Noninvasive prenatal screening in twin pregnancies with cell-free DNA using the IONA test: a prospective multicenter study.

BACKGROUND: In singleton pregnancies, studies investigating cell-free DNA in maternal blood have consistently reported high detection rate and low false-positive rate for the 3 common fetal trisomies (trisomies 21, 18, and 13). The potential advantages of noninvasive prenatal testing in twin pregnancies are even greater than in singletons, in particular lower need for invasive testing and consequent fetal loss rate. However, several organizations do not recommend cell-free DNA in twin pregnancies and call for larger prospective studies. OBJECTIVE: In response to this, we undertook a large prospective multicenter study to establish the screening performance of cell-free DNA for the 3 common trisomies in twin pregnancies. Moreover, we combined our data with that reported in published studies to obtain the best estimate of screening performance. STUDY DESIGN: This was a prospective multicenter blinded study evaluating the screening performance of cell-free DNA in maternal plasma for the detection of fetal trisomies in twin pregnancies. The study took place in 6 fetal medicine centers in England, United Kingdom. The primary outcome was the screening performance and test failure rate of cell-free DNA using next generation sequencing (the IONA test). Maternal blood was taken at the time of (or after) a conventional screening test. Data were collected at enrolment, at any relevant invasive testing throughout pregnancy, and after delivery until the time of hospital discharge. Prospective detailed outcome ascertainment was undertaken on all newborns. The study was undertaken and reported according to the Standards for Reporting of Diagnostic Accuracy Studies. A pooled analysis was also undertaken using our data and those in the studies identified by a literature search (MEDLINE, Embase, CENTRAL, Cochrane Library, and ClinicalTrials.gov) on June 6, 2020. RESULTS: A total of 1003 women with twin pregnancies were recruited, and complete data with follow-up and reference data were available for 961 (95.8%); 276 were monochorionic and 685 were dichorionic. The failure rate was 0.31%. The mean fetal fraction was 12.2% (range, 3%-36%); all 9 samples with a 3% fetal fraction provided a valid result. There were no false-positive or false-negative results for trisomy 21 or trisomy 13, whereas there was 1 false-negative and 1 false-positive result for trisomy 18. The IONA test had a detection rate of 100% for trisomy 21 (n=13; 95% confidence interval, 75-100), 0% for trisomy 18 (n=1; 95% confidence interval, 0-98), and 100% for trisomy 13 (n=1; 95% confidence interval, 3-100). The corresponding false-positive rates were 0% (95% confidence interval, 0-0.39), 0.10% (95% confidence interval, 0-0.58), and 0% (95% confidence interval, 0-0.39), respectively. By combining data from our study with the 11 studies identified by literature search, the detection rate for trisomy 21 was 95% (n=74; 95% confidence interval, 90-99) and the false-positive rate was 0.09% (n=5598; 95% confidence interval, 0.03-0.19). The corresponding values for trisomy 18 were 82% (n=22; 95% confidence interval, 66-93) and 0.08% (n=4869; 95% confidence interval, 0.02-0.18), respectively. There were 5 cases of trisomy 13 and 3881 non-trisomy 13 pregnancies, resulting in a computed average detection rate of 80% and a false-positive rate of 0.13%. CONCLUSION: This large multicenter study confirms that cell-free DNA testing is the most accurate screening test for trisomy 21 in twin pregnancies, with screening performance similar to that in singletons and very low failure rates (0.31%). The predictive accuracy for trisomies 18 and 13 may be less. However, given the low false-positive rate, offering first-line screening with cell-free DNA to women with twin pregnancy is appropriate in our view and should be considered a primary screening test for trisomy 21 in twins.

The Association of Intrapair Birth-Weight Differences With Internalizing and Externalizing Behavior Problems.

Problem behaviors are of increasing public health concern. Twin studies have revealed substantial genetic and environmental influences on children's behavior, and examining birth-weight difference could allow the identification of the specific contribution of multiple non-shared prenatal environmental factors. The Twins and Multiple Births Association Heritability Study, a UK, volunteer-based study, recruited mothers of twins aged 18 months to 5 years; 960 twins (480 pairs) were included in the analysis. Twins' mothers answered questions relative to their pregnancy and their twins' characteristics, and completed the Child Behavior Checklist (CBCL) 1½-5. The association between the absolute birth-weight difference and each CBCL scale's score difference was analyzed by means of multiple linear regressions. Expected mean CBCL score differences were calculated. In monozygotic (MZ) twins, statistically and clinically significant associations were found between intrapair birth-weight difference and difference in total problems, internalizing problems, and emotional reactiveness. No significant results were observed neither in dizygotic (DZ) twins when analyzed as a separate group nor in MZ and DZ twins combined. The results of the present study suggest that with increasing the absolute birth-weight difference, the intrapair difference in total problems, internalizing behaviors and emotionality increases, with smaller twins being at major risk for later behavior problems. Moreover, these results suggest a causal association between birth weight and behavior development.

