Dosage escalation of antenatal steroids in preterm twin pregnancies does not improve long-term outcome.

OBJECTIVES: To analyze long-term effects of antenatal betamethasone (≤16 mg, =24 mg and >24 mg) in preterm twins on infant and childhood morbidity. METHODS: Retrospective cohort study among 198 preterm twins. Three follow up time points, including a total of 84 outcomes, were evaluated: first neonatal examination after birth and in the neonatal period up to 10 days after birth using data from the clinic charts; examination from the 21st to the 24th month of life and examination from the 60th to the 64th months, using data from copies of the children's examination booklets sent back by the parents. Dosage-dependent and sex-specific long-term effects of antenatal betamethasone treatment on neonatal, infant and early childhood development and morbidity up to 5.3 years of age were analyzed. RESULTS: Dosage escalation of >24 mg was not associated with improved neonatal, infant or early child hood outcome, independent of twin pair structure. In contrast, higher doses >24 mg were significantly linked to increased rates of congenital infections (OR 5.867, 95% CI 1.895-18.167). Male sex as a factor was obvious for lower rates of apnea-bradycardia-syndrome in neonates, higher rates of no free steps after 15 months in infancy and highest rates of motor clumsiness in early childhood. CONCLUSIONS: Betamethasone dosage escalation >24 mg in twins born between 23+5 and 33+6 weeks of gestation did not improve neonatal, infant or early childhood morbidity. In contrast, higher doses >24 mg total dose resulted in significantly higher rates of congenital infections and are not recommended. For males, 24 mg betamethasone appears to be the preferable dose.

Mode of delivery and neonatal outcomes in extremely preterm Vertex/nonVertex twins.

BACKGROUND: One of the controversies in the management of twin gestations relates to mode of delivery, especially when the second twin is in a nonvertex presentation (Vertex/nonVertex pairs) and birth is imminent at extremely low gestation. OBJECTIVE: We hypothesized that, for Vertex/nonVertex twins born before 28 weeks' gestation, cesarean delivery would be associated with a lower risk of adverse neonatal outcomes than trial of vaginal delivery. Our aim was to test this hypothesis by comparing the neonatal outcomes of Vertex/nonVertex twins born before 28 weeks' gestation by mode of delivery using a large national cohort. STUDY DESIGN: This work is a retrospective cohort study of all twin infants born at 240/7 to 276/7 weeks' gestation and admitted to level III neonatal intensive care units participating in the Canadian Neonatal Network (2010-2017). Exposure is defined a trial of vaginal delivery for Vertex/nonVertex twins. Nonexposed (control) groups are defined as cases where both twins were delivered by cesarean delivery, either in vertex or nonvertex presentation (control group 1) or owing to the nonvertex presentation of the first twin (control group 2). Outcome measures are defined as a composite of neonatal death, severe neurologic injury, or birth trauma. RESULTS: A total of 1082 twin infants (541 twin pairs) met the inclusion criteria: 220 Vertex/nonVertex pairs, of which 112 had a trial of vaginal delivery (study group) and 108 had cesarean delivery for both twins (control group 1); 170 pairs with the first twin in nonvertex presentation, all of which were born by cesarean delivery (control group 2); and 151 pairs with both twins in vertex presentation (vertex or nonvertex). In the study group, the rate of urgent cesarean delivery for the second twin was 30%. The rate of the primary outcome in the study group was 42%, which was not significantly different compared with control group 1 (37%; adjusted relative risk, 0.93; 95% confidence interval, 0.71-1.22) or control group 2 (34%; adjusted relative risk, 1.20; 95% confidence interval, 0.92-1.58). The findings remained similar when outcomes were analyzed separately for the first and second twins. CONCLUSION: For preterm Vertex/nonVertex twins born at <28 weeks' gestation, we found no difference in the risk of adverse neonatal outcome between a trial of vaginal delivery and primary cesarean delivery. However, a trial of vaginal delivery was associated with a high rate of urgent cesarean delivery for the second twin.

Antenatal Corticosteroids and Outcomes in Preterm Twins.

