleared anti-HPV antibodies within six to 12 months. Funding: The Canadian Institutes of Health Research (CIHR).

Renal functional markers in extremely premature infants with and without twin-twin transfusion syndrome.

OBJECTIVE: Describe renal function of preterm infants <29 weeks of gestational age (GA) with twin-twin transfusion syndrome (TTTS) who received laser therapy. DESIGN: Retrospective analysis of premature TTTS compared with dichorionic-diamniotic (di-di) twins from 2006 to 2015. Primary outcome was biomarkers of renal injury. RESULTS: Thirty-three TTTS-laser and 101 di-di newborns with similar GA at birth (26.4 ± 1.4 vs 26.9 ± 1.6 weeks, p = 0.07) were included. Creatinine and urea levels were higher in TTTS-laser group at day of life (DOL) 2-7 (123.5 ± 12.4 vs 75.8 ± 2 µmol/L, p = 0.0001 and 11.9 ± 1.1 mmol/L vs 8.7 ± 0.3 mmol/L, p = 0.0001) and DOL 8-14, (98.1 ± 14.2 vs 64.8 ± 2.3 µmol/L, p = 0.0001 and 9.1 ± 1.2 vs 5.4 ± 0.3 mmol/L, p = 0.0001). There was a significant effect of TTTS status on creatinine level at DOL 8-14. CONCLUSION: In extremely preterm with TTTS treated by laser, biomarkers of renal function were higher compared with di-di twins in the first 2 weeks of life.

Exploration of the effect of human papillomavirus (HPV) vaccination in a cohort of pregnant women in Montreal, 2010-2016.

HPV vaccination efficacy has been shown in clinical trials but it is important to verify population level vaccine effectiveness (VE). We aimed to explore VE and herd effect using HPV infection data from a cohort study of Canadian pregnant women. We analyzed the baseline data of the HERITAGE study, which includes pregnant women recruited in Montreal between 2010-2012 and 2015-2016. Cervicovaginal samples self-collected in the first trimester were tested for 36 HPV types. Vaccination status was self-reported. VE and 95% confidence intervals (CI) were estimated by comparing the prevalence of HPV between vaccinated and unvaccinated women. Herd effect was explored by comparing HPV prevalence in unvaccinated women between the 2 recruitment periods. Adjusted ORs (95%CI) were estimated using exact logistic regression. The proportion of vaccinated women with at least one dose of 4vHPV was 7.5%. Although most of them were vaccinated after the onset of sexual activity, a high VE was found for HPV-16/18 (86.1% (95%CI: 15.0-99.7)). For HPV-6/11/16/18 and for HPV-31/33/45, VE was 61.9% (-23.5-92.6) and 57.0% (-47.7-92.0%), respectively. We also observed a non-statistically significant reduction in the prevalence of HPV-6/11/16/18 and HPV-31/33/45 among unvaccinated women recruited during the second recruitment period (adjusted OR: 0.8 (0.4-1.8) and 0.8 (0.3-1.7), respectively).

Whole exome sequencing identifies novel predisposing genes in neural tube defects.

BACKGROUND: Neural tube defects (NTD) are among the most common defects affecting 1:1000 births. They are caused by a failure of neural tube closure during development. Their clinical presentation is diverse and dependent on the site and severity of the original defect on the embryonic axis. The etiology of NTD is multifactorial involving environmental factors and genetic variants that remain largely unknown. METHODS: We have conducted a whole exome sequencing (WES) study in five new NTD families and pooled the results with WES data from three NTD families and 43 trios that were previously investigated by our group. We analyzed the data using biased candidate gene and unbiased gene burden approaches. RESULTS: We identified four novel loss-of-function variants in three genes, MTHFR, DLC1, and ITGB1, previously associated with NTD. Notably, DLC1 carried two protein truncating variants in two independent cases. We also demonstrated an enrichment of variants in MYO1E involved in cytoskeletal remodeling. This enrichment reached borderline significance in a replication cohort supporting the association of this new candidate gene to NTD. CONCLUSION: These data provide some key insights into the pathogenic mechanisms of human NTD and demonstrate the power of next-generation sequencing in deciphering the genetics of this complex trait.

Outcomes of extremely premature infants with twin-twin transfusion syndrome treated by laser therapy.

