The Art of Controlling Multiples

The most common complication of assisted reproductive technologies is multiple gestation, particularly triplet and higher-order pregnancy. As we all know, multiple gestation leads to an increased risk of complications in both the fetuses and the mother.

Ovulation induction results in a 20% increase in multiples, the majority of which are twins. In vitro fertilization (IVF) results in a 40% increase in multiples; 32% of these are twins. Unfortunately, we're not making progress in decreasing these rates. Knowing that most patients look at two things—pregnancy rates and cost—when they choose an infertility clinic, many competitive clinics are implanting more than the recommended number of embryos in order to achieve the highest pregnancy rates.

At any opportunity along the spectrum of general to specialized ob.gyn. care, we need to educate and encourage patients to look beyond the pregnancy rates and instead focus on the numbers of embryos transferred and the implantation rates. If we are successful, we could probably make some progress in decreasing the multiple pregnancies associated with assisted reproductive technology (ART). At a basic level, we can ensure that infertility evaluations and treatments are timely, thorough, individualized, and well explained to our patients. In doing so, we will provide good care, and perhaps we can keep the patients' feelings of desperation, which are valid and understandable, somewhat in check.

Infertility Diagnosis, Work-Up

A diagnosis of infertility is usually made when couples have been trying for more than 1 year to become pregnant. Fecundity drops after the age of 27 years, more significantly after the age of 35 years, and dramatically after 40 years. I recommend that, for women older than age 35, we not wait until a year is up, but rather begin a basic infertility work-up after 6 months. These women deserve a more aggressive approach.

After 6 months in a patient who is older than 35, or after 1 year in younger patients, we should provide the basics: blood testing to check ovarian reserve, a hysterosalpingogram to ensure that the uterus is normal and that tubes are patent, and a semen analysis. It is important to use an infertility laboratory for the semen analysis. Regular laboratories usually do not check for Kruger morphology, which is critical.

Examinations should include a check on thyroid function. Approximately 2% of women in the reproductive age group have hypothyroidism or subclinical hypothyroidism, which can affect fertility but is treatable. It's also important to know if a woman has had endometriosis or previous pelvic surgeries. Diagnostic operative laparoscopies can be performed by general ob.gyns. to rule out or treat endometriosis if they feel comfortable doing the procedure.

When you take the patient's history, certain questions—such as “When did your mother enter menopause?”—are critical because they may lead to an early diagnosis and, appropriately, to a more aggressive treatment approach. Perimenopause—during which time ovarian reserve is compromised—usually begins 5-10 years earlier than menopause. If I know that a patient's mother went into menopause at age 40, I will work through infertility treatment more quickly, as I would with older patients. Testing for ovarian reserve in women younger than 35 is too often dismissed. It shouldn't be.

It's well known that smoking and exposure to secondhand smoke decrease fecundity. They increase rates of abnormal ovarian reserve, oocyte atresia, and miscarriage. In IVF patients, they increase IVF failure and the number of IVF cycles needed to conceive. One prospective study showed that for each year of active smoking, there is a 9% decrease in the success of ART. Smoking also affects the sperm cell. Even if sperm look normal, smoking has been shown to lead to damage of the genetic material, causing abnormalities in sperm count, motility, morphology, and function.

The good news is that many of the effects of smoking are reversible. The duration of smoking may affect the degree of reversibility, but certainly we have the opportunity to improve fecundity and the success of fertility treatment if we identify smokers and work hard to help them with cessation.

Starting Treatment

If all of these basic work-ups are normal and the patient is younger than 32 years of age we can proceed with a trial of Clomid (clomiphene citrate). I recommend treatment with Clomid for 3-4 months, because most patients who will achieve pregnancy will do so within the first three to four cycles. After several months, the chances of a pregnancy are significantly decreased, and other treatment options need to be considered. Treatment with Clomid alone for longer than 6 months really isn't fair to the patient, and neither is the use of Clomid in patients older than age 37.

Keep in mind that even in small doses, Clomid can have a negative effect on the endometrium. I recommend ultrasonography to check for normal follicular development and to check the lining. If the lining is thin, the implantation rate will be low.

