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• W2939662325 abstract "We sought to review the state of the science for research on multiple gestations. A literature search was performed with the use of PubMed for studies to quantify the representation of multiple gestations for a sample period (2012–2016) that were limited to phase III and IV randomized controlled trials, that were written in English, and that addressed at least 1 of 4 major pregnancy complications: fetal growth restriction or small-for-gestational-age fetus, gestational diabetes mellitus, preeclampsia, and preterm delivery.Of the 226 studies that are included in the analysis, multiple pregnancies were most represented in studies of preterm delivery: 17% of trials recruited both singleton and multiple pregnancies; another 18% of trials recruited only multiple pregnancies. For trials that studied preeclampsia, fetal growth restriction, and gestational diabetes mellitus, 17%, 8%, and 2%, respectively, recruited both singleton and multiple gestations. None of the trials on these 3 topics were limited to women with a multiple pregnancy.Women with a multiple pregnancy are at risk for complications similar to those of women with singleton pregnancies, but their risk is usually higher. Also, the pathophysiologic condition for some complications differs in multiple gestations from those that occur in singleton gestations. Conditions that are unique to multiple pregnancies include excess placenta, placental crowding or inability of the uteroplacental unit to support the normal growth of multiple fetuses, or suboptimal placental implantation sites with an increased risk of abnormal placental location. Other adverse outcomes in multiple gestations are also influenced by twin-specific risk factors, most notably chorionicity.Although twins have been well represented in many studies of preterm birth, these studies have failed to identify adequate predictive tests (short cervical length established over 2 decades ago remains the single best predictor), to establish effective interventions, and to differentiate the underlying pathophysiologic condition of twin preterm birth.Questions about fetal growth also remain. Twin growth deviates from that of singleton gestations starting at approximately 32 weeks of gestation; however, research with long-term follow-up is needed to better distinguish pathologic and physiologic growth deviations, which include growth discordance among pairs (or more). There are virtually no clinical trials that are specific to twins for gestational diabetes mellitus or preeclampsia, and subgroups for multiple pregnancies in existing trials are not large enough to allow definite conclusions. Another important area is the determination of appropriate maternal nutrition or micronutrient supplementation to optimize pregnancy and child health.There are also unique aspects to consider for research design in multiple gestations, such as designation and tracking of the correct fetus prenatally and through delivery. The correct statistical methods must be used to account for correlated data because multiple fetuses share the same mother and intrauterine environment.In summary, multiple gestations often are excluded from research studies, despite a disproportionate contribution to national rates of perinatal morbidity, mortality, and health-care costs. It is important to consider the enrollment of multifetal pregnancies in studies that target mainly women with singleton gestations, even when sample size is inadequate, so that insights that are specific to multiple gestations can be obtained when results of smaller studies are pooled together. The care of pregnant women with multiple gestations presents unique challenges; unfortunately, evidence-based clinical management that includes the diagnosis and treatment of common obstetrics problems are not well-defined for this population. We sought to review the state of the science for research on multiple gestations. A literature search was performed with the use of PubMed for studies to quantify the representation of multiple gestations for a sample period (2012–2016) that were limited to phase III and IV randomized controlled trials, that were written in English, and that addressed at least 1 of 4 major pregnancy complications: fetal growth restriction or small-for-gestational-age fetus, gestational diabetes mellitus, preeclampsia, and preterm delivery. Of the 226 studies that are included in the analysis, multiple pregnancies were most represented in studies of preterm delivery: 17% of trials recruited both singleton and multiple pregnancies; another 18% of trials recruited only multiple pregnancies. For trials that studied preeclampsia, fetal growth restriction, and gestational diabetes mellitus, 17%, 8%, and 2%, respectively, recruited both singleton and multiple gestations. None of the trials on these 3 topics were limited to women with a multiple pregnancy. Women with a multiple pregnancy are at risk for complications similar to those of women with