Mary E. Abusief, MD

The first human birth from a frozen oocyte was reported in 1986.¹ Nearly 3 decades later, mature oocyte cryopreservation has emerged as a meaningful technology to preserve reproductive potential in women of reproductive age. In 2013, the American Society for Reproductive Medicine (ASRM) removed the “experimental” label from egg freezing but cautioned that more data on safety and efficacy were needed prior to widespread adoption of the technique.²

In this Update, we present the ­current protocols for oocyte cryopreservation, how we arrived at them, and the questions regarding outcomes that still remain. In addition, we discuss the ethical dilemmas egg freezing presents, according to the varying rhetoric within the media and our own profession. Finally, we consider what preliminary data suggest as to the live-birth rate using frozen eggs from women of varying ages and what the costs are associated with using oocyte cryopreservation as the approach to fertility treatment.

Vitrification and slow freezing: How did we get here and how effective are they?
Fertility preservation is a rapidly advancing area of reproductive medicine. Cryopreservation is the cooling of cells to subzero temperatures to halt biologic activity and preserve the cells for future use. Clinically, oocyte cryopreservation requires a patient to undergo in vitro fertilization (IVF). After egg retrieval, the oocytes are cryopreserved for use at a later time.

The prefix “cryo” originated from the Greek word “kryos,” meaning icy cold or frost. Cryopreservation is not a new science. In 1776, the Italian priest and scientist Lazzaro Spallanzani reported that sperm became motionless when cooled by snow. A pivotal discovery in the field came in 1949, when Christopher Polge, an English scientist, showed that glycerol, a permeating solute, could provide protection to cells at low temperatures.³ Progress in sperm cryopreservation advanced quickly, partly due to the ease of observing sperm motility as a marker of postthaw function.⁴

The ongoing evolution of cryopreservation science led to landmark achievements, including the first birth using human cryopreserved sperm in the 1950s, and the first human birth after embryo thaw in 1983. Since that time cryopreservation has become a cornerstone in the field of reproductive medicine.

Initial problems encountered with egg freezing
Although the first birth after thaw of a human oocyte occurred in 1986, oocyte cryopreservation was fraught with technical difficulties. Oocytes (vs sperm and embryos) proved challenging to successfully cryopreserve. The problem lay in the damage caused by water crystals forming ice and rising concentrations of intracellular solutes as cells were cooled to freezing temperatures.⁵ The large size and high water content of the human oocyte made it particularly vulnerable to the detrimental effects of freezing. In addition, freeze−thaw hardening of the zone pellucida led to decreased postthaw fertilization. The delicate meiotic spindle within the oocyte was prone to injury from ice crystals.⁶

Use of cryoprotectants, such as ethylene glycol, glycerol, and dimethylsulfoxide (DMSO), can prevent ice crystal formation, but high concentrations are theoretically toxic. The fine balance between protection and toxicity led to the development of diverse egg freezing protocols using various types and concentrations of cryoprotectants. Inconsistent results and lack of reproducibility among labs, together with concerns about postthaw oocyte function and safety, slowed the progression of oocyte freezing. By the end of the 1980s, clinical oocyte cryopreservation had been effectively halted and the field was confined to small groups of researchers who continued laboratory experiments with limited success.⁵

In 1997, clinical work with frozen oocytes resumed with a Bologna team reporting postthawing oocyte survival rates of up to 80% using propanediol as the primary cryoprotectant, and viable pregnancies with the use of intracytoplasmic sperm injection (ICSI) for fertilization.^7,8 Since the late 1990s, further modifications in freezing technologies have resulted in greater success. And currently, both slow freezing and vitrification methods are used to preserve oocytes.

Slow freezing
Slow freezing involves a low rate of oocyte temperature decline with a simultaneous gradual increase in the concentration of cryoprotectants. As the metabolic activity of the oocyte decreases, the concentration of ­cryoprotectant can be increased to prevent ice crystal formation. Once solidification of the oocyte is achieved, the oocyte can be exposed to freezing at colder temperatures. Results of a meta-analysis of 26 studies revealed that, compared with using fresh oocytes, eggs thawed after slow-freezing yielded significantly lower rates of fertilization (61.0% [1,346/2,217] vs 76.7% [2,788/3,637]), clinical pregnancy rate per transfer (27.1% [95/351] vs 68.5% [272/397]), and live birth per transfer (21.6% [76/351] vs 32.4% [24/72]).⁹

Vitrification
Vitrification involves the rapid cooling of cells to extremely low temperatures. During vitrification, oocytes are exposed to high concentrations of cryoprotectants and, after a short equilibration time, rapidly cooled. The rate of cooling is dramatic, up to 20,000°C per minute—so fast that ice does not have time to form and a glass-like state is achieved within the oocyte. Studies suggest that the use of vitrification improves oocyte survival and function compared with slow freezing.^9-11 A prospective randomized controlled trial ­comparing frozen/thawed with ­vitrified/warmed oocytes demonstrated superior oocyte function in the vitrification group, with higher oocyte survival (81% for ­vitrification/warming vs 67% for slow ­freezing/thawing); higher rates of fertilization, cleavage, and embryo morphology; as well as higher clinical pregnancy rates (38% for vitrified/warmed vs 13% for frozen/thawed).¹⁰

The Practice Committee of ASRM published a guideline for mature cryopreservation in 2013.² The committee reviewed the literature on efficacy and safety of mature oocyte cryopreservation. Although data are limited, studies comparing outcomes of IVF using cryopreserved versus fresh oocytes, including four randomized controlled trials and a meta-analysis, provide evidence that previously vitrified/thawed eggs result in similar fertilization and pregnancy rates as IVF/ICSI with fresh oocytes. Similar to data from fresh IVF cycles, decreased success with oocyte vitrification is seen in women with advanced age, and delivery rates, not unexpectedly, are inversely correlated with maternal age.¹²

Safety outcomes data are limited but reassuring
Two major factors limit our current understanding of egg cryopreservation outcomes. First, many women who have cryopreserved their eggs have not yet used them and, second, babies born after use of cryopreserved oocytes have not reached ages in which safety of the technique can be fully evaluated. Despite this important gap in our knowledge, to date, results of studies examining safety outcomes of the procedure have been reassuring.

For instance, chromosomal analysis via fluorescence in-situ hybridization of embryos created with thawed oocytes versus controls revealed no difference in the incidence of chromosomal abnormalities, decreasing concerns about damage to the oocyte spindle secondary to freezing.¹³

Data from a review of 900 live births resulting from embryos created from thawed oocytes frozen via the slow freeze technique revealed no increase in the risk of congenital anomalies.¹⁴ Similarly, no increased risk of congenital anomalies or difference in birth weights was noted in a study of 200 live births after transfers with embryos derived from vitrified oocytes compared with fresh oocytes.¹⁵

In a study of 954 clinical pregnancies occurring in 855 couples with cryopreserved oocytes after assisted reproductive technology, the outcomes of 197 ­pregnancies from frozen/thawed oocytes were compared with 757 obtained from fresh sibling oocyte cycles. A significantly higher rate of spontaneous abortions at 12 weeks or less was observed in the frozen/thawed oocyte group. No statistically significant differences were noted in gestational age at delivery or in the incidence of major congenital anomalies at birth, but mean birth weights were significantly lower in fresh oocyte pregnancies. Interestingly, in the group of 63 women who had pregnancies derived from both fresh and thawed oocytes, no differences were noted in the abortion rate or mean birth weight.¹⁶

We can freeze eggs, but when should we?
Based on media presentations and professional perspectives, it appears that many people differentiate between “medical” and “social” egg freezing.

Medical versus social freezing
Medical egg freezing is done when there is an immediate medical need to preserve fertility, such as before cancer treatment when the woman can’t reproduce now and will have reduced or no capacity later. Social freezing, on the other hand, occurs when there is no immediate need, such as when there is a desire to delay parenthood so that educational, professional, or other goals can be met. The difference is important because medical freezing is usually seen as a “need” and is therefore acceptable, whereas social freezing is elective or a “wish” and therefore is questionable.¹⁷

The labels are important for both ethical and political reasons because most people would consider medical freezing to be ethically acceptable and also worthy of societal support, perhaps even financial coverage, while some might consider social freezing to be neither ethically acceptable nor worthy of coverage.

What’s the difference?
But is the difference really all that clear? If a woman has a mother and a sister who have undergone premature menopause in their 30s and she now has signs of diminishing ovarian reserve in her late 20s, would a desire to freeze eggs be medical or social? She has no immediate need for treatment but a reasonable expectation of need later. One could argue that she should go to a sperm bank now if she has no partner, or change her life plans—but is this a reasonable expectation? If a woman is perfectly healthy but her husband has severe sperm problems and she elects IVF to treat male-factor infertility, is it medical or social? There are many situations in which it is unclear whether the reason for egg freezing would be medical or social.

Does it matter?
In any event, are social reasons to freeze eggs not legitimate? Many would argue that medical services should be used to treat diseases, not social causes. Yet we use medicine all the time to treat problems caused by social factors (obesity, depression, anxiety).

Some would argue that it is a personal decision to delay reproduction, and that health problems caused by personal decisions do not merit medical intervention. However, it is common to provide medical services to people who require the services only because of personal decisions—for instance, professional and amateur athletes who injure themselves pursuing activities for compensation or pleasure, or smokers or persons with alcoholism.

Others have argued that social freezing is inappropriate because it is only being done to avoid the consequences of aging, and that its need could be avoided by not waiting too long to get pregnant. But we treat many conditions that occur primarily as a result of aging (hypertension, dementia, poor eyesight).

Because it has become generally accepted to treat older women with diminished ovarian reserve and infertility, why is it inappropriate to treat women—when they are younger—with egg freezing to mitigate the impact of aging on reproductive performance that we know will occur later? If we could prevent or limit the impact of aging on the cardiovascular or neurologic systems by interventions earlier in a person’s life, would we not provide that medical service? Do we not provide statins and other medications to delay or limit the sequelae of aging? What is the difference with egg freezing?

