Clinical Review


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Addressing the risks of multiple gestation, a new method of cryopreservation of embryos, and the unique value of anti-Müllerian hormone as a marker of ovarian reserve



Dr. Adamson reports that he receives research grants from LabCorp and Auxogyn, and is the founder and CEO of Advanced Reproductive Care. Dr. Abusief reports no financial relationships relevant to this article.

The field of reproductive endocrinology has advanced at warp speed over the past few decades—and shows no sign of stopping any time soon. In this article, we outline noteworthy developments of the past year:

  • publication of two important Committee Opinions from the American Society for Reproductive Medicine (ASRM)—one of them on the need to reduce the rate of multiple gestation among women undergoing treatment for infertility and the other focusing on a method of achieving this goal: elective single embryo transfer
  • two studies of vitrification for cryopreservation of embryos and oocytes
  • a trio of investigations into the utility of anti-Müllerian hormone as a means of assessing ovarian reserve and reproductive potential.

Goal of non-ART infertility therapy should be to produce a single child

Practice Committee of the American Society for Reproductive Medicine. Multiple gestation associated with infertility therapy: an American Society for Reproductive Medicine Practice Committee opinion [published online ahead of print December 20, 2011]. Fertil Steril. doi:10.1016/j.fertnstert.2011.11.048.

The goal of infertility treatment is for each patient to have one healthy child at a time, according to a new Practice Committee Opinion from the American Society for Reproductive Medicine (ASRM).

In women who experience oligo-ovulation or anovulation, ovulation induction is typically offered. For ovulatory women who have unexplained or age-related infertility, the treatment often is controlled ovarian stimulation. Either intervention can lead to ovulation from multiple follicles and, ultimately, increase the risk of multiple gestation.

Multiple gestation increases maternal morbidity and both fetal and neonatal morbidity and mortality. Most of the poor perinatal outcomes relate directly to preterm birth. Treatment of women who have infertility, therefore, requires achieving a balance between two competing needs:

  • maximizing the probability of pregnancy
  • minimizing the risk of multiple (two fetuses or more) or high-order multiple (more than two fetuses) gestation.

Many multiple births are iatrogenic

Approximately 60% of twin births result from natural conception, 30% from ovulation induction and controlled ovarian stimulation, and 10% from assisted reproductive technologies (ART). For high-order multiple gestation, the figures are 20% for natural conception, 50% for ovulation induction and controlled ovarian stimulation, and 30% for ART. These statistics reveal that a very large percentage of multiple births are iatrogenic, with fertility treatment increasing the risk of twins by a factor of approximately 20 and the risk of high-order multiples by a factor of more than 100. The risk of monozygotic twinning also increases by a factor of 2 or 3 after ovulation induction, compared with natural conception.

Triplets should be a rarity

Three-dimensional sonogram of triplets.

Multiple gestation is expensive

The economic costs associated with excess perinatal and maternal morbidity are substantial. They include the immediate costs associated with maternal hospitalization and neonatal intensive care and lifetime costs associated with care for chronic illness, rehabilitation, and special education. Although these costs might be offset by the productivity of individuals, the overall benefit to society is clearly greater when a singleton is born. Personal and familial nonfinancial costs of morbidity and mortality can also be significant.

A sense of urgency on the part of the patient may contribute to an increased risk of multiple gestation by prompting more aggressive treatment. Other contributors include limited health coverage, which creates a personal financial burden, and inadequate patient education about the risks of multiple gestation.

Strategies for limiting the risk of multiple gestation

Appropriate treatment goals are the foundation of risk-reducing strategies. For example, ovulation induction in women who have oligo-ovulation or anovulation should aim toward producing a single oocyte. These women tend to respond to lower dosages of ovarian-stimulation drugs than are typically given. Therefore, women undergoing ovulation induction should receive a lower dosage of gonadotropins and be monitored very carefully for the number of developing follicles and ovarian hyperstimulation syndrome.

In contrast, the goal of controlled ovarian stimulation in ovulatory women who have unexplained or age-related subfertility is to stimulate the development and ovulation of more than one mature follicle to increase cycle fecundity.

Regrettably, efforts have failed to identify estradiol levels and the specific size and number of follicles that prevent multiple gestation. The most likely reason is that follicular size cannot accurately predict the maturity of the oocyte within—follicles as small as 10 mm sometimes yield mature and fertilizable oocytes. Moreover, the population that undergoes ovulation induction or controlled ovarian stimulation is very heterogenous. Therefore, it is not possible to propose valid guidelines to reduce the rate of multiple gestation.


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