Pregnancy outcomes of monochorionic diamniotic and dichorionic diamniotic twin pregnancies conceived by assisted reproductive technology and conceived naturally: a study based on chorionic comparison.

OBJECTIVE: To evaluate monochorionic diamniotic (MCDA) and dichorionic diamniotic (DCDA) twin pregnancies conceived by assisted reproductive technology (ART) and conceived naturally. METHODS: We retrospectively analyzed the data on twin pregnancies conceived by ART from January 2015 to January 2022,and compared pregnancy outcomes of MCDA and DCDA twins conceived by ART with those of MCDA and DCDA twins conceived naturally, pregnancy outcomes between MCDA and DCDA twins conceived by ART, and pregnancy outcomes of DCT and TCT pregnancies reduced to DCDA pregnancies with those of DCDA pregnancies conceived naturally. RESULT: MCDA pregnancies conceived by ART accounted for 4.21% of the total pregnancies conceived by ART and 43.81% of the total MCDA pregnancies. DCDA pregnancies conceived by ART accounted for 95.79% of the total pregnancies conceived by ART and 93.26% of the total DCDA pregnancies. Women with MCDA pregnancies conceived by ART had a higher premature delivery rate, lower neonatal weights, a higher placenta previa rate, and a lower twin survival rate than those with MCDA pregnancies conceived naturally (all p < 0.05). Women with DCDA pregnancies conceived naturally had lower rates of preterm birth, higher neonatal weights, and higher twin survival rates than women with DCDA pregnancies conceived by ART and those with DCT and TCT pregnancies reduced to DCDA pregnancies (all p < 0.05). CONCLUSION: Our study confirms that the pregnancy outcomes of MCDA pregnancies conceived by ART are worse than those of MCDA pregnancies conceived naturally. Similarly, the pregnancy outcomes of naturally-conceived DCDA pregnancies are better than those of DCDA pregnancies conceived by ART and DCT and TCT pregnancies reduced to DCDA pregnancies.

Tissue-specific nonheritable influences drive endometrial immune system variation.

Although human twin studies have revealed the combined contribution of heritable and environmental factors in shaping immune system variability in blood, the contribution of these factors to immune system variability in tissues remains unexplored. The human uterus undergoes constant regeneration and is exposed to distinct environmental factors. To assess uterine immune system variation, we performed a system-level analysis of endometrial and peripheral blood immune cells in monozygotic twins. Although most immune cell phenotypes in peripheral blood showed high genetic heritability, more variation was found in endometrial immune cells, indicating a stronger influence by environmental factors. Cytomegalovirus infection was identified to influence peripheral blood immune cell variability but had limited effect on endometrial immune cells. Instead, hormonal contraception shaped the local endometrial milieu and immune cell composition with minor influence on the systemic immune system. These results highlight that the magnitude of human immune system variation and factors influencing it can be tissue specific.

Heritability of Gene Expression Measured from Peripheral Blood in Older Adults.

The contributions of genetic variation and the environment to gene expression may change across the lifespan. However, few studies have investigated the heritability of blood gene expression in older adults. The current study therefore aimed to investigate this question in a community sample of older adults. A total of 246 adults (71 MZ and 52 DZ twins, 69.91% females; mean age-75.79 ± 5.44) were studied. Peripheral blood gene expression was assessed using Illumina microarrays. A heritability analysis was performed using structural equation modelling. There were 5269 probes (19.9%) from 4603 unique genes (23.9%) (total 26,537 probes from 19,256 genes) that were significantly heritable (mean h2 = 0.40). A pathway analysis of the top 10% of significant genes showed enrichment for the immune response and ageing-associated genes. In a comparison with two other gene expression twin heritability studies using adults from across the lifespan, there were 38 out of 9479 overlapping genes that were significantly heritable. In conclusion, our study found ~24% of the available genes for analysis were heritable in older adults, with only a small number common across studies that used samples from across adulthood, indicating the importance of examining gene expression in older age groups.

Can flow proneness be protective against mental and cardiovascular health problems? A genetically informed prospective cohort study.

