Familial confounding or measurement error? How to interpret findings from sibling and co-twin control studies.

Epidemiological researchers often examine associations between risk factors and health outcomes in non-experimental designs. Observed associations may be causal or confounded by unmeasured factors. Sibling and co-twin control studies account for familial confounding by comparing exposure levels among siblings (or twins). If the exposure-outcome association is causal, the siblings should also differ regarding the outcome. However, such studies may sometimes introduce more bias than they alleviate. Measurement error in the exposure may bias results and lead to erroneous conclusions that truly causal exposure-outcome associations are confounded by familial factors. The current study used Monte Carlo simulations to examine bias due to measurement error in sibling control models when the observed exposure-outcome association is truly causal. The results showed that decreasing exposure reliability and increasing sibling-correlations in the exposure led to deflated exposure-outcome associations and inflated associations between the family mean of the exposure and the outcome. The risk of falsely concluding that causal associations were confounded was high in many situations. For example, when exposure reliability was 0.7 and the observed sibling-correlation was r = 0.4, about 30-90% of the samples (n = 2,000) provided results supporting a false conclusion of confounding, depending on how p-values were interpreted as evidence for a family effect on the outcome. The current results have practical importance for epidemiological researchers conducting or reviewing sibling and co-twin control studies and may improve our understanding of observed associations between risk factors and health outcomes. We have developed an app (SibSim) providing simulations of many situations not presented in this paper.

Second-versus first-born twin: comparison of short- and long-term outcomes.

PURPOSE: An ancient description of the competition between twins for first breath is found in the biblical story of Jacob and Esau (Genesis 25:26) when Jacob pulled his older brother's heel in the hope of becoming firstborn but to no avail. In this study, we sought to evaluate the short and long-term outcomes of twin pairs, comparing between the second- and first-born twin. METHODS: A population-based cohort study, including dichorionic twin deliveries occurring between the years 1991 and 2021 at Soroka University Medical Center. A General estimation equation (GEE) was applied to adjust for confounders. The incidence of offspring's hospitalizations due to various medical conditions was compared. Kaplan-Meier survival analyses compared cumulative morbidity. Cox proportional hazards models were used to control for confounders. RESULTS: 5507 twin deliveries met the inclusion criteria. Second-born twins had higher rates of cesarean deliveries, statistically significant in the GEE multivariable analysis. More first-twin fetuses were experiencing non-reassuring fetal heart rate patterns, although other obstetrical outcomes as well as mortality rates were comparable between groups. Second twins weighed lower than their older sibling (mean difference 33 g) and were more frequently SGA and low birthweight (1500-2500 g); (p < 0.05). Later during childhood, offspring of twin deliveries experienced notable morbidity due to infectious (23.8-24.1%), respiratory (10.5-10.9%), neurological (7.0-7.8%) and cardiovascular pathologies (1.7-1.9%) during childhood, that was unaffected by birth order. CONCLUSION: Other than birthweight differences, the birth order of dichorionic twins is not associated with adverse neonatal health indices, nor does it predict excess risk for morbidity during childhood.

Genetic and environmental influences on the progression from alcohol use disorder to alcohol-related medical conditions.

BACKGROUND: Medical conditions related to alcohol use disorders (AUD) represent a substantial public health concern. However, only a subset of individuals with AUD develop these conditions and the extent to which genetic and environmental factors that are shared with AUD, versus those distinct from it, contribute to this progression has not yet been determined. METHODS: Using data from Swedish national registries for a cohort born from 1932 to 1970 (N = 1,319,214, 48.9% women), we conducted twin-sibling biometric model fitting to examine the genetic and environmental sources of variance that contribute to the liability to alcohol-related medical conditions (AMC). Progression to AMC, determined using medical registry data, was contingent on an AUD registration, which was determined using medical and criminal registry data. RESULTS: We identified AUD registrations in 3.2% of women and 9.2% of men. Among individuals with an AUD registration, 14.4% of women and 15.4% of men had an AMC registration. In the final models, we constrained the beta pathway from AUD to AMC and the genetic and unique environmental paths to be equal across sexes. The beta path was estimated at 0.59. AMC was modestly heritable in women (A = 0.32) and men (A = 0.30). The proportion of total heritability unique to AMC was 39.6% among women and 41.3% among men. A higher proportion of total environmental variance was unique to AMC: 76.7% for women and 77.2% for men. In a sensitivity analysis limited to liver-related AMC, we observed similar results, with a slightly lower beta path from AUD to AMC (0.46) and higher proportions of AMC-specific genetic (70.0% in women; 71.7% in men) and environmental (84.5% in both sexes) variance. CONCLUSIONS: A moderate-to-substantial proportion of genetic and environmental variance that contributes to AMC risk is not shared with AUD, underscoring the need for additional gene identification efforts for AMC. Furthermore, the prominent influence of environmental factors specific to AMC provides a promising area for the identification of prevention targets. We did not observe significant sex differences in the etiology of AMC, although follow-up is warranted in other well-powered studies.