You may decide, after 2 months of Clomid treatment, to try another two to three cycles along with intrauterine insemination. You may also decide that ovulation induction or IVF is more appropriate.

If you are a general ob.gyn. who is performing superovulation induction with hormones, my advice is to judge your comfort level with hormonal stimulation, and to establish and maintain a good relationship with an infertility clinic.

Controlling Multiples

With both ovulation induction/enhancement and IVF, there are ways to control the rate of multiple gestations. Your degree of control is less with ovarian stimulation and intrauterine insemination, but you do have some control and it is important to proceed cautiously. If you see that a patient has more than two or three mature follicles and that her estradiol is elevated above the appropriate level at day 3, it's often best to cancel that cycle. The patient may prefer to proceed knowing the risks, but at least she is being counseled.

The guidelines of the Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine are age based, and are meant to help determine the appropriate number of cleavage-stage embryos to transfer.

According to the guidelines, no more than two good-quality embryos should be transferred in patients under age 35. If the embryos are not necessarily of good quality as judged by morphologic criteria, I believe a third embryo can be considered; but in no case should more than three be transferred.

The guidelines also say that for patients with a favorable prognosis, such as those with good-quality embryos or previous successes with IVF, consideration should be given to transferring only a single embryo. I do believe that if embryos are of excellent quality and the patient is young, and especially if the embryos can be cultured to the blastocyst stage and then transferred, it is worth pushing for a single embryo transfer, which dramatically decreases the risk of multiple births.

For patients aged 35-37, the guidelines are that no more than two good-quality embryos—and no more than three in any other case—should be transferred. Patients who are 38-40 years old should receive no more than three good-quality embryos, and no more than four in any other case.

For patients older than age 40, the guidelines state that no more than five embryos should be transferred. And I would recommend that no more than four be transferred in many cases. All these numbers should be decreased, of course, when embryos are transferred as blastocysts.

European specialists routinely transfer no more than two embryos. They usually transfer embryos at the more advanced blastocyst stage, and because they work in systems of socialized medicine, it doesn't matter whether the patient gets pregnant after just one cycle or more. In the United States, a cycle costs $10,000-$15,000, and patients want to get pregnant the first time.

I encourage my patients who have come for ART consultations to visit the neonatal ICU. The visits give them some perspective on the complications associated with higher-order births. I will often raise the issue of selective fetal reduction—posing it as theoretical—when I see a patient for an IVF consultation. Asking patients how they would feel about this possibility prompts them to think and be prepared for it. It also impresses upon patients that the risk of multiples is real if too many embryos are implanted. Selective fetal reduction is an option, but it has its own complications and risks. We always prefer not to reach that point.

One of the most important things we can do to reduce the rate of multiple gestations is to ensure that we work with an experienced laboratory staffed with excellent embryologists and an excellent director. Certain elements of the visual inspection of embryos are standard and reliably consistent, whereas other elements are more subjective. To some extent, each laboratory director has his or her own way of grading embryos, so our attentiveness to outcomes is critical.

Preimplantation genetic diagnosis (PGD) is typically not performed unless a patient requests it. It is recommended for patients who are older or who have certain chromosomal or genetic abnormalities. It is also recommended in some patients with repeat pregnancy wastage. Single cells can be sent out on day 3 of embryo culture and results can be obtained within 24 hours, in time for embryo transfer at day 5.

The other step we can routinely take is to encourage our patients to thoroughly examine the Society for Assisted Reproductive Technology's clinic-specific IVF data. Asking patients to step back and look at more than pregnancy rates could be the biggest key to reducing multiple gestations with IVF.

Multiples and Mortality

Infant mortality is a problem of major concern to the industrialized world, and it continues to be an important marker for assessing the health and welfare of countries. Despite the fact that the United States spends 15% of its gross national product on health care, it ranks 21st in the world in its infant mortality rate, below countries that spend much less.