Flow is a phenomenon where one experiences optimal challenge, marked by an intense, effortless, and rewarding concentration on a task. Past research shows that flow proneness is associated with good mental and cardiovascular health. However, this research has been primarily cross-sectional, based on self-report data, and has not controlled for potential confounding effects of neuroticism. In a large, longitudinal twin sample (N = 9361), we used nationwide patient registry data to test whether flow proneness predicted registry-based diagnoses of depression, anxiety, schizophrenia, bipolar disorder, stress-related disorders, or cardiovascular diseases. We used survival analyses taking time to diagnosis into account to test if (a) there is a relationship between flow proneness and health diagnoses over time, (b) neuroticism confounds this relationship, and (c) the relationship remains present within discordant monozygotic twin pairs (N = 952), thereby controlling for genetic and shared environmental confounding. Individuals with higher flow proneness had a decreased risk of receiving diagnoses for depression (16%; CI [14%, 18%]), anxiety (16%; CI [13%, 18%]), schizophrenia (15%; CI [4%, 25%]), bipolar (12%; CI [6%, 18%]), stress-related (9%; CI [9%, 12%]), and cardiovascular disorders (4%; CI [1%, 8%]). When controlling for neuroticism, higher flow proneness still decreased the risk of depression (6%; CI [3%, 9%]) and anxiety diagnoses (5%; CI [1%, 8%]). Monozygotic twins who experienced more flow than their co-twin had a lower risk for depression (16%; CI [5%, 26%]) and anxiety (13%; CI [1%, 24%]), though only the association with depression remained significant when also controlling for neuroticism (13%; CI [1%, 24%]). Findings are in line with a causal protective role of flow experiences on depression and potentially anxiety and highlight that neuroticism and familial factors are notable confounding factors in observed associations between flow proneness and health outcomes.

Common genetic factors for uncontrolled eating mechanisms.

OBJECTIVE: Reward-based eating drives are putative mechanisms of uncontrolled eating implicated in obesity and disordered eating (e.g., binge eating). Uncovering the genetic and environmental contributions to reward-related eating, and their genetic correlation with BMI, could shed light on key mechanisms underlying eating and weight-related disorders. METHOD: We conducted a classical twin study to examine how much variance in uncontrolled eating phenotypes and body mass index (BMI) was explained by genetic factors, and the extent that these phenotypes shared common genetic factors. 353 monozygotic twins and 128 dizygotic twins completed the Reward-based Eating Drive 13 scale, which measures three distinct uncontrolled eating phenotypes (loss of control over eating, preoccupation with thoughts about food, and lack of satiety), and a demographic questionnaire which included height and weight for BMI calculation. We estimated additive genetic (A), common environmental (C), and unique environmental (E) factors for each phenotype, as well as their genetic correlations, with a multivariate ACE model. A common pathway model also estimated whether genetic variance in the uncontrolled eating phenotypes was better explained by a common latent uncontrolled eating factor. RESULTS: There were moderate genetic correlations between uncontrolled eating phenotypes and BMI (.26-.41). Variance from the uncontrolled eating phenotypes was also best explained by a common latent uncontrolled eating factor that was explained by additive genetic factors (52%). DISCUSSION: These results suggest that uncontrolled eating phenotypes are heritable traits that also share genetic variance with BMI. This has implications for understanding the cognitive mechanisms that underpin obesity and disordered eating. PUBLIC SIGNIFICANCE: Our study clarifies the degree to which uncontrolled eating phenotypes and BMI are influenced by shared genetics and shows that vulnerability to uncontrolled eating traits is impacted by common genetic factors.

Second twin outcome at birth: retrospective analysis in a single tertiary centre in Malaysia.