singleton pregnancies, but their risk is usually higher. Also, the pathophysiologic condition for some complications differs in multiple gestations from those that occur in singleton gestations. Conditions that are unique to multiple pregnancies include excess placenta, placental crowding or inability of the uteroplacental unit to support the normal growth of multiple fetuses, or suboptimal placental implantation sites with an increased risk of abnormal placental location. Other adverse outcomes in multiple gestations are also influenced by twin-specific risk factors, most notably chorionicity. Although twins have been well represented in many studies of preterm birth, these studies have failed to identify adequate predictive tests (short cervical length established over 2 decades ago remains the single best predictor), to establish effective interventions, and to differentiate the underlying pathophysiologic condition of twin preterm birth. Questions about fetal growth also remain. Twin growth deviates from that of singleton gestations starting at approximately 32 weeks of gestation; however, research with long-term follow-up is needed to better distinguish pathologic and physiologic growth deviations, which include growth discordance among pairs (or more). There are virtually no clinical trials that are specific to twins for gestational diabetes mellitus or preeclampsia, and subgroups for multiple pregnancies in existing trials are not large enough to allow definite conclusions. Another important area is the determination of appropriate maternal nutrition or micronutrient supplementation to optimize pregnancy and child health. There are also unique aspects to consider for research design in multiple gestations, such as designation and tracking of the correct fetus prenatally and through delivery. The correct statistical methods must be used to account for correlated data because multiple fetuses share the same mother and intrauterine environment. In summary, multiple gestations often are excluded from research studies, despite a disproportionate contribution to national rates of perinatal morbidity, mortality, and health-care costs. It is important to consider the enrollment of multifetal pregnancies in studies that target mainly women with singleton gestations, even when sample size is inadequate, so that insights that are specific to multiple gestations can be obtained when results of smaller studies are pooled together. The care of pregnant women with multiple gestations presents unique challenges; unfortunately, evidence-based clinical management that includes the diagnosis and treatment of common obstetrics problems are not well-defined for this population. In 2016, the twin birth rate was 33.4 per 1000 total children born, and the triplet/higher-order birth rate was 101.4 per 100,000 total children born in the United States.1Martin J.A. Hamilton B.E. Osterman M.J.K. Driscoll A.K. Drake P. Births: final data for 2016.Natl Vital Stat Rep. 2018; 67: 1-55PubMed Google Scholar Collectively in the United States in 2016, there were 133,155 twin, 3871 triplet, and 252 quadruplet and higher-order multiple births. Until recently, multiple gestation births had been increasing, with approximately one-third of this increase associated with delayed maternal age at childbearing and two-thirds associated with an increase in the use of assisted reproductive technology (ART).2Blondel B. Kaminski M. Trends in the occurrence, determinants, and consequences of multiple births.Semin Perinatol. 2002; 26: 239-249Crossref PubMed Scopus (246) Google Scholar, 3Adashi E.Y. Gutman R. Delayed childbearing as a growing, previously unrecognized contributor to the national plural birth excess.Obstet Gynecol. 2018; 132: 999-1006Crossref PubMed Scopus (24) Google Scholar Recent modest decreases in multiple births might be attributed to changes in ART practices, which includes the increasing use of single-embryo transfer in vitro fertilization.4Stern J.E. Cedars M.I. Jain T. et al.Assisted reproductive technology practice patterns and the impact of embryo transfer guidelines in the United States.Fertil Steril. 2007; 88: 275-282Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar Nonetheless, multiple gestations constitute a considerable percentage of pregnancies in the United States and contribute to a disproportionate degree to national rates of perinatal morbidity, mortality, and health-care costs.5Stulberg D.B. Jackson R.A. Freedman L.R. Referrals for services prohibited in Catholic health care facilities.Perspect Sex Reprod Health. 