The causes of our high infant mortality rate are complex and multifaceted, and we will not attempt in Master Class to address them all. We will, however, address one component: the rising rate of multiple gestations.

Between 1996 and 2002, multiple births in the United States increased more than 22%, from 2.7% to 3.3% of all live births. In 2002, the preterm birth rate among multiple deliveries was approximately 60%, six times higher than the preterm birth rate among singleton births, according to the National Center for Health Statistics. In its preliminary report on births for 2004, the NCHS said that increases in multiple births “have strongly influenced recent upswings” in preterm and low-birth-weight births.

Assisted reproduction plays a role. There is evidence that the percentage of higher-order pregnancies resulting from assisted reproductive technology has been decreasing, but multiple pregnancies with ART remain a problem.

One has to ask whether, with greater care and improved protocols in assisted reproduction, we wouldn't be able to address the continuing effect that infertility treatment has on the rate of multiple pregnancies.

It is a subject that has caught national attention and has been addressed in many quarters. The Society for Assisted Reproductive Technology, an affiliate of the American Society for Reproductive Medicine has examined the issue and made recommendations for improved practice (see sidebar).

My guest professor this month is Dr. Aida Shanti, who is the director of the division of reproductive endocrinology and infertility at the University of Arkansas, Little Rock. She will address these contemporary recommendations and explore how such guidance can potentially have a real impact.

Age-Based Embryo Transfer Guidelines

▸ In patients under the age of 35, no more than two embryos should be transferred in the absence of extraor-dinary circumstances. For patients with the most favorable prognosis, consideration should be given to transferring only a single embryo. Patients having the most favorable prognosis include those who are un-dergoing their first cycle of IVF, have good-quality embryos as judged by morphologic criteria, and have ex-cess of embryos of sufficient quality to warrant cryopreservation. Patients who have had previous success with IVF should also be considered in the most favorable prognostic category.

▸ For patients between 35 and 37 years of age having a more favorable prognosis, no more than two em-bryos should be transferred. All oth-ers in this age group should have no more than three embryos transferred.

▸ For patients between 38 and 40 years of age, no more than four em-bryos should be transferred. For pa-tients in this age group having a more favorable prognosis, considera-tion should be given to transfer of no more than three embryos.

▸ For most patients greater than 40 years of age, no more than five em-bryos should be transferred.

▸ For patients with two or more pre-vious failed IVF cycles and those hav-ing a less favorable prognosis, addi-tional embryos may be transferred according to individual circumstances after appropriate consultation.

▸ In donor egg cycles, the donor's age should determine the appropriate number of embryos to transfer.

Since all oocytes may not fertilize when GIFT is performed, one more oocyte than embryo may be trans-ferred for each prognostic category.

Source: Fertil. Steril. 2004;82:773-4.

The most common complication of assisted reproductive technologies is multiple gestation, particularly triplet and higher-order pregnancy. As we all know, multiple gestation leads to an increased risk of complications in both the fetuses and the mother.

Ovulation induction results in a 20% increase in multiples, the majority of which are twins. In vitro fertilization (IVF) results in a 40% increase in multiples; 32% of these are twins. Unfortunately, we're not making progress in decreasing these rates. Knowing that most patients look at two things—pregnancy rates and cost—when they choose an infertility clinic, many competitive clinics are implanting more than the recommended number of embryos in order to achieve the highest pregnancy rates.

At any opportunity along the spectrum of general to specialized ob.gyn. care, we need to educate and encourage patients to look beyond the pregnancy rates and instead focus on the numbers of embryos transferred and the implantation rates. If we are successful, we could probably make some progress in decreasing the multiple pregnancies associated with assisted reproductive technology (ART). At a basic level, we can ensure that infertility evaluations and treatments are timely, thorough, individualized, and well explained to our patients. In doing so, we will provide good care, and perhaps we can keep the patients' feelings of desperation, which are valid and understandable, somewhat in check.