OBJECTIVE: To compare short-term and long-term outcomes of preterm infants born at <29 weeks of gestational age (GA) with twin-twin transfusion syndrome (TTTS) treated with laser therapy to preterm twin infants without TTTS. DESIGN: Retrospective case-control study comparing 33 preterm TTTS twins to 101 preterm diamniotic-dichorionic (di-di) twins born at our institution between 2006 and 2015. RESULTS: GA at birth were 26.4 ± 1.4 weeks (TTTS) and 26.9 ± 1.6 weeks (di-di) (p = 0.07). TTTS premature newborns were less exposed to antenatal steroids (p = 0.01), more frequently born by C-section (p = 0.005), received more surfactant therapy (p = 0.004, and were smaller for GA (p < 0.001). When adjusted for antenatal steroids and birth weight, TTTS status was not associated with increased mortality (HR 1.66, 95% CI 0.77-3.56, p = 0.20). No differences were found on neurodevelopmental outcomes at 18 months of corrected GA. CONCLUSION: Premature TTTS newborns treated with fetal laser therapy had similar survival and neurodevelopmental outcomes compared to preterm di-di twins without TTTS.

Large-for-Gestational-Age May Be Associated With Lower Fetal Insulin Sensitivity and ß-Cell Function Linked to Leptin.

Context: Fetal overgrowth is associated with increased risk for type 2 diabetes in adulthood. It is unclear whether there are alterations in insulin sensitivity and ß-cell function in early life. Objective: To determine whether large-for-gestational-age (LGA) (birth weight > 90th percentile), an indicator of fetal overgrowth, is associated with altered fetal insulin sensitivity and ß-cell function. Study Design, Population, and Outcomes: In the Design, Development, and Discover birth cohort in Canada, we studied 106 pairs of LGA and optimal-for-gestational-age (OGA; birth weight, 25th to 75th percentiles) infants matched by maternal ethnicity, smoking status, and gestational age. Cord plasma glucose-to-insulin ratio was used as an indicator of fetal insulin sensitivity, and proinsulin-to-insulin ratio was used as an indicator of ß-cell function. Cord plasma leptin and high-molecular-weight (HMW) adiponectin concentrations were measured. Results: Comparisons of infants who were born LGA vs OGA, adjusted for maternal and newborn characteristics, showed that cord blood insulin, proinsulin, and leptin concentrations were significantly higher, whereas HWM adiponectin concentrations were similar. Glucose-to-insulin ratios were significantly lower (15.4 ± 28.1 vs 22.0 ± 24.9; P = 0.004), and proinsulin-to-insulin ratios significantly higher (0.73 ± 0.82 vs 0.60 ± 0.78; P = 0.005) in LGA vs OGA newborns, indicating lower insulin sensitivity and ß-cell function in LGA newborns. These significant differences were almost unchanged after further adjustment for cord blood adiponectin levels but disappeared upon additional adjustment for cord blood leptin levels. Conclusions: This study demonstrates that LGA may be associated with decreases in both fetal insulin sensitivity and ß-cell function. The alterations appear to be linked to elevated leptin levels.

Factors associated to early intrauterine fetal demise after laser for TTTS by preoperative fetal heart and Doppler ultrasound.

OBJECTIVE: To determine the prognostic value of fetal Doppler and echocardiographic parameters for intrauterine fetal demise (IUFD) within 24 hours and within 1 week after laser coagulation in monochorionic pregnancies complicated by twin-twin transfusion syndrome. METHOD: This retrospective study correlated the preoperative hemodynamic and echocardiography parameters to the outcome in fetuses with twin-twin transfusion syndrome undergoing laser therapy. RESULTS: One hundred and twelve laser coagulations were performed between February 2006 and June 2015. The total (single and double) IUFD rate was 27.7%. Further, 59% of IUFD occurred within 24 hours and 74.4% occurred within 1 week after laser. The following were associated to IUFD within 24 hours: the middle cerebral arterial pulsatility index in the donor, abnormal umbilical artery (UA) end diastolic flow, increased middle cerebral artery peak systolic velocity, and right ventricular myocardial performance index (RV-MPI) z-score in the recipient. For IUFD within 1 week were the pulsatility index in the donor UA and the recipient abnormalities in UA, ductus venosus, middle cerebral artery-peak systolic velocity, and RV-MPI z-score. CONCLUSION: Following laser was early IUFD that was associated with Doppler findings suggesting donor cerebroplacental redistribution, and recipient overload cardiomyopathy, such as abnormal ductus venosus and UA Dopplers as well as an increase of RV-MPI.