OBJECTIVE: To estimate whether improvement in outcomes from antenatal corticosteroid treatment in extremely and very preterm twins is similar to that observed in singletons, and to investigate whether antenatal corticosteroid treatment has different effects according to chorionicity or birth order. METHODS: This population-based study was based on an analysis of data collected by the Neonatal Research Network of Japan from 2003 to 2015 of neonates weighing 1,500 g or less at birth, from gestational ages of 24 0/7 to 31 6/7 weeks of gestation. After propensity score matching, univariate logistic and interaction analyses were performed to compare short-term (neonatal period) and medium-term (3 years of age) outcomes of the children of mothers who received antenatal corticosteroids with those of children of mothers who did not receive antenatal corticosteroids. We focused on differences between singletons and twins, between monochorionic and dichorionic twins and between the first and second twin. RESULTS: The study comprised 23,502 singletons and 6,546 twins. Antenatal corticosteroid treatment was associated with significant decreased short-term neurologic outcomes in both singletons and twins. However, antenatal corticosteroid treatment was associated with significantly decreased mortality (odds ratio [OR] 0.61; 95% CI 0.53-0.70), respiratory distress syndrome (OR 0.71, 95% CI 0.67-0.76), and cerebral palsy (OR 0.85, 95% CI 0.72-0.99) in singletons but not in twins (OR 0.89, 95% CI 0.68-1.17; OR 0.99, 95% CI 0.87-1.12; and OR 0.82, 95% CI 0.61-1.11, respectively). No association was found between chorionicity and the efficacy of antenatal corticosteroid treatment on outcomes. Further, no association was found between birth order and the efficacy of antenatal corticosteroid treatment on outcomes, except for periventricular leukomalacia and necrotizing enterocolitis (interaction: P=.02 and P=.04, respectively). CONCLUSION: Antenatal corticosteroid treatment in twins was associated with a beneficial effect on short-term neurologic outcomes only, without improvement in other short-term and medium-term outcomes. There was no difference related to chorionicity.

Effects of antenatal corticosteroids in twin neonates with late preterm birth (ACTWIN [Antenatal Corticosteroids in TWIN late preterm neonates] trial): study protocol for a randomized controlled trial.

BACKGROUND: Antenatal corticosteroids have been proven to prevent adverse outcomes including respiratory morbidities in preterm neonates before 34 weeks of gestation. Recently, it has been suggested that antenatal corticosteroids may also be effective in singleton late preterm pregnancies, and guidelines recommend the use of corticosteroids in singleton pregnant women who are at risk for late preterm birth. On the contrary, there is a paucity of information regarding the effectiveness of corticosteroids in twin neonates with late preterm birth. This study aims to determine the effectiveness of antenatal corticosteroids in late preterm twin neonates. METHODS: In this multicentre randomized controlled trial, women who are at risk for late preterm birth will be enrolled at 34 0/7 to 36 5/7 weeks of gestation. The participants will be randomly assigned to receive antenatal corticosteroids (betamethasone 12 mg, 3 mL intramuscularly [IM]) or placebo (normal saline 3 mL IM). The perinatal outcomes will be compared between the two groups of cases. The primary outcome is severe respiratory complications (the use of continuous positive airway pressure or high-flow nasal cannula for at least 12 h, supplemental oxygen administration with a fraction of oxygen 0.3 or more for at least 24 h, mechanical ventilation, or extracorporeal membranes oxygenation) or perinatal death within the first 72 h of delivery. The secondary outcomes are neonatal mortality and/or other neonatal morbidities. DISCUSSION: This study will be the first randomized controlled trial that evaluates the effectiveness of antenatal corticosteroids in late preterm twin neonates. TRIAL REGISTRATION: NCT03547791 (ClinicalTrials.gov), first submitted date: March 29, 2018, first posted date: June 6, 2018 (retrospectively registered).

Population-based study on antenatal corticosteroid treatment in preterm small for gestational age and non-small for gestational age twin infants.