Nutritional advice for improving outcomes in multiple pregnancies.

BACKGROUND: Multiple pregnancies are associated with higher rates of perinatal mortality and morbidity than singleton pregnancies, mainly due to an increased risk of preterm birth. Because fetal outcome is best at a particular range of maternal weight gain, it has been suggested that women with multiple pregnancies should take special diets (particularly high-calorie diets) designed to boost weight gain. However, 'optimal weight gain' in the mother in retrospective studies may merely reflect good growth of her babies and delivery at or near term (both associated with a good outcome) and artificially boosting weight gain by nutritional input may confer no advantage. Indeed, a high-calorie diet may be unpleasant to consume, and could lead to long-term problems of being overweight. It is therefore important to establish if specialised diets are actually of benefit to women with multiple pregnancies and their babies. OBJECTIVES: To assess the effects of specialised diets or nutritional advice for women with multiple pregnancies (two or more fetuses). SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (15 June 2015). SELECTION CRITERIA: Randomised controlled trials, 'quasi-random' studies, and cluster-randomised trials of women with multiple pregnancies (two or more fetuses) either nulliparous or multiparous and their babies. Cross-over trials and studies reported only as abstracts were not eligible for inclusion. DATA COLLECTION AND ANALYSIS: We identified no trials for inclusion in this review. MAIN RESULTS: A comprehensive search of the Cochrane Pregnancy and Childbirth Group's Trials Register found no potentially eligible trial reports. AUTHORS' CONCLUSIONS: There is no robust evidence from randomised trials to indicate whether specialised diets or nutritional advice for women with multiple pregnancies do more good than harm. There is a clear need to undertake a randomised controlled trial.

Randomised placebo-controlled trial of antenatal corticosteroids for planned birth in twins (STOPPIT-3): study protocol.

INTRODUCTION: The aim of the STOPPIT-3 study is to determine the clinical and cost effectiveness of antenatal corticosteroids (ACS) prior to planned birth of twins in a multicentre placebo-controlled trial with internal pilot. METHODS AND ANALYSIS: This study will comprise a multicentre, double-blinded, randomised, placebo-controlled trial in at least 50 UK obstetric units. The target population is 1552 women with a twin pregnancy and a planned birth between 35 and 38+6 weeks' gestation recruited from antenatal clinics. Women will be randomised to Dexamethasone Phosphate (24 mg) or saline administered via two intramuscular injections 24 hours apart, 24-120 hours prior to scheduled birth. OUTCOMES: The primary outcome is need for respiratory support within 72 hours of birth. Secondary and safety outcomes will be included. Cognitive and language development at age 2 years will be assessed in a subset of participants using the Parent report of Children's Abilities-Revised questionnaire. We will also determine the cost effectiveness of the treatment with ACS compared with placebo. ETHICS AND DISSEMINATION: STOPPIT-3 has been funded and approved by the National Institute of Healthcare Research. It has been approved by the West Midlands Research Ethics Committee (22/WM/0018). The results will be disseminated via publication in peer-reviewed journals and conference presentation and will also be communicated to the public via links with charity partners and social media. TRIAL SPONSOR: The University of Edinburgh and Lothian Health Board ACCORD, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ. TRIAL REGISTRATION NUMBER: ISRCTN59959611.

Nutritional advice for improving outcomes in multiple pregnancies.

