Small for gestational age in twin pregnancies and the risk of offspring pediatric neurologic morbidity

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Scarce data exist regarding the long-term implications of SGA in twins. We opted to study the association between SGA of one twin and long- term neurologic related morbidity in dichorionic diamniotic twins. Study design: A population-based retrospective cohort study including consecutive dichorionic diamniotic twins, born between the years 1991–2021 at a tertiary medical center was conducted. Total and subtypes of neurologic related pediatric hospitalizations among SGA versus non-SGA twins were compared. A Kaplan-Meier survival curve was used to compare the cumulative neurologic morbidity incidence, and a Cox proportional hazards model was constructed to adjust for confounders. Results The study population included 4,222 newborns; 180 (4.3%) were SGA. Rate of long- term neurologic related hospitalizations was comparable between the two groups (8.7% vs. 8.0%, p = 0.755; Kaplan-Meier survival curve Log- rank p = 0.652). Using a Cox proportional hazards model, controlling for gender and birth order, no association was found between SGA and the risk for subsequent neurologic pediatric morbidity of the offspring (Adjusted HR = 1.0, 95% CI 0.6–1.8, p = 0.973). Conclusions SGA is not associated with an increased risk for long-term pediatric neurologic morbidity in dichorionic diamniotic twins. Fetal growth restriction Multiple preganancy Neurology Small for gestational age Figures Figure 1 Introduction Small for gestational age (SGA) is typically defined by birthweight below the 10th percentile for gestational age and gender [ 1 ]. Previous studies demonstrated higher short- term morbidity and mortality in singleton SGA infants which were assumed to happen due to compromised growth and reduced energy reserves that increase vulnerability of these infants during labor and perinatal period [ 2 – 7 ]. SGA fetuses may have difficulties during labor and delivery due to hypoxic stress at the time of uterine contractions. Impaired placental function results in hypoxia and metabolic acidosis and increases the risk of multiple organ dysfunction such as hypoxic-ischemic encephalopathy, ischemic heart failure, meconium aspiration, pulmonary hypertension, and acute gastrointestinal and kidney injury which were all demonstrated to be higher in deliveries of SGA fetuses [ 8 ]. As for the long-term outcome, SGA singletons are at increased risk for morbidities including respiratory morbidity [ 9 ], hematological [ 10 ], gastrointestinal complications [ 11 ] and ophthalmic morbidity [ 12 ]. A special focus addressed neurodevelopmental abnormalities [ 13 ] and decreased cognitive performance [ 14 – 17 ]. A systematic review evaluated early childhood neurodevelopment (up to three years of age) and reported motor, cognitive, and language neurodevelopmental delay in children who were born SGA [ 18 ]. In addition, adolescents who were SGA had lower intelligence and cognitive scores, as well as higher rates of learning difficulties and cerebral palsy [ 19 – 21 ]. As to our knowledge, scarce data exists regarding the long-term implications of SGA among twin pregnancies. Therefore, we aimed to study the association between SGA of one twin and long- term neurologic related morbidity in dichorionic diamniotic twins. Methods This population-based retrospective cohort study included all offspring of dichorionic diamniotic twin gestations, born between the years 1991–2021 at the Soroka University Medical Center (SUMC), the sole tertiary medical center in the region of southern Israel. Total and subtypes of neurologic related pediatric hospitalizations among SGA versus non-SGA twins were compared. The outcome assessed included hospitalizations with different subtypes of neurologic morbidities in the offspring up to the age of 18 years. Neurologic related morbidity included hospitalizations involving a pre-defined set of ICD-9 codes, as recorded in the hospital computerized medical files, detailed in the Supplemental Table. For the analyses two databases were cross-linked and merged: the computerized perinatal database of the Obstetrics and Gynecology department and the computerized hospitalization database of SUMC (“Demog-ICD9”). The Demog-ICD9 database includes demographic information and ICD-9 codes for all medical diagnoses made during hospitalizations at SUMC. The perinatal database consists of information recorded immediately following delivery by an obstetrician and includes perinatal assessments, maternal morbidities and maternal and fetal outcome and complications. Records were anonymized prior to analysis. The study received the approval of the Institutional Review Board Committee of the SUMC (IRB # 0357-19-SOR). consent was not obtained due to retrospective data collection. Newborns with congenital malformations were excluded from the study. Cases of perinatal mortality were excluded from the long- term analysis. Follow up time was defined as time to a neurologic related hospitalization (time to an event), or until censored in case of death, age of 18 years, or end of study period. Only the first neurologic related hospitalization for each offspring was included in the analyses. Statistical analysis was performed using the SPSS package 29th ed. (IBM/SPSS, Chicago, IL). Differences in categorical variables were assessed by chi-square test for general association. Paired t-test was used for comparison of continuous variables with normal distribution. Kaplan-Meier survival curves were used to compare cumulative neurologic related hospitalization