Therefore, could it be discriminatory not to consider egg freezing ethical and acceptable, even if the reason for the procedure is considered social? Why should egg freezing for social reasons not be acceptable and widely available?

Who should pay for egg freezing?
Even if egg freezing performed because of social reasons is considered ethical and is supported by society, it does not necessarily follow that it will or should be paid for by society. The creation of policies determining coverage for health-care services is a complex process and is based on overall societal needs, economic capabilities, and relative social value of the services. Because infertility carries such a large personal burden and childbearing is so essential to any society, one can argue that infertility, per se, should be covered by society and, in the United States, its surrogate employers and insurance companies. This is often not the case, however. So, while it can be argued that egg freezing should be covered by insurance for both medical and social reasons, even the success of that argument does not mean it will be so in the current US health-care system.

Because egg freezing involves two major steps: (1) ovarian stimulation, egg retrieval, egg freezing, and egg storage followed at a later date by (2) egg thawing, fertilization, embryo culture, and embryo replacement in the uterus, what would be socially justified coverage of egg freezing? Society could cover just the first step or just the second, or both. Such decisions would depend on an assessment of the social benefit from coverage of these services. Such analysis is not yet available because of limited experience.

Is the cost worth it?
A major issue for women considering egg freezing for social reasons is whether a sufficient number of eggs will be retrieved to provide a reasonable chance for pregnancy later when they are used. The FIGURE illustrates the probability of a live birth after egg freezing. It should be noted that while most, but not all, eggs survive thawing after vitrification, not all eggs will become fertilized. Only about half of the fertilized eggs will grow to a day 3 embryo, and not all of those embryos will be viable. Therefore, constant reproductive loss occurs after the eggs are retrieved.
 

Source: Cil AP, et al.18 18

Furthermore, even after embryo replacement, pregnancy does not occur in every case, and some pregnancies are lost to miscarriage as well as other complications of pregnancy and childbirth. The FIGURE shows that a 25-year-old woman with 12 eggs frozen would have an estimated pregnancy rate much greater than 50%. However, the numbers also indicate that egg freezing is not very successful for older women who, at this time, constitute many of those considering the procedure.18

Another consideration is that a significant, but currently unknown, number of women who freeze their eggs will never use them for a variety of reasons. This is especially true of younger women, for whom many of the factors determining their eventual reproductive life might well change. They may eventually decide not to have children or they might become pregnant naturally or after fertility treatments that are cheaper than using the frozen eggs.

A $200,000 price tag?
Let’s consider the near 20% estimated pregnancy rate for age 35 in the FIGURE. If only half of the women aged 35 who freeze 6 eggs eventually use them (but, again, only about 20% have a baby), it means that only one of every 10 women who freeze their eggs eventually will have a baby as a result of the procedure. The number needed to treat (NNT) is therefore 10, and if the cost is $20,000 for the egg freezing procedure and storage over 5 to 10 years, the overall cost per baby born is about $200,000. If 12 eggs are frozen, the cost is $100,000. This clearly is a significant cost, and a greater cost than most other fertility treatments to achieve a baby, even in the older population. Therefore, the cost-effectiveness of social egg freezing is yet to be determined.

What should we do as we move forward?
Abandon the medical versus social rhetoric
It is difficult to argue against egg freezing for medical reasons, and the distinction between medical and social freezing is largely an artificial construct. In general, therefore, the differentiation between medical and social egg freezing should be abandoned, and egg freezing to preserve future fertility should be considered ethical for whatever reasons.

Consider the ideal time frame for health insurance coverage of egg freezing
That does not mean that egg freezing should always be reimbursed. The decision for coverage by employers, insurers, and other payers should be based on a cost–benefit analysis of the social benefit, individual benefit, biological chances of success, probability that the frozen eggs will be used, medical risks/sequelae, and the financial costs. Therefore, whether or not egg freezing for fertility preservation is covered will vary among countries and even within countries and among different individuals. Such an approach to coverage should apply to all medical interventions, including both medical and social egg freezing.

This approach could possibly result in findings and resulting policies that do not cover egg freezing before age 30 because too few women will return to use their eggs, or after age 38 because the chances of success are too low. Other instances of freezing should not be forbidden but would not be reimbursed by public or payer money.¹⁷

Many considerations must go into the development of social, professional, and payment policies. Policies that are seen as family-friendly that promote childbearing, especially at an earlier age, can be seen as limiting women’s academic and career opportunities and therefore women-unfriendly. Policies supporting women’s reproductive autonomy and ability to delay childbearing can be seen as women- but not family-friendly. Therefore, reproductive policies affect not only the individual woman but also society, its demographics, politics, and economics.¹⁷

The future
The new technology of egg freezing is a wonderful advance for many people. We are learning innovative ways to apply this technology for both infertile and noninfertile people. Research, better evidence, public education, informed consent, ethical practice of medicine, societal support for reproductive rights, and consideration of patient autonomy and social justice will enable us to optimize egg freezing as a treatment intervention.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

The first human birth from a frozen oocyte was reported in 1986.¹ Nearly 3 decades later, mature oocyte cryopreservation has emerged as a meaningful technology to preserve reproductive potential in women of reproductive age. In 2013, the American Society for Reproductive Medicine (ASRM) removed the “experimental” label from egg freezing but cautioned that more data on safety and efficacy were needed prior to widespread adoption of the technique.²

In this Update, we present the ­current protocols for oocyte cryopreservation, how we arrived at them, and the questions regarding outcomes that still remain. In addition, we discuss the ethical dilemmas egg freezing presents, according to the varying rhetoric within the media and our own profession. Finally, we consider what preliminary data suggest as to the live-birth rate using frozen eggs from women of varying ages and what the costs are associated with using oocyte cryopreservation as the approach to fertility treatment.

Vitrification and slow freezing: How did we get here and how effective are they?
Fertility preservation is a rapidly advancing area of reproductive medicine. Cryopreservation is the cooling of cells to subzero temperatures to halt biologic activity and preserve the cells for future use. Clinically, oocyte cryopreservation requires a patient to undergo in vitro fertilization (IVF). After egg retrieval, the oocytes are cryopreserved for use at a later time.

The prefix “cryo” originated from the Greek word “kryos,” meaning icy cold or frost. Cryopreservation is not a new science. In 1776, the Italian priest and scientist Lazzaro Spallanzani reported that sperm became motionless when cooled by snow. A pivotal discovery in the field came in 1949, when Christopher Polge, an English scientist, showed that glycerol, a permeating solute, could provide protection to cells at low temperatures.³ Progress in sperm cryopreservation advanced quickly, partly due to the ease of observing sperm motility as a marker of postthaw function.⁴

The ongoing evolution of cryopreservation science led to landmark achievements, including the first birth using human cryopreserved sperm in the 1950s, and the first human birth after embryo thaw in 1983. Since that time cryopreservation has become a cornerstone in the field of reproductive medicine.

Initial problems encountered with egg freezing
Although the first birth after thaw of a human oocyte occurred in 1986, oocyte cryopreservation was fraught with technical difficulties. Oocytes (vs sperm and embryos) proved challenging to successfully cryopreserve. The problem lay in the damage caused by water crystals forming ice and rising concentrations of intracellular solutes as cells were cooled to freezing temperatures.⁵ The large size and high water content of the human oocyte made it particularly vulnerable to the detrimental effects of freezing. In addition, freeze−thaw hardening of the zone pellucida led to decreased postthaw fertilization. The delicate meiotic spindle within the oocyte was prone to injury from ice crystals.⁶

Use of cryoprotectants, such as ethylene glycol, glycerol, and dimethylsulfoxide (DMSO), can prevent ice crystal formation, but high concentrations are theoretically toxic. The fine balance between protection and toxicity led to the development of diverse egg freezing protocols using various types and concentrations of cryoprotectants. Inconsistent results and lack of reproducibility among labs, together with concerns about postthaw oocyte function and safety, slowed the progression of oocyte freezing. By the end of the 1980s, clinical oocyte cryopreservation had been effectively halted and the field was confined to small groups of researchers who continued laboratory experiments with limited success.⁵

In 1997, clinical work with frozen oocytes resumed with a Bologna team reporting postthawing oocyte survival rates of up to 80% using propanediol as the primary cryoprotectant, and viable pregnancies with the use of intracytoplasmic sperm injection (ICSI) for fertilization.^7,8 Since the late 1990s, further modifications in freezing technologies have resulted in greater success. And currently, both slow freezing and vitrification methods are used to preserve oocytes.

Slow freezing
Slow freezing involves a low rate of oocyte temperature decline with a simultaneous gradual increase in the concentration of cryoprotectants. As the metabolic activity of the oocyte decreases, the concentration of ­cryoprotectant can be increased to prevent ice crystal formation. Once solidification of the oocyte is achieved, the oocyte can be exposed to freezing at colder temperatures. Results of a meta-analysis of 26 studies revealed that, compared with using fresh oocytes, eggs thawed after slow-freezing yielded significantly lower rates of fertilization (61.0% [1,346/2,217] vs 76.7% [2,788/3,637]), clinical pregnancy rate per transfer (27.1% [95/351] vs 68.5% [272/397]), and live birth per transfer (21.6% [76/351] vs 32.4% [24/72]).⁹

Vitrification
Vitrification involves the rapid cooling of cells to extremely low temperatures. During vitrification, oocytes are exposed to high concentrations of cryoprotectants and, after a short equilibration time, rapidly cooled. The rate of cooling is dramatic, up to 20,000°C per minute—so fast that ice does not have time to form and a glass-like state is achieved within the oocyte. Studies suggest that the use of vitrification improves oocyte survival and function compared with slow freezing.^9-11 A prospective randomized controlled trial ­comparing frozen/thawed with ­vitrified/warmed oocytes demonstrated superior oocyte function in the vitrification group, with higher oocyte survival (81% for ­vitrification/warming vs 67% for slow ­freezing/thawing); higher rates of fertilization, cleavage, and embryo morphology; as well as higher clinical pregnancy rates (38% for vitrified/warmed vs 13% for frozen/thawed).¹⁰

The Practice Committee of ASRM published a guideline for mature cryopreservation in 2013.² The committee reviewed the literature on efficacy and safety of mature oocyte cryopreservation. Although data are limited, studies comparing outcomes of IVF using cryopreserved versus fresh oocytes, including four randomized controlled trials and a meta-analysis, provide evidence that previously vitrified/thawed eggs result in similar fertilization and pregnancy rates as IVF/ICSI with fresh oocytes. Similar to data from fresh IVF cycles, decreased success with oocyte vitrification is seen in women with advanced age, and delivery rates, not unexpectedly, are inversely correlated with maternal age.¹²

Safety outcomes data are limited but reassuring
Two major factors limit our current understanding of egg cryopreservation outcomes. First, many women who have cryopreserved their eggs have not yet used them and, second, babies born after use of cryopreserved oocytes have not reached ages in which safety of the technique can be fully evaluated. Despite this important gap in our knowledge, to date, results of studies examining safety outcomes of the procedure have been reassuring.