Infertility Diagnosis, Work-Up

A diagnosis of infertility is usually made when couples have been trying for more than 1 year to become pregnant. Fecundity drops after the age of 27 years, more significantly after the age of 35 years, and dramatically after 40 years. I recommend that, for women older than age 35, we not wait until a year is up, but rather begin a basic infertility work-up after 6 months. These women deserve a more aggressive approach.

After 6 months in a patient who is older than 35, or after 1 year in younger patients, we should provide the basics: blood testing to check ovarian reserve, a hysterosalpingogram to ensure that the uterus is normal and that tubes are patent, and a semen analysis. It is important to use an infertility laboratory for the semen analysis. Regular laboratories usually do not check for Kruger morphology, which is critical.

Examinations should include a check on thyroid function. Approximately 2% of women in the reproductive age group have hypothyroidism or subclinical hypothyroidism, which can affect fertility but is treatable. It's also important to know if a woman has had endometriosis or previous pelvic surgeries. Diagnostic operative laparoscopies can be performed by general ob.gyns. to rule out or treat endometriosis if they feel comfortable doing the procedure.

When you take the patient's history, certain questions—such as “When did your mother enter menopause?”—are critical because they may lead to an early diagnosis and, appropriately, to a more aggressive treatment approach. Perimenopause—during which time ovarian reserve is compromised—usually begins 5-10 years earlier than menopause. If I know that a patient's mother went into menopause at age 40, I will work through infertility treatment more quickly, as I would with older patients. Testing for ovarian reserve in women younger than 35 is too often dismissed. It shouldn't be.

It's well known that smoking and exposure to secondhand smoke decrease fecundity. They increase rates of abnormal ovarian reserve, oocyte atresia, and miscarriage. In IVF patients, they increase IVF failure and the number of IVF cycles needed to conceive. One prospective study showed that for each year of active smoking, there is a 9% decrease in the success of ART. Smoking also affects the sperm cell. Even if sperm look normal, smoking has been shown to lead to damage of the genetic material, causing abnormalities in sperm count, motility, morphology, and function.

The good news is that many of the effects of smoking are reversible. The duration of smoking may affect the degree of reversibility, but certainly we have the opportunity to improve fecundity and the success of fertility treatment if we identify smokers and work hard to help them with cessation.

Starting Treatment

If all of these basic work-ups are normal and the patient is younger than 32 years of age we can proceed with a trial of Clomid (clomiphene citrate). I recommend treatment with Clomid for 3-4 months, because most patients who will achieve pregnancy will do so within the first three to four cycles. After several months, the chances of a pregnancy are significantly decreased, and other treatment options need to be considered. Treatment with Clomid alone for longer than 6 months really isn't fair to the patient, and neither is the use of Clomid in patients older than age 37.

Keep in mind that even in small doses, Clomid can have a negative effect on the endometrium. I recommend ultrasonography to check for normal follicular development and to check the lining. If the lining is thin, the implantation rate will be low.

You may decide, after 2 months of Clomid treatment, to try another two to three cycles along with intrauterine insemination. You may also decide that ovulation induction or IVF is more appropriate.

If you are a general ob.gyn. who is performing superovulation induction with hormones, my advice is to judge your comfort level with hormonal stimulation, and to establish and maintain a good relationship with an infertility clinic.

Controlling Multiples

With both ovulation induction/enhancement and IVF, there are ways to control the rate of multiple gestations. Your degree of control is less with ovarian stimulation and intrauterine insemination, but you do have some control and it is important to proceed cautiously. If you see that a patient has more than two or three mature follicles and that her estradiol is elevated above the appropriate level at day 3, it's often best to cancel that cycle. The patient may prefer to proceed knowing the risks, but at least she is being counseled.

The guidelines of the Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine are age based, and are meant to help determine the appropriate number of cleavage-stage embryos to transfer.

According to the guidelines, no more than two good-quality embryos should be transferred in patients under age 35. If the embryos are not necessarily of good quality as judged by morphologic criteria, I believe a third embryo can be considered; but in no case should more than three be transferred.