2016; 48: 111-117Crossref PubMed Scopus (27) Google Scholar, 6Callahan T.L. Hall J.E. Ettner S.L. Christiansen C.L. Greene M.F. Crowley Jr., W.F. The economic impact of multiple-gestation pregnancies and the contribution of assisted-reproduction techniques to their incidence.N Engl J Med. 1994; 331: 244-249Crossref PubMed Scopus (369) Google Scholar Given their high-risk status, our objective was to review the state of the science on women with multiple gestations. This review includes an estimation of how often multiple gestations are included in studies, whether we can translate findings from studies of singleton gestations to multiple gestations in instances in which data gaps exist, unique aspects of research on multiple gestations, and a call for future research. This article is not meant to be a comprehensive review of all data on multiple gestations; in most instances, we have limited the discussion to twins for illustration. For many perinatal complications, including preeclampsia, gestational diabetes mellitus, preterm birth, growth restriction, perinatal death, operative delivery, and maternal morbidity, women with multiple gestations are at increased risk compared with women with singleton gestations.5Stulberg D.B. Jackson R.A. Freedman L.R. Referrals for services prohibited in Catholic health care facilities.Perspect Sex Reprod Health. 2016; 48: 111-117Crossref PubMed Scopus (27) Google Scholar Fetal growth in multiple gestations can be characterized additionally by the discrepancy in sizes or discordance.7Breathnach F.M. McAuliffe F.M. Geary M. et al.Definition of intertwin birth weight discordance.Obstet Gynecol. 2011; 118: 94-103Crossref PubMed Scopus (94) Google Scholar Although many pregnancy complications are not unique to multiple gestations, it is likely that many have a different pathophysiologic condition, which includes excess placenta in some cases (eg, gestational diabetes mellitus8Sivan E. Maman E. Homko C.J. Lipitz S. Cohen S. Schiff E. Impact of fetal reduction on the incidence of gestational diabetes.Obstet Gynecol. 2002; 99: 91-94Crossref PubMed Scopus (63) Google Scholar and preeclampsia9Sibai B.M. Hauth J. Caritis S. et al.Hypertensive disorders in twin versus singleton gestations. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.Am J Obstet Gynecol. 2000; 182: 938-942Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar), placental crowding or inability of the uteroplacental unit to support the normal growth of multiple fetuses (eg, small for gestational age [SGA] or growth restriction),10Blickstein I. Normal and abnormal growth of multiples.Semin Neonatol. 2002; 7: 177-185Abstract Full Text PDF PubMed Scopus (103) Google Scholar or suboptimal placental implantation sites with increased risk of placenta previa, velamentous cord insertion, and vasa previa, than do singleton gestations.11Ananth C.V. Demissie K. Smulian J.C. Vintzileos A.M. Placenta previa in singleton and twin births in the United States, 1989 through 1998: a comparison of risk factor profiles and associated conditions.Am J Obstet Gynecol. 2003; 188: 275-281Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 12Jauniaux E. Melcer Y. Maymon R. Prenatal diagnosis and management of vasa previa in twin pregnancies: a case series and systematic review.Am J Obstet Gynecol. 2017; 216: 568-575Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar In addition, excess carbohydrates and inadequate protein, iron, and other micronutrient deficiencies may all contribute to the higher rates of prematurity, growth restriction, preeclampsia, and possibly gestational diabetes mellitus that are observed in multiple gestations compared with singleton pregnancies.13Goodnight W. Newman R. Society of Maternal-Fetal MedicineOptimal nutrition for improved twin pregnancy outcome.Obstet Gynecol. 2009; 114: 1121-1134Crossref PubMed Scopus (63) Google Scholar Spontaneous preterm birth of multiple gestations may also have unique predisposing factors. Multiple gestations have been hypothesized to be at higher risk of spontaneous preterm delivery because of uterine stretch, which is associated with increased expression of gap junctions, oxytocin receptors, and labor-associated signaling proteins in the myometrium.14Stock S. Norman J. Preterm and term labour in multiple pregnancies.Semin Fetal Neonatal Med. 2010; 15: 336-341Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar Increased placental mass is associated with higher levels of corticotrophin-releasing hormone, which is correlated with the onset of parturition.14Stock S. Norman J. Preterm and term labour in multiple pregnancies.Semin Fetal Neonatal Med. 2010; 15: 336-341Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar However, there is also likely to be some element of a shared cause for preterm birth, because women with a preterm birth of twins have an increased risk of preterm birth of a singleton in a subsequent pregnancy.15Facco F.L. Nash K. Grobman W.A. Are women who have had a preterm twin delivery at greater risk of preterm birth in a subsequent singleton pregnancy?.Am J Obstet Gynecol. 2007; 197: 253.e1-253.e3Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 16Kazemier B.M. Buijs P.E. Mignini L. et al.Impact of obstetric history on the risk of spontaneous preterm birth in singleton and multiple pregnancies: a systematic review.BJOG. 2014; 121: 1197-1209Crossref PubMed Scopus (65) Google Scholar Some adverse outcomes in twin gestations are due to twin-specific risk factors, most notably chorionicity. There are unique problems that pertain only to monochorionic twins, including twin-twin transfusion syndrome, certain congenital anomalies, disproportionate placental sharing, and a higher incidence of cord abnormalities, such as velamentous insertion.17Society for Maternal Fetal MedicineTwin-twin transfusion syndrome.Am J Obstet Gynecol. 