For instance, chromosomal analysis via fluorescence in-situ hybridization of embryos created with thawed oocytes versus controls revealed no difference in the incidence of chromosomal abnormalities, decreasing concerns about damage to the oocyte spindle secondary to freezing.¹³

Data from a review of 900 live births resulting from embryos created from thawed oocytes frozen via the slow freeze technique revealed no increase in the risk of congenital anomalies.¹⁴ Similarly, no increased risk of congenital anomalies or difference in birth weights was noted in a study of 200 live births after transfers with embryos derived from vitrified oocytes compared with fresh oocytes.¹⁵

In a study of 954 clinical pregnancies occurring in 855 couples with cryopreserved oocytes after assisted reproductive technology, the outcomes of 197 ­pregnancies from frozen/thawed oocytes were compared with 757 obtained from fresh sibling oocyte cycles. A significantly higher rate of spontaneous abortions at 12 weeks or less was observed in the frozen/thawed oocyte group. No statistically significant differences were noted in gestational age at delivery or in the incidence of major congenital anomalies at birth, but mean birth weights were significantly lower in fresh oocyte pregnancies. Interestingly, in the group of 63 women who had pregnancies derived from both fresh and thawed oocytes, no differences were noted in the abortion rate or mean birth weight.¹⁶

We can freeze eggs, but when should we?
Based on media presentations and professional perspectives, it appears that many people differentiate between “medical” and “social” egg freezing.

Medical versus social freezing
Medical egg freezing is done when there is an immediate medical need to preserve fertility, such as before cancer treatment when the woman can’t reproduce now and will have reduced or no capacity later. Social freezing, on the other hand, occurs when there is no immediate need, such as when there is a desire to delay parenthood so that educational, professional, or other goals can be met. The difference is important because medical freezing is usually seen as a “need” and is therefore acceptable, whereas social freezing is elective or a “wish” and therefore is questionable.¹⁷

The labels are important for both ethical and political reasons because most people would consider medical freezing to be ethically acceptable and also worthy of societal support, perhaps even financial coverage, while some might consider social freezing to be neither ethically acceptable nor worthy of coverage.

What’s the difference?
But is the difference really all that clear? If a woman has a mother and a sister who have undergone premature menopause in their 30s and she now has signs of diminishing ovarian reserve in her late 20s, would a desire to freeze eggs be medical or social? She has no immediate need for treatment but a reasonable expectation of need later. One could argue that she should go to a sperm bank now if she has no partner, or change her life plans—but is this a reasonable expectation? If a woman is perfectly healthy but her husband has severe sperm problems and she elects IVF to treat male-factor infertility, is it medical or social? There are many situations in which it is unclear whether the reason for egg freezing would be medical or social.

Does it matter?
In any event, are social reasons to freeze eggs not legitimate? Many would argue that medical services should be used to treat diseases, not social causes. Yet we use medicine all the time to treat problems caused by social factors (obesity, depression, anxiety).

Some would argue that it is a personal decision to delay reproduction, and that health problems caused by personal decisions do not merit medical intervention. However, it is common to provide medical services to people who require the services only because of personal decisions—for instance, professional and amateur athletes who injure themselves pursuing activities for compensation or pleasure, or smokers or persons with alcoholism.

Others have argued that social freezing is inappropriate because it is only being done to avoid the consequences of aging, and that its need could be avoided by not waiting too long to get pregnant. But we treat many conditions that occur primarily as a result of aging (hypertension, dementia, poor eyesight).

Because it has become generally accepted to treat older women with diminished ovarian reserve and infertility, why is it inappropriate to treat women—when they are younger—with egg freezing to mitigate the impact of aging on reproductive performance that we know will occur later? If we could prevent or limit the impact of aging on the cardiovascular or neurologic systems by interventions earlier in a person’s life, would we not provide that medical service? Do we not provide statins and other medications to delay or limit the sequelae of aging? What is the difference with egg freezing?

Therefore, could it be discriminatory not to consider egg freezing ethical and acceptable, even if the reason for the procedure is considered social? Why should egg freezing for social reasons not be acceptable and widely available?

Who should pay for egg freezing?
Even if egg freezing performed because of social reasons is considered ethical and is supported by society, it does not necessarily follow that it will or should be paid for by society. The creation of policies determining coverage for health-care services is a complex process and is based on overall societal needs, economic capabilities, and relative social value of the services. Because infertility carries such a large personal burden and childbearing is so essential to any society, one can argue that infertility, per se, should be covered by society and, in the United States, its surrogate employers and insurance companies. This is often not the case, however. So, while it can be argued that egg freezing should be covered by insurance for both medical and social reasons, even the success of that argument does not mean it will be so in the current US health-care system.

Because egg freezing involves two major steps: (1) ovarian stimulation, egg retrieval, egg freezing, and egg storage followed at a later date by (2) egg thawing, fertilization, embryo culture, and embryo replacement in the uterus, what would be socially justified coverage of egg freezing? Society could cover just the first step or just the second, or both. Such decisions would depend on an assessment of the social benefit from coverage of these services. Such analysis is not yet available because of limited experience.

Is the cost worth it?
A major issue for women considering egg freezing for social reasons is whether a sufficient number of eggs will be retrieved to provide a reasonable chance for pregnancy later when they are used. The FIGURE illustrates the probability of a live birth after egg freezing. It should be noted that while most, but not all, eggs survive thawing after vitrification, not all eggs will become fertilized. Only about half of the fertilized eggs will grow to a day 3 embryo, and not all of those embryos will be viable. Therefore, constant reproductive loss occurs after the eggs are retrieved.
 

Source: Cil AP, et al.18 18

Furthermore, even after embryo replacement, pregnancy does not occur in every case, and some pregnancies are lost to miscarriage as well as other complications of pregnancy and childbirth. The FIGURE shows that a 25-year-old woman with 12 eggs frozen would have an estimated pregnancy rate much greater than 50%. However, the numbers also indicate that egg freezing is not very successful for older women who, at this time, constitute many of those considering the procedure.18

Another consideration is that a significant, but currently unknown, number of women who freeze their eggs will never use them for a variety of reasons. This is especially true of younger women, for whom many of the factors determining their eventual reproductive life might well change. They may eventually decide not to have children or they might become pregnant naturally or after fertility treatments that are cheaper than using the frozen eggs.

A $200,000 price tag?
Let’s consider the near 20% estimated pregnancy rate for age 35 in the FIGURE. If only half of the women aged 35 who freeze 6 eggs eventually use them (but, again, only about 20% have a baby), it means that only one of every 10 women who freeze their eggs eventually will have a baby as a result of the procedure. The number needed to treat (NNT) is therefore 10, and if the cost is $20,000 for the egg freezing procedure and storage over 5 to 10 years, the overall cost per baby born is about $200,000. If 12 eggs are frozen, the cost is $100,000. This clearly is a significant cost, and a greater cost than most other fertility treatments to achieve a baby, even in the older population. Therefore, the cost-effectiveness of social egg freezing is yet to be determined.

What should we do as we move forward?
Abandon the medical versus social rhetoric
It is difficult to argue against egg freezing for medical reasons, and the distinction between medical and social freezing is largely an artificial construct. In general, therefore, the differentiation between medical and social egg freezing should be abandoned, and egg freezing to preserve future fertility should be considered ethical for whatever reasons.

Consider the ideal time frame for health insurance coverage of egg freezing
That does not mean that egg freezing should always be reimbursed. The decision for coverage by employers, insurers, and other payers should be based on a cost–benefit analysis of the social benefit, individual benefit, biological chances of success, probability that the frozen eggs will be used, medical risks/sequelae, and the financial costs. Therefore, whether or not egg freezing for fertility preservation is covered will vary among countries and even within countries and among different individuals. Such an approach to coverage should apply to all medical interventions, including both medical and social egg freezing.

This approach could possibly result in findings and resulting policies that do not cover egg freezing before age 30 because too few women will return to use their eggs, or after age 38 because the chances of success are too low. Other instances of freezing should not be forbidden but would not be reimbursed by public or payer money.¹⁷

Many considerations must go into the development of social, professional, and payment policies. Policies that are seen as family-friendly that promote childbearing, especially at an earlier age, can be seen as limiting women’s academic and career opportunities and therefore women-unfriendly. Policies supporting women’s reproductive autonomy and ability to delay childbearing can be seen as women- but not family-friendly. Therefore, reproductive policies affect not only the individual woman but also society, its demographics, politics, and economics.¹⁷

The future
The new technology of egg freezing is a wonderful advance for many people. We are learning innovative ways to apply this technology for both infertile and noninfertile people. Research, better evidence, public education, informed consent, ethical practice of medicine, societal support for reproductive rights, and consideration of patient autonomy and social justice will enable us to optimize egg freezing as a treatment intervention.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

The first human birth from a frozen oocyte was reported in 1986.¹ Nearly 3 decades later, mature oocyte cryopreservation has emerged as a meaningful technology to preserve reproductive potential in women of reproductive age. In 2013, the American Society for Reproductive Medicine (ASRM) removed the “experimental” label from egg freezing but cautioned that more data on safety and efficacy were needed prior to widespread adoption of the technique.²

In this Update, we present the ­current protocols for oocyte cryopreservation, how we arrived at them, and the questions regarding outcomes that still remain. In addition, we discuss the ethical dilemmas egg freezing presents, according to the varying rhetoric within the media and our own profession. Finally, we consider what preliminary data suggest as to the live-birth rate using frozen eggs from women of varying ages and what the costs are associated with using oocyte cryopreservation as the approach to fertility treatment.

