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Is There Still Hope After 40?

In what's being touted as the largest study to date of assisted reproductive success in women over 40, doctors have concluded there's still a "reasonable" chance of success in their efforts to achieve a pregnancy.1

"Reproductive success is certainly attainable for a select subgroup of women in the fifth decade of life," wrote researchers at Boston IVF, a fertility clinic in Waltham, Massachusetts, as well as Beth Israel Deaconess Medical Center in Boston and Harvard Medical School.

Trend: Delayed Parenting
The researchers cited a national trend among couples in delaying parenthood—nearly a fifth of all women using assisted reproductive technologies (ART) to get pregnant are above age 40—as well as debates about the age at which attempts to become pregnant using a doctor's help is still "reasonable and feasible" and what indicators can be used to predict this success.

"The biggest obstacle most women over 40 face is two-fold: diminishing ovarian reserve coupled with poor embryo quality," explained the study's first author, reproductive endocrinologist Sigal Klipstein, MD, who practices at Karande & Associates, a fertility clinic near Chicago.  This in turn, boosts the risk of miscarriage, the investigators pointed out.

Examining ART Results
But the research team wanted to know if those challenging prospects should preclude women over age 40 from undergoing assisted reproductive technologies (ART). To better clarify this, the investigators pulled patient records related to more than 2,700 cycles involving women over 40 using in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI) between 1999 and 2002. The team performed a second analysis, pulling records of a smaller group of patients whose first IVF or ICSI occurred after age 40, during the same period. This was done to determine any differences in outcome between women who started using assisted reproductive technologies (ART) before age 40, then continued past their 40th birthday, and those who began ART for the first time in their 40s.

In the larger group, only outcomes after age 40 were included in the study. "I wanted to look particularly at cumulative pregnancy rates in women starting IVF at age 40, 41, etc.," said Klipstein. "I believe that this is a different subgroup than women who started IVF in their late 30's."

Information on miscarriages and selective fetal reduction was also obtained.

ART Protocols Used
Each patient had undergone a standard IVF protocol, which included a long Lupron regimen with or without a pretreatment oral contraceptive, an oral contraceptive/Lupron flare, and a gonadotropin-releasing hormone (GnRH) antagonist protocol, which included Cetrotide or Antagon. The antagonist was given to the patient when their lead follicles reached a certain size. Human menopausal gonadotropins, such as Pergonal, Humegon, and Repronex, were also included in the cycles, as well as an FSH therapy like Follistim or Gonal-F.

Decisions on canceling a cycle were made based on patient age, a history of poor response to ovarian stimulation, low peak estrogen levels, and a poor response to controlled ovarian hyperstimulation. A human chorionic gonadotropin (hCG) (Profasi, Novarel, Pregnyl, Ovidrel), a medication used to induce a follicle to release its egg, was given to patients who had at least two to three dominant follicles toward the end of the cycle.

Thirty-six hours after hCG was given, eggs were retrieved, and IVF and/or ICSI was performed subsequently. In most cases, resulting embryos were transferred to begin pregnancy three days later, the research team reported. Pregnancies were confirmed using ultrasound exams.

Factors Affecting Treatment Success
The researchers then studied the relationship between each patient's age, the number of embryos transferred after IVF/ICSI, whether there had been any excess embryos frozen, and follicle stimulating hormone (FSH) levels with each patient's treatment outcome, such as pregnancy or miscarriage. (FSH levels are used as indicators of ovulation).

After analyzing all of the patient data, the investigators found that the overall live birth rate per cycle, on average, was nearly 10% for these older women. Those aged 40 were more likely to give birth to a healthy child than older women—nearly 14 percent were successful—yet those successful outcomes slowly declined with increasing age. While pregnancy rates weren't much different in those aged 41 through 43, the number of successful outcomes dropped off significantly starting with women aged 44 and above. In those aged 45, only one healthy birth resulted, and no births occurred in women beyond that age. About one-fifth of all the women, on average, cancelled their cycles for one reason or another.

By comparison, in the smaller group of women who began ART for the first time after age 40, the trend was the same. About 28 percent of those aged 40 gave birth (73 of 257 women), but that number slowly declined with age. By age 44, only one in 62 women had successfully given birth. Successful outcomes weren't much different for those aged 40 through 42, but were significantly lower in older women.

The researchers also found an overwhelming majority of women who gave birth had successfully conceived within their first three ART cycles.

