Am J Obstet Gynecol 2019 Apr 16. Epub 2019 Apr 16.
Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, United States.
We sought to review the state of the science for research on multiple gestations. A literature search was performed using PubMed to quantify the representation of multiple gestations for a sample period (2012-2016) limited to Phase III and IV randomized controlled trials and written in English addressing at least one of four major pregnancy complications for illustration: fetal growth restriction or small-for-gestational-age fetus, gestational diabetes, preeclampsia, and preterm delivery. Of the 226 studies included in the analysis, multiple pregnancies were most represented in studies of 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, 17%, 8%, and 2% recruited both singletons and multiples, respectively. None of the trials on these three topics was limited to women with a multiple pregnancy. Women with a multiple pregnancy are at risk for similar complications as women with singleton pregnancies, but their risk is usually higher. Also, the pathophysiology for some complications differs in multiple gestations from those occurring in singleton gestations. Conditions unique to multiple pregnancies include excess placenta, placental crowding or inability of the utero-placental 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), establish effective interventions, and to differentiate the underlying pathophysiology of twin preterm birth. Questions about fetal growth also remain. Twin growth deviates from that of singletons starting at approximately 32 weeks of gestation; however, research with long-term follow-up is needed to better distinguish pathologic and physiologic growth deviations, including growth discordance among pairs (or more). There are virtually no clinical trials specific to twins for gestational diabetes or preeclampsia, and subgroups for multiple pregnancy in existing trials are not large enough to allow definite conclusions. Another important area is to determine the 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, since multiples share the same mother and intrauterine environment. In summary, multiple gestations are often excluded from research studies despite a disproportionate contribution to national rates of perinatal morbidity, mortality, and health care costs. It is important to consider enrolling multifetal pregnancies in studies that mainly target women with singletons, even when sample size is inadequate, so that insights specific to multiples can be obtained when results of smaller studies are pooled together. The care of multiple gestations presents unique challenges, but unfortunately, evidence-based clinical management, including diagnosis and treatment of common obstetrical problems, are not well-defined for multiple gestations.