incidences over time. A Cox proportional hazards model was used to adjust for potential confounders and for the twin pairs. All analyses were two-sided and a p value < 0.05 was considered statistically significant. Results The study population included 4,222 newborns which met the inclusion criteria. Among them, 180 (4.3%) were SGA. The obstetrical and neonatal characteristics of both groups are presented in Table 1 . Similar rates of non-reassuring fetal heart rate monitoring (NRFHR) and cesarean deliveries were noted between the groups (3.9% vs. 2.4%; p = 0.198 and 50.0% vs. 55.8%; p = 0.126, for NRFHR and cesarean delivery, respectively). SGA twins were at an increased risk for adverse perinatal outcomes, including low Apgar scores at 5 minutes (< 7) was significantly higher in the SGA group (11.5% vs. 1.8%; p < 0.001), intrauterine fetal death (IUFD) (11.7% vs. 0.4%; p < 0.001), as well as postpartum death (PPD) (11.7% vs. 1.4%; p < 0.001) and total mortality (23.3% vs. 1.8%; p < 0.001) were noted in the SGA group. Table 1 – Obstetrical and neonatal characteristics of both study groups SGA %(n = 180) No SGA %(n = 4042) OR (95% CI) P Value Gender Male Female 45 (81) 55 (99) 50.2 (2030) 49.8 (2012) 0.8 (0.6–1.1) 0.170 Non-reassuring fetal heart rate monitoring 3.9 (7) 2.4 (96) 1.7 (0.8–3.6) 0.198 % Cesarean delivery 50 (90) 55.8 (2255) 0.8 (0.6–1.1) 0.126 Apgar 5 minutes < 7 11.5% (17) 1.8% (72) 7.0(4.0-12.2) < 0.001 Intrauterine fetal death 11.7% (21) 0.4% (17) 31.3(16.2–60.4) < 0.001 Post-partum death 11.7% (21) 1.4% (56) 9.4(5.6–16.0) < 0.001 Total mortality 23.3% (42) 1.8% (73) 16.5(10.9–25.1) < 0.001 Long-term neurologic morbidity of the offspring and the different subtypes of neurologic morbidities are summarized in Table 2 . The rate of long- term neurologic related hospitalizations was comparable between the two groups (8.7% vs. 8.0%, p = 0.755; Kaplan-Meier survival curve Log- rank p = 0.654; Figure). Using a Cox proportional hazards model, controlling for gender and birth order, no association was found between SGA and the risk for subsequent neurologic pediatric morbidity of the offspring (Adjusted HR = 1.0, 95% CI 0.6–1.8, p = 0.973). Table 2 Long-term neurologic morbidity of both groups Neurologic morbidity SGA (n = 138) No SGA (n = 3969) 95% CI P value Autism 0% (0) 0.1% (5) 1.0(0.9-1.0) 0.677 Eating disorder 0.7% (1) 0.4% (17) 1.7(0.2–12.8) 0.604 Sleep disorder 0.7% (1) 0.1% (5) 5.8(0.7–49.8) 0.070 Movement disorder 4.3% (6) 3.0% (121) 1.4(0.6–3.3) 0.386 Cerebral palsy 0% (0) 0.3%(13) `1.0 (1.0–1.0) 0.501 Psychiatric disorder 1.4% (2) 3.0% (119) 0.5(0.1–1.9) 0.290 Attention deficit hyperactivity disorder 0% (0) 0.2% (6) 1.0 (1.0–1.0) 0.648 Developmental disorder 5.1% (7) 1.5%(58) 3.6 (1.6-8.0) 0.001 Myopathy 0% (0) 0.2%(9) 1.0 (1.0–1.0) 0.575 Total hospitalizations 8.7% (12) 8.0% (316) 1.1(0.6-2.0) 0.755 Table 3 – Cox proportional hazards model for the association between SGA and total neurologic morbidity in dichorionuc diamniotic twins. Variable Adjusted HR (95% CI) P value SGA 1.0 (0.6-1.8) 0.973 Birth order (first versus second) 1.3 (1.0-1.6) 0.043 Gender 1.2 (0.9-1.5) 0.125 Discussion In this large retrospective cohort study of dichorionic diamniotic twins followed up to 18 years, SGA twin newborns were found to have comparable risk for pediatric neurologic-related hospitalizations. No association was found between SGA and the risk for subsequent neurologic pediatric morbidity while controlling for important clinical confounders, such as gender and birth order. To the best of our knowledge, this is the first study investigating the association between SGA in dichorionic twin pregnancies and long-term pediatric morbidities. Delivery of an SGA infant remains a significant problem in current obstetric and neonatal practice, and is a well-known cause of perinatal mortality and morbidity [ 2 , 3 ]. In a meta-analysis that included twenty-nine studies and 21,034,114 neonates born at term (37 weeks of gestation and above), birthweight was strongly associated with mortality, with birthweight < 1.5 kg giving the strongest association (OR 48.6, 95% CI 28.62–82.53)[ 4 ]. Several mechanisms may explain delivery of an SGA infant. The first mechanism may be related to intra- uterine environmental factors, such as placental insufficiency or maternal health status. Other mechanisms may be related to structural or chromosomal abnormality that affects fetal growth. Finally, being constitutionally small also represent a large group of SGA infants [ 1 ]. Placental insufficiency adversely affects total nutrient, blood and oxygen active transfer and reduces glucose, lipids and protein synthesis, which leads to fetal undergrowth [ 22 – 24 ]. It is hypothesized that SGA fetuses are more vulnerable to hypoxic injury during labor due to their diminished reserve. The impaired placental function leads to hypoxia and acidosis and thus increases short term morbidity, such as: hypoglycemia, hyperbilirubinemia, polycythemia, pulmonary hemorrhage and apnea [ 25 – 26 ]. In addition, acute brain injury rates were shown to be higher in SGA newborn, including hypoxic-ischemic encephalopathy, periventricular leukomalacia and intracranial hemorrhage [ 8 ]. As for the long-term morbidity, previous studies have found that SGA is associated with higher rates of neuro-disabilities, such as cerebral palsy and mental retardation, as well as developmental delay [ 27 ]. One hypothesis that was suggested to explain the associations between cognitive deficiency and growth restriction is hypoxia caused by placental insufficiency that affects the gray matter despite brain-sparing [ 28 – 29 ]. Consistent with