Risk For Multiple Gestations

ARTs

Multiple gestations are more common as a result of assisted reproduction than as a result of natural conception because of the transfer of multiple embryos and a higher incidence of spontaneous twinning with any single embryo. The risk of monozygotic twinning after implantation of a single embryo appears to be increased in pregnancies conceived by IVF compared with the rate during spontaneous conceptions; however, this risk is relatively low, with only a 1 to 2 percent chance of having twins with implantation of a single embryo (Adashi et al., 2004). Therefore, the major cause underlying the increased risk of multiple births as a result of the use of ARTs is the number of embryos transferred. Results from a recent study suggest that IVF with a single blastocyst-stage embryo (at 5 days) versus the typical transfer with an embryo at the cleavage stage (3 days) in women under age 36 results in a higher rate of pregnancy and delivery. Of the two cases of multiple pregnancies, both occurred in the cleavage stage group (Pa-panikolaou et al., 2006).

National data indicate that in the United States, the majority of ART cycles involve the transfer of more than one embryo, with more embryos transferred as maternal age increases. In 2003, for women under age 35, an average of 2.6 fresh nondonor eggs were transferred per cycle (CDC, 2003d). For women ages 35 to 37, 38 to 40, and 41 to 42, the average numbers of embryos transferred were 2.9, 3.1, and 3.5, respectively. As the techniques involving ARTs have improved, the relationship between the number of embryos transferred and the achievement of a successful live birth is less clear. With the exception of women older than 40 years of age, there appears to be no improvement in the rates of live births when two or more embryos are transferred. Evidence suggests that for women under age 35, the transfer of more than two embryos is not associated with an increased likelihood of conception (Filicori et al., 2005). The transfer of more than two embryos in women over age 40, however, may prove beneficial, as it may result in a successful pregnancy, with fewer risks of multiple gestations (Filicori et al., 2005).

There is a direct relationship between the rise in the use of assisted reproduction and the increase in the numbers of multiple gestations. Fifty-three percent of 45,751 infants born in the United States as a result of the use of ART in 2002 were part of multiple gestations. Although approximately 1 percent of the infants born were conceived through the use of ARTs, these infants represented 0.5 percent of all singleton births and 17 percent of all multiple births. Sixteen percent of twins and 44 percent of higher-order multiple births were conceived by the use of ARTs (CDC, 2005g).

Ovulation Promotion

Much of the focus on the causes of multiple gestations has been placed on the role of ARTs, particularly IVF. Much less attention has been paid to the role of ovulation promotion (superovulation or intrauterine insemination and conventional ovulation induction), which is equally important in terms of its contribution to multiple gestations. The risk of multiple gestations secondary to infertility treatments such as ovulation stimulation with injectable hormones is less well documented, as the collection of data on the frequency of use of these treatments is not mandated. Nonetheless, limited data suggest that these treatments may be associated with an even higher risk of multiple gestations than IVF and ICSI, particularly if the number of developing oocytes is not monitored during the cycle (Adashi et al., 2004).

In 2000, ovulation promotion accounted for 21 percent of twin births, whereas IVF accounted for 12 percent (Figure 5-4) (Reynolds et al., 2003). Ovulation promotion was implicated in 40 percent of higher-order multiple births (Figure 5-5). Forty-two percent of these higherorder multiple births were the result of IVF, whereas 18 percent occurred spontaneously.

Ovulation mu

Ovulation mu

FIGURE 5-4 Contributions (percent) of IVF and ovulation promotion to twin births: 2000. SOURCE: Reynolds et al. (2003).

Reprinted from American Journal of Obstetrics and Gynecology, Vol. 190, Pg. 887, © 2004, with permis sion from Elsevier.

FIGURE 5-4 Contributions (percent) of IVF and ovulation promotion to twin births: 2000. SOURCE: Reynolds et al. (2003).

Reprinted from American Journal of Obstetrics and Gynecology, Vol. 190, Pg. 887, © 2004, with permis sion from Elsevier.

FIGURE 5-5 Contributions (percent) of IVF and ovulation promotion to higher-order multiple births: 2000. SOURCE: Reynolds et al. (2003).