OBJECTIVES: To investigate factors associated with outcome of second twin during labour. METHODS: The study was a retrospective cohort study in a single tertiary centre in Malaysia from 2014 until 2018 involving all twin pregnancies delivered at or more than 24 weeks of gestation. RESULTS: Total of 409 twin pregnancies were included. Dichorionic twin comprises of 54.5 % (n=223) and 45.5 % (n=186) are monochorionic. Women with dichorionic pregnancies are significantly older (p<0.001), have more pre-existing medical disorders (p=0.011) and fetal structural anomalies (p=0.009). Monochorionic pregnancies are significantly more amongst Malay (p=0.01) and conceived spontaneously (p<0.001). There are significantly more fetuses both in cephalic presentation (p=0.026), birthweight discrepancy more than 20 % (p=0.038) and shorter mean inter-twin delivery duration (p=0.048) in monochorionic pregnancies. Second twin delivered with Apgar score <7 is significantly more in dichorionic pregnancies (p=0.006). The second twin is associated with lower birthweight, small for gestational age and arterial cord pH<7.25. Within the group of women who delivered both fetuses vaginally, there was significantly more second twins with intertwin delivery duration less than 30 min who were delivered vaginally without instrumentation (p=0.018). There was significantly more second twin with intertwin delivery duration of 30 min and more with arterial cord pH<7.25 (p=0.045). Those who delivered spontaneously had inter-twin delivery duration within 15-29 min. The outcome of second twin is not influenced by type of twin, gestational age at delivery, inter-twin delivery duration, mode of delivery and presentation at birth. CONCLUSIONS: The neonatal outcome for the second twin at birth is not influenced by type of twin, gestational age at delivery, inter-twin delivery duration, mode of delivery and presentation at birth in a cohort managed with non-active management of the second twin in Malaysia.

Twin studies as an innovative approach to address research questions in cancer care within primary care settings.

This paper proposes the utilisation of twin studies as a novel and powerful methodological approach to investigate critical research questions pertaining to cancer prevention, screening, diagnosis, treatment and survivorship within primary care contexts. The inherent genetic similarity between monozygotic (MZ) (identical) twins provides a unique opportunity to disentangle genetic and environmental influences on cancer-related outcomes. MZ twins share virtually identical genetic makeup, offering a unique opportunity to discern the relative contributions of genetic and environmental factors to cancer-related outcomes. In contrast, dizygotic (DZ) twins, also known as fraternal twins, develop from two separate eggs fertilised by two different sperm and share on average 50% of their genetic material, the same level of genetic similarity found in non-twin siblings. Comparisons between MZ and DZ twins enable researchers to disentangle hereditary factors from shared environmental influences. This methodology has the potential to advance our understanding of the multifaceted interplay between genetic predisposition, lifestyle factors and healthcare interventions in the context of cancer care. This paper outlines the rationale, design considerations and potential applications of twin studies in primary care-based cancer research.

Surgically treated degenerative disk disease in twins.

PURPOSE: Previous studies have suggested that genetic factors are important in the development of degenerative disk disease (DDD). However, the concordance rates for the phenotypes requiring surgery are unknown. The purpose of this study was to determine the concordance rates for DDD requiring surgery by studying monozygotic (MZ) and dizygotic (DZ) twin pairs. METHODS: Patients, aged between 18 and 85 years, operated for DDD between 1996 and 2022 were identified in the national Swedish spine register (Swespine) and matched with the Swedish twin registry (STR) to identify MZ and DZ twins. Pairwise and probandwise concordance rates were calculated. RESULTS: We identified 11,207 patients, 53% women, operated for DDD. By matching the Swespine patients with the STR, we identified 121 twin pairs (37 MZ and 84 DZ) where one or both twins were surgically treated for DDD. The total twin incidence for operated DDD was 1.1%. For DDD requiring surgery, we found no concordant MZ pair and no concordant DZ pair where both twins were operated for DDD. When we evaluated pairs where at least one twin was operated for DDD, we found two concordant MZ pairs (the co-twins were operated for spinal stenosis) and two  concordant DZ pairs (one co-twin operated for spinal stenosis and one (co-twin operated for disk herniation). CONCLUSIONS: Our findings suggest that genetic factors are probably not a major etiologic component in most cases of DDD requiring surgery. The findings of this study can be used for counseling patients about the risk for requiring DDD surgery.

Selective feticide in dichorionic diamniotic (DCDA) twins complicated with previable premature rupture of membrane before 24 weeks may be a safe therapeutic alternative to ongoing pregnancy.