The guidelines also say that for patients with a favorable prognosis, such as those with good-quality embryos or previous successes with IVF, consideration should be given to transferring only a single embryo. I do believe that if embryos are of excellent quality and the patient is young, and especially if the embryos can be cultured to the blastocyst stage and then transferred, it is worth pushing for a single embryo transfer, which dramatically decreases the risk of multiple births.

For patients aged 35-37, the guidelines are that no more than two good-quality embryos—and no more than three in any other case—should be transferred. Patients who are 38-40 years old should receive no more than three good-quality embryos, and no more than four in any other case.

For patients older than age 40, the guidelines state that no more than five embryos should be transferred. And I would recommend that no more than four be transferred in many cases. All these numbers should be decreased, of course, when embryos are transferred as blastocysts.

European specialists routinely transfer no more than two embryos. They usually transfer embryos at the more advanced blastocyst stage, and because they work in systems of socialized medicine, it doesn't matter whether the patient gets pregnant after just one cycle or more. In the United States, a cycle costs $10,000-$15,000, and patients want to get pregnant the first time.

I encourage my patients who have come for ART consultations to visit the neonatal ICU. The visits give them some perspective on the complications associated with higher-order births. I will often raise the issue of selective fetal reduction—posing it as theoretical—when I see a patient for an IVF consultation. Asking patients how they would feel about this possibility prompts them to think and be prepared for it. It also impresses upon patients that the risk of multiples is real if too many embryos are implanted. Selective fetal reduction is an option, but it has its own complications and risks. We always prefer not to reach that point.

One of the most important things we can do to reduce the rate of multiple gestations is to ensure that we work with an experienced laboratory staffed with excellent embryologists and an excellent director. Certain elements of the visual inspection of embryos are standard and reliably consistent, whereas other elements are more subjective. To some extent, each laboratory director has his or her own way of grading embryos, so our attentiveness to outcomes is critical.

Preimplantation genetic diagnosis (PGD) is typically not performed unless a patient requests it. It is recommended for patients who are older or who have certain chromosomal or genetic abnormalities. It is also recommended in some patients with repeat pregnancy wastage. Single cells can be sent out on day 3 of embryo culture and results can be obtained within 24 hours, in time for embryo transfer at day 5.

The other step we can routinely take is to encourage our patients to thoroughly examine the Society for Assisted Reproductive Technology's clinic-specific IVF data. Asking patients to step back and look at more than pregnancy rates could be the biggest key to reducing multiple gestations with IVF.

Multiples and Mortality

Infant mortality is a problem of major concern to the industrialized world, and it continues to be an important marker for assessing the health and welfare of countries. Despite the fact that the United States spends 15% of its gross national product on health care, it ranks 21st in the world in its infant mortality rate, below countries that spend much less.

The causes of our high infant mortality rate are complex and multifaceted, and we will not attempt in Master Class to address them all. We will, however, address one component: the rising rate of multiple gestations.

Between 1996 and 2002, multiple births in the United States increased more than 22%, from 2.7% to 3.3% of all live births. In 2002, the preterm birth rate among multiple deliveries was approximately 60%, six times higher than the preterm birth rate among singleton births, according to the National Center for Health Statistics. In its preliminary report on births for 2004, the NCHS said that increases in multiple births “have strongly influenced recent upswings” in preterm and low-birth-weight births.

Assisted reproduction plays a role. There is evidence that the percentage of higher-order pregnancies resulting from assisted reproductive technology has been decreasing, but multiple pregnancies with ART remain a problem.

One has to ask whether, with greater care and improved protocols in assisted reproduction, we wouldn't be able to address the continuing effect that infertility treatment has on the rate of multiple pregnancies.

It is a subject that has caught national attention and has been addressed in many quarters. The Society for Assisted Reproductive Technology, an affiliate of the American Society for Reproductive Medicine has examined the issue and made recommendations for improved practice (see sidebar).

My guest professor this month is Dr. Aida Shanti, who is the director of the division of reproductive endocrinology and infertility at the University of Arkansas, Little Rock. She will address these contemporary recommendations and explore how such guidance can potentially have a real impact.