Reprinted from American Journal of Obstetrics and Gynecology, Vol. 190, Pg. 887, © 2004, with permission from Elsevier.

FIGURE 5-5 Contributions (percent) of IVF and ovulation promotion to higher-order multiple births: 2000. SOURCE: Reynolds et al. (2003).

Reprinted from American Journal of Obstetrics and Gynecology, Vol. 190, Pg. 887, © 2004, with permission from Elsevier.

Finding 5-1: The prevalence of the use of superovulation with or without artificial insemination is unknown, and no systematic mechanisms are in place to collect these data.

ARTs and Preterm Birth

The primary concern regarding the use of ARTs and ovulation promotion is the risk of preterm delivery that is associated with multiple gestations. For twins, the average gestational age at delivery is approximately 35 weeks, with 58 percent of these deliveries occurring before term (37 weeks of gestation) and with more than 12 percent occurring before 32 weeks of gestation (CDC, 2003d) (Figure 5-6). The risks are even greater for higher-order multiple births. The mean gestational ages of triplets, quadruplets, and quintuplets and higher-order multiples were 32.2, 29.9, and 28.5 weeks, respectively. More than 90 percent of triplets were born at less than 37 weeks of gestation, and approximately 36 percent were born at less than 32 weeks of gestation.

Among the infants conceived through the use of ARTs specifically, 14.5 percent of singleton births, 61.7 percent of twin births, and 97.2 percent of higher-order multiple births were born at gestational ages of less than 37 weeks (CDC, 2005f).

40

38.8

32 2

■ ■ .. 29 9 28.5 Singeltons Twins Triplets Quadruplets Quintuplets/+

FIGURE 5-6 Mean gestational age (weeks) by number of infants born, United States, 2002. SOURCE: CDC (2003d).

FIGURE 5-6 Mean gestational age (weeks) by number of infants born, United States, 2002. SOURCE: CDC (2003d).

Singletons Conceived through ARTs and Preterm Birth

Singletons conceived through the use of IVF are twice as likely to be born preterm and die within 1 week of birth than those not conceived through IVF and 2.7 times more likely to have a low birth weight (Hampton, 2004). A meta-analysis that compiled information from 12,283 singleton births conceived through the use of IVF and 1.9 million spontaneously conceived singleton births noted a twofold increase in the risk of preterm delivery (Jackson et al., 2004). Similarly, the results of a meta-analysis conducted by McGovern and colleagues (2004) found that singleton pregnancies resulting from IVF (embryo transfer) and GIFT were twice as likely as naturally conceived singletons to be delivered preterm. The etiology of this type of preterm birth remains unknown. Recent evidence suggests the possibility of placentation problems in ART pregnancies. A study from the First And Second Trimester Evaluation of Risk trial examined whether the use of ART was associated with an increased risk of chromosomal abnormalities, fetal malformations, or adverse pregnancy outcomes among singleton births (Shevell et al, 2005). Approximately 95 percent of patients did not use any form of ART, 3.4 percent used ovulation induction, and 1.5 percent received IVF treatment. Results indicate that patients who used ovulation induction had an increased risk of placental abruption (OR; 95% CI: 2.4; 1.3-4.2) and fetal loss after 24 weeks (OR; 95% CI: 2.1; 1.3-3.6) compared to women who did not receive ART. Patients who used IVF were more likely to develop preeclampsia (OR; 95% CI: 2.7; 1.7-4.4) have a placental abruption(OR; 95% CI: 2.4; 1.1-5.2), placenta previa (OR; 95% CI: 6.0; 3.4-10.7), and undergo a cesarean delivery (OR; 95% CI: 2.3; 1.8-2.9) compared to women who did not undergo ART. There was no association between ART and fetal growth restriction, aneuploidy, or fetal anomalies after adjusting for a number of sociodemographic and health variables.

Finding 5-2: Fertility treatments are a significant contributor to preterm birth among both multiple and singleton pregnancies.

Finding 5-3: The mechanisms by which conditions of infertility, subfertility, and fertility treatments increase the risk of preterm birth, particularly among singleton pregnancies, are unknown. The mechanisms may be markedly different from the mechanisms suggested when racial and socioeconomic causes of preterm birth are considered.

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