BACKGROUND: To date, there are no clinical guidelines for dichorionic diamniotic (DCDA) twins complicated with previable premature rupture of membrane (PV-ROM) before 24 weeks of gestation. The typical management options including expectant management and/or pregnant termination, induce the risks of fetal mortality and morbidity. OBJECTIVE: To explore the feasibility selective feticide in DCDA twins complicated with PV-ROM. STUDY DESIGN: A Retrospective cohort study, enrolling 28 DCDA twins suffering from PV-ROM in a tertiary medical center from Jan 01 2012 to Jan 01 2022. The obstetric outcome was compared between selective feticide group and expectant management group. RESULTS: There were 12 cases managed expectantly and 16 underwent selective feticide. More cases suffered from oligohydramnios in expectant management group compared to selective feticide group (P = 0.008). Among 13 cases with ROM of upper sac, the mean gestational age at delivery was (33.9 ± 4.9) weeks in the selective feticide group, which was significantly higher than that in the expectant management (P = 0.038). Five fetuses (83.3%) with selective feticide delivered after 32 weeks, whereas only one (14.3%) case in expectant management group (P = 0.029). However, in the subgroup with ROM of lower sac, no significant difference of the mean gestation age at delivery between groups and none of cases delivered after 32 weeks. CONCLUSION: There was a trend towards an increase in latency interval in DCDA twins with PV-ROM following selective feticide, compared to that with expectant management. Furthermore, selective feticide in cases with PV-ROM of upper sac has a favorable outcome.

Heritability of tear fluid cytokines in healthy twins.

PURPOSE: Ocular surface disease is common and it is associated with elevated concentration levels of cytokines in tear fluid. Studies of the normal variation in tear fluid inflammatory markers are lacking. New knowledge may help guide research into ocular surface disease biomarkers and therapeutics. METHODS: In this prospective twin cohort study, healthy individuals were recruited from a population-based registry. Tear fluid was collected with the Schirmer test strips was submerged in phosphate buffered saline and stored at -80° before undergoing 27-cytokine multiplex immunoassay analysis. Broad-sense heritability (h2) of cytokine concentrations was analyzed. RESULTS: 90 participants (23 monozygotic and 22 dizygotic twin pairs) were included. Data availability allowed for heritability analysis of 15 cytokines, and a h2 >50% was seen for 10 cytokines. A statistical power of >80% was achieved for heritability analyses of the cytokines interferon gamma induced protein 10 (h2 = 94.8%), eotaxin (89.8%), interleukin 7 (86.6%), interleukin 1ß (82.2%) and monocyte chemoattractant protein 1 (68.2%). CONCLUSIONS: The tear fluid concentration of several analyzed cytokines was found to be highly heritable. A considerable amount of the inter-individual variation observed for the concentration of certain tear fluid cytokines can be linked to hereditary factors that cannot easily be modified by changing factors in the environment of patients. This suggests that a higher success in ocular surface disease drug discovery may be anticipated for drugs that have targets in specific populations, and points to the importance of emphasizing known preventive measures of ocular surface disease and examinations of close relatives of patients with ocular surface disease, such as dry eye disease.

Surgically Treated Degenerative Lumbar Spine Diseases in Twins.