Age-Based Embryo Transfer Guidelines

▸ In patients under the age of 35, no more than two embryos should be transferred in the absence of extraor-dinary circumstances. For patients with the most favorable prognosis, consideration should be given to transferring only a single embryo. Patients having the most favorable prognosis include those who are un-dergoing their first cycle of IVF, have good-quality embryos as judged by morphologic criteria, and have ex-cess of embryos of sufficient quality to warrant cryopreservation. Patients who have had previous success with IVF should also be considered in the most favorable prognostic category.

▸ For patients between 35 and 37 years of age having a more favorable prognosis, no more than two em-bryos should be transferred. All oth-ers in this age group should have no more than three embryos transferred.

▸ For patients between 38 and 40 years of age, no more than four em-bryos should be transferred. For pa-tients in this age group having a more favorable prognosis, considera-tion should be given to transfer of no more than three embryos.

▸ For most patients greater than 40 years of age, no more than five em-bryos should be transferred.

▸ For patients with two or more pre-vious failed IVF cycles and those hav-ing a less favorable prognosis, addi-tional embryos may be transferred according to individual circumstances after appropriate consultation.

▸ In donor egg cycles, the donor's age should determine the appropriate number of embryos to transfer.

Since all oocytes may not fertilize when GIFT is performed, one more oocyte than embryo may be trans-ferred for each prognostic category.

Source: Fertil. Steril. 2004;82:773-4.

The most common complication of assisted reproductive technologies is multiple gestation, particularly triplet and higher-order pregnancy. As we all know, multiple gestation leads to an increased risk of complications in both the fetuses and the mother.

Ovulation induction results in a 20% increase in multiples, the majority of which are twins. In vitro fertilization (IVF) results in a 40% increase in multiples; 32% of these are twins. Unfortunately, we're not making progress in decreasing these rates. Knowing that most patients look at two things—pregnancy rates and cost—when they choose an infertility clinic, many competitive clinics are implanting more than the recommended number of embryos in order to achieve the highest pregnancy rates.

At any opportunity along the spectrum of general to specialized ob.gyn. care, we need to educate and encourage patients to look beyond the pregnancy rates and instead focus on the numbers of embryos transferred and the implantation rates. If we are successful, we could probably make some progress in decreasing the multiple pregnancies associated with assisted reproductive technology (ART). At a basic level, we can ensure that infertility evaluations and treatments are timely, thorough, individualized, and well explained to our patients. In doing so, we will provide good care, and perhaps we can keep the patients' feelings of desperation, which are valid and understandable, somewhat in check.

Infertility Diagnosis, Work-Up

A diagnosis of infertility is usually made when couples have been trying for more than 1 year to become pregnant. Fecundity drops after the age of 27 years, more significantly after the age of 35 years, and dramatically after 40 years. I recommend that, for women older than age 35, we not wait until a year is up, but rather begin a basic infertility work-up after 6 months. These women deserve a more aggressive approach.

After 6 months in a patient who is older than 35, or after 1 year in younger patients, we should provide the basics: blood testing to check ovarian reserve, a hysterosalpingogram to ensure that the uterus is normal and that tubes are patent, and a semen analysis. It is important to use an infertility laboratory for the semen analysis. Regular laboratories usually do not check for Kruger morphology, which is critical.

Examinations should include a check on thyroid function. Approximately 2% of women in the reproductive age group have hypothyroidism or subclinical hypothyroidism, which can affect fertility but is treatable. It's also important to know if a woman has had endometriosis or previous pelvic surgeries. Diagnostic operative laparoscopies can be performed by general ob.gyns. to rule out or treat endometriosis if they feel comfortable doing the procedure.

When you take the patient's history, certain questions—such as “When did your mother enter menopause?”—are critical because they may lead to an early diagnosis and, appropriately, to a more aggressive treatment approach. Perimenopause—during which time ovarian reserve is compromised—usually begins 5-10 years earlier than menopause. If I know that a patient's mother went into menopause at age 40, I will work through infertility treatment more quickly, as I would with older patients. Testing for ovarian reserve in women younger than 35 is too often dismissed. It shouldn't be.