Association of body mass index and its long-term changes with cardiometabolic diseases: A nationwide twin study.

BACKGROUND & AIMS: The association between higher body mass index (BMI) and cardiometabolic diseases (CMDs, including type 2 diabetes and cardiovascular diseases) is not well understood. We aimed to examine the association of BMI and its long-term changes with cardiometabolic diseases (CMDs) and explore the role of familial background and healthy lifestyle in this association. METHODS: Within the Swedish Twin Registry, 36 622 CMD-free individuals aged ≥40 were followed for up to 16 years. BMI data was collected at baseline and 25-35 years prior to baseline. Healthy lifestyle (non-smoking, no/mild alcohol consumption, and regular physical activity) was assessed as unfavourable (none or only one of these factors) vs. favourable (two or three). Incident CMDs were identified by linkage with the Swedish National Patient Registry. Two strategies were followed: 1) Cox models in all twin individuals; 2) stratified Cox models in CMD-discordant twin pairs. RESULTS: At baseline, 16 195 (44.2%) study participants had overweight/obesity (BMI ≥ 25 kg/m2) and 11 202 (30.6%) developed CMDs over follow-up. Among all participants, the hazard ratio (HR) and 95% confidence interval (CI) of developing any CMD was 1.52 (1.45-1.58) for people with overweight/obesity compared to normal BMI (20-25 kg/m2). Compared to stable normal BMI, HRs (95% CIs) of CMDs were 1.28 (1.02-1.59) and 1.33 (1.24-1.43) for only earlier life or only later life overweight/obesity, respectively, and 1.69 (1.55-1.85) for overweight/obesity both in earlier and later life. In stratified Cox analyses conducted among all CMD-discordant twin pairs, overweight/obesity was associated with greater risk of CMDs (1.37, 95% CI 1.18-1.61). In joint effect analysis, the risk of CMDs related to overweight/obesity was diminished 32% among people with a favourable lifestyle (1.51, 95% CI 1.44-1.58) compared to those with overweight/obesity and an unfavourable lifestyle (2.20, 95% CI 2.03-2.38). CONCLUSIONS: Overweight/obesity is associated with an increased risk of CMDs, and shared genetic and early-life environmental factors might not account for this association. However, a favourable lifestyle could attenuate the risk of high BMI-related CMDs.

Dual demise following laser surgery for twin-twin transfusion syndrome: Analysis of 52 cases at a single fetal surgery center.

OBJECTIVE: To evaluate all individual cases of dual twin demise following laser surgery for twin-twin transfusion syndrome (TTTS). METHOD: This is an analysis of all monochorionic diamniotic twin gestations with TTTS complicated by dual demise following laser surgery from 2006 to 2019. Cases were reviewed by (1) a fetal surgeon researcher and (2) a panel of independent experienced maternal-fetal medicine specialists to code an etiology of demise for the donor and recipient, and to assess for possible preventability. RESULTS: Of 753 twins that underwent laser surgery for TTTS, 52 (6.9%) had postoperative dual demise. In this subgroup, gestational age at surgery was 19.5 (16.1-24.9) weeks, and 36 (69.2%) patients were Quintero stage III and IV. The most common etiology was the spectrum of disorders leading to preterm delivery, which included cervical insufficiency, preterm premature rupture of membranes, and preterm labor (44.2% and 48.1%, donor and recipient, respectively). Some degree of preventability was estimated for 23.1% of dual demises. CONCLUSIONS: The most common cause of dual demise post laser surgery for TTTS was preterm birth, reinforcing the need for studies regarding the etiology and prevention of post-fetoscopy prematurity. Nearly one-quarter of dual demise cases were deemed potentially preventable.