BACKGROUND: There is growing evidence to suggest a potential genetic component underlying the development and progression of lumbar spine diseases. However, the heritability and the concordance rates for the phenotypes requiring surgery for the common spine diseases lumbar spinal stenosis (LSS) and lumbar disc herniation (LDH) are unknown. The aim of this study was to determine the heritability and the concordance rates for LSS and LDH requiring surgery by studying monozygotic (MZ) and dizygotic (DZ) twin pairs. METHODS: Patients between 18 and 85 years of age who underwent surgery for LSS or LDH between 1996 and 2022 were identified in the national Swedish spine registry (LSS: 45,110 patients; LDH: 39,272 patients), and matched with the Swedish Twin Registry to identify MZ and DZ twins. Pairwise and probandwise concordance rates, heritability estimates, and MZ/DZ concordance ratios were calculated. RESULTS: We identified 414 twin pairs (92 MZ and 322 DZ pairs) of whom 1 or both twins underwent surgery for LSS. The corresponding number for LDH was 387 twin pairs (118 MZ and 269 DZ pairs). The probandwise concordance rate for LSS requiring surgery was 0.25 (26 of 105) (95% confidence interval [CI], 0.14 to 0.34) for MZ twins and 0.04 (12 of 328) (95% CI, 0.01 to 0.07) for DZ twins. The corresponding values for LDH requiring surgery were 0.03 (4 of 120) (95% CI, 0 to 0.08) and 0.01 (4 of 271) (95% CI, 0 to 0.04), respectively. The probandwise MZ/DZ concordance ratio was 6.8 (95% CI, 2.9 to 21.5) for LSS and 2.3 (95% CI, 0 to 8.9) for LDH. The heritability was significantly higher in LSS compared with LDH (0.64 [95% CI, 0.50 to 0.74] versus 0.19 [95% CI, 0.08 to 0.35]). CONCLUSIONS: Our findings suggest that genetic factors may play an important role in the risk of developing LSS requiring surgery, whereas heredity seems to be of less importance in LDH requiring surgery. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Predictive value of maternal serum placental growth factor levels for discordant fetal growth in twins: a retrospective cohort study.

BACKGROUND: Accurate prenatal recognition of discordant fetal growth in twins is critical for deciding suitable management strategies. We explored the predictive value of the level of maternal second-trimester placental growth factor (PLGF) as a novel indicator of discordant fetal growth. METHODS: A total of 860 women pregnant with twins were enrolled, including 168 women with monochorionic twins (31 cases of discordant fetal growth and 137 without) and 692 with dichorionic twins (79 cases of discordant fetal growth and 613 without). Maternal second-trimester PLGF concentrations were measured via immunofluorescence. RESULTS: Maternal second-trimester PLGF levels were significantly lower in women pregnant with twins who subsequently developed discordant fetal growth than in those who did not (monochorionic twin pregnancy: P < 0.001; dichorionic twin pregnancy: P < 0.001). A 3-4 fold difference in median PLGF concentrations was detected between the two groups with both monochorionic and dichorionic twin pregnancies. Maternal second-trimester PLGF levels were significantly correlated with birth weight differences (monochorionic twin pregnancy: r = - 0.331, P < 0.001; dichorionic twin pregnancy: r = - 0.234, P < 0.001). A receiver operating characteristic curve was used to evaluate the predictive efficiency. In monochorionic twin pregnancies, the area under the curve (AUC) was 0.751 (95% confidence interval [CI]: 0.649-0.852), and the cutoff value was 187.5 pg/mL with a sensitivity of 77.4% and specificity of 71.0%. In dichorionic twin pregnancies, the AUC was 0.716 (95% CI; 0.655-0.777), and the cutoff value was 252.5 pg/mL with a sensitivity of 65.1% and specificity of 69.6%. Based on the above cutoff values, univariate and multivariate logistic regression analyses were performed to calculate the odds ratios (OR) for the PLGF levels. After adjustment for potential confounding factors, low PLGF concentrations still significantly increased the risk of discordant fetal growth (monochorionic twin pregnancy: adjusted OR: 7.039, 95% CI: 2.798-17.710, P < 0.001; dichorionic twin pregnancy: adjusted OR: 4.279, 95% CI: 2.572-7.120, P < 0.001). CONCLUSIONS: A low maternal second-trimester PLGF level is considered a remarkable risk factor and potential predictor of discordant fetal growth. This finding provides a complementary screening strategy for the prediction of discordant fetal growth and offers a unique perspective for the subsequent research in this field.

Genetic and environmental impact on mandibular growth in mono- and dizygotic twins during adolescence: A retrospective cohort study.