previous studies [ 30 ], our study demonstrated significant differences in immediate perinatal outcomes between the groups, such as higher rates of low Apgar scores at 5 minutes (< 7), IUFD, PPD and total mortality. Nevertheless, the rate of long- term neurologic related hospitalizations of the offspring was comparable between the two groups. Different physiology in twin pregnancies may explain the study results. Another explanation may be related to the mechanism of the growth restriction. As one of the major mechanism of SGA is being constituently small, placental insufficiency and hostile intra- uterine environment may not be present and may not effect neurological morbidity of the SGA twin. Another reason for the lack of association may be inadequate power of our study. The main strength of our study is the large cohort size. In addition, the fact that SUMC is the sole tertiary hospital in the entire Negev region in an area characterized by positive immigration, resulting in probable minimal loss to follow-up and selection bias. Nevertheless, this study has few disadvantages. The main limitation lies within its retrospective design. As a population-level analysis, our study can provide evidence only of association and not of causation. Nevertheless, there seems to be a biological plausibility for the observed association. Another limitation relates to the fact that many of the investigated neurologic related morbidities are usually managed in an ambulatory setting and therefore not accounted for. In addition, several potentially relevant covariates were not available for analysis, such as childhood exposures, breastfeeding and placental pathology which may spread some light regarding the mechanism of the growth restriction.. These essential points remain to be investigated in future studies. In conclusion, our results suggest that SGA is not associated with increased risk of pediatric neurologic morbidity in dichorionic diamniotic twins. Further research is needed to in order to investigate the impact of other environmental and postnatal factors on long-term morbidity of the offspring. Additional information This study was not funded and there are no financial disclosures. There is no conflict of interest. The study received the approval of the Institutional Review Board Committee of the Soroka University Medical Center No honorarium, grant, or other form of payment was given to anyone to produce the manuscript. This is a database study and as such has no clinical trial registration number. All authors on the manuscript contributed to the concept, design, results interpretation, and drafting of the manuscript. Noa Leybovitz Haleluya wrote the draft of the manuscript, Tamar Wainstock performed the statistical analysis and all authors contributed to the revision the manuscript. Data is available to review upon request. Declarations Funding /Support: This study was not funded. b. Financial Disclosures: No financial disclosures. c. Leybovitz-Haleluya Noa, MD wrote the first draft of the manuscript. No honorarium, grant, or other form of payment was given to anyone to produce the manuscript. d. This is a database study and as such has no clinical trial registration number. e. All authors on the manuscript contributed to the concept, design, results interpretation, and drafting of the manuscript. f. Data is available to review by request ACKNOWLEDGMENTS / DISCLOSURE : The authors report no conflict of interest References Battaglia FC, Lubchenco LO (1967) A practical classification of newborn infants by weight and gestational age. 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Arch Dis Child Fetal Neonatal Ed 92:F473 Cite Share Download PDF Status: Published Journal Publication published 02 Aug, 2024 Read the published version in Archives of Gynecology and Obstetrics → Version 1 posted Editorial decision: Minor revisions 01 Jul, 2024 Reviewers agreed at journal 22 Jun, 2024 Reviewers invited by journal 04 Jun, 2024 Editor assigned by journal 04 Jun, 2024 First submitted to journal 03 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4522802","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":310388208,"identity":"ae0c28a0-e03d-41ff-b6b8-12d8b60c9457","order_by":0,"name":"Noa leybovitz Haleluya","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDElEQVRIiWNgGAWjYJCCA4wNDDIM7CBmBRAzMzcQ1nKwgYGHgRnEPAPSwkhYCwNcC2MbiEtAi3z78YuHP+6w4+Fn5jGT+DmvNpq/HajlR8U2nFoMzuQUHDh4JplHspnHTLJ32/HcGYcZGxh7ztzGrYUhJ+HAwTZmHoPDQFt4tx3LbQBqYWZsw61Fvv8NSEs9jz1Qi+TfOcdy5xPSwnAj/QBQy2EeA6BfpHkbanI3ENJicOMNw4Gzbcd5JA6zFVvLHDuQuxGo5SA+v8j3pz/+UNlWLcff3rzx5puautx55w8ffPCjAo/DGHgMYCwWCQaGw2DWATzqgYD9AYzF/IGBoQ6/4lEwCkbBKBiRAADLwGAO1crMmAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-8759-5323","institution":"Soroka Hospital: Soroka Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Noa","middleName":"leybovitz","lastName":"Haleluya","suffix":""},{"id":310388209,"identity":"e4250328-f046-4519-9e0a-a40fc8ad4c0c","order_by":1,"name":"Tamar Wainstock","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Tamar","middleName":"","lastName":"Wainstock","suffix":""},{"id":310388210,"identity":"f71723c6-ff34-4107-b1bf-a329c1dddffb","order_by":2,"name":"Gali Pariente","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Gali","middleName":"","lastName":"Pariente","suffix":""},{"id":310388211,"identity":"bbb51106-5bf9-4f46-b475-da5850a80616","order_by":3,"name":"Eyal Sheiner","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Eyal","middleName":"","lastName":"Sheiner","suffix":""}],"badges":[],"createdAt":"2024-06-03 15:26:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4522802/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4522802/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00404-024-07662-4","type":"published","date":"2024-08-02T15:57:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":58760421,"identity":"a996565e-9995-4105-88cd-7bffddf6abfe","added_by":"auto","created_at":"2024-06-20 18:49:56","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":200214,"visible":true,"origin":"","legend":"\u003cp\u003eA Kaplan-Meier cumulative hazard function of neurologic morbidity in both groups (Log rank p value 0.652).