Feeding Twins with Human Milk and Factors Associated with Its Duration: A Qualitative and Quantitative Study in Southern Italy.

BACKGROUND: Over the past year, there has been a rise in twin births. The current scientific consensus recommended breast-feed milk for all newborns for at least 6 months. They stated that it is possible to meet the nutritional needs of two or more newborns with only one mother's milk. More information would be desirable about the factors that influence or lead to the initiation and interruption of breastfeeding. The quality of the evidence available from multiple studies has been inconclusive and therefore led to controversial interpretations and practices. AIMS: The first aim of this study was to analyze the extent of the feeding of multiples with breast milk in the experience of our clinical unit in terms of incidence and duration. The second objective was to evaluate the correlation between maternal, perinatal and neonatal variables with breast milk feeding rates and duration. METHODS: The study was conducted between 2015 and 2020, in a NICU in Southern Italy (San Giovanni Rotondo, Foggia). Sixty-one women who have given birth to multiples were enrolled into the study. Newborn data were retrospectively collected by informatic database and breastfeeding information were collected by a questionnaire. RESULTS: In our centre, the percentage of twins out of the total number of births over the years has almost doubled from 1.28% in 2015 to 2.48% in 2020 and the 88% of twins are premature. 18.1% received breast milk for more than 6 months and 6.3% received it for more than 12 months. Infants of lower gestational age and weight, born to multiparous, more mature and medium-high schooling mothers received breast milk for a longer period. 35% of women explained that the interruption of breastfeeding was due to the insufficient milk production and 41% to the stress and difficulties in managing the twins. Qualitative analysis of maternal narrative revealed, for many of them, the awareness of the importance of breastfeeding and the efforts made to try to give breast milk, but also fears about the quantity of milk and satiety of their children. CONCLUSIONS: It is important to identify the factors both favoring and obstructing maternal milk feeding of multiples and it would be desirable the activation of a network of training and support for mothers after discharge, with particular regard to the categories found to be less inclined.

Adolescent cannabis use and adult psychoticism: A longitudinal co-twin control analysis using data from two cohorts.

Observational studies have repeatedly linked cannabis use and increased risk of psychosis. We sought to clarify whether this association reflects a causal effect of cannabis exposure or residual confounding. We analyzed data from two cohorts of twins who completed repeated, prospective measures of cannabis use (N = 1544) and cannabis use disorder symptoms (N = 1458) in adolescence and a dimensional measure of psychosis-proneness (the Personality Inventory for DSM-5 Psychoticism scale) in adulthood. Twins also provided molecular genetic data, which were used to estimate polygenic risk of schizophrenia. Both cumulative adolescent cannabis use and use disorder were associated with higher Psychoticism scores in adulthood. However, we found no evidence of an effect of cannabis on Psychoticism or any of its facets in co-twin control models that compared the greater-cannabis-using twin to the lesser-using co-twin. We also observed no evidence of a differential effect of cannabis on Psychoticism by polygenic risk of schizophrenia. Although cannabis use and disorder are consistently associated with increased risk of psychosis, the present results suggest this association is likely attributable to familial confounds rather than a causal effect of cannabis exposure. Efforts to reduce the prevalence and burden of psychotic illnesses thus may benefit from greater focus on other therapeutic targets. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Cohort Selection In Utero against Male Twins and Childhood Cancers: A Population-Based Register Study.

BACKGROUND: Cancer ranks as the second leading cause of death among children ages 1 to 14 years in the United States. Previous research finds that strong cohort selection in utero against males precedes a reduction in live-born males considered frail. We examine whether such cohort selection in utero may similarly affect the frequency of childhood cancers among male live births. METHODS: We examined 1,368 childhood cancers among males born in Sweden over 144 months, from January 1990 to December 2001, and followed to age 15 in the Swedish Cancer Registry. We retrieved the count of male twins by birth month from the Swedish Birth Registry. We applied autoregressive, integrated, moving average time-series methods to identify and control for temporal patterns in monthly childhood cancers and to evaluate robustness of results. RESULTS: Fewer childhood cancers occur among monthly male birth cohorts with elevated selection in utero (i.e., a low count of live-born male twins). This association appears in the concurrent month (coef = 0.04; 95% CI, 0.001-0.079) as well as in the following month in which most births from the twin's conception cohort are "scheduled" to be born (coef = 0.055; 95% CI, 0.017-0.094). CONCLUSIONS: Elevated cohort selection in utero may reduce the number of frail male gestations that would otherwise have survived to birth and received a cancer diagnosis during childhood. IMPACT: This novel result warrants further investigation of prenatal exposures, including those at the population level, that may induce cohort selection in utero for some cancer types but not others.