BACKGROUND: Multiple pregnancies are associated with higher rates of perinatal mortality and morbidity than singleton pregnancies, mainly due to an increased risk of preterm birth. Because fetal outcome is best at a particular range of maternal weight gain, it has been suggested that women with multiple pregnancies should take special diets (particularly high-calorie diets) designed to boost weight gain. However, 'optimal weight gain' in the mother in retrospective studies may merely reflect good growth of her babies and delivery at or near term (both associated with good outcome) and artificially boosting weight gain by nutritional input may confer no advantage. Indeed, a high-calorie diet may be unpleasant to consume, and could lead to long-term problems of being overweight. It is therefore important to establish if specialised diets are actually of benefit to women with multiple pregnancies and their babies. OBJECTIVES: To assess the effects of specialised diets or nutritional advice for women with multiple pregnancies (two or more fetuses). SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2011). SELECTION CRITERIA: Randomised controlled trials, 'quasi-random' studies, and cluster-randomised trials of women with multiple pregnancies (two or more fetuses) either nulliparous or multiparous and their babies. Crossover trials and studies reported only as abstracts were not eligible for inclusion. DATA COLLECTION AND ANALYSIS: We identified no trials for inclusion in this review. MAIN RESULTS: A comprehensive search of the Cochrane Pregnancy and Childbirth Group's Trials Register found no potentially eligible trial reports. AUTHORS' CONCLUSIONS: There is no robust evidence from randomised trials to indicate whether specialised diets or nutritional advice for women with multiple pregnancies do more good than harm. There is a clear need to undertake a randomised controlled trial.

An empirical study on the preferred size of the participant information sheet in research.

BACKGROUND: Informed consent is a requirement for all research. It is not, however, clear how much information is sufficient to make an informed decision about participation in research. Information on an online questionnaire about childhood development was provided through an unfolding electronic participant sheet in three levels of information. METHODS: 552 participants, who completed the web-based survey, accessed and spent time reading the participant information sheet (PIS) between July 2008 and November 2009. The information behaviour of the participants was investigated. The first level contained less information than might be found on a standard PIS, the second level corresponded to a standard PIS, and the third contained more information than on a standard PIS. The actual time spent on reading the information provided in three incremental levels and the participants' evaluation of the information were calculated. RESULTS: 77% of the participants chose to access the first level of information, whereas 12% accessed the first two levels, 6% accessed all three levels of information and 23% participated without accessing information. The most accessed levels of information were those that corresponded to the average reading times. CONCLUSION: The brief information provided in the first level was sufficient for participants to make informed decisions, while a sizeable minority of the participants chose not to access any information at all. This study adds to the debate about how much information is required to make a decision about participation in research and the results may help inform the future development of information sheets by providing data on participants' actual needs when deciding about questionnaire surveys.

Are Twin Pregnancies Complicated by Weight Discordance or Fetal Growth Restriction at Higher Risk of Preeclampsia?

Studies have reported controversial findings on the association between fetal growth restriction (FGR) or intertwin weight discordance and the risk of hypertensive disorders of pregnancy (HDP) in twin pregnancies. The aim of this study was to investigate the association between twin growth disorders and HDP. Twin pregnancies resulting in two live births at St George's Hospital between 2000 and 2019 were included. FGR or small-for-gestational-age (SGA) at birth was assessed using singleton and twin reference charts. Intertwin discordance [(large birthweight - small birthweight)/(large birthweight) × 100%)] was calculated. Logistic regression models were performed. SGA (aOR 2.34, 95% CI 1.60-3.44, p < 0.001), intertwin discordance ≥25% (aOR 2.10, 95% CI 1.26-3.49, p = 0.004) and their co-existence (aOR 2.03, 95% CI 1.16-3.54, p = 0.013) were significantly associated with HDP. After adjusting for the known maternal risk factors of HDP and the intertwin discordance, SGA (using the twin charts) was the strongest independent risk factor associated with HDP (aOR 2.12, 95% CI 1.40-3.22, p < 0.001) and preeclampsia (aOR 2.34, 95% CI 1.45-3.76, p < 0.001). This study highlights that the presence of at least one SGA twin is significantly associated with HDP during pregnancy. Therefore, maternal blood pressure should be closely monitored in twin pregnancies complicated by SGA with or without intertwin discordance.

Maternal pre-pregnancy weight and twins' temperament.

Maternal pre-pregnancy weight has been related with young singletons' cognitive and behavioral development, but it is not clear if it has an effect on temperament. We used a twin cohort to evaluate the association between maternal pre-pregnancy body mass index (BMI) and infants' temperament. The mothers of 834 twins answered questions regarding their pre-pregnancy BMI and their 0- to 18-month-old children's temperament using the Revised Infant Behavior Questionnaire. Three temperamental dimensions were examined: activity level, distress to limitation and duration of orienting. The relationship between maternal pre-pregnancy BMI and each temperamental component was investigated by means of multilevel mixed-effects linear regression analysis. We found no clear evidence of an association of maternal pre-pregnancy BMI with twins' temperament. The development of temperament is influenced by a large number of factors, probably different from those influencing children's emotional and behavioral development.