\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4522802/v1/c17d34613f93deadcddea943.jpeg"},{"id":61793327,"identity":"ab3d9087-eb50-4387-af23-520d41085216","added_by":"auto","created_at":"2024-08-05 16:10:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":563042,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4522802/v1/e276c318-0254-431e-ada7-b355fa639f0a.pdf"}],"financialInterests":"","formattedTitle":"Small for gestational age in twin pregnancies and the risk of offspring pediatric neurologic morbidity","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSmall for gestational age (SGA) is typically defined by birthweight below the 10th percentile for gestational age and gender [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Previous studies demonstrated higher short- term morbidity and mortality in singleton SGA infants which were assumed to happen due to compromised growth and reduced energy reserves that increase vulnerability of these infants during labor and perinatal period [\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSGA fetuses may have difficulties during labor and delivery due to hypoxic stress at the time of uterine contractions. Impaired placental function results in hypoxia and metabolic acidosis and increases the risk of multiple organ dysfunction such as hypoxic-ischemic encephalopathy, ischemic heart failure, meconium aspiration, pulmonary hypertension, and acute gastrointestinal and kidney injury which were all demonstrated to be higher in deliveries of SGA fetuses [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs for the long-term outcome, SGA singletons are at increased risk for morbidities including respiratory morbidity [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], hematological [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], gastrointestinal complications [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] and ophthalmic morbidity [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. A special focus addressed neurodevelopmental abnormalities [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and decreased cognitive performance [\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA systematic review evaluated early childhood neurodevelopment (up to three years of age) and reported motor, cognitive, and language neurodevelopmental delay in children who were born SGA [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In addition, adolescents who were SGA had lower intelligence and cognitive scores, as well as higher rates of learning difficulties and cerebral palsy [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs to our knowledge, scarce data exists regarding the long-term implications of SGA among twin pregnancies. Therefore, we aimed to study the association between SGA of one twin and long- term neurologic related morbidity in dichorionic diamniotic twins.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis population-based retrospective cohort study included all offspring of dichorionic diamniotic twin gestations, born between the years 1991\u0026ndash;2021 at the Soroka University Medical Center (SUMC), the sole tertiary medical center in the region of southern Israel.\u003c/p\u003e \u003cp\u003eTotal and subtypes of neurologic related pediatric hospitalizations among SGA versus non-SGA twins were compared. The outcome assessed included hospitalizations with different subtypes of neurologic morbidities in the offspring up to the age of 18 years. Neurologic related morbidity included hospitalizations involving a pre-defined set of ICD-9 codes, as recorded in the hospital computerized medical files, detailed in the Supplemental Table.\u003c/p\u003e \u003cp\u003eFor the analyses two databases were cross-linked and merged: the computerized perinatal database of the Obstetrics and Gynecology department and the computerized hospitalization database of SUMC (\u0026ldquo;Demog-ICD9\u0026rdquo;). The Demog-ICD9 database includes demographic information and ICD-9 codes for all medical diagnoses made during hospitalizations at SUMC. The perinatal database consists of information recorded immediately following delivery by an obstetrician and includes perinatal assessments, maternal morbidities and maternal and fetal outcome and complications. Records were anonymized prior to analysis. The study received the approval of the Institutional Review Board Committee of the SUMC (IRB # 0357-19-SOR). consent was not obtained due to retrospective data collection.\u003c/p\u003e \u003cp\u003eNewborns with congenital malformations were excluded from the study. Cases of perinatal mortality were excluded from the long- term analysis. Follow up time was defined as time to a neurologic related hospitalization (time to an event), or until censored in case of death, age of 18 years, or end of study period. Only the first neurologic related hospitalization for each offspring was included in the analyses.