Perinatal risk factors of neurodevelopmental impairment after fetoscopic laser photocoagulation for twin-twin transfusion syndrome: systematic review and meta-analysis.

OBJECTIVE: Monochorionic twins with twin-twin transfusion syndrome (TTTS) treated with fetoscopic laser photocoagulation (FLP) are at increased risk of neurodevelopmental impairment (NDI). This meta-analysis aimed to identify the prevalence of and perinatal risk factors for NDI in TTTS survivors treated with FLP. METHODS: We performed a search in PubMed, EMBASE, Scopus and Web of Science, from inception to 13 February 2021, for studies evaluating perinatal risk factors for NDI in children diagnosed prenatally with TTTS managed by FLP. Data on severity of TTTS at the time of diagnosis, defined according to the Quintero staging system, FLP-related complications and perinatal outcomes were compared between children with a history of TTTS treated with FLP with and those without NDI, which was defined as performance on a cognitive or developmental assessment tool ≥ 2 SD below the mean or a defined motor or sensory disability. A random-effects model was used to pool the mean differences or odds ratios (OR) with the corresponding 95% CIs. Heterogeneity was assessed using the I2 statistic. RESULTS: Nine studies with a total of 1499 TTTS survivors were included. The overall incidence of NDI was 14.0% (95% CI, 9.0-18.0%). The occurrence of NDI in TTTS survivors was associated with later gestational age (GA) at FLP (mean difference, 0.94 weeks (95% CI, 0.50-1.38 weeks); P < 0.0001, I2 = 0%), earlier GA at delivery (mean difference, -1.44 weeks (95% CI, -2.28 to -0.61 weeks); P = 0.0007, I2 = 49%) and lower birth weight (mean difference, -343.26 g (95% CI, -470.59 to -215.92 g); P < 0.00001, I2 = 27%). Evaluation of different GA cut-offs showed that preterm birth before 32 weeks was associated with higher risk for NDI later in childhood (OR, 2.25 (95% CI, 1.02-4.94); P = 0.04, I2 = 35%). No statistically significant difference was found between cases with and those without NDI with respect to Quintero stage of TTTS, recipient or donor status, development of postlaser twin anemia-polycythemia sequence, recurrence of TTTS and incidence of small- for-gestational age or cotwin fetal demise. CONCLUSIONS: TTTS survivors with later GA at the time of FLP, earlier GA at delivery and lower birth weight are at higher risk of developing NDI. No significant association was found between Quintero stage of TTTS and risk of NDI. Our findings may be helpful for parental counseling and highlight the need for future studies to understand better the risk factors for NDI in TTTS survivors. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Early expressions of psychopathology and risk associated with trans-diagnostic transition to mood and psychotic disorders in adolescents and young adults.