Study protocol: developing, disseminating, and implementing a core outcome set for selective fetal growth restriction in monochorionic twin pregnancies.

BACKGROUND: Selective fetal growth restriction in monochorionic twin pregnancies is associated with an increased risk of perinatal mortality and morbidity and represents a clinical dilemma. Interventions include expectant management with early preterm delivery if there are signs of fetal compromise, selective termination of the compromised twin, fetoscopic laser coagulation of the communicating placental vessels or termination of the whole pregnancy. Previous studies evaluating interventions have reported many different outcomes and outcome measures. Such variation makes comparing, contrasting, and combining results challenging, limiting ongoing research on this uncommon condition to inform clinical practice. We aim to produce, disseminate, and implement a core outcome set for selective fetal growth restriction research in monochorionic twin pregnancies. METHODS: An international steering group, including professionals, researchers, and lay experts, has been established to oversee the development of this core outcome set. The methods have been guided by the Core Outcome Measures in Effectiveness Trials Initiative Handbook. Potential core outcomes will be developed by undertaking a systematic review of studies evaluating interventions for selective fetal growth restriction in monochorionic twin pregnancies. Potential core outcomes will be entered into a three-round Delphi survey and key stakeholders including clinical professionals, researchers, and lay experts will be invited to participate. Repeated reflection and rescoring of individual outcomes should encourage group and individual stakeholder convergence towards consensus outcomes which will be entered into a modified Nominal Group Technique to finalize the core outcome set. Once core outcomes have been agreed, we will establish standardized definitions and recommend high-quality measurement instruments for each outcome. DISCUSSION: The development, dissemination, and implementation of a core outcome set for selective fetal growth restriction should ensure that future research protocols select, collect, and report outcomes and outcome measures in a standardized manner. Data synthesis will be possible on a broad level and rigorous implementation should advance the quality of research studies and their effective use in order to guide clinical practice, improve patient care, maternal, short-term perinatal outcomes, and long-term neurodevelopmental outcomes. TRIAL REGISTRATION: Core Outcome Measures in Effectiveness Trials (COMET) registration number: 998. International Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD42018092697 . 18th April 2018.

Companion planting with white yarrow or with feverfew for squash bug, Anasa tristis (Hemiptera: Coreidae), management on summer squash.

BACKGROUND: The squash bug, Anasa tristis (De Geer), is a major insect pest of cucurbits. Control of squash bugs with insecticidal chemicals is difficult to achieve. We investigated the potential of companion planting with white yarrow (Achillea millefolium L.) or feverfew [Tanacetum parthenium (L.) Sch. Bip.] for squash bug management in field plantings of summer squash (Cucurbita pepo L.). RESULTS: Companion planting with white yarrow had few effects. Companion planting with feverfew tended to reduce squash bug populations, but results often were not statistically significant (P ≥ 0.05). Early-season ventilated row covers (without herbs) neither reduced squash bug populations nor increased squash yields. Herbs reduced marketable squash yields compared with the control only once out of seven experiments. CONCLUSION: The tested companion planting strategies inconsistently affected squash bug populations on summer squash. Therefore, these strategies are not recommended to commercial producers. © 2016 Society of Chemical Industry.

Twin-Twin Transfusion Syndrome: study protocol for developing, disseminating, and implementing a core outcome set.

BACKGROUND: Twin-Twin Transfusion Syndrome (TTTS) is associated with an increased risk of perinatal mortality and morbidity. Several treatment interventions have been described for TTTS, including fetoscopic laser surgery, amnioreduction, septostomy, expectant management, and pregnancy termination. Over the last decade, fetoscopic laser surgery has become the primary treatment. The literature to date reports on many different outcomes, making it difficult to compare results or combine data from individual studies, limiting the value of research to guide clinical practice. With the advent and ongoing development of new therapeutic techniques, this is more important than ever. The development and use of a core outcome set has been proposed to address these issues, prioritising outcomes important to the key stakeholders, including patients. We aim to produce, disseminate, and implement a core outcome set for TTTS. METHODS: An international steering group has been established to oversee the development of this core outcome set. This group includes healthcare professionals, researchers and patients. A systematic review is planned to identify previously reported outcomes following treatment for TTTS. Following completion, the identified outcomes will be evaluated by stakeholders using an international, multi-perspective online modified Delphi method to build consensus on core outcomes. This method encourages the participants towards consensus 'core' outcomes. All key stakeholders will be invited to participate. The steering group will then hold a consensus meeting to discuss results and form a core outcome set to be introduced and measured. Once core outcomes have been agreed, the next step will be to determine how they should be measured, disseminated, and implemented within an international context. DISCUSSION: The development, dissemination, and implementation of a core outcome set in TTTS will enable its use in future clinical trials, systematic reviews and clinical practice guidelines. This is likely to advance the quality of research studies and their effective use in order to guide clinical practice and improve patient care, maternal, short-term perinatal outcomes and long-term neurodevelopmental outcomes. TRIAL REGISTRATION: Core Outcome Measures in Effectiveness Trials (COMET), 921 Registered on July 2016. International Prospective Register of Systematic Reviews (PROSPERO), CRD42016043999 . Registered on 2 August 2016.