It's well known that smoking and exposure to secondhand smoke decrease fecundity. They increase rates of abnormal ovarian reserve, oocyte atresia, and miscarriage. In IVF patients, they increase IVF failure and the number of IVF cycles needed to conceive. One prospective study showed that for each year of active smoking, there is a 9% decrease in the success of ART. Smoking also affects the sperm cell. Even if sperm look normal, smoking has been shown to lead to damage of the genetic material, causing abnormalities in sperm count, motility, morphology, and function.

The good news is that many of the effects of smoking are reversible. The duration of smoking may affect the degree of reversibility, but certainly we have the opportunity to improve fecundity and the success of fertility treatment if we identify smokers and work hard to help them with cessation.

Starting Treatment

If all of these basic work-ups are normal and the patient is younger than 32 years of age we can proceed with a trial of Clomid (clomiphene citrate). I recommend treatment with Clomid for 3-4 months, because most patients who will achieve pregnancy will do so within the first three to four cycles. After several months, the chances of a pregnancy are significantly decreased, and other treatment options need to be considered. Treatment with Clomid alone for longer than 6 months really isn't fair to the patient, and neither is the use of Clomid in patients older than age 37.

Keep in mind that even in small doses, Clomid can have a negative effect on the endometrium. I recommend ultrasonography to check for normal follicular development and to check the lining. If the lining is thin, the implantation rate will be low.

You may decide, after 2 months of Clomid treatment, to try another two to three cycles along with intrauterine insemination. You may also decide that ovulation induction or IVF is more appropriate.

If you are a general ob.gyn. who is performing superovulation induction with hormones, my advice is to judge your comfort level with hormonal stimulation, and to establish and maintain a good relationship with an infertility clinic.

Controlling Multiples

With both ovulation induction/enhancement and IVF, there are ways to control the rate of multiple gestations. Your degree of control is less with ovarian stimulation and intrauterine insemination, but you do have some control and it is important to proceed cautiously. If you see that a patient has more than two or three mature follicles and that her estradiol is elevated above the appropriate level at day 3, it's often best to cancel that cycle. The patient may prefer to proceed knowing the risks, but at least she is being counseled.

The guidelines of the Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine are age based, and are meant to help determine the appropriate number of cleavage-stage embryos to transfer.

According to the guidelines, no more than two good-quality embryos should be transferred in patients under age 35. If the embryos are not necessarily of good quality as judged by morphologic criteria, I believe a third embryo can be considered; but in no case should more than three be transferred.

The guidelines also say that for patients with a favorable prognosis, such as those with good-quality embryos or previous successes with IVF, consideration should be given to transferring only a single embryo. I do believe that if embryos are of excellent quality and the patient is young, and especially if the embryos can be cultured to the blastocyst stage and then transferred, it is worth pushing for a single embryo transfer, which dramatically decreases the risk of multiple births.

For patients aged 35-37, the guidelines are that no more than two good-quality embryos—and no more than three in any other case—should be transferred. Patients who are 38-40 years old should receive no more than three good-quality embryos, and no more than four in any other case.

For patients older than age 40, the guidelines state that no more than five embryos should be transferred. And I would recommend that no more than four be transferred in many cases. All these numbers should be decreased, of course, when embryos are transferred as blastocysts.

European specialists routinely transfer no more than two embryos. They usually transfer embryos at the more advanced blastocyst stage, and because they work in systems of socialized medicine, it doesn't matter whether the patient gets pregnant after just one cycle or more. In the United States, a cycle costs $10,000-$15,000, and patients want to get pregnant the first time.

I encourage my patients who have come for ART consultations to visit the neonatal ICU. The visits give them some perspective on the complications associated with higher-order births. I will often raise the issue of selective fetal reduction—posing it as theoretical—when I see a patient for an IVF consultation. Asking patients how they would feel about this possibility prompts them to think and be prepared for it. It also impresses upon patients that the risk of multiples is real if too many embryos are implanted. Selective fetal reduction is an option, but it has its own complications and risks. We always prefer not to reach that point.