INTRODUCTION: This study aimed to discover the genetic and environmental factors that contribute to the mandibular development of untreated monozygotic and dizygotic twins. MATERIAL AND METHODS: The sample, taken from the Forsyth Moorrees Twin Study, included 52 untreated monozygotic twins (36 male, 16 female) and 46 untreated dizygotic twins (23 male, 23 female). At the ages of 12 and 17, lateral cephalograms were collected and traced to assess total mandibular length, mandibular ramus length, mandibular corpus length, gonial angle, SNB, and bony chin prominence. The genetic and environmental components of variation were assessed using multilevel mixed-effects structural equation modelling. RESULTS: At 12 years of age, high additive genetic influences were observed for total mandibular length (74%), gonial angle (76%), SNB (41%), and bony chin prominence (64%), whereas strong dominant genetic components were observed for corpus length (72%), and mandibular ramus length was under unique environment influence (54%). At 17 years of age, only total mandibular length (45%), ramus length (53%), gonial angle (76%), and bony chin prominence (68%) were under strong additive genetic control, while the remainder were under strong dominant genetic control. CONCLUSIONS: Although monozygotic and dizygotic twins share at least a portion of their DNA, additive, dominant, or environmental components were discovered during adolescence. Nonetheless, by the age of 17, the majority of the mandibular traits are under either additive or dominant genetic impact.

The Colombo Twin and Singleton Study (COTASS): Piloting the Feasibility of Collecting Nutritional Data and Extension of the Sample to Include Children of Twins.

Nutrition and diet are key modifiable risk factors for the rising burden of non-communicable diseases like cardio-vascular diseases and diabetes in low- and middle- income countries (LMICs). The nutritional transition in dietary behaviours in LMICs has most likely contributed to this problem. Although traditionally assumed to be environmental, dietary choices are also genetically influenced. Twin study designs can be used to investigate the relative influence of genes and environment on nutrition intake, eating behaviours and associated psychological health. The overall aim of this project is to: provide proof-of-concept for the feasibility of using dietary (biomarker) data within the Children-of-Twin design in nutrition studies, develop laboratory skills and statistical genetic skills and establish a Sri Lankan-specific food composition database. Currently, a pilot study is being conducted with 304 individuals (38 Monozygotic twin pairs, 38 Dizygotic twin pairs and their male or female adult offspring). Questionnaire data on nutritional intake, eating behaviours, psychological well-being, physical health, and bio-specimens are being collected. A Sri Lankan-specific food composition database was developed, training sessions on macro and micro element analysis in biological samples and statistical genetics skills development were conducted and Community Engagement and Involvement programs were carried out in two districts of Sri Lanka.

New insights into the (epi)genetics of twinning.

Spontaneous dizygotic (DZ) twins, i.e. twins conceived without the use of ARTs, run in families and their prevalence varies widely around the globe. In contrast, monozygotic (MZ) twins occur at a constant rate across time and geographical regions and, with some rare exceptions, do not cluster in families. The leading hypothesis for MZ twins, which arise when a zygote splits during preimplantation stages of development, is random occurrence. We have found the first series of genes underlying the liability of being the mother of DZ twins and have shown that being an MZ twin is strongly associated with a stable DNA methylation signature in child and adult somatic tissues. Because identical twins keep this molecular signature across the lifespan, this discovery opens up completely new possibilities for the retrospective diagnosis of whether a person is an MZ twin whose co-twin may have vanished in the early stages of pregnancy. Here, we summarize the gene finding results for mothers of DZ twins based on genetic association studies followed by meta-analysis, and further present the striking epigenetic results for MZ twins.

Dementia and mortality in older adults: A twin study.

INTRODUCTION: Dementia predicts increased mortality. We used case-control and co-twin control models to investigate genetic and shared environmental influences on this association. METHODS: Case-control design, including 987 twins with dementia and 2938 age- and sex-matched controls in the Swedish Twin Registry. Co-twin control design, including 90 monozygotic (MZ) and 288 dizygotic (DZ) twin pairs discordant for dementia. To test for genetic and environmental confounding, differences were examined in mortality risk between twins with dementia and their matched or co-twin controls. RESULTS: Twins with dementia showed greater mortality risk than age- and sex-matched controls (HR = 2.02 [1.86, 2.18]). Mortality risk is significantly elevated but attenuated substantially in discordant twin pairs, for example, comparing MZ twins with dementia to their co-twin controls (HR = 1.48 [1.08, 2.04]). DISCUSSION: Findings suggest that genetic factors partially confound the association between dementia and mortality and provide an alternative hypothesis to increased mortality due to dementia itself. Highlights We studied dementia and mortality in twin pairs discordant for dementia. People without dementia outlived people with dementia. Identical twins with dementia and their co-twin controls had similar survival time. Findings suggest genotype may explain the link between dementia and mortality.