2013; 208 ([Published erratum appears in Am J Obstet Gynecol 2013;208:392]): 3-18Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, 18Hanley M.L. Ananth C.V. Shen-Schwarz S. Smulian J.C. Lai Y.L. Vintzileos A.M. Placental cord insertion and birth weight discordancy in twin gestations.Obstet Gynecol. 2002; 99: 477-482Crossref PubMed Scopus (94) Google Scholar Placental disease also demonstrates differences by chorionicity. Dichorionic placentas have been associated with more maternal vascular malperfusion lesions compared with monochorionic placentas, although monochorionic placentas have been associated with more fetal vascular malperfusion lesions compared with dichorionic placentas.19Weiner E. Barber E. Feldstein O. et al.Placental histopathology differences and neonatal outcome in dichorionic-diamniotic as compared to monochorionic-diamniotic twin pregnancies.Reprod Sci. 2018; 25: 1067-1072Crossref PubMed Scopus (10) Google Scholar Monochorionicity (compared with dichorionicity) is also associated with a higher preterm birth risk and associated morbidity and death.20Hack K.E. Derks J.B. Elias S.G. et al.Increased perinatal mortality and morbidity in monochorionic versus dichorionic twin pregnancies: clinical implications of a large Dutch cohort study.BJOG. 2008; 115: 58-67Crossref PubMed Scopus (284) Google Scholar In monochorionic twins, increased rates of morbidity and mortality have been attributed primarily to the increased risk of twin-twin transfusion syndrome. In 1 study, the rates of hypertensive disease and preterm premature rupture of membranes were the same for monochorionic and dichorionic twins.21Morikawa M. Yamada T. Sato S. Minakami H. Contribution of twin-to-twin transfusion syndrome to preterm birth among monochorionic biamniotic and bichorionic biamniotic twin pregnancies.J Perinat Med. 2011; 39: 557-561Crossref PubMed Google Scholar Another risk factor that affects adverse outcomes in twin gestations is ART. Twin pregnancies that result from treatment with fertility drugs or ART are at higher risk of many adverse outcomes that include low birth weight, preterm delivery, and placental disorders such as bleeding, placental abruption, placenta previa and vasa previa, compared with twin pregnancies that are achieved without the use of fertility drugs or ART.22Luke B. Gopal D. Cabral H. Stern J.E. Diop H. Adverse pregnancy, birth, and infant outcomes in twins: effects of maternal fertility status and infant gender combinations: the Massachusetts Outcomes Study of Assisted Reproductive Technology.Am J Obstet Gynecol. 2017; 217: 330.e1-330.e15Abstract Full Text Full Text PDF Scopus (54) Google Scholar, 23Qin J.B. Wang H. Sheng X. Xie Q. Gao S. Assisted reproductive technology and risk of adverse obstetric outcomes in dichorionic twin pregnancies: a systematic review and meta-analysis.Fertil Steril. 2016; 105: 1180-1192Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar Certain maternal characteristics independently affect outcomes in multiple pregnancies. These characteristics include race/ethnicity (increased risk of cesarean delivery and gestational diabetes mellitus in nonwhite vs white women with twins),24Soffer M.D. Naqvi M. Melka S. Gottlieb A. Romero J. Fox N.S. The association between maternal race and adverse outcomes in twin pregnancies with similar healthcare access.J Matern Fetal Neonatal Med. 2018; 31: 2424-2428Crossref PubMed Scopus (6) Google Scholar parity (increased risks of cesarean and preterm delivery in nulliparous vs multiparous women with twins),25Hannoun A. Usta I.M. Awwad J. et al.Effect of parity on maternal and neonatal outcomes in twin gestations.Acta Obstet Gynecol Scand. 2012; 91: 117-121Crossref PubMed Scopus (9) Google Scholar maternal weight (increased risks of preterm delivery, gestational diabetes mellitus, gestational hypertension, and preeclampsia with increasing maternal body mass index [BMI] in women with twins),26Dickey R.P. Xiong X. Xie Y. Gee R.E. Pridjian G. Effect of maternal height and weight on risk for preterm singleton and twin births resulting from IVF in the United States, 2008-2010.Am J Obstet Gynecol. 2013; 209: 349.e1-349.e6Abstract Full Text Full Text PDF Scopus (33) Google Scholar, 27Fox N.S. Roman A.S. Saltzman D.H. Klauser C.K. Rebarber A. Obesity and adverse pregnancy outcomes in twin pregnancies.J Matern Fetal Neonatal Med. 2014; 27: 355-359Crossref PubMed Scopus (20) Google Scholar and maternal height (increased risk of preterm delivery with shorter stature in women with twins).26Dickey R.P. Xiong X. Xie Y. Gee R.E. Pridjian G. Effect of maternal height and weight on risk for preterm singleton and twin births resulting from IVF in the United States, 2008-2010.Am J Obstet Gynecol. 