One of the most important things we can do to reduce the rate of multiple gestations is to ensure that we work with an experienced laboratory staffed with excellent embryologists and an excellent director. Certain elements of the visual inspection of embryos are standard and reliably consistent, whereas other elements are more subjective. To some extent, each laboratory director has his or her own way of grading embryos, so our attentiveness to outcomes is critical.

Preimplantation genetic diagnosis (PGD) is typically not performed unless a patient requests it. It is recommended for patients who are older or who have certain chromosomal or genetic abnormalities. It is also recommended in some patients with repeat pregnancy wastage. Single cells can be sent out on day 3 of embryo culture and results can be obtained within 24 hours, in time for embryo transfer at day 5.

The other step we can routinely take is to encourage our patients to thoroughly examine the Society for Assisted Reproductive Technology's clinic-specific IVF data. Asking patients to step back and look at more than pregnancy rates could be the biggest key to reducing multiple gestations with IVF.

Multiples and Mortality

Infant mortality is a problem of major concern to the industrialized world, and it continues to be an important marker for assessing the health and welfare of countries. Despite the fact that the United States spends 15% of its gross national product on health care, it ranks 21st in the world in its infant mortality rate, below countries that spend much less.

The causes of our high infant mortality rate are complex and multifaceted, and we will not attempt in Master Class to address them all. We will, however, address one component: the rising rate of multiple gestations.

Between 1996 and 2002, multiple births in the United States increased more than 22%, from 2.7% to 3.3% of all live births. In 2002, the preterm birth rate among multiple deliveries was approximately 60%, six times higher than the preterm birth rate among singleton births, according to the National Center for Health Statistics. In its preliminary report on births for 2004, the NCHS said that increases in multiple births “have strongly influenced recent upswings” in preterm and low-birth-weight births.

Assisted reproduction plays a role. There is evidence that the percentage of higher-order pregnancies resulting from assisted reproductive technology has been decreasing, but multiple pregnancies with ART remain a problem.

One has to ask whether, with greater care and improved protocols in assisted reproduction, we wouldn't be able to address the continuing effect that infertility treatment has on the rate of multiple pregnancies.

It is a subject that has caught national attention and has been addressed in many quarters. The Society for Assisted Reproductive Technology, an affiliate of the American Society for Reproductive Medicine has examined the issue and made recommendations for improved practice (see sidebar).

My guest professor this month is Dr. Aida Shanti, who is the director of the division of reproductive endocrinology and infertility at the University of Arkansas, Little Rock. She will address these contemporary recommendations and explore how such guidance can potentially have a real impact.

Age-Based Embryo Transfer Guidelines

▸ In patients under the age of 35, no more than two embryos should be transferred in the absence of extraor-dinary circumstances. For patients with the most favorable prognosis, consideration should be given to transferring only a single embryo. Patients having the most favorable prognosis include those who are un-dergoing their first cycle of IVF, have good-quality embryos as judged by morphologic criteria, and have ex-cess of embryos of sufficient quality to warrant cryopreservation. Patients who have had previous success with IVF should also be considered in the most favorable prognostic category.

▸ For patients between 35 and 37 years of age having a more favorable prognosis, no more than two em-bryos should be transferred. All oth-ers in this age group should have no more than three embryos transferred.

▸ For patients between 38 and 40 years of age, no more than four em-bryos should be transferred. For pa-tients in this age group having a more favorable prognosis, considera-tion should be given to transfer of no more than three embryos.

▸ For most patients greater than 40 years of age, no more than five em-bryos should be transferred.

▸ For patients with two or more pre-vious failed IVF cycles and those hav-ing a less favorable prognosis, addi-tional embryos may be transferred according to individual circumstances after appropriate consultation.

▸ In donor egg cycles, the donor's age should determine the appropriate number of embryos to transfer.

Since all oocytes may not fertilize when GIFT is performed, one more oocyte than embryo may be trans-ferred for each prognostic category.

Source: Fertil. Steril. 2004;82:773-4.