OBJECTIVES: The heterogeneity and comorbidity of major mental disorders presenting in adolescents and young adults has fostered calls for trans-diagnostic research. This study examines early expressions of psychopathology and risk and trans-diagnostic caseness in a community cohort of twins and non-twin siblings. METHODS: Using data from the Brisbane Longitudinal Twin Study, we estimated median number of self-rated psychiatric symptoms, prevalence of subthreshold syndromes, family history of mood and/or psychotic disorders, and likelihood of subsequent trans-diagnostic caseness (individuals meeting diagnostic criteria for mood and/or psychotic syndromes). Next, we used cross-validated Chi-Square Automatic Interaction Detector (CHAID) analyses to identify the nature and relative importance of individual self-rated symptoms that predicted trans-diagnostic caseness. We examined the positive and negative predictive values (PPV; NPV) and accuracy of all classifications (Area under the Curve and 95% confidence intervals: AUC; 95% CI). RESULTS: Of 1815 participants (Female 1050, 58%; mean age 26.40), more than one in four met caseness criteria for a mood and/or psychotic disorder. Examination of individual factors indicated that the AUC was highest for subthreshold syndromes, followed by family history then self-rated psychiatric symptoms, and that NPV always exceeded PPV for caseness. In contrast, the CHAID analysis (adjusted for age, sex, twin status) generated a classification tree comprising six trans-diagnostic symptoms. Whilst the contribution of two symptoms (need for sleep; physical activity) to the model was more difficult to interpret, CHAID analysis indicated that four self-rated symptoms (sadness; feeling overwhelmed; impaired concentration; paranoia) offered the best discrimination between cases and non-cases. These four symptoms showed different associations with family history status. CONCLUSIONS: The findings need replication in independent cohorts. However, the use of CHAID might provide a means of identifying specific subsets of trans-diagnostic symptoms representing clinical phenotypes that predict transition to caseness in individuals at risk of onset of major mental disorders.

Should singleton birth weight standards be applied to identify small-for-gestational age twins?: analysis of a retrospective cohort study.

BACKGROUND: Twin birth weight percentiles are less popular in clinical management among twin pregnancies compared with singleton ones in China. This study aimed to compare the incidence and neonatal outcomes of small for gestational age (SGA) twins between the use of singleton and twin birth weight percentiles. METHODS: This was a retrospective cohort study of 3,027 pregnancies with liveborn twin pairs at gestational age of > 28 weeks. The newborns were categorized as SGA when a birthweight was less than the 10th percentile based on the singleton and twin references derived from Chinese population. Logistic regression models with generalized estimated equation (GEE) were utilized to evaluate the association between SGA twins and neonatal outcomes including neonatal unit admission, neonatal jaundice, neonatal respiratory distress (NRDS), neonatal asphyxia, ventilator support, hypoxic ischemic encephalopathy (HIE), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), intracranial hemorrhage (ICH), culture-proven sepsis, neonatal death within 28 days after birth as well as the composite outcome. RESULTS: The incidence of SGA was 33.1 % based on the singleton reference and 7.3 % based on the twin reference. Both of SGA newborns defined by the singleton and twin references were associated with increases in neonatal unit admission, neonatal jaundice and ventilator support. In addition, SGA newborns defined by the twin reference were associated with increased rates of BPD (aOR, 2.61; 95 % CI: 1.18-5.78) as well as the severe composite outcome (aOR, 1.93; 95 % CI: 1.07-3.47). CONCLUSIONS: The use of singleton birth weight percentiles may result in misdiagnosed SGA newborns in twin gestations and the twin birth weight percentiles would be more useful to identify those who are at risk of adverse outcomes.

Fetal loss after chorionic villus sampling in twin pregnancy.

OBJECTIVE: To estimate the chorionic villus sampling (CVS)-related risk of fetal loss in twin pregnancy after adjustment for chorionicity, nuchal translucency thickness (NT), intertwin discordance in crown-rump length (CRL), maternal demographic characteristics and serum pregnancy-associated plasma protein-A (PAPP-A) and free ß-human chorionic gonadotropin (ß-hCG). METHODS: This was a multicenter study from eight fetal medicine units in which the leadership were trained at the Harris Birthright Research Centre for Fetal Medicine in London, UK, and in which the protocols for screening, invasive testing and pregnancy management are similar. Data were obtained prospectively from women with twin pregnancy undergoing routine ultrasound examination at 11-13 weeks' gestation. Multivariable logistic regression analysis with backward stepwise elimination was used to examine whether CVS provided a significant independent contribution to the prediction of risk of fetal loss after adjusting for maternal and pregnancy characteristics, including maternal age, racial origin and weight, method of conception, smoking status, parity, chorionicity, intertwin discordance in CRL, fetal NT ≥ 95th percentile and free ß-hCG and PAPP-A multiples of the median. Similarly, within the CVS group, multivariable logistic regression analysis was used to investigate the effect of the number of intrauterine needle insertions and size of the needle on the risk of fetal loss. RESULTS: The study population of 8581 twin pregnancies undergoing ultrasound examination at 11-13 weeks' gestation included 316 dichorionic and 129 monochorionic twins that had CVS. First, in twin pregnancies undergoing CVS, compared to those not undergoing CVS, there was a 2-fold increased risk of fetal loss at < 24 weeks' gestation and of loss at any stage in pregnancy. Second, the factors providing a significant independent contribution to the prediction of miscarriage or fetal loss in twin pregnancy were increased maternal weight, black racial origin, monochorionicity, and more so monoamnionicity, large intertwin discordance in CRL and increased fetal NT, and, in the case of fetal loss at any stage, there was also a contribution from assisted conception and low serum PAPP-A. Third, after adjustment for maternal and pregnancy characteristics, CVS did not provide a significant contribution to the risk of fetal loss. Fourth, in twin pregnancies that had CVS, there was no significant contribution to fetal loss from the number of intrauterine needle insertions or needle size. CONCLUSION: The 2-fold increased risk of fetal loss following CVS in twin pregnancy can, to a great extent, be explained by maternal and pregnancy characteristics rather than the invasive procedure itself. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Gestational diabetes mellitus and risks of gynecologic cancers: Results from a nationwide Swedish twin study.