\u003c/p\u003e \u003cp\u003eStatistical analysis was performed using the SPSS package 29th ed. (IBM/SPSS, Chicago, IL). Differences in categorical variables were assessed by chi-square test for general association. Paired t-test was used for comparison of continuous variables with normal distribution. Kaplan-Meier survival curves were used to compare cumulative neurologic related hospitalization incidences over time. A Cox proportional hazards model was used to adjust for potential confounders and for the twin pairs. All analyses were two-sided and a p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe study population included 4,222 newborns which met the inclusion criteria. Among them, 180 (4.3%) were SGA. The obstetrical and neonatal characteristics of both groups are presented in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Similar rates of non-reassuring fetal heart rate monitoring (NRFHR) and cesarean deliveries were noted between the groups (3.9% vs. 2.4%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.198 and 50.0% vs. 55.8%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.126, for NRFHR and cesarean delivery, respectively). SGA twins were at an increased risk for adverse perinatal outcomes, including low Apgar scores at 5 minutes (\u0026lt;\u0026thinsp;7) was significantly higher in the SGA group (11.5% vs. 1.8%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), intrauterine fetal death (IUFD) (11.7% vs. 0.4%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), as well as postpartum death (PPD) (11.7% vs. 1.4%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and total mortality (23.3% vs. 1.8%;\u0026nbsp;\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were noted in the SGA group.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003e\u0026ndash; Obstetrical and neonatal characteristics of both study groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSGA\u003c/p\u003e\n \u003cp\u003e%(n\u0026thinsp;=\u0026thinsp;180)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNo SGA %(n\u0026thinsp;=\u0026thinsp;4042)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eP Value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45 (81)\u003c/p\u003e\n \u003cp\u003e55 (99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50.2 (2030)\u003c/p\u003e\n \u003cp\u003e49.8 (2012)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.8 (0.6\u0026ndash;1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.170\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon-reassuring fetal heart rate monitoring\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.9 (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.4 (96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1.7 (0.8\u0026ndash;3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.198\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e% Cesarean delivery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50 (90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55.8 (2255)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.8 (0.6\u0026ndash;1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.126\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eApgar 5 minutes\u0026thinsp;\u0026lt;\u0026thinsp;7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.5% (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.8% (72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e7.0(4.0-12.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntrauterine fetal death\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.7% (21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.4% (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e31.3(16.2\u0026ndash;60.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePost-partum death\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.7% (21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.4% (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e9.4(5.6\u0026ndash;16.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal mortality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.3% (42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.8% (73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e16.5(10.9\u0026ndash;25.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eLong-term neurologic morbidity of the offspring and the different subtypes of neurologic morbidities are summarized in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The rate of long- term neurologic related hospitalizations was comparable between the two groups (8.7% vs. 8.0%, p\u0026thinsp;=\u0026thinsp;0.755; Kaplan-Meier survival curve Log- rank p\u0026thinsp;=\u0026thinsp;0.654; Figure). Using a Cox proportional hazards model, controlling for gender and birth order, no association was found between SGA and the risk for subsequent neurologic pediatric morbidity of the offspring (Adjusted HR\u0026thinsp;=\u0026thinsp;1.0, 95% CI 0.6\u0026ndash;1.8,\u0026nbsp;\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.973).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eLong-term neurologic morbidity of both groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNeurologic morbidity\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSGA\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;138)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNo SGA (n\u0026thinsp;=\u0026thinsp;3969)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAutism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0% (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.1% (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.0(0.9-1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.677\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEating disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.7% (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.4% (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.7(0.2\u0026ndash;12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.604\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSleep disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.7% (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.1% (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.8(0.7\u0026ndash;49.