2013; 209: 349.e1-349.e6Abstract Full Text Full Text PDF Scopus (33) Google Scholar However, the extent to which these factors differentially affect multiple vs singleton pregnancies is less clear. Another important factor is fetal sex; male and female fetuses in a dichorionic twin pregnancy benefit from a higher birth weight and longer gestation if they have an intrauterine female counterpart (ie, male-female pairs fare better than male-male, and female-female pairs fare better than female-male).28Melamed N. Yogev Y. Glezerman M. Effect of fetal sex on pregnancy outcome in twin pregnancies.Obstet Gynecol. 2009; 114: 1085-1092Crossref PubMed Scopus (47) Google Scholar One example of an important pathophysiologic question that remains unanswered is appropriate maternal nutrition in multiple gestations. The 2009 Institute of Medicine (IOM) recommendations on BMI-specific weight gain in twins is provisional, and there are no recommendations for underweight women who are likely to be at the greatest risk.29Bertino E. Coscia A. Boni L. et al.Weight growth velocity of very low birth weight infants: role of gender, gestational age and major morbidities.Early Hum Dev. 2009; 85: 339-347Crossref PubMed Scopus (33) Google Scholar These recommendations were formulated based on the weight gain patterns of almost 2500 women with twin pregnancies and optimal outcomes, which include normal fetal growth and birthweights, that was published by Luke et al30Luke B. Hediger M.L. Nugent C. et al.Body mass index: specific weight gains associated with optimal birth weights in twin pregnancies.J Reprod Med. 2003; 48: 217-224PubMed Google Scholar in 2003. Underweight women were excluded from the IOM recommendations because of a change in the definition of underweight BMI from <19.8 to <18.5 kg/m2, which resulted in a smaller sample of underweight women. Despite the provisional nature of the IOM recommendations, the impact of appropriate maternal weight gain on twin birth weight has been relatively well studied.31Bodnar L.M. Pugh S.J. Abrams B. Himes K.P. Hutcheon J.A. Gestational weight gain in twin pregnancies and maternal and child health: a systematic review.J Perinatol. 2014; 34: 252-263Crossref PubMed Scopus (33) Google Scholar Two recent investigations noted higher rates of preterm birth and lower birthweights in women with twin gestations who failed to meet 2009 IOM weight gain recommendations.32Fox N.S. Rebarber A. Roman A.S. Klauser C.K. Peress D. Saltzman D.H. Weight gain in twin pregnancies and adverse outcomes: examining the 2009 Institute of Medicine guidelines.Obstet Gynecol. 2010; 116: 100-106Crossref PubMed Scopus (59) Google Scholar, 33Gonzalez-Quintero V.H. Kathiresan A.S. Tudela F.J. Rhea D. Desch C. Istwan N. The association of gestational weight gain per Institute of Medicine guidelines and prepregnancy body mass index on outcomes of twin pregnancies.Am J Perinatol. 2012; 29: 435-440Crossref PubMed Scopus (38) Google Scholar Neither of these studies included underweight women or determined the impact of achieving weight gain goals on neonatal outcomes. Pettit et al34Pettit K.E. Lacoursiere D.Y. Schrimmer D.B. Alblewi H. Moore T.R. Ramos G.A. The association of inadequate mid-pregnancy weight gain and preterm birth in twin pregnancies.J Perinatol. 2015; 35: 85-89Crossref PubMed Scopus (26) Google Scholar found that inadequate weight gain between 20 and 28 weeks of gestation was the strongest predictor of preterm birth at <32 weeks of gestation for multiple gestations. Women with inadequate weight gain also had increased rates of adverse neonatal outcomes that included admission to the neonatal intensive care unit, intraventricular hemorrhage, and necrotizing enterocolitis. Since the publication of the IOM guidelines, a retrospective cohort study was performed of twin gestations that were delivered at a single center from 2000–2010.35Greenan C.W. Newman R.B. Wojciechowski B. Christensen C.J. Achievement of body mass index specific weight gain recommendations: impact on preterm birth in twin pregnancies.Am J Perinatol. 2017; 34: 1293-1301Crossref PubMed Scopus (6) Google Scholar Women were grouped as either having met or not met weight gain guidelines established by Luke et al30Luke B. Hediger M.L. Nugent C. et al.Body mass index: specific weight gains associated with optimal birth weights in twin pregnancies.J Reprod Med. 2003; 48: 217-224PubMed Google Scholar for a given gestational age at delivery. Of 588 twin gestations with deliveries at >24 weeks of gestation, BMI-specific weight gain was within guidelines for 59.9% of women. This group had a 1.5-fold reduction in the rate of preterm birth at <32 weeks of gestation, had larger mean birthweights, and were significantly less likely to deliver either twin with a birth weight less than the <10th percentile for gestational age than the group who had weight gains below the guidelines. A composite of neonatal morbidity, days on the respirator, length of neonatal hospital