BACKGROUND: Type 2 diabetes has been associated with increased risk of gynecologic cancers, yet the effect of gestational diabetes mellitus (GDM) on gynecologic cancers is unclear. OBJECTIVES: To examine associations between GDM history and subsequent gynecologic cancers in parous women, and to explore whether gestational hypertension (GH) plays a role in the associations. STUDY DESIGN: The population-based cohort study included 15,941 individuals from the Swedish Twin Registry. The history of GDM and GH was ascertained based on self-reports. Incident cases of gynecologic cancers (including cancers of the cervix, uterus, ovaries and other female genitalia) were obtained from the National Patients Registry and the Swedish Cancer Registry. Generalized estimating equation models were applied to analyze associations between GDM and gynecologic cancers. Stratified analysis was used to explore whether associations between GDM and gynecologic cancers differed by GH. Additive and multiplicative interactions were calculated between GDM and GH. RESULTS: Of all participants, 350 (2.2%) had GDM, and 1762 (11.1%) had incident gynecologic cancers. No statistically significant associations were found between GDM and risks of any gynecologic cancers. However, GDM was associated with an increased risk of ovarian cancer (OR = 5.29, 95% CI: 1.63-17.19) in women with GH. Interactions between GDM and GH were observed on the additive scale (Attributable proportion due to interaction: 0.86, 95% CI 0.42-1.30, P < 0.001). CONCLUSIONS: The associations between GDM and risks of gynecologic cancers were not evident, but the effect of GDM on the risk of ovarian cancer was modified by GH. Further validation in larger cohorts is warranted.

Body Mass Index Differentially Moderates Heritability of Total Joint Replacement Due to Hip and Knee Osteoarthritis: A Cohort Study of 29,893 Swedish Twin Pairs.

BACKGROUND: Osteoarthritis and obesity are diseases with high prevalence, and they share common etiologies. We investigated the sex-specific genetic susceptibility to hip and knee osteoarthritis necessitating total joint replacement (TJR), and how body mass index (BMI) moderated the heritability of these osteoarthritis phenotypes. METHODS: We linked 29,893 twin pairs with information on BMI in the Swedish Twin Registry with the Swedish National Patient Register to identify twins who underwent primary TJR of the hip or knee combined with a concomitant diagnosis of primary osteoarthritis of these joints. Structural equation modeling was used to calculate the heritability of hip and knee osteoarthritis treated with TJR, with estimates adjusted for the first available BMI, birth year, and sex. We also investigated how heritability varied with BMI treated as a continuous variable. RESULTS: Similar heritability estimates for hip replacement (0.65 [95% confidence interval (CI), 0.59 to 0.70]) and knee replacement (0.57 [95% CI, 0.50 to 0.64]) were found. Heritability decreased with higher BMI in both sexes for hip replacement and in men for knee replacement. In contrast, heritability for knee replacement increased with higher BMI in women; the estimate was 0.37 (90% likelihood interval [LI], 0.25 to 0.49) for a BMI of 20 kg/m2 and 0.87 (90% LI, 0.68 to 0.94) for a BMI of 35 kg/m2. CONCLUSIONS: In our population, heritability explained, on average, about half of the susceptibility to undergo primary TJR of the hip or knee with the indication of primary osteoarthritis, but it varied with BMI and sex. We demonstrated substantial heritability for knee replacement in obese women. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

The association between maternal and foetal factors with birth weight discordance in twins from Yucatan, Mexico.