OBJECTIVES: To assess the associations between antenatal corticosteroid use (ACU), mortality and severe morbidities in preterm, twin neonates and compare these between small for gestational age (SGA) and non-SGA twins. MATERIALS AND METHODS: Population-based study using data collected by the Israel National Very Low Birth Weight infant database from 1995 to 2012, comprising twin infants of 24-31 weeks' gestation, without major malformations. Univariate and multivariable logistic regression analyses were performed. RESULTS: Among the 6195 study twin infants, 784 were SGA. Among SGA neonates, ACU were associated with decreased mortality (23.9% vs. 39.2%, p < 0.0001) and composite adverse outcome including mortality or severe neonatal morbidity (43.8% vs. 56.8%, p = 0.0015), similar to the effect in non-SGA neonates (mortality 13.0% vs. 24.5%, p < 0.0001; composite outcome 34.2% vs. 44.8%, p < 0.0001). In the multivariable logistic regression analyses, ACU were associated with an almost 50% reduced mortality risk among SGA twin neonates (OR = 0.52, 95% CI 0.31-0.88) similar to the effect in non-SGA twin neonates (OR = 0.56, 95% CI 0.45-0.70), Pinteraction = 0.69. Composite adverse outcome risk was also reduced in SGA (OR = 0.78, 95% CI 0.50-1.23) and non-SGA groups (OR = 0.78, 95% CI 0.65-0.95), Pinteraction = 0.95. CONCLUSIONS: ACU should be considered in all mothers with twin gestation, at risk for preterm delivery at 24-31 weeks, in order to improve perinatal outcome.

Efficacy of antenatal corticosteroids in preterm twins: the EPIPAGE-2 cohort study.

OBJECTIVES: To investigate the efficacy of antenatal corticosteroid (ACS) therapy on short-term neonatal outcomes in preterm twins, and further document the influence of the ACS-to-delivery interval. DESIGN: EPIPAGE-2 is a nationwide observational multicentre prospective cohort study of neonates born between 22 and 34 completed weeks of gestation. SETTING: All French maternity units, except in a single administrative region, between March and December 2011. POPULATION: A total of 750 twin neonates born between 24 and 31 weeks of gestation. METHODS: Exposure to ACSs was examined in four groups: single complete course, with an ACS administration-to-delivery interval of ≤7 days; single complete course, with an ACS-to-delivery interval of >7 days; repeated courses; or no ACS treatment. MAIN OUTCOME MEASURES: Neonatal outcomes analysed were severe bronchopulmonary dysplasia, periventricular leukomalacia or intraventricular haemorrhage grade III/IV, in-hospital mortality, and a composite indicator of severe outcomes. RESULTS: Compared with no ACSs, in multivariable analysis, a single course of ACSs with an administration-to-delivery interval of ≤7 days was significantly associated with a reduced rate of periventricular leukomalacia or intraventricular haemorrhage grade III/IV (aOR 0.2; CI 95% 0.1-0.5), in-hospital mortality (0.3; 0.1-0.6), and the composite indicator (0.1; 0.1-0.3), whereas a single course of ACDs with an administration-to-delivery interval of >7 days did not significantly reduce the frequency of in-hospital mortality (0.7; 0.3-1.8). No significant differences in terms of benefit or risk were found when comparing repeated courses with a single complete course. CONCLUSION: In preterm twins, a single complete course of antenatal corticosteroids was associated with an improvement of severe neurological outcome, whereas reduced in-hospital mortality was seen only when the ACS-to-delivery interval was ≤7 days. TWEETABLE ABSTRACT: A single complete course of antenatal steroids reduced severe neurological morbidity in preterm twins (24-31 weeks).

A randomized clinical trial of the efficacy of single versus double-daily dose of oral iron for prevention of iron deficiency anemia in women with twin gestations.

OBJECTIVE: The study aims to assess the efficacy of single versus double-daily oral iron dose on prevention of iron deficiency anemia in women with twin gestations. MATERIALS AND METHODS: A randomized controlled trial (NCT02858505) conducted at Woman's Health Hospital, Assiut, Egypt, between August 2015 and June 2016 included 120 non-anemic pregnant women with twin gestations in the first trimester. Women were randomly assigned to either group I (27 mg elemental iron) or group II (54 mg elemental iron) daily starting from 12 weeks of pregnancy till 36 weeks. The primary outcomes included the mean level of hemoglobin, hematocrit and serum ferritin at 36 weeks' gestation. RESULTS: Both iron doses maintained the mean hemoglobin and hematocrit within the normal level from 12 weeks to 36 weeks (p = 0.378 and p = 0.244, respectively). However, the mean serum ferritin level was higher in group II than group I (p = 0.000) at 36 weeks' gestation. Moreover, women in group II reported more side effects than group I at 36 weeks' gestation. CONCLUSIONS: Doubling the prophylactic iron dose is comparable to single dose in the prevention of iron deficiency anemia among women with twin gestations with more side effects.