stay, and rate of neonatal intensive care admission was decreased significantly in the guideline group. Furthermore, the timing of weight gain during pregnancy also appears to be important. Greater maternal weight gain from 14–20 and from 21–27 weeks of gestation has been found to be associated differentially with increases in multiple fetal biometric parameters that include abdominal circumference, biparietal diameter, and femur and humerus lengths.36Hinkle S.N. Hediger M.L. Kim S. et al.Maternal weight gain and associations with longitudinal fetal growth in dichorionic twin pregnancies: a prospective cohort study.Am J Clin Nutr. 2017; 106: 1449-1455Crossref PubMed Scopus (8) Google Scholar Additional research is needed to evaluate the impact of maternal weight gain goals on prematurity, fetal growth, and neonatal outcomes in multiple gestations. Determination of whether trimester-specific rates, as opposed to total weight gain recommendations, leads to better outcomes may also be more clinically useful given the increased risk of preterm delivery in twins and the potential importance of timing of weight gain. In the absence of randomized control trials (RCTs), future studies need to combine data from multiple institutions to ensure adequate sample sizes when stratifying by prepregnancy BMI, including underweight women, so that a stronger argument can be made for the IOM to revise their provisional and incomplete recommendations. More data regarding the potential consequences or benefits that are associated with overachieving the recommended maternal weight gain goals would also be informative. In summary, important questions remain about the pathophysiologic conditions that are associated with twin pregnancy complications and potentially effective interventions. For multiple gestations, there are even more data gaps to consider than in the care of complicated singleton gestations. To quantify the representation of twins and multiple gestations, we performed a literature search in PubMed for a sample period (2012–2016) limited to phases III and IV RCTs that were written in English and that addressed at least 1 of 4 major pregnancy complications that were used for illustration: fetal growth restriction or SGA, gestational diabetes mellitus, preeclampsia, and preterm delivery. Search terms included controlled vocabulary terms (ie, medical subject headings) and variations of the following keywords: singleton, twin, triplet, and multiple births. See the Appendix for search details. Our search resulted in 1285 articles. Because some articles might have addressed multiple topics, this number includes double-count results (Figure 1). Articles from the search were reviewed individually and excluded if they had any of the following subjects: nonrandomized controlled trials; study subjects who were not pregnant women (eg, neonatal, childhood, or postpartum studies); the primary study outcome was not 1 of the 4 outcomes of interest; and studies that were secondary analyses of a primary RCT. This process resulted in 226 articles for analysis. The 226 articles were further reviewed and coded by 3 reviewers (A.C., T.K,. and R.N. with adjudication by K.L.G.), based on subject inclusion of singleton gestations, twins, or both. In cases in which singleton or multiple births were not stated, we contacted the authors for clarification. If there was no response, the study was placed in the unidentified category. Figure 2 presents the percentages of RCTs for singleton gestation, twin or multiple gestation only, both singleton and multiple gestations, or unidentified pregnancies from 2012–2016 for the 4 major outcomes. Most studies were performed in only singleton gestations for all 4 outcomes. Of the 226 studies that were included in the analysis, multiple pregnancies were most represented in RCTs studying preterm delivery: 17% of trials recruited both singleton and multiple pregnancies, and another 18% of trials recruited only multiple pregnancies. For trials studying preeclampsia, fetal growth restriction, and gestational diabetes mellitus, 17%, 8%, and 2% recruited both singleton and multiple gestations, respectively. None of the trials on these 3 topics included only women with a multiple pregnancy. There did not appear to be a trend towards increasing or decreasing inclusion of multiple gestations over time.Figure 2Representation of twins or multiple gestations in researchShow full captionA, Fetal growth restriction, overall. B, Fetal growth restriction, by year. The percent of randomized controlled trials for singleton; twin" @default.
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• W2939662325 date "2019-08-01" @default.
• W2939662325 modified "2023-10-12" @default.
• W2939662325 title "SMFM Special Statement: State of the science on multifetal gestations: unique considerations and importance" @default.
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• W2939662325 doi "https://doi.org/10.1016/j.ajog.2019.04.013" @default.
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