Birth weight discordance (BWD) is not an uncommon event in twin pregnancies and can be associated with maternal and newborn characteristics. We aimed to analyse the association between maternal sociodemographic and newborn characteristics with BWD in twin infants born in Yucatan, Mexico, during 2008-2017 (n = 2091 pairs). BWD was calculated as the percentage of birth weight of the heavier twin. We defined three categories of BWD: concordant twins: <15%, mild-discordant: 15-24%, and severe discordant: ≥25%. A multinomial logistic regression model was used to analyse the association between maternal sociodemographic and newborn characteristics with BWD. Seventy-four percent (n = 1547) of twin pairs were classified as concordant, 17% (n = 356) met the criteria for mild-discordance and 9% (n = 188) for severe discordance. The odds for mild-discordance were significantly lower for mothers with medium level of education and in the highest quartile of total twin birth weight (TBW). Opposite-sex twin pairs showed increased odds for mild-discordance compared with same-sex pairs. The odds for severe discordance increased as mothers were in older age groups and decreased as TBW increased. Our rates of BWD are similar to those reported in populations from wealthier countries and maternal age and education, infants' sex, and TBW are associated with BWD.

Twin chorionicity-specific population birth-weight charts adjusted for estimated fetal weight.

OBJECTIVES: To construct chorionicity-specific birth-weight reference charts for dichorionic diamniotic (DCDA) and monochorionic diamniotic (MCDA) twin pregnancies, incorporating estimated-fetal-weight (EFW) data in order to adjust for the relationship between suboptimal growth and preterm delivery. An additional aim was to determine if the inclusion of complicated twin pregnancies impacts on the reference charts produced. METHODS: The inclusion criteria for this retrospective cohort study were twin pregnancy of known DCDA or MCDA chorionicity, known pregnancy outcome, last ultrasound scan within 14 days before birth and delivery between 25 and 38 weeks' gestation (Analysis A). An analysis was also conducted excluding pregnancies with complications recorded (Analysis B). Previously published twin EFW reference ranges were used in the analysis. A joint statistical model for EFW and observed birth weight for each pregnancy was created in order to estimate population birth-weight reference ranges corresponding to the distribution expected if all pregnancies delivered at any given gestational age. It was not assumed that the median EFW was equal to birth weight for any given gestational age. The models were fitted using a Bayesian approach. RESULTS: We retrieved data on 1664 twin pregnancies, of which 707 DCDA and 241 MCDA pregnancies met the inclusion criteria. In Analysis A, the estimated population median birth weight was similar to the median EFW at around 27 weeks' gestation but fell below the EFW values with increasing gestation, being 156 g lower in both DCDA and MCDA pregnancies at 35 weeks; this finding was confirmed by direct comparison of the last EFW and birth-weight values in each pregnancy. When the analysis was repeated after excluding complicated twin pregnancies (Analysis B), compared with Analysis A, there was very little difference in the median birth-weight results obtained across gestation. The largest absolute difference between Analyses A and B for DCDA twins was at 31, 32 and 33 weeks, with a 9-g lower median birth weight in Analysis A compared with Analysis B. The largest absolute difference for MCDA twins was greater than that for DCDA twins, with a 21-g lower median birth weight at 25 weeks in Analysis A compared with Analysis B. CONCLUSIONS: We have established population chorionicity-specific birth-weight reference charts for DCDA and MCDA twin pregnancies, corresponding to the range expected were all pregnancies to deliver at any given gestational age. In this population of twins, the median birth weight was consistently lower than that reported for singletons, and there was variation in the median birth weight at different gestational ages according to chorionicity. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. - Legal Statement: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Twins Compared with Singletons.