Maternal pre-pregnancy weight and externalising behaviour problems in preschool children: a UK-based twin study.

OBJECTIVE: To estimate the heritability of child behaviour problems and investigate the association between maternal pre-pregnancy overweight and child behaviour problems in a genetically sensitive design. DESIGN: Observational cross-sectional study. SETTING: The Twins and Multiple Births Association Heritability Study (TAMBAHS) is an online UK-wide volunteer-based study investigating the development of twins from birth until 5 years of age. PARTICIPANTS: A total of 443 (16% of the initial registered members) mothers answered questions on pre-pregnancy weight and their twins' internalising and externalising problems using the Child Behavior Checklist and correcting for important covariates including gestational age, twins' birth weight, age and sex, mother's educational level and smoking (before, during and after pregnancy). PRIMARY OUTCOMES: The heritability of behaviour problems and their association with maternal pre-pregnancy weight. RESULTS: The genetic analysis suggested that genetic and common environmental factors account for most of the variation in externalising disorders (an ACE model was the most parsimonious with genetic factors (A) explaining 46% (95% CI 33% to 60%) of the variance, common environment (C) explaining 42% (95% CI 27% to 54%) and non-shared environmental factors (E) explaining 13% (95% CI 10% to 16%) of the variance. For internalising problems, a CE model was the most parsimonious model with the common environment explaining 51% (95% CI 44% to 58%) of the variance and non-shared environment explaining 49% (95% CI 42% to 56%) of the variance. Moreover, the regression analysis results suggested that children of overweight mothers showed a trend (OR=1.10, 95% CI 0.58% to 2.06) towards being more aggressive and exhibit externalising behaviours compared to children of normal weight mothers. CONCLUSIONS: Maternal pre-pregnancy weight may play a role in children's aggressive behaviour.

Intraurethral fluorouracil and lidocaine for intraurethral condyloma acuminata.

PURPOSE: A new and convenient means of administering fluorouracil and lidocaine for the treatment of intraurethral condyloma acuminata is discussed. SUMMARY: Condyloma acuminata are warts of the genital and perianal region caused by various types of human papillomavirus (HPV). Intraurethral condylomas are associated with complications such as urinary burning, frequency, urgency, urethral bleeding, obstruction, fistula formation, and dyspareunia. A 55-year-old white man had a chief complaint of profuse, but painless, hematuria when he urinated. Cystourethroscopy confirmed extensive intraurethral condylomatous lesions at the external urethral meatus. A biopsy revealed mild squamous dysplasia and cellular changes consistent with HPV infection. A treatment was prepared that included fluorouracil 250 mg combined with 0.18% lidocaine hydrochloride gel. This mixture was given intraurethrally once weekly, and the tip of the penis was clamped immediately after administration using an occlusive penile clamp. The clamp was retained for 10 minutes for the first treatment, 15 minutes for the second, and 20 minutes for the remainder of the treatments. Six treatments were given initially and were well tolerated, although the patient did report occasional pain while urinating and occasional drops of urine. After six weeks of rest, another cycle of six weekly treatments was given. Two weeks after the second course of treatment, one small condyloma was observed in the distal anterior urethra. The urethra was found to be unblocked after three months, and the six-month evaluation revealed no new growth and a clear urethra. CONCLUSION: Urethral instillation via urethral syringe of fluorouracil injection mixed with lidocaine gel reduced the size and number of a man's intraurethral condyloma acuminata, allowed cystourethroscopy, and eliminated hematuria. There was no new growth of condyloma acuminata after six months.