The role of antenatal corticosteroids in twin pregnancies complicated by preterm birth.

BACKGROUND: Data regarding the effects of antenatal corticosteroids in twin pregnancies are limited because of the insufficient number of women with twins enrolled in randomized controlled trials on antenatal corticosteroids. Furthermore, the interpretation of available data is limited by the fact that the interval from the administration of antenatal corticosteroids to delivery is greater than 7 days in a large proportion of twins, a factor that has been shown to affect the efficacy of antenatal corticosteroids and has not been controlled for in previous studies. OBJECTIVE: The objective of the study was to compare neonatal mortality and morbidity in preterm twins receiving a complete course of antenatal corticosteroids 1-7 days before birth to those who did not receive antenatal corticosteroids and to compare these outcome effects with those observed in singletons. STUDY DESIGN: We performed a retrospective cohort study using data collected on singleton and twin neonates born between 24(0/7) and 33(6/7) weeks' gestational age and were admitted to tertiary neonatal units in Canada between 2010 and 2014. A comparison of neonatal outcomes between twin neonates who received a complete course of antenatal corticosteroids 1-7 days before birth (n = 1758) and those who did not receive antenatal corticosteroids (n = 758) and between singleton neonates who received a complete course of antenatal corticosteroids 1-7 days before birth (n = 4638) and those did not receive antenatal corticosteroids (n = 2312) was conducted after adjusting for gestational age, sex, hypertension, outborn status, small for gestational age, parity, and cesarean birth. Adjusted odds ratios and 95% confidence intervals for various neonatal outcomes were calculated. RESULTS: Administration of a complete course of antenatal corticosteroids within 1-7 days before birth in both twins and singletons was associated with similar reduced odds of neonatal death (for twins adjusted odds ratio 0.42 [95% confidence interval, 0.24-0.76] and for singletons adjusted odds ratios, 0.38 [95% confidence interval, 0.28-0.50]; P = .7 for comparison of twins vs singletons), mechanical ventilation (for twins adjusted odds ratio, 0.47 [95% confidence interval, 0.35-0.63] and for singletons adjusted odds ratio, 0.47 [95% confidence interval, 0.41-0.55]; P = .9), respiratory distress syndrome (for twins adjusted odds ratio, 0.53 [95% confidence interval, 0.40-0.69], and for singletons adjusted odds ratio, 0.54 [95% confidence interval, 0.47-0.62]; P = .9) and severe neurological injury (for twins adjusted odds ratio, 0.50 [95% confidence interval, 0.30-0.83] and for singletons adjusted odds ratio, 0.45 [95% confidence interval, 0.34-0.59]; P = .7). Administration of a complete course of antenatal corticosteroids was not associated with a reduced odds of bronchopulmonary dysplasia, severe retinopathy of prematurity, or necrotizing enterocolitis in both twins and singletons. CONCLUSION: Administration of a complete course of antenatal corticosteroids 1-7 days before birth in twin pregnancies is associated with a clinically significant decrease in neonatal mortality, short-term respiratory morbidity, and severe neurological injury that is similar in magnitude to that observed among singletons.

A clinical opinion on how to manage the risk of preterm birth in twins based on literature review.

Twin pregnancies are prone to preterm birth and consequent morbidity. There is an increasing evidence base concerning the prediction and prevention of preterm birth in singletons, including the reduction of morbidity with therapies such as magnesium sulphate and antenatal corticosteroids. However, the research in twins is less clear, partly due to fewer numbers being investigated, but also evidence is largely based on twins without a previous history. Prophylactic interventions such as cerclage, progesterone and vaginal pessaries are increasingly showing benefit in singleton pregnancies with a prior history and when the cervix is short. Cerclage in twins has not been adequately researched in women with previous preterm birth, and as with singletons should not be used on the basis of a short cervix alone. Vaginal progesterone does not work in twins, but its value in high-risk twins, with a prior history and short cervix is uncertain. The vaginal pessary may be valuable in the twin with a short cervix. Currently, it is reasonable to extrapolate some of the evidence from singletons to twins, e.g. with antenatal corticosteroids and magnesium sulphate. Cerclage, vaginal pessaries and progesterone should not be routinely used in twin pregnancies without an additional high-risk factor such as prior history of preterm birth or short cervix, until further evidence is obtained.