OBJECTIVES: It is well known that twin pregnancies confer a high degree of adverse perinatal outcomes. Fetal growth restriction, preterm labor/delivery, and hypertensive disorders of pregnancy are among the causal etiologies associated. Hematologic parameters, specifically, the neutrophil:lymphocyte ratio (NLR), the platelet:lymphocyte ratio (PLR), and some of the routine complete blood cell count components denote a peculiar inflammatory and immunologic profile and have been used as clinical markers for specific obstetric syndromes. To our knowledge, no study has ever evaluated NLR/PLR in twins as a distinct population from singletons. Our primary objective was to analyze NLR/PLR in twins compared with singletons. Our secondary objective was to compare white blood cells, neutrophils, lymphocytes, and platelets between twins and singletons. METHODS: We conducted a retrospective case-control study comparing NLR/PLR markers in twin gestations (dichorionic/diamniotic and monochorionic/dichorionic) versus singleton pregnancies, from January 2019 to April 2020. We excluded pregnancies with potential confounding factors such as human immunodeficiency virus, chronic hypertension, smoking, pregestational diabetes mellitus, or cases with miscarriage/intrauterine fetal demise. We included twin pregnancies (two fetuses) as cases and singletons as controls. RESULTS: We recruited 29 twins and 29 singletons, matched for age, body mass index, and parity. NLR was statistically significantly higher in the first trimester in twins compared with singletons (3.3 vs 2.7, P < 0.01) and the platelet value was lower in the second trimester in twins compared with singletons (199 vs 251, P = 0.01). CONCLUSIONS: We speculate that a decrease in NLR from the first to the second trimester and a decrease in platelet in the second trimester reflect both the physiologic inflammatory/immune reaction of early pregnancy and denote a vital response for the development of normal placentation in twin gestations.

Planned Cesarean or planned vaginal delivery for twins: secondary analysis of randomized controlled trial.

OBJECTIVE: To evaluate whether there is a differential benefit of planned Cesarean delivery (CD) over planned vaginal delivery (VD) in women with a twin pregnancy and the first twin in cephalic presentation, depending on prespecified baseline maternal and pregnancy characteristics, and/or gestational age (GA) at delivery. METHODS: This was a secondary analysis of the Twin Birth Study, which included 2804 women with a twin pregnancy and the first twin (Twin A) in cephalic presentation between 32 + 0 and 38 + 6 weeks' gestation at 106 centers in 25 countries. Women were assigned randomly to either planned CD or planned VD. The main outcome measure was composite adverse perinatal outcome, defined as the occurrence of perinatal mortality or serious neonatal morbidity in at least one twin. The baseline maternal and pregnancy characteristics (markers) considered were maternal age, parity, history of CD, use of antenatal corticosteroids, estimated fetal weight (EFW) of Twin A, EFW of Twin B, > 25% difference in EFW between the twins, presentation of Twin B, chorionicity on ultrasound, method of conception, complications of pregnancy, ruptured membranes at randomization and GA at randomization. Separate logistic regression models were developed for each marker in order to model composite adverse perinatal outcome as a function of the specific marker, planned delivery mode and the interaction between these two terms. In addition, multivariable logistic regression analysis with backward variable elimination was performed separately in each arm of the trial. The association between planned mode of delivery and composite adverse perinatal outcome, according to GA at delivery, was assessed using logistic regression analysis. RESULTS: Of the 2804 women initially randomized, 1391 were included in each study arm. None of the studied baseline markers was associated with a differential benefit of planned CD over planned VD in the rate of composite adverse perinatal outcome. GA at delivery was associated differentially with composite adverse perinatal outcome in the treatment arms (P for interaction < 0.001). Among pregnancies delivered at 32 + 0 to 36 + 6 weeks, there was a trend towards a lower rate of composite adverse perinatal outcome in those in the planned-VD group compared with those in planned-CD group (29 (2.2%) vs 48 (3.6%) cases; odds ratio (OR) 0.62 (95% CI, 0.37-1.03)). In pregnancies delivered at or after 37 + 0 weeks, planned VD was associated with a significantly higher rate of composite adverse perinatal outcome, as compared with planned CD (23 (1.5%) vs 10 (0.7%) cases; OR, 2.25 (95% CI, 1.06-4.77)). CONCLUSION: The perinatal outcome of twin pregnancies with the first twin in cephalic presentation may differ depending on GA at delivery and planned mode of delivery. At 32-37 weeks, planned VD seems to be favorable, while, from around 37 weeks onwards, planned CD might be safer. The absolute risks of adverse perinatal outcomes at term are low and must be weighed against the increased maternal risks associated with planned CD. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.