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.070\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMovement disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.3% (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.0% (121)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.4(0.6\u0026ndash;3.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.386\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCerebral palsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0% (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.3%(13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e`1.0 (1.0\u0026ndash;1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.501\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePsychiatric disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.4% (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.0% (119)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.5(0.1\u0026ndash;1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.290\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAttention deficit hyperactivity disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0% (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.2% (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.0 (1.0\u0026ndash;1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.648\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDevelopmental disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.1% (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5%(58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.6 (1.6-8.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMyopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0% (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.2%(9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.0 (1.0\u0026ndash;1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.575\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal hospitalizations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.7% (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.0% (316)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.1(0.6-2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.755\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eTable 3 \u0026ndash; Cox proportional hazards model for the association between SGA and total neurologic morbidity in dichorionuc diamniotic twins.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.493589743589745%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdjusted HR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.17307692307692%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.493589743589745%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSGA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e1.0 (0.6-1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.17307692307692%\" valign=\"top\"\u003e\n \u003cp\u003e0.973\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.493589743589745%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBirth order (first versus second) \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e1.3 (1.0-1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.17307692307692%\" valign=\"top\"\u003e\n \u003cp\u003e0.043\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.493589743589745%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e1.2 (0.9-1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.17307692307692%\" valign=\"top\"\u003e\n \u003cp\u003e0.125\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003e In this large retrospective cohort study of dichorionic diamniotic twins followed up to 18 years, SGA twin newborns were found to have comparable risk for pediatric neurologic-related hospitalizations. No association was found between SGA and the risk for subsequent neurologic pediatric morbidity while controlling for important clinical confounders, such as gender and birth order. To the best of our knowledge, this is the first study investigating the association between SGA in dichorionic twin pregnancies and long-term pediatric morbidities.\u003c/p\u003e \u003cp\u003eDelivery of an SGA infant remains a significant problem in current obstetric and neonatal practice, and is a well-known cause of perinatal mortality and morbidity [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In a meta-analysis that included twenty-nine studies and 21,034,114 neonates born at term (37 weeks of gestation and above), birthweight was strongly associated with mortality, with birthweight\u0026thinsp;\u0026lt;\u0026thinsp;1.5 kg giving the strongest association (OR 48.6, 95% CI 28.62\u0026ndash;82.53)[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral mechanisms may explain delivery of an SGA infant. The first mechanism may be related to intra- uterine environmental factors, such as placental insufficiency or maternal health status. Other mechanisms may be related to structural or chromosomal abnormality that affects fetal growth. Finally, being constitutionally small also represent a large group of SGA infants [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePlacental insufficiency adversely affects total nutrient, blood and oxygen active transfer and reduces