Cohort Profile: Swedish Twin Study on Prediction and Prevention of Asthma (STOPPA).

Asthma is a common childhood disease and several risk factors have been identified; however, the impact of genes and environment is not fully understood. The aim of the Swedish Twin study On Prediction and Prevention of Asthma (STOPPA) is to identify environmental (birth characteristics and early life) and genetic (including epigenetic) factors as determinants for asthmatic disease. Based on the Child and Adolescent Twin Study in Sweden (CATSS) (parental interview at 9 or 12 years, N ~23,900) and an asthma and/or wheezing algorithm, we identified a sample of monozygotic (MZ) and dizygotic (DZ) same-sexed twin pairs. The twin pairs were classified as asthma concordant (ACC), asthma discordant (ADC) and healthy concordant (HCC). A sample of 9- to 14-year-old twins and their parents were invited to participate in a clinical examination. Background characteristics were collected in questionnaires and obtained from the National Health Registers. A clinical examination was performed to test lung function and capacity (spirometry with reversibility test and exhaled nitric oxide) and collect blood (serology and DNA), urine (metabolites), feces (microbiota), and saliva (cortisol). In total, 376 twin pairs (752 individual twins) completed the study, response rate 52%. All participating twins answered the questionnaire and >90% participated in lung function testing, blood-, and saliva sampling. This article describes the design, recruitment, data collection, measures, and background characteristics, as well as ongoing and planned analyses in STOPPA. Potential gains of the study include the identification of biomarkers, the emergence of candidates for drug development, and new leads for prevention of asthma and allergic disease.

Preimplantation genetic diagnosis (PGD) for genetic prion disorder due to F198S mutation in the PRNP gene.

IMPORTANCE: To describe the first case of preimplantation genetic diagnosis (PGD) and in vitro fertilization (IVF) performed for the prevention of genetic prion disease in the children of a 27-year-old asymptomatic woman with a family history of Gerstmann-Sträussler-Sheinker syndrome (GSS). OBSERVATIONS: PGD and fertilization cycles resulted in detection of 6 F198S mutation-free embryos. Of these, 2 were selected for embryo transfer to the patient's uterus, yielding a clinical twin pregnancy and birth of healthy but slightly premature offspring with normal development at age 27 months. CONCLUSION AND RELEVANCE: IVF with PGD is a viable option for couples who wish to avoid passing the disease to their offspring. Neurologists should be aware of PGD to be able to better consult at-risk families on their reproductive choices.

[Selective intrauterine growth restriction in monochorionic twin pregnancies]. / Selektywne wewnatrzmaciczne ograniczenie wzrastania w ciazach blizniaczych jednokosmówkowych.

Selective intrauterine growth restriction (sIUGR) is a major complication of monochorionic pregnancies, with potentially high risk of intrauterine fetal death or neurological dysfunction in both fetuses. Diagnostic ultrasound has contributed to the understanding of the pathophysiology of sIUGR and allowed to propose a classification. That, in turn, allows to interpret a wide clinical variety of sIUGR and, depending on the type, to propose a specific clinical management. The introduction of diagnosis based on Doppler studies enables the correct diagnosis of the disorders, fetal monitoring, to determine the prognosis and optimal strategies, and to propose the best therapeutic intervention.

Selective intrauterine growth restriction in monochorionic twins: pathophysiology, diagnostic approach and management dilemmas.