Vitrification and slow freezing: How did we get here and how effective are they?
Fertility preservation is a rapidly advancing area of reproductive medicine. Cryopreservation is the cooling of cells to subzero temperatures to halt biologic activity and preserve the cells for future use. Clinically, oocyte cryopreservation requires a patient to undergo in vitro fertilization (IVF). After egg retrieval, the oocytes are cryopreserved for use at a later time.

The prefix “cryo” originated from the Greek word “kryos,” meaning icy cold or frost. Cryopreservation is not a new science. In 1776, the Italian priest and scientist Lazzaro Spallanzani reported that sperm became motionless when cooled by snow. A pivotal discovery in the field came in 1949, when Christopher Polge, an English scientist, showed that glycerol, a permeating solute, could provide protection to cells at low temperatures.³ Progress in sperm cryopreservation advanced quickly, partly due to the ease of observing sperm motility as a marker of postthaw function.⁴

The ongoing evolution of cryopreservation science led to landmark achievements, including the first birth using human cryopreserved sperm in the 1950s, and the first human birth after embryo thaw in 1983. Since that time cryopreservation has become a cornerstone in the field of reproductive medicine.

Initial problems encountered with egg freezing
Although the first birth after thaw of a human oocyte occurred in 1986, oocyte cryopreservation was fraught with technical difficulties. Oocytes (vs sperm and embryos) proved challenging to successfully cryopreserve. The problem lay in the damage caused by water crystals forming ice and rising concentrations of intracellular solutes as cells were cooled to freezing temperatures.⁵ The large size and high water content of the human oocyte made it particularly vulnerable to the detrimental effects of freezing. In addition, freeze−thaw hardening of the zone pellucida led to decreased postthaw fertilization. The delicate meiotic spindle within the oocyte was prone to injury from ice crystals.⁶

Use of cryoprotectants, such as ethylene glycol, glycerol, and dimethylsulfoxide (DMSO), can prevent ice crystal formation, but high concentrations are theoretically toxic. The fine balance between protection and toxicity led to the development of diverse egg freezing protocols using various types and concentrations of cryoprotectants. Inconsistent results and lack of reproducibility among labs, together with concerns about postthaw oocyte function and safety, slowed the progression of oocyte freezing. By the end of the 1980s, clinical oocyte cryopreservation had been effectively halted and the field was confined to small groups of researchers who continued laboratory experiments with limited success.⁵

In 1997, clinical work with frozen oocytes resumed with a Bologna team reporting postthawing oocyte survival rates of up to 80% using propanediol as the primary cryoprotectant, and viable pregnancies with the use of intracytoplasmic sperm injection (ICSI) for fertilization.^7,8 Since the late 1990s, further modifications in freezing technologies have resulted in greater success. And currently, both slow freezing and vitrification methods are used to preserve oocytes.

Slow freezing
Slow freezing involves a low rate of oocyte temperature decline with a simultaneous gradual increase in the concentration of cryoprotectants. As the metabolic activity of the oocyte decreases, the concentration of ­cryoprotectant can be increased to prevent ice crystal formation. Once solidification of the oocyte is achieved, the oocyte can be exposed to freezing at colder temperatures. Results of a meta-analysis of 26 studies revealed that, compared with using fresh oocytes, eggs thawed after slow-freezing yielded significantly lower rates of fertilization (61.0% [1,346/2,217] vs 76.7% [2,788/3,637]), clinical pregnancy rate per transfer (27.1% [95/351] vs 68.5% [272/397]), and live birth per transfer (21.6% [76/351] vs 32.4% [24/72]).⁹

Vitrification
Vitrification involves the rapid cooling of cells to extremely low temperatures. During vitrification, oocytes are exposed to high concentrations of cryoprotectants and, after a short equilibration time, rapidly cooled. The rate of cooling is dramatic, up to 20,000°C per minute—so fast that ice does not have time to form and a glass-like state is achieved within the oocyte. Studies suggest that the use of vitrification improves oocyte survival and function compared with slow freezing.^9-11 A prospective randomized controlled trial ­comparing frozen/thawed with ­vitrified/warmed oocytes demonstrated superior oocyte function in the vitrification group, with higher oocyte survival (81% for ­vitrification/warming vs 67% for slow ­freezing/thawing); higher rates of fertilization, cleavage, and embryo morphology; as well as higher clinical pregnancy rates (38% for vitrified/warmed vs 13% for frozen/thawed).¹⁰

The Practice Committee of ASRM published a guideline for mature cryopreservation in 2013.² The committee reviewed the literature on efficacy and safety of mature oocyte cryopreservation. Although data are limited, studies comparing outcomes of IVF using cryopreserved versus fresh oocytes, including four randomized controlled trials and a meta-analysis, provide evidence that previously vitrified/thawed eggs result in similar fertilization and pregnancy rates as IVF/ICSI with fresh oocytes. Similar to data from fresh IVF cycles, decreased success with oocyte vitrification is seen in women with advanced age, and delivery rates, not unexpectedly, are inversely correlated with maternal age.¹²

Safety outcomes data are limited but reassuring
Two major factors limit our current understanding of egg cryopreservation outcomes. First, many women who have cryopreserved their eggs have not yet used them and, second, babies born after use of cryopreserved oocytes have not reached ages in which safety of the technique can be fully evaluated. Despite this important gap in our knowledge, to date, results of studies examining safety outcomes of the procedure have been reassuring.

For instance, chromosomal analysis via fluorescence in-situ hybridization of embryos created with thawed oocytes versus controls revealed no difference in the incidence of chromosomal abnormalities, decreasing concerns about damage to the oocyte spindle secondary to freezing.¹³

Data from a review of 900 live births resulting from embryos created from thawed oocytes frozen via the slow freeze technique revealed no increase in the risk of congenital anomalies.¹⁴ Similarly, no increased risk of congenital anomalies or difference in birth weights was noted in a study of 200 live births after transfers with embryos derived from vitrified oocytes compared with fresh oocytes.¹⁵

In a study of 954 clinical pregnancies occurring in 855 couples with cryopreserved oocytes after assisted reproductive technology, the outcomes of 197 ­pregnancies from frozen/thawed oocytes were compared with 757 obtained from fresh sibling oocyte cycles. A significantly higher rate of spontaneous abortions at 12 weeks or less was observed in the frozen/thawed oocyte group. No statistically significant differences were noted in gestational age at delivery or in the incidence of major congenital anomalies at birth, but mean birth weights were significantly lower in fresh oocyte pregnancies. Interestingly, in the group of 63 women who had pregnancies derived from both fresh and thawed oocytes, no differences were noted in the abortion rate or mean birth weight.¹⁶

We can freeze eggs, but when should we?
Based on media presentations and professional perspectives, it appears that many people differentiate between “medical” and “social” egg freezing.

Medical versus social freezing
Medical egg freezing is done when there is an immediate medical need to preserve fertility, such as before cancer treatment when the woman can’t reproduce now and will have reduced or no capacity later. Social freezing, on the other hand, occurs when there is no immediate need, such as when there is a desire to delay parenthood so that educational, professional, or other goals can be met. The difference is important because medical freezing is usually seen as a “need” and is therefore acceptable, whereas social freezing is elective or a “wish” and therefore is questionable.¹⁷

The labels are important for both ethical and political reasons because most people would consider medical freezing to be ethically acceptable and also worthy of societal support, perhaps even financial coverage, while some might consider social freezing to be neither ethically acceptable nor worthy of coverage.

What’s the difference?
But is the difference really all that clear? If a woman has a mother and a sister who have undergone premature menopause in their 30s and she now has signs of diminishing ovarian reserve in her late 20s, would a desire to freeze eggs be medical or social? She has no immediate need for treatment but a reasonable expectation of need later. One could argue that she should go to a sperm bank now if she has no partner, or change her life plans—but is this a reasonable expectation? If a woman is perfectly healthy but her husband has severe sperm problems and she elects IVF to treat male-factor infertility, is it medical or social? There are many situations in which it is unclear whether the reason for egg freezing would be medical or social.

Does it matter?
In any event, are social reasons to freeze eggs not legitimate? Many would argue that medical services should be used to treat diseases, not social causes. Yet we use medicine all the time to treat problems caused by social factors (obesity, depression, anxiety).

Some would argue that it is a personal decision to delay reproduction, and that health problems caused by personal decisions do not merit medical intervention. However, it is common to provide medical services to people who require the services only because of personal decisions—for instance, professional and amateur athletes who injure themselves pursuing activities for compensation or pleasure, or smokers or persons with alcoholism.

Others have argued that social freezing is inappropriate because it is only being done to avoid the consequences of aging, and that its need could be avoided by not waiting too long to get pregnant. But we treat many conditions that occur primarily as a result of aging (hypertension, dementia, poor eyesight).

Because it has become generally accepted to treat older women with diminished ovarian reserve and infertility, why is it inappropriate to treat women—when they are younger—with egg freezing to mitigate the impact of aging on reproductive performance that we know will occur later? If we could prevent or limit the impact of aging on the cardiovascular or neurologic systems by interventions earlier in a person’s life, would we not provide that medical service? Do we not provide statins and other medications to delay or limit the sequelae of aging? What is the difference with egg freezing?