Genetic and Environmental Causes of Variation in an Automated Breast Cancer Risk Factor Based on Mammographic Textures.

BACKGROUND: Cirrus is an automated risk predictor for breast cancer that comprises texture-based mammographic features and is mostly independent of mammographic density. We investigated genetic and environmental variance of variation in Cirrus. METHODS: We measured Cirrus for 3,195 breast cancer-free participants, including 527 pairs of monozygotic (MZ) twins, 271 pairs of dizygotic (DZ) twins, and 1,599 siblings of twins. Multivariate normal models were used to estimate the variance and familial correlations of age-adjusted Cirrus as a function of age. The classic twin model was expanded to allow the shared environment effects to differ by zygosity. The SNP-based heritability was estimated for a subset of 2,356 participants. RESULTS: There was no evidence that the variance or familial correlations depended on age. The familial correlations were 0.52 (SE, 0.03) for MZ pairs and 0.16(SE, 0.03) for DZ and non-twin sister pairs combined. Shared environmental factors specific to MZ pairs accounted for 20% of the variance. Additive genetic factors accounted for 32% (SE = 5%) of the variance, consistent with the SNP-based heritability of 36% (SE = 16%). CONCLUSION: Cirrus is substantially familial due to genetic factors and an influence of shared environmental factors that was evident for MZ twin pairs only. The latter could be due to nongenetic factors operating in utero or in early life that are shared by MZ twins. IMPACT: Early-life factors, shared more by MZ pairs than DZ/non-twin sister pairs, could play a role in the variation in Cirrus, consistent with early life being recognized as a critical window of vulnerability to breast carcinogens.

Clinical implications of crown-rump length discordance at 11 to 14 weeks in dichorionic twins.

BACKGROUND: Crown-rump length discordance, defined as ≥10% discordance, has been investigated as an early sonographic marker of subsequent growth abnormalities and is associated with an increased risk of fetal loss in twin pregnancies. Previous studies have not investigated the prevalence of fetal aneuploidy or structural anomalies in twins with discordance or the independent association of crown-rump length discordance with adverse perinatal outcomes. Moreover, data are limited on cell-free DNA screening for aneuploidy in dichorionic twins with discordance. OBJECTIVE: This study aimed to evaluate whether crown-rump length discordance in dichorionic twins between 11 and 14 weeks of gestation is associated with a higher risk of aneuploidy, structural anomalies, or adverse perinatal outcomes and to assess the performance of cell-free DNA screening in dichorionic twin pregnancies with crown-rump length discordance. STUDY DESIGN: This was a secondary analysis of a multicenter retrospective cohort study that evaluated the performance of cell-free DNA screening for the common trisomies in twin pregnancies from December 2011 to February 2020. For this secondary analysis, we included live dichorionic pregnancies with crown-rump length measurements between 11 and 14 weeks of gestation. First, we compared twin pregnancies with discordant crown-rump lengths with twin pregnancies with concordant crown-rump lengths and analyzed the prevalence of aneuploidy and fetal structural anomalies in either twin. Second, we compared the prevalence of a composite adverse perinatal outcome, which included preterm birth at <34 weeks of gestation, hypertensive disorders of pregnancy, stillbirth or miscarriage, small-for-gestational-age birthweight, and birthweight discordance. Moreover, we assessed the performance of cell-free DNA screening in pregnancies with and without crown-rump length discordance. Outcomes were compared with multivariable regression to adjust for confounders. RESULTS: Of 987 dichorionic twins, 142 (14%) had crown-rump length discordance. The prevalence of aneuploidy was higher in twins with crown-rump length discordance than in twins with concordance (9.9% vs 3.9%, respectively; adjusted relative risk, 2.7; 95% confidence interval, 1.4-4.9). Similarly, structural anomalies (adjusted relative risk, 2.5; 95% confidence interval, 1.4-4.4]) and composite adverse perinatal outcomes (adjusted relative risk, 1.2; 95% confidence interval, 1.04-1.3) were significantly higher in twins with discordance. A stratified analysis demonstrated that even without other ultrasound markers, there were increased risks of aneuploidy (adjusted relative risk, 3.5; 95% confidence interval, 1.5-8.4) and structural anomalies (adjusted relative risk, 2.7; 95% confidence interval, 1.5-4.8) in twins with CRL discordance. Cell-free DNA screening had high negative predictive values for trisomy 21, trisomy 18, and trisomy 13, regardless of crown-rump length discordance, with 1 false-negative for trisomy 21 in a twin pregnancy with discordance. CONCLUSION: Crown-rump length discordance in dichorionic twins is associated with an increased risk of aneuploidy, structural anomalies, and adverse perinatal outcomes, even without other sonographic abnormalities. Cell-free DNA screening demonstrated high sensitivity and negative predictive values irrespective of crown-rump length discordance; however, 1 false-negative result illustrated that there is a role for diagnostic testing. These data may prove useful in identifying twin pregnancies that may benefit from increased screening and surveillance and are not ascertained by other early sonographic markers.