When the research team looked at miscarriages, age also played a key role. About one-fourth of those who were 40 years old had miscarriages after IVF/ICSI, but that slowly increased with age. In those aged 45, nearly two-thirds had experienced pregnancy loss, the study found. But the researchers found that the numbers of miscarriages in all age groups were lower when more than one fetal heartbeat was seen on ultrasound initially. Multiple embryos that implant create "a type of insurance policy" on the pregnancy, Klipstein explained, reducing the odds that all of them will be lost.

Another factor related to successful outcomes was the number of embryos transferred in a cycle. "Overall, there was a significantly increased success rate in terms of live birth with each additional embryo available for transfer," Klipstein and her colleagues wrote. Experts frown on higher numbers of embryos transferred during ART cycles due to the increased risks associated with a multiple pregnancy. However, the researchers found the multiple pregnancy rate in this study was very low.

A minority of the patients had excess embryos available for freezing. However, of those who did, their likelihood of pregnancy and childbirth was significantly higher, the study noted. That's because in those women who had a "robust" response that resulted in additional embryos for freezing tended to have significantly higher quality embryos than those women who had a limited number for transfer, Klipstein explained. However, she added she does not recommended to her patients over age 40 that they freeze embryos. All resulting embryos are transferred for these women in hopes of increasing the success rate. At the same time, the odds of a higher order multiple pregnancy (triplets and higher) "is miniscule in this age group," said Klipstein.

In this study, nearly 16 percent of the women gave birth to multiples, with the overwhelming majority having twins. The average age of these women was about 41 years.

A Guide for Older Patients
It's hoped the results of this study will help guide older women when making decisions about pursuing assisted reproduction, the researchers stressed. "Most are faced with diminishing opportunities to achieve pregnancies using their own [eggs], and they should be provided with the best information possible to help them decide on the proper course of action for their particular situations," they wrote.

While treatment success has continued to expand in all age groups, it's likely that trend will plateau eventually, write the study investigators. "Since it is not possible to know when this peak will be reached, there is every reason to continue attempts to improve outcomes in this age group," they wrote. "This is particularly true for women between the ages of 40 and 43 years."

'Favorable' Prospects After 40
While it was once thought that success using IVF or ICSI dropped in a woman's early forties, this study suggests that outcomes "remain favorable" through age 43, they pointed out.

"I believe that this type of analysis will help couples elect whether to proceed with IVF using their own eggs versus donor eggs," said Klipstein. "Perhaps a 2.6% chance is not worth $15,000 when donor eggs provide a 50% to 70% chance of success (depending on the IVF center).

Setting the Record Straight
False perceptions in the media, supported by several highly publicized pregnancies, have suggested that women can continue to bear children until menopause, Klipstein added. But these reports have failed to note that many of these pregnancies were achieved using donor eggs, she said. "This study serves to illustrate that the actual end of natural fertility is closer to the 45th year of life, but is only about 5% per cycle until the end of the 43rd year."

Due to the risk of higher order multiple pregnancies (triplets, quadruplets, quintuplets) in older women, "relative caution" should still be used, and embryo freezing should be made available when five or more embryos are available for transfer to begin a pregnancy in women under age 42, the research team stressed.

Otherwise, "reasonable" success using ART can be expected for women in their early 40s, they concluded. "Although rare pregnancies will occur at age 44 years and beyond, women in this age group should be strongly advised to consider other options, including egg donation and adoption, as the rates of success quickly fall from below 3% per cycle at age 44 years, to well below 1% within 1 to 2 years," the researchers wrote.

Making Treatment Decisions With Your Doctor
Can doctors use certain biological indicators to help them predict which of their patients will be successful using ART? "Yes, absolutely," added Klipstein. Higher FSH levels (above 10-12 mIU per mL), low ovarian volume, and fewer or absent smaller follicles in the unstimulated ovary can predict poor outcomes, she said.

"Interestingly, in women under age 40, a previous liveborn or even a previous miscarriage or ectopic [pregnancy] with IVF predicts increased success in subsequent cycles. In women over 40, this does not hold true."

1. Klipstein S, Regan M, Ryley DA, Goldman MB, Alper MM, Reindollar RH. One last chance for pregnancy: a review of 2,705 in vitro fertilization cycles initiated in women age 40 years and above. Fertil Steril 2005 Aug;84(2):435-45.

John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include overseeing health news coverage for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.

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