Aortic Isthmus Flow Recording Predicts the Outcome of the Recipient Twin after Laser Coagulation in Twin-Twin Transfusion Syndrome.

INTRODUCTION: The objective was to assess the prognostic value of the systolic flow through the aortic isthmus in monochorionic pregnancies complicated by twin-twin transfusion syndrome (TTTS) treated by placental laser ablation. MATERIAL AND METHODS: Fetal echocardiography and outcome data of 105 cases of TTTS treated by laser photocoagulation of placental anastomoses were reviewed. Hemodynamic parameters were collected before and after treatment. The isthmic systolic index (ISI) was calculated as the peak systolic velocity/systolic nadir ratio. RESULTS: A total of 105 laser coagulations were studied. Fetal echocardiography pre- and post-laser were available in 68 cases, including 55 with data on aortic isthmic Doppler. Survival rates were 17, 22, and 61% for 0, 1, or 2 twins, respectively. At least 1 twin was delivered alive in 83% of the pregnancies. The mean gestational age at surgery was 21 weeks (range 16-26). Median ISI values were similar for donor and recipient twins, before and after laser ablation (all p > 0.05). A lower recipient ISI before laser was related to early recipient demise within 24 h (p = 0.04). DISCUSSION: A lower ISI before placental laser ablation for TTTS is associated with postoperative demise of the recipient twin.

Genomic study of severe fetal anomalies and discovery of GREB1L mutations in renal agenesis.

PURPOSE: Fetal anomalies represent a poorly studied group of developmental disorders. Our objective was to assess the impact of whole-exome sequencing (WES) on the investigation of these anomalies. METHODS: We performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies, including renal a/dysgenesis, VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities), brain anomalies, suspected ciliopathies, multiple major malformations, and akinesia. RESULTS: A molecular diagnosis was obtained in 19 cases (19%). In 13 of these cases, the diagnosis was not initially suspected by the clinicians because the phenotype was nonspecific or atypical, corresponding in some cases to the severe end of the spectrum of a known disease (e.g., MNX1-, RYR1-, or TUBB-related disorders). In addition, we identified likely pathogenic variants in genes (DSTYK, ACTB, and HIVEP2) previously associated with phenotypes that were substantially different from those found in our cases. Finally, we identified variants in novel candidate genes that were associated with perinatal lethality, including de novo mutations in GREB1L in two cases with bilateral renal agenesis, which represents a significant enrichment of such mutations in our cohort. CONCLUSION: Our study opens a window on the distinctive genetic landscape associated with fetal anomalies and highlights the power-but also the challenges-of WES in prenatal diagnosis.

Comparison of first-tier cell-free DNA screening for common aneuploidies with conventional publically funded screening.

OBJECTIVE: This study evaluates the impact of offering cell-free DNA (cfDNA) screening as a first-tier test for trisomies 21 and 18. METHODS: This is a prospective study of pregnant women undergoing conventional prenatal screening who were offered cfDNA screening in the first trimester with clinical outcomes obtained on all pregnancies. RESULTS: A total of 1198 pregnant women were recruited. The detection rate of trisomy 21 with standard screening was 83% with a false positive rate (FPR) of 5.5% compared with 100% detection and 0% FPR for cfDNA screening. The FPR of cfDNA screening for trisomies 18 and 13 was 0.09% for each. Two percent of women underwent an invasive diagnostic procedure based on screening or ultrasound findings; without the cfDNA screening, it could have been as high as 6.8%. Amongst the 640 women with negative cfDNA results and a nuchal translucency (NT) ultrasound, only 3 had an NT greater or equal to 3.5 mm: one had a normal outcome and two lost their pregnancy before 20 weeks. CONCLUSIONS: cfDNA screening has the potential to be a highly effective first-tier screening approach leading to a significant reduction of invasive diagnostic procedures. For women with a negative cfDNA screening result, NT measurement has limited clinical utility.