Longitudinal maternal hemodynamic evaluation in uncomplicated twin pregnancies according to chorionicity: physiological cardiovascular dysfunction in monochorionic twin pregnancy.

OBJECTIVE: Maternal cardiac function plays a crucial role in placental function and development. The maternal hemodynamic changes in twin pregnancy are more pronounced than those in singleton pregnancy, presumably due to a greater plasma volume expansion. In view of the correlation between maternal cardiac and placental function, it is plausible that chorionicity could influence maternal cardiac function. The aim of this study was to compare the longitudinal maternal hemodynamic changes between uncomplicated dichorionic (DC) and monochorionic (MC) twin pregnancies and in comparison to singleton pregnancies. METHODS: Included in the study were 40 MC diamniotic and 35 DC diamniotic uncomplicated twin pregnancies. These were compared with a group of 294 healthy singleton pregnancies from a previous cross-sectional study. All participants underwent a hemodynamic evaluation using an Ultrasound Cardiac Output Monitor (USCOM®), at three different stages in pregnancy (11-15 weeks, 20-24 weeks and 29-33 weeks). The following parameters were recorded: mean arterial pressure (MAP), stroke volume (SV), stroke volume index (SVI), heart rate, cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR), systemic vascular resistance index (SVRI), stroke volume variation, Smith-Madigan inotropy index (INO) and potential-to-kinetic-energy ratio (PKR). RESULTS: In the first trimester, DC and MC twin pregnancies showed lower MAP, SVR and PKR and higher CO and SV in comparison to singleton pregnancy. In the second trimester, maternal CO (8.33 vs 7.30 L/min, P = 0.03) and CI (4.52 vs 4.00 L/min/m2 , P = 0.02) were significantly higher in MC compared with DC twin pregnancy. In the third trimester, compared with in singleton pregnancy, women with MC twin pregnancy showed significantly higher PKR (24.06 vs 20.13, P = 0.03) and SVRI (1837.20 vs 1698.48 dynes × s/cm5 /m2 , P = 0.03), and significantly lower SV (78.80 vs 88.80 mL, P = 0.01), SVI (42.79 vs 50.31 mL/m2 , P < 0.01) and INO (1.70 vs 1.87 W/m2 , P = 0.03); these differences were not observed between DC twin and singleton pregnancies. CONCLUSIONS: Maternal cardiovascular function undergoes significant change during uncomplicated twin pregnancy and chorionicity influences maternal hemodynamics. In both MC and DC twin pregnancy, hemodynamic changes are detectable as early as the first trimester, showing higher maternal CO and lower SVR compared with singleton pregnancy. In DC twin pregnancy, the maternal hemodynamics remain stable during the rest of pregnancy. In contrast, in MC twin pregnancy, the rise in maternal CO continues in the second trimester in order to sustain the greater placental growth. There is a subsequent crossover, with a reduction in cardiovascular performance during the third trimester. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.