Selective intrauterine growth restriction (sIUGR) in monochorionic twins is associated with a substantial increase in perinatal mortality and morbidity for both twins. Clinical evolution depends on the combination of the effects of placental insufficiency in the IUGR twin with inter-twin blood transfer through placental anastomoses. Classification of sIUGR into types according to the characteristics of umbilical artery diastolic flow in the IUGR twin permits the differentiation of clinical and prognostic groups. sIUGR type I has normal diastolic flow and relatively good outcome. Type II is defined by persistently absent/reverse end-diastolic flow and is associated with a high risk of intrauterine demise of the IUGR twin and/or very preterm delivery. Type III is defined by the presence of intermittent absent/reverse end-diastolic flow (iAREDF), and is associated with 10-20% risk of unexpected fetal demise of the smaller twin and 10-20% risk of neurological injury in the larger twin. The management strategy for sIUGR with abnormal umbilical artery Doppler (types II and III) remains a challenge, and may include elective fetal therapy or close surveillance with fetal therapy or elective delivery in the presence of severe fetal deterioration. Small clinical series reporting the use of cord occlusion or laser therapy in severe cases suggest that the outcome of the larger twin might be improved. There is probably no single optimal strategy, since decisions will ultimately be influenced by the severity of IUGR, gestational age, parents' wishes and technical issues.

Single twin demise: consequence for survivors.

Multiple pregnancies, the majority of which are twins, are at substantially higher risk of fetal morbidity and mortality when compared with singleton pregnancies. Single fetal demise occurs in up to 6.2% of all twin pregnancies. It may cause considerable risk for the co-twin including increased risk of fetal loss, premature delivery, neurovascular injury and end-organ damage. In this review we seek to summarise the most contemporary literature on the aetiology of single twin demise, the pathophysiology of injury to the surviving twin and the evidence for current management strategies.

Case report: A unique presentation of severe tongue biting in 10 month-old twins with a novel approach to management.

BACKGROUND: Tongue biting in infants has a variety of aetiological factors and is a distressing problem. CASE REPORT: 10 month-old twin boys presented with severe ulceration of the tongue caused by self-mutilation and a maternal family history of this condition. TREATMENT: Thermoplastic splints were used to protect the tongue and facilitate healing, with denture fixative added to aid retention in the mouth. FOLLOW-UP: The twins have been recalled regularly and at their most recent review, two years after initial presentation, one twin did not need a splint at all, and the other suffered only from very occasional episodes of tongue biting. CONCLUSION: A conservative and well-tolerated approach to treatment for such problems is presented.

An examination of the relationship between movement problems and four common developmental disorders.

It has been well recognized since the days of "minimal brain dysfunction" (Clements, 1966) that various developmental disorders have a shared aetiology. Poor motor coordination has been implicated as one of the factors in these relationships. This study examines the different patterns in symptomatology of five developmental disorders, namely developmental coordination disorder (DCD), attention-deficit/hyperactivity disorder (ADHD), reading disorder (RD), oppositional defiant disorder (ODD), and conduct disorder (CD) in order to build on the genetic work from Martin, Levy, Piek, and Hay (2006) and Martin, Piek, and Hay (2006) examining the overlap of these disorders. Latent class analysis was used on questionnaire data from 1304 families from the Australian twin ADHD project (ATAP) to examine the patterns of comorbidity of the five disorders. We confirmed and added detail to the shared symptoms between DCD, ADHD, RD, and ODD, but found no links between CD symptoms and any other disorders. Despite the close link previously identified with ODD and CD, this finding suggests a different aetiology for CD.

Midlife fruit and vegetable consumption and risk of dementia in later life in Swedish twins.

OBJECTIVE: Diet may be associated with risk of dementia and Alzheimer disease (AD). The authors examined the association between fruit and vegetable consumption in midlife and risk for all types of dementia and AD. METHODS: Participants were 3,779 members of the Swedish Twin Registry who completed a diet questionnaire approximately 30 years before cognitive screening and full clinical evaluation for dementia as part of the study of dementia in Swedish Twins (HARMONY) study. Among the participants, 355 twins were diagnosed with dementia. Among these, 81 twin pairs were discordant for dementia (50 discordant for AD). Data were analyzed with logistic regression for the entire sample using generalized estimating equations to adjust for relatedness of twins and with conditional logistic regression for the co-twin control design. RESULTS: In fully adjusted models, a medium or great proportion of fruits and vegetables in the diet, compared with no or small, was associated with a decreased risk of dementia and AD. This effect was observed among women and those with angina. Similar, but nonsignificant, odds ratios were found in the co-twin control analyses. CONCLUSION: The findings suggest that higher fruit and vegetable consumption may reduce the risk of dementia, especially among women and those with angina pectoris in midlife.