glucose, lipids and protein synthesis, which leads to fetal undergrowth [\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. It is hypothesized that SGA fetuses are more vulnerable to hypoxic injury during labor due to their diminished reserve. The impaired placental function leads to hypoxia and acidosis and thus increases short term morbidity, such as: hypoglycemia, hyperbilirubinemia, polycythemia, pulmonary hemorrhage and apnea [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In addition, acute brain injury rates were shown to be higher in SGA newborn, including hypoxic-ischemic encephalopathy, periventricular leukomalacia and intracranial hemorrhage [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs for the long-term morbidity, previous studies have found that SGA is associated with higher rates of neuro-disabilities, such as cerebral palsy and mental retardation, as well as developmental delay [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. One hypothesis that was suggested to explain the associations between cognitive deficiency and growth restriction is hypoxia caused by placental insufficiency that affects the gray matter despite brain-sparing [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eConsistent with previous studies [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], our study demonstrated significant differences in immediate perinatal outcomes between the groups, such as higher rates of low Apgar scores at 5 minutes (\u0026lt;\u0026thinsp;7), IUFD, PPD and total mortality. Nevertheless, the rate of long- term neurologic related hospitalizations of the offspring was comparable between the two groups. Different physiology in twin pregnancies may explain the study results. Another explanation may be related to the mechanism of the growth restriction. As one of the major mechanism of SGA is being constituently small, placental insufficiency and hostile intra- uterine environment may not be present and may not effect neurological morbidity of the SGA twin. Another reason for the lack of association may be inadequate power of our study.\u003c/p\u003e \u003cp\u003eThe main strength of our study is the large cohort size. In addition, the fact that SUMC is the sole tertiary hospital in the entire Negev region in an area characterized by positive immigration, resulting in probable minimal loss to follow-up and selection bias. Nevertheless, this study has few disadvantages. The main limitation lies within its retrospective design. As a population-level analysis, our study can provide evidence only of association and not of causation. Nevertheless, there seems to be a biological plausibility for the observed association. Another limitation relates to the fact that many of the investigated neurologic related morbidities are usually managed in an ambulatory setting and therefore not accounted for. In addition, several potentially relevant covariates were not available for analysis, such as childhood exposures, breastfeeding and placental pathology which may spread some light regarding the mechanism of the growth restriction.. These essential points remain to be investigated in future studies.\u003c/p\u003e \u003cp\u003eIn conclusion, our results suggest that SGA is not associated with increased risk of pediatric neurologic morbidity in dichorionic diamniotic twins. Further research is needed to in order to investigate the impact of other environmental and postnatal factors on long-term morbidity of the offspring.\u003c/p\u003e"},{"header":"Additional information","content":"\u003cp\u003eThis study was not funded and there are no financial disclosures. There is no conflict of interest.\u003c/p\u003e \u003cp\u003e The study received the approval of the Institutional Review Board Committee of the Soroka University Medical Center\u003c/p\u003e \u003cp\u003eNo honorarium, grant, or other form of payment was given to anyone to produce the manuscript.\u003c/p\u003e \u003cp\u003eThis is a database study and as such has no clinical trial registration number.\u003c/p\u003e \u003cp\u003eAll authors on the manuscript contributed to the concept, design, results interpretation, and drafting of the manuscript. Noa Leybovitz Haleluya wrote the draft of the manuscript, Tamar Wainstock performed the statistical analysis and all authors contributed to the revision the manuscript.\u003c/p\u003e \u003cp\u003eData is available to review upon request.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003e/Support: This study was not funded. b. Financial Disclosures: No financial disclosures. c. Leybovitz-Haleluya Noa, MD wrote the first draft of the manuscript. No honorarium, grant, or other form of payment was given to anyone to produce the manuscript. d. This is a database study and as such has no clinical trial registration number. e. All authors on the manuscript contributed to the concept, design, results interpretation, and drafting of the manuscript. f. Data is available to review by request\u003c/p\u003e\u003ch2\u003eACKNOWLEDGMENTS\u003c/h2\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e/ DISCLOSURE\u003c/span\u003e: \u003cb\u003eThe authors report no conflict of interest\u003c/b\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBattaglia FC, Lubchenco LO (1967) A practical classification of newborn infants by weight and gestational age. J Pediatr 71:159\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZeitlin J, El Ayoubi M, Jarreau PH et al (2010) Impact of fetal growth restriction on mortality and morbidity in a very preterm birth cohort. J Pediatr 157:733\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilliams RL, Creasy