Therefore, could it be discriminatory not to consider egg freezing ethical and acceptable, even if the reason for the procedure is considered social? Why should egg freezing for social reasons not be acceptable and widely available?

Who should pay for egg freezing?
Even if egg freezing performed because of social reasons is considered ethical and is supported by society, it does not necessarily follow that it will or should be paid for by society. The creation of policies determining coverage for health-care services is a complex process and is based on overall societal needs, economic capabilities, and relative social value of the services. Because infertility carries such a large personal burden and childbearing is so essential to any society, one can argue that infertility, per se, should be covered by society and, in the United States, its surrogate employers and insurance companies. This is often not the case, however. So, while it can be argued that egg freezing should be covered by insurance for both medical and social reasons, even the success of that argument does not mean it will be so in the current US health-care system.

Because egg freezing involves two major steps: (1) ovarian stimulation, egg retrieval, egg freezing, and egg storage followed at a later date by (2) egg thawing, fertilization, embryo culture, and embryo replacement in the uterus, what would be socially justified coverage of egg freezing? Society could cover just the first step or just the second, or both. Such decisions would depend on an assessment of the social benefit from coverage of these services. Such analysis is not yet available because of limited experience.

Is the cost worth it?
A major issue for women considering egg freezing for social reasons is whether a sufficient number of eggs will be retrieved to provide a reasonable chance for pregnancy later when they are used. The FIGURE illustrates the probability of a live birth after egg freezing. It should be noted that while most, but not all, eggs survive thawing after vitrification, not all eggs will become fertilized. Only about half of the fertilized eggs will grow to a day 3 embryo, and not all of those embryos will be viable. Therefore, constant reproductive loss occurs after the eggs are retrieved.
 

Source: Cil AP, et al.18 18

Furthermore, even after embryo replacement, pregnancy does not occur in every case, and some pregnancies are lost to miscarriage as well as other complications of pregnancy and childbirth. The FIGURE shows that a 25-year-old woman with 12 eggs frozen would have an estimated pregnancy rate much greater than 50%. However, the numbers also indicate that egg freezing is not very successful for older women who, at this time, constitute many of those considering the procedure.18

Another consideration is that a significant, but currently unknown, number of women who freeze their eggs will never use them for a variety of reasons. This is especially true of younger women, for whom many of the factors determining their eventual reproductive life might well change. They may eventually decide not to have children or they might become pregnant naturally or after fertility treatments that are cheaper than using the frozen eggs.

A $200,000 price tag?
Let’s consider the near 20% estimated pregnancy rate for age 35 in the FIGURE. If only half of the women aged 35 who freeze 6 eggs eventually use them (but, again, only about 20% have a baby), it means that only one of every 10 women who freeze their eggs eventually will have a baby as a result of the procedure. The number needed to treat (NNT) is therefore 10, and if the cost is $20,000 for the egg freezing procedure and storage over 5 to 10 years, the overall cost per baby born is about $200,000. If 12 eggs are frozen, the cost is $100,000. This clearly is a significant cost, and a greater cost than most other fertility treatments to achieve a baby, even in the older population. Therefore, the cost-effectiveness of social egg freezing is yet to be determined.

What should we do as we move forward?
Abandon the medical versus social rhetoric
It is difficult to argue against egg freezing for medical reasons, and the distinction between medical and social freezing is largely an artificial construct. In general, therefore, the differentiation between medical and social egg freezing should be abandoned, and egg freezing to preserve future fertility should be considered ethical for whatever reasons.

Consider the ideal time frame for health insurance coverage of egg freezing
That does not mean that egg freezing should always be reimbursed. The decision for coverage by employers, insurers, and other payers should be based on a cost–benefit analysis of the social benefit, individual benefit, biological chances of success, probability that the frozen eggs will be used, medical risks/sequelae, and the financial costs. Therefore, whether or not egg freezing for fertility preservation is covered will vary among countries and even within countries and among different individuals. Such an approach to coverage should apply to all medical interventions, including both medical and social egg freezing.

This approach could possibly result in findings and resulting policies that do not cover egg freezing before age 30 because too few women will return to use their eggs, or after age 38 because the chances of success are too low. Other instances of freezing should not be forbidden but would not be reimbursed by public or payer money.¹⁷

Many considerations must go into the development of social, professional, and payment policies. Policies that are seen as family-friendly that promote childbearing, especially at an earlier age, can be seen as limiting women’s academic and career opportunities and therefore women-unfriendly. Policies supporting women’s reproductive autonomy and ability to delay childbearing can be seen as women- but not family-friendly. Therefore, reproductive policies affect not only the individual woman but also society, its demographics, politics, and economics.¹⁷

The future
The new technology of egg freezing is a wonderful advance for many people. We are learning innovative ways to apply this technology for both infertile and noninfertile people. Research, better evidence, public education, informed consent, ethical practice of medicine, societal support for reproductive rights, and consideration of patient autonomy and social justice will enable us to optimize egg freezing as a treatment intervention.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

These experts discuss three recent American Society for Reproductive Medicine Committee Opinions. The first is on the optimal use of the most widely prescribed medication for fertility, clomiphene citrate. The second highlights the currently recommended vaccinations for women who are of reproductive age. And the third is on the current evidence for prevention of postsurgical adhesions, which have the potential to cause infertility. Their discussions could affect how you approach your infertile patients. 

SAFE, EFFECTIVE USE OF CLOMIPHENE

Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in infertile women: A committee opinion. Fertil Steril. 2013;100(2):341–348.

Clomiphene citrate (CC) is the fertility medication most commonly used by gynecologists. However, important principles in its use often are not followed, resulting in suboptimal patient care. The American Society for Reproductive Medicine published a recent Committee Opinion on CC’s indications, use, and alternative treatments. We summarize the essential aspects of CC use.

Who should be treated?
CC can be used to treat both anovulation/oligo-ovulation and unexplained infertility, but it is not effective in hypothalamic amenorrhea or hypergonadotropic hypogonadism (usually premature ovarian insufficiency). Anovulation/oligo-ovulation may be due to polycystic ovary syndrome (PCOS), obesity, hypothalamic dysfunction related to eating disorders, weight, exercise, stress, hyper­prolactinemia, pituitary tumors, or thyroid disease. The exact cause is often indeterminable, however.

Related Article: Polycystic ovary syndrome: Where we stand with diagnosis and treatment and where we're going Steven R. Lindheim, MD, MMM, and Leah Whigham, PhD (First of a 4-part series, September 2012)

There is no evidence CC is effective treatment for “luteal phase defect.” ­Unexplained infertility also can be treated with CC with intrauterine insemination (IUI).¹

Pretreatment evaluation
Diagnosis of ovulatory dysfunction is usually made by menstrual history alone (normal menses, ≥24 and ≥35 days). Testing with luteal phase serum progesterone or serial transvaginal ultrasound generally is unnecessary.

Use the history, physical examination, and other testing, as necessary, to rule out other endocrinopathies, including diabetes mellitus (screening for impaired glucose tolerance), thyroid disorders (measurement of thyroid-stimulating hormone, or TSH), hyperprolactinemia (prolactin assessment), congenital adrenal hyperplasia (measurement of 17-alpha hydroxyprogesterone acetate), and virilization (assessment of testosterone and dehydroepiandrosterone sulfate, or DHEA-S).

If disease-specific treatment does not result in normal ovulation, then CC can be used. Although it may be difficult for them, obese women should be encouraged to lose weight. In infertile couples with a normal menstrual cycle and no other identifiable infertility factors, if hysterosalpingogram and semen analysis are normal, treatment of their unexplained infertility with CC and IUI may be effective. Ovulation induction or ovarian stimulation has little benefit when severe male, uterine, or tubal factors are present.

Treatment regimens
CC is usually given 50 mg/day orally for 5 days starting on the second to fifth spontaneous or progestin-induced menstrual cycle day, with equivalent treatment outcomes regardless of start day 2, 3, 4, or 5. If the patient’s response to this dose is inadequate, treatment can be increased 50 mg/day in each subsequent cycle, to a maximum of 250 mg/day. However, the maximum FDA-approved dose is 100 mg/day, and only 20% of patients respond when given doses higher than this. Obese patients may respond at the higher doses.

The luteinizing hormone (LH) surge occurs 5 to 12 days after the last CC dose is taken. There is no benefit to giving human chorionic gonadotropin (hCG) if the patient has a spontaneous LH surge. The pregnancy rate might actually be reduced by 25% when hCG is given unnecessarily.²

In anovulatory/oligo-ovulatory women, there is no benefit of IUI over timed intercourse for achieving pregnancy. For unexplained infertility, however, CC with timed intercourse does not appear effective, but CC combined with IUI is effective.³ Timed intercourse should occur approximately every 2 days (1–3 days) starting about 3 to 4 days before expected ovulation.

Treatment should continue 3 to 4 months. Younger patients (<35 years) with a short duration of infertility (<2 years) who respond to CC can receive up to 6 months of treatment. Treatment beyond 6 months is not recommended.

Ovulation and pregnancy rates
Half of anovulatory/oligo-ovulatory women will ovulate with a 50-mg dose of CC and half of the remaining will ovulate with a 100-mg dose. Among women who ovulate with CC, cumulative pregnancy rates for 50 mg/day, 100 mg/day, or 150 mg/day at 3 months are 50%, 45%, and 33%, respectively, and at 6 months are 62%, 66%, and 38%, respectively. In general, a 55% to 73% pregnancy rate can be expected.⁴ Increasing age, duration of infertility, and obesity are associated with lower pregnancy rates and treatment failure.

Alternative and adjunctive regimens
For patients who are not using progestin to induce menses and who have not responded with ovulation by day 14 to 21, longer courses of CC treatment (7 to 8 days) and a step-up protocol to the next highest CC dose are alternative regimens that may work in some cases.

Some anovulatory or oligo-ovulatory women with PCOS who do not respond to CC alone may respond to CC combined with metformin at 1,500 to 1,700 mg/day. Metformin combined with diet and exercise for weight loss is recommended. Metformin is associated with gastrointestinal side effects and rare hepatic toxicity or lactic acidosis; therefore, liver and renal functions should be assessed prior to treatment and monitored afterward.

Women with DHEA-S serum concentrations of 200 µg/dL or greater, and even some women with normal DHEA-S levels, may be more responsive to CC and achieve higher pregnancy rates when given dexamethasone 0.5 mg/daily on cycle days 3 to 12. Glucocorticoids have significant side effects and should be discontinued if treatment is unsuccessful or when pregnancy occurs.

Related Article: Clomiphene failure? Try adding dexamethasone to your clomiphene infertility regimen Robert L. Barbieri, MD (Editorial, May 2012)

Some CC-resistant anovulatory women and women with unexplained infertility may benefit from a trial of sequential CC/gonadotropin treatment consisting of standard CC treatment followed by human menopausal gonadotropins (hMG) or follicle-stimulating hormone (FSH) 75 to 150 IU/day for 3 days. Some, but not all, studies show pregnancy rates in these patients equivalent to those undergoing gonadotropin treatment alone (at a reduced cost). There are no studies directly comparing the treatment regimens, however, and risks of multiple pregnancy might be increased for patients taking both CC and gonadotropin, so this treatment should only be provided by clinicians with requisite training and experience.

Other alternatives to CC therapy in CC-resistant patients include aromatase inhibitors, tamoxifen, insulin-sensitizing agents, ovarian drilling, gonadotropins, and in vitro fertilization.

Monitoring of CC cycles
Objective evidence of ovulation is key to successful treatment. Ovulation predictor kits are more than 90% successful, if used properly, in identifying the LH surge 5 to 12 days after CC is finished (usually around cycle day 16 or 17). Ovulation occurs about one-half day to 2 days after the LH surge. Serum progesterone is the most certain test of prior ovulation (other than pregnancy) but cannot predict time of ovulation. Serial ultrasound shows the size and number of follicles and presumptive ovulation with follicle collapse, as well as echogenic corpus luteum and cul de sac fluid, but it is expensive and often not cost-effective.

It is prudent to postpone further treatment if the patient has large ovaries or a cyst, but routine baseline ultrasound monitoring is no longer considered necessary. However, regular contact with the patient should be maintained to review response to treatment and to ensure that any additional or alternative treatments are not delayed.

Side effects of CC treatment
Mood swings, visual disturbances, breast tenderness, pelvic discomfort, and nausea are reported in less than 10% of patients. Mild ovarian hyperstimulation syndrome (OHSS) is not uncommon, but severe OHSS is rare.

Related Article: Avoiding ovarian hyperstimulation syndrome G. David Adamson, MD (Audiocast, February 2011)

The major risk to CC treatment is twin (8% risk) and triplet (0.5% risk) pregnancies. There is no evidence of increased risk of congenital anomalies, miscarriage, or ovarian cancer.^1,5,6

WHAT THIS EVIDENCE MEANS FOR PRACTICE
All gynecologists should be able to diagnose and treat infertility with clomiphene. It is effective for many patients with anovulatory/oligo-ovulatory infertility, and also for unexplained infertility when combined with IUI. Careful evaluation of fertility and endocrinologic status is necessary before treatment, as is monitoring during treatment. Although this treatment may appear to be simple, there are many important principles that need to be followed if treatment is to be effective and safe, and if the patient is to receive quality infertility care. Treatment is safe, (the major risk is multiple pregnancy) but should not be continued for more than 3 to 6 months.

STRIVE FOR PREPREGNANCY VACCINATION

Practice Committee of American Society for Reproductive Medicine. Vaccination guidelines for female infertility patients: A committee opinion. Fertil Steril. 2013;99(2):337–339.

Patients presenting for fertility treatment may have incomplete or unknown immunization status. Encounters with women who desire conception offer an opportunity for providers to optimize their patients’ health prior to pregnancy. Vaccination before or, when appropriate, during pregnancy protects women from preventable disease, decreases the risk for vertical fetal transmission, and enables the passage of maternal immunoglobulins to the fetus, conferring passive immunity to the newborn.

National standards for vaccination have been established by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC). This yearly updated vaccination schedule is available at the CDC’s Web site (http://www.cdc.gov/vaccines/schedules/hcp/adult.html).⁷ Ideally, a woman’s immunization status should be evaluated and made complete prior to pregnancy. Some vaccines are safe and appropriate for administration during pregnancy, provided the benefits clearly outweigh the risks. The recommended vaccines during pregnancy include inactivated influenza (seasonal and H1N1) and the combined tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap).

Related Article: CDC urges flu vaccination for all, especially pregnant women (News for Your Practice, October 2013)

Many physicians avoid giving vaccinations during pregnancy because of the concern that a spontaneous abortion or congenital anomaly might be incorrectly attributed to vaccine administration, but few vaccines are contradicted during pregnancy. Those that are contraindicated are those containing live virus, including measles, mumps, and rubella (MMR); varicella; and herpes zoster. Concerns also have been raised regarding the safety of administering influenza vaccines containing the mercury-based preservative thimerosol. However, no scientific evidence has conclusively linked adverse effects on offspring with thimerosol-containing vaccines administered during pregnancy.

Immunizations recommended for women of reproductive age
Measles, mumps, rubella (MMR). This vaccine is recommended for all women lacking confirmed immunity to rubella. The vaccine contains live, attenuated virus and is given as a single dose. Women should avoid pregnancy for 1 month after vaccination.

Varicella. This vaccine is for all women lacking confirmed immunity to varicella. It also contains a live, attenuated virus. It is administered in two doses, 1 month apart, and women should avoid pregnancy for 1 month after vaccination.

Influenza. The flu vaccine is recommended annually for individuals 6 months of age and older. The injectable vaccine contains inactivated virus and may be administered during pregnancy—at any time but optimally in October or November because the flu season occurs January through March. (The intranasal influenza vaccine contains live, attenuated virus and should be avoided in pregnancy.) Either method is administered as a single dose. 

Thimerosal is a mercury-based preservative used in vaccines, including the influenza vaccine, and is appropriate for use in pregnant women; studies have not shown an association between vaccines containing thimerosal and adverse effects in pregnant women or their offspring.

Tetanus-diptheria-pertussis (Tdap) and tetanus-diphtheria (Td). Tdap or Td is recommended for adults aged 19 to 64 years who have or anticipate having close contact with an infant less than 12 months of age. Due to the recent increase in pertussis infection, Tdap should be given to all women who have not previously received the vaccine and who are pregnant or might become pregnant. It can be given anytime during pregnancy, but optimal administration is during the third trimester or late second trimester (after 20 weeks’ gestation) to confer the greatest amount of fetal protection.

If the vaccine is not being administered during pregnancy, it should be given in the immediate postpartum period to ensure pertussis immunity and to reduce transmission to the newborn. Tdap is administered as a single dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis. 

Non-routine vaccines include pneumococcus, hepatitis A, hepatitis B, and meningococcus (TABLE). These vaccines should be administered as indicated in high-risk patients.

Health-care providers caring for women with infertility are urged to assess patients’ immunization status prior to attempting pregnancy, to counsel patients about the importance of protecting them and their potential offspring from preventable disease, and to facilitate vaccination prior to conception attempts. 

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Vaccination is a very important aspect of pre-pregnancy care but is especially important for infertile women who desire pregnancy. Planning of infertility treatment should include assessment of the patient’s vaccination status and completion of appropriate vaccinations before infertility treatment is initiated.

DO CURRENT OPTIONS EFFECTIVELY PREVENT POSTSURGICAL ADHESIONS?

Practice Committee of American Society for Reproductive Medicine in collaboration with Society of Reproductive Surgeons. Pathogenesis, consequences, and control of peritoneal adhesions in gynecologic surgery: A committee opinion. Fertil Steril. 2013;99(6):1550–1555.

Postoperative adhesions are a natural consequence of surgery and a major problem in gynecology. They may cause postsurgical infertility, abdominal/pelvic pain, or bowel obstruction as well as complicate subsequent surgeries by increasing operative times and the risk of bowel injury. The American Society for Reproductive Medicine (ASRM) and the Society of Reproductive Surgeons (SRS) recently evaluated the epidemiology, pathogenesis, and clinical consequences of adhesion formation and the evidence behind strategies for reducing adhesion formation.

In their joint Committee Opinion, they noted that open and laparoscopic approaches to surgery carry comparable levels of risk for adhesion-related hospital readmission. Ovarian surgery has the highest risk for adhesion-related readmission, at 7.5 per 100 initial operations, and the incidence of small bowel obstruction after hysterectomy was found to be 1.6 per 100 procedures. Adhesion-related US health-care costs are estimated at approximately $1 billion annually.

The Societies noted that more severe adnexal adhesions are associated with lower pregnancy rates, and treatment of adnexal adhesions appears to improve pregnancy rates. Investigators found adhesions to cause about three-quarters of postoperative small bowel obstructions; however, the relationship between adhesions and pelvic pain remains unclear. It is thought that adhesions may cause visceral pain by impairing organ mobility, but there is no relationship between the extent of adhesions and the severity of pain. It appears that only dense adhesions ­involving the bowel are associated with chronic pelvic pain. Predicting the outcome of lysis of adnexal or bowel adhesions is difficult.

Reduction of adhesion formation
Theoretically, adhesions may be reduced by minimizing peritoneal injury during surgery, avoiding intraoperative reactive foreign bodies, reducing local inflammatory response, inhibiting the coagulation cascade and promoting fibrinolysis, or by placing barriers between damaged tissues.

Related Article: Update on Fertility G. David Adamson, MD (February 2008)

Careful surgical technique includes gentle tissue handling, meticulous hemostasis, excision of necrotic tissue, minimizing ischemia and desiccation, using fine and nonreactive suture, and preventing foreign-body reaction and infection, all “microsurgical principles.”

ASRM and SRS reported that the surgical approach (laparoscopy vs laparotomy) is much less important than the extent of tissue injury. However, laparoscopy may result in less tissue and organ handling and trauma, avoid contamination with foreign bodies, enable more precise tissue handling, and result in less postoperative infection. The pneumoperitoneum has a tamponade effect that facilitates hemostasis during laparoscopy, but the process also can be associated with peritoneal desiccation and reduced temperatures that can increase injury.

Laparoscopic myomectomy was found to have a 70% risk of postoperative adhesions, compared with a 90% risk after laparotomy. It is unclear whether peritoneal closure at laparotomy reduces or increases adhesions, but parietal peritoneal closure at primary cesarean delivery results in fewer dense and filmy adhesions.

Related Article: How to avoid intestinal and urinary tract injuries during gynecologic laparoscopy Michael Baggish, MD (Second of a 2-part series on laparoscopic complications, October 2012)

Adjuncts to surgical technique
SRM and SRS reported on three adjuncts to surgical technique that have been proposed to reduce the risk of postoperative adhesions: anti-inflammatory agents, peritoneal instillates, and adhesion barriers.

Dexamethasone, promethazine, and other local and systemic anti-inflammatory drugs and adhesion-reducing substances have not been found effective for reducing postoperative adhesions.

Peritoneal instillates—which create “hydroflotation” and include antibiotic solutions, 32% dextran 70, and crystalloid solutions such as normal saline and Ringer’s lactate with or without heparin or corticosteroids—have not been found effective.⁸ Icodextrin 4% (Adept Adhesion Reduction Solution, Baxter Healthcare) is FDA approved as an adjunct to good surgical technique for the reduction of postoperative adhesions in patients undergoing gynecologic laparoscopic adhesiolysis. However, a systematic review concluded that there is insufficient evidence for its use as an adhesion-preventing agent.⁸

Adhesion barriers may help reduce postoperative adhesions but cannot compensate for poor surgical technique. Although the bioresorbable membrane sodium hyaluronic acid and carboxymethyl cellulose (Seprafilm, Genzyme Corp) is FDA-approved, there is limited evidence that it prevents adhesions after myomectomy.⁹ Because it fragments easily, it is mostly used at laparotomy.

Oxidized regenerated cellulose (Interceed, Ethicon Women’s Health and Urology) is an FDA-approved absorbable adhesion barrier for use at laparotomy that requires no suturing and has been shown to reduce the incidence and extent of new and recurrent adhesions at both laparoscopy and laparotomy by 40% to 50%, although there is little evidence that this improves fertility.⁹ Complete hemostasis must be achieved to use Interceed, and the addition of heparin confers no benefit.

Another product is expanded polytetrafluoroethylene (ePTFE, Gore-Tex Surgical Membrane, WL Gore and Associates), a nonabsorbable adhesion barrier produced in thin sheets and approved by the FDA for peritoneal repair. ePTFE must be sutured to tissue and helps prevent adhesion formation and reformation regardless of the type of injury or whether complete hemostasis has been achieved. In a small trial, it decreased postmyomectomy adhesions.¹⁰ ePTFE also was more effective than oxidized regenerated cellulose in preventing adhesions after adnexal surgery.¹¹ Its use has been limited by the need for suturing and later reoperation for removal, although it probably does not have to be removed if it will not interfere with normal organ function since it has been used as a pericardial graft for many years.¹²

Hyaluronic acid (HA) solution (Sepracoat, Genzyme) is a natural bioabsorbable component of the extracellular matrix. Women undergoing laparotomy have fewer new adhesions with HA solution, but it is not approved for use in the United States.¹³ Polyethylene glycol (PEG; SprayGel, Confluent Surgical) was effective in early clinical trials but is not FDA-approved.¹² Fibrin sealant (Tisseel VH, Baxter Healthcare) has been reported to decrease the formation of adhesions after salpingostomy, salpingolysis, and ovariolysis. Because it is a biologic product derived from human blood donors, it poses a risk for transmission of infectious agents. It is FDA-approved for use in cardiothoracic surgery, splenic injuries, and colostomy closure for hemostasis.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Adhesions are the most common complication following gynecologic surgery, and they pose potential longstanding consequences to patients. There is no evidence that anti-inflammatory agents reduce postoperative adhesions and insufficient evidence to recommend peritoneal instillates. FDA-approved surgical barriers reduce postoperative adhesions but there is not substantial evidence that their use improves fertility, decreases pain, or reduces the incidence of postoperative bowel obstruction. All gynecologists need to understand the importance of using microsurgical principles rather than relying on adhesion barriers to reduce postoperative adhesions.

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: obg@frontlinemedcom.com

These experts discuss three recent American Society for Reproductive Medicine Committee Opinions. The first is on the optimal use of the most widely prescribed medication for fertility, clomiphene citrate. The second highlights the currently recommended vaccinations for women who are of reproductive age. And the third is on the current evidence for prevention of postsurgical adhesions, which have the potential to cause infertility. Their discussions could affect how you approach your infertile patients. 

SAFE, EFFECTIVE USE OF CLOMIPHENE

Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in infertile women: A committee opinion. Fertil Steril. 2013;100(2):341–348.

Clomiphene citrate (CC) is the fertility medication most commonly used by gynecologists. However, important principles in its use often are not followed, resulting in suboptimal patient care. The American Society for Reproductive Medicine published a recent Committee Opinion on CC’s indications, use, and alternative treatments. We summarize the essential aspects of CC use.

Who should be treated?
CC can be used to treat both anovulation/oligo-ovulation and unexplained infertility, but it is not effective in hypothalamic amenorrhea or hypergonadotropic hypogonadism (usually premature ovarian insufficiency). Anovulation/oligo-ovulation may be due to polycystic ovary syndrome (PCOS), obesity, hypothalamic dysfunction related to eating disorders, weight, exercise, stress, hyper­prolactinemia, pituitary tumors, or thyroid disease. The exact cause is often indeterminable, however.

Related Article: Polycystic ovary syndrome: Where we stand with diagnosis and treatment and where we're going Steven R. Lindheim, MD, MMM, and Leah Whigham, PhD (First of a 4-part series, September 2012)

There is no evidence CC is effective treatment for “luteal phase defect.” ­Unexplained infertility also can be treated with CC with intrauterine insemination (IUI).¹

Pretreatment evaluation
Diagnosis of ovulatory dysfunction is usually made by menstrual history alone (normal menses, ≥24 and ≥35 days). Testing with luteal phase serum progesterone or serial transvaginal ultrasound generally is unnecessary.

Use the history, physical examination, and other testing, as necessary, to rule out other endocrinopathies, including diabetes mellitus (screening for impaired glucose tolerance), thyroid disorders (measurement of thyroid-stimulating hormone, or TSH), hyperprolactinemia (prolactin assessment), congenital adrenal hyperplasia (measurement of 17-alpha hydroxyprogesterone acetate), and virilization (assessment of testosterone and dehydroepiandrosterone sulfate, or DHEA-S).

If disease-specific treatment does not result in normal ovulation, then CC can be used. Although it may be difficult for them, obese women should be encouraged to lose weight. In infertile couples with a normal menstrual cycle and no other identifiable infertility factors, if hysterosalpingogram and semen analysis are normal, treatment of their unexplained infertility with CC and IUI may be effective. Ovulation induction or ovarian stimulation has little benefit when severe male, uterine, or tubal factors are present.

Treatment regimens
CC is usually given 50 mg/day orally for 5 days starting on the second to fifth spontaneous or progestin-induced menstrual cycle day, with equivalent treatment outcomes regardless of start day 2, 3, 4, or 5. If the patient’s response to this dose is inadequate, treatment can be increased 50 mg/day in each subsequent cycle, to a maximum of 250 mg/day. However, the maximum FDA-approved dose is 100 mg/day, and only 20% of patients respond when given doses higher than this. Obese patients may respond at the higher doses.

The luteinizing hormone (LH) surge occurs 5 to 12 days after the last CC dose is taken. There is no benefit to giving human chorionic gonadotropin (hCG) if the patient has a spontaneous LH surge. The pregnancy rate might actually be reduced by 25% when hCG is given unnecessarily.²

In anovulatory/oligo-ovulatory women, there is no benefit of IUI over timed intercourse for achieving pregnancy. For unexplained infertility, however, CC with timed intercourse does not appear effective, but CC combined with IUI is effective.³ Timed intercourse should occur approximately every 2 days (1–3 days) starting about 3 to 4 days before expected ovulation.

Treatment should continue 3 to 4 months. Younger patients (<35 years) with a short duration of infertility (<2 years) who respond to CC can receive up to 6 months of treatment. Treatment beyond 6 months is not recommended.

Ovulation and pregnancy rates
Half of anovulatory/oligo-ovulatory women will ovulate with a 50-mg dose of CC and half of the remaining will ovulate with a 100-mg dose. Among women who ovulate with CC, cumulative pregnancy rates for 50 mg/day, 100 mg/day, or 150 mg/day at 3 months are 50%, 45%, and 33%, respectively, and at 6 months are 62%, 66%, and 38%, respectively. In general, a 55% to 73% pregnancy rate can be expected.⁴ Increasing age, duration of infertility, and obesity are associated with lower pregnancy rates and treatment failure.

Alternative and adjunctive regimens
For patients who are not using progestin to induce menses and who have not responded with ovulation by day 14 to 21, longer courses of CC treatment (7 to 8 days) and a step-up protocol to the next highest CC dose are alternative regimens that may work in some cases.

Some anovulatory or oligo-ovulatory women with PCOS who do not respond to CC alone may respond to CC combined with metformin at 1,500 to 1,700 mg/day. Metformin combined with diet and exercise for weight loss is recommended. Metformin is associated with gastrointestinal side effects and rare hepatic toxicity or lactic acidosis; therefore, liver and renal functions should be assessed prior to treatment and monitored afterward.

Women with DHEA-S serum concentrations of 200 µg/dL or greater, and even some women with normal DHEA-S levels, may be more responsive to CC and achieve higher pregnancy rates when given dexamethasone 0.5 mg/daily on cycle days 3 to 12. Glucocorticoids have significant side effects and should be discontinued if treatment is unsuccessful or when pregnancy occurs.

Related Article: Clomiphene failure? Try adding dexamethasone to your clomiphene infertility regimen Robert L. Barbieri, MD (Editorial, May 2012)

Some CC-resistant anovulatory women and women with unexplained infertility may benefit from a trial of sequential CC/gonadotropin treatment consisting of standard CC treatment followed by human menopausal gonadotropins (hMG) or follicle-stimulating hormone (FSH) 75 to 150 IU/day for 3 days. Some, but not all, studies show pregnancy rates in these patients equivalent to those undergoing gonadotropin treatment alone (at a reduced cost). There are no studies directly comparing the treatment regimens, however, and risks of multiple pregnancy might be increased for patients taking both CC and gonadotropin, so this treatment should only be provided by clinicians with requisite training and experience.

Other alternatives to CC therapy in CC-resistant patients include aromatase inhibitors, tamoxifen, insulin-sensitizing agents, ovarian drilling, gonadotropins, and in vitro fertilization.

Monitoring of CC cycles
Objective evidence of ovulation is key to successful treatment. Ovulation predictor kits are more than 90% successful, if used properly, in identifying the LH surge 5 to 12 days after CC is finished (usually around cycle day 16 or 17). Ovulation occurs about one-half day to 2 days after the LH surge. Serum progesterone is the most certain test of prior ovulation (other than pregnancy) but cannot predict time of ovulation. Serial ultrasound shows the size and number of follicles and presumptive ovulation with follicle collapse, as well as echogenic corpus luteum and cul de sac fluid, but it is expensive and often not cost-effective.

It is prudent to postpone further treatment if the patient has large ovaries or a cyst, but routine baseline ultrasound monitoring is no longer considered necessary. However, regular contact with the patient should be maintained to review response to treatment and to ensure that any additional or alternative treatments are not delayed.

Side effects of CC treatment
Mood swings, visual disturbances, breast tenderness, pelvic discomfort, and nausea are reported in less than 10% of patients. Mild ovarian hyperstimulation syndrome (OHSS) is not uncommon, but severe OHSS is rare.

Related Article: Avoiding ovarian hyperstimulation syndrome G. David Adamson, MD (Audiocast, February 2011)

The major risk to CC treatment is twin (8% risk) and triplet (0.5% risk) pregnancies. There is no evidence of increased risk of congenital anomalies, miscarriage, or ovarian cancer.^1,5,6

WHAT THIS EVIDENCE MEANS FOR PRACTICE
All gynecologists should be able to diagnose and treat infertility with clomiphene. It is effective for many patients with anovulatory/oligo-ovulatory infertility, and also for unexplained infertility when combined with IUI. Careful evaluation of fertility and endocrinologic status is necessary before treatment, as is monitoring during treatment. Although this treatment may appear to be simple, there are many important principles that need to be followed if treatment is to be effective and safe, and if the patient is to receive quality infertility care. Treatment is safe, (the major risk is multiple pregnancy) but should not be continued for more than 3 to 6 months.

STRIVE FOR PREPREGNANCY VACCINATION

Practice Committee of American Society for Reproductive Medicine. Vaccination guidelines for female infertility patients: A committee opinion. Fertil Steril. 2013;99(2):337–339.

Patients presenting for fertility treatment may have incomplete or unknown immunization status. Encounters with women who desire conception offer an opportunity for providers to optimize their patients’ health prior to pregnancy. Vaccination before or, when appropriate, during pregnancy protects women from preventable disease, decreases the risk for vertical fetal transmission, and enables the passage of maternal immunoglobulins to the fetus, conferring passive immunity to the newborn.

National standards for vaccination have been established by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC). This yearly updated vaccination schedule is available at the CDC’s Web site (http://www.cdc.gov/vaccines/schedules/hcp/adult.html).⁷ Ideally, a woman’s immunization status should be evaluated and made complete prior to pregnancy. Some vaccines are safe and appropriate for administration during pregnancy, provided the benefits clearly outweigh the risks. The recommended vaccines during pregnancy include inactivated influenza (seasonal and H1N1) and the combined tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap).

Related Article: CDC urges flu vaccination for all, especially pregnant women (News for Your Practice, October 2013)

Many physicians avoid giving vaccinations during pregnancy because of the concern that a spontaneous abortion or congenital anomaly might be incorrectly attributed to vaccine administration, but few vaccines are contradicted during pregnancy. Those that are contraindicated are those containing live virus, including measles, mumps, and rubella (MMR); varicella; and herpes zoster. Concerns also have been raised regarding the safety of administering influenza vaccines containing the mercury-based preservative thimerosol. However, no scientific evidence has conclusively linked adverse effects on offspring with thimerosol-containing vaccines administered during pregnancy.

Immunizations recommended for women of reproductive age
Measles, mumps, rubella (MMR). This vaccine is recommended for all women lacking confirmed immunity to rubella. The vaccine contains live, attenuated virus and is given as a single dose. Women should avoid pregnancy for 1 month after vaccination.

Varicella. This vaccine is for all women lacking confirmed immunity to varicella. It also contains a live, attenuated virus. It is administered in two doses, 1 month apart, and women should avoid pregnancy for 1 month after vaccination.

Influenza. The flu vaccine is recommended annually for individuals 6 months of age and older. The injectable vaccine contains inactivated virus and may be administered during pregnancy—at any time but optimally in October or November because the flu season occurs January through March. (The intranasal influenza vaccine contains live, attenuated virus and should be avoided in pregnancy.) Either method is administered as a single dose. 

Thimerosal is a mercury-based preservative used in vaccines, including the influenza vaccine, and is appropriate for use in pregnant women; studies have not shown an association between vaccines containing thimerosal and adverse effects in pregnant women or their offspring.

Tetanus-diptheria-pertussis (Tdap) and tetanus-diphtheria (Td). Tdap or Td is recommended for adults aged 19 to 64 years who have or anticipate having close contact with an infant less than 12 months of age. Due to the recent increase in pertussis infection, Tdap should be given to all women who have not previously received the vaccine and who are pregnant or might become pregnant. It can be given anytime during pregnancy, but optimal administration is during the third trimester or late second trimester (after 20 weeks’ gestation) to confer the greatest amount of fetal protection.

If the vaccine is not being administered during pregnancy, it should be given in the immediate postpartum period to ensure pertussis immunity and to reduce transmission to the newborn. Tdap is administered as a single dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis. 

Non-routine vaccines include pneumococcus, hepatitis A, hepatitis B, and meningococcus (TABLE). These vaccines should be administered as indicated in high-risk patients.

Health-care providers caring for women with infertility are urged to assess patients’ immunization status prior to attempting pregnancy, to counsel patients about the importance of protecting them and their potential offspring from preventable disease, and to facilitate vaccination prior to conception attempts. 

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Vaccination is a very important aspect of pre-pregnancy care but is especially important for infertile women who desire pregnancy. Planning of infertility treatment should include assessment of the patient’s vaccination status and completion of appropriate vaccinations before infertility treatment is initiated.

DO CURRENT OPTIONS EFFECTIVELY PREVENT POSTSURGICAL ADHESIONS?

Practice Committee of American Society for Reproductive Medicine in collaboration with Society of Reproductive Surgeons. Pathogenesis, consequences, and control of peritoneal adhesions in gynecologic surgery: A committee opinion. Fertil Steril. 2013;99(6):1550–1555.

Postoperative adhesions are a natural consequence of surgery and a major problem in gynecology. They may cause postsurgical infertility, abdominal/pelvic pain, or bowel obstruction as well as complicate subsequent surgeries by increasing operative times and the risk of bowel injury. The American Society for Reproductive Medicine (ASRM) and the Society of Reproductive Surgeons (SRS) recently evaluated the epidemiology, pathogenesis, and clinical consequences of adhesion formation and the evidence behind strategies for reducing adhesion formation.

In their joint Committee Opinion, they noted that open and laparoscopic approaches to surgery carry comparable levels of risk for adhesion-related hospital readmission. Ovarian surgery has the highest risk for adhesion-related readmission, at 7.5 per 100 initial operations, and the incidence of small bowel obstruction after hysterectomy was found to be 1.6 per 100 procedures. Adhesion-related US health-care costs are estimated at approximately $1 billion annually.

The Societies noted that more severe adnexal adhesions are associated with lower pregnancy rates, and treatment of adnexal adhesions appears to improve pregnancy rates. Investigators found adhesions to cause about three-quarters of postoperative small bowel obstructions; however, the relationship between adhesions and pelvic pain remains unclear. It is thought that adhesions may cause visceral pain by impairing organ mobility, but there is no relationship between the extent of adhesions and the severity of pain. It appears that only dense adhesions ­involving the bowel are associated with chronic pelvic pain. Predicting the outcome of lysis of adnexal or bowel adhesions is difficult.

Reduction of adhesion formation
Theoretically, adhesions may be reduced by minimizing peritoneal injury during surgery, avoiding intraoperative reactive foreign bodies, reducing local inflammatory response, inhibiting the coagulation cascade and promoting fibrinolysis, or by placing barriers between damaged tissues.

Related Article: Update on Fertility G. David Adamson, MD (February 2008)

Careful surgical technique includes gentle tissue handling, meticulous hemostasis, excision of necrotic tissue, minimizing ischemia and desiccation, using fine and nonreactive suture, and preventing foreign-body reaction and infection, all “microsurgical principles.”

ASRM and SRS reported that the surgical approach (laparoscopy vs laparotomy) is much less important than the extent of tissue injury. However, laparoscopy may result in less tissue and organ handling and trauma, avoid contamination with foreign bodies, enable more precise tissue handling, and result in less postoperative infection. The pneumoperitoneum has a tamponade effect that facilitates hemostasis during laparoscopy, but the process also can be associated with peritoneal desiccation and reduced temperatures that can increase injury.

Laparoscopic myomectomy was