The incidence of multiple gestation has risen significantly over several decades, primarily due to increased use of fertility drugs for ovulation induction, superovulation, and assisted reproductive technologies (ART), such as in vitro fertilization (IVF) . In 1960, before the commercial availability of drugs for treatment of infertility, there were approximately 4.3 million births in the United States, with 1244 triplets and higher order multiples . In 2011, the total number of births was slightly lower (3.9 million), but there were 5417 triplet and higher order multiples; these numbers do not include those high order multiple gestations (ie, pregnancies with at least three fetuses) reduced naturally or iatrogenically . Approximately 20 percent of high order multiple births are naturally conceived, 39 to 67 percent are related to ovulation induction/superovulation, and 13 to 44 percent are associated with ART .
Among women undergoing IVF with fresh nondonor embryos in 2009, the rates of singleton, twin, and triplets-or-more pregnancies were 61.7, 28.5, and 3.1 percent, respectively (6.7 percent undetermined at early miscarriage) . By comparison, in 2011, 3.5 percent of all live births in the United States were multiple gestations (twins 3.3 percent, triplets or more 0.14 percent) .
The lack of insurance coverage for ART in most of the United States, as well as competition among ART programs, has generated pressure to achieve success in a minimal number of cycles [6,7]. One strategy has been to increase the number of embryos transferred per IVF procedure. An analysis of 1998 Society of Assisted Reproductive Technology (SART) data demonstrated that providers in states without insurance coverage for IVF transferred more embryos per cycle, had a higher percentage of cycles resulting in pregnancy, and encountered an increased frequency of high order gestations compared to providers in states with IVF insurance coverage .
Infertility patients often consider the birth of twins acceptable, or even desirable, since it may result in a completed family after (sometimes) years of infertility [8-12]. Nevertheless, there is a need for effective methods to reduce the frequency of multiple gestation, particularly high order pregnancies. Multiple gestations are at significantly increased risk of fetal, neonatal, and maternal complications, as well as complete pregnancy loss, when compared to singleton pregnancies (table 1) . As an example, in one review, the risk of delivery <32 weeks of gestation for singleton, twin, triplet, and quadruplet pregnancies was 2, 8, 26, and >95 percent, respectively . In another study that compared twin pregnancy outcome with outcome of two successive singleton pregnancies delivered by the same mother, adverse pregnancy and neonatal outcomes were significantly increased for IVF twins compared with two successive IVF singleton pregnancies .
The economic and psychological impact on families raising children of a multiple gestation is also important [14-17]. In one study, for example, 22 percent of mothers of multiples had Parenting Stress Index scores indicating severe parenting stress, compared with 5 percent of mothers of IVF singletons and 9 percent of mothers of naturally conceived singletons . Another study found that each additional child more than tripled the odds of not being able to meet basic material needs and doubled the odds of a lowered quality of life for the family . (See "Neonatal outcome, complications, and management of multiple births", section on 'Impact on family'.)