RK, Cunningham GC et al (1982) Fetal growth and perinatal viability in California. Obstet Gynecol 59:624\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMalin GL, Morris RK, Riley R et al (2014) When is birthweight at term abnormally low? A systematic review and meta-analysis of the association and predictive ability of current birthweight standards for neonatal outcomes. BJOG 121:515\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGriffin IJ, Lee HC, Profit J, Tancedi DJ (2015) The smallest of the small: short-term outcomes of profoundly growth restricted and profoundly low birth weight preterm infants. J Perinatol 35:503\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaer RJ, Rogers EE, Partridge JC et al (2016) Population-based risks of mortality and preterm morbidity by gestational age and birth weight. J Perinatol 36:1008\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChavkin U, Wainstock T, Sheiner E, Sergienko R, Walfisch A (2019) Perinatal outcome of pregnancies complicated with extreme birth weights at term. J Matern Fetal Neonatal Med 32(2):198\u0026ndash;202 Epub 2017 Sep 12.PMID: 28866958\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu J, Wang XF, Wang Y et al (2014) The incidence rate, high-risk factors, and short- and long-term adverse outcomes of fetal growth restriction: a report from Mainland China. 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Arch Dis Child Fetal Neonatal Ed 92:F473\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"archives-of-gynecology-and-obstetrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arch","sideBox":"Learn more about [Archives of Gynecology and Obstetrics](https://www.springer.com/journal/404)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/arch/default.aspx","title":"Archives of Gynecology and Obstetrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Fetal growth restriction, Multiple preganancy, Neurology, Small for gestational age","lastPublishedDoi":"10.21203/rs.3.rs-4522802/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4522802/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eSmall for gestational age (SGA) singletons are at increased risk for neurodevelopmental abnormalities. Scarce data exist regarding the long-term implications of SGA in twins. We opted to study the association between SGA of one twin and long- term neurologic related morbidity in dichorionic diamniotic twins.\u003c/p\u003e\u003ch2\u003eStudy design:\u003c/h2\u003e \u003cp\u003eA population-based retrospective cohort study including consecutive dichorionic diamniotic twins, born between the years 1991\u0026ndash;2021 at a tertiary medical center was conducted. Total and subtypes of neurologic related pediatric hospitalizations among SGA versus non-SGA twins were compared. A Kaplan-Meier survival curve was used to compare the cumulative neurologic morbidity incidence, and a Cox proportional hazards model was constructed to adjust for confounders.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe study population included 4,222 newborns; 180 (4.3%) were SGA. Rate of long- term neurologic related hospitalizations was comparable between the two groups (8.7% vs. 8.0%, p\u0026thinsp;=\u0026thinsp;0.755; Kaplan-Meier survival curve Log- rank p\u0026thinsp;=\u0026thinsp;0.652). Using a Cox proportional hazards model, controlling for gender and birth order, no association was found between SGA and the risk for subsequent neurologic pediatric morbidity of the offspring (Adjusted HR\u0026thinsp;=\u0026thinsp;1.0, 95% CI 0.6\u0026ndash;1.8, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.973).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eSGA is not associated with an increased risk for long-term pediatric neurologic morbidity in dichorionic diamniotic twins.\u003c/p\u003e","manuscriptTitle":"Small for gestational age in twin pregnancies and the risk of offspring pediatric neurologic morbidity","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-20 18:49:48","doi":"10.21203/rs.3.rs-4522802/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revisions","date":"2024-07-01T16:21:10+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-06-22T06:44:34+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-04T09:34:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-04T05:13:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"Archives of Gynecology and Obstetrics","date":"2024-06-03T10:39:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"archives-of-gynecology-and-obstetrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arch","sideBox":"Learn more about [Archives of Gynecology and Obstetrics](https://www.springer.com/journal/404)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/arch/default.aspx","title":"Archives of Gynecology and Obstetrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"6bf83e75-242a-4254-8239-949693abb313","owner":[],"postedDate":"June 20th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-05T15:59:44+00:00","versionOfRecord":{"articleIdentity":"rs-4522802","link":"https://doi.org/10.1007/s00404-024-07662-4","journal":{"identity":"archives-of-gynecology-and-obstetrics","isVorOnly":false,"title":"Archives of Gynecology and Obstetrics"},"publishedOn":"2024-08-02 15:57:00","publishedOnDateReadable":"August 2nd, 2024"},"versionCreatedAt":"2024-06-20 18:49:48","video":"","vorDoi":"10.1007/s00404-024-07662-4","vorDoiUrl":"https://doi.org/10.1007/s00404-024-07662-4","workflowStages":[]},"version":"v1","identity":"rs-4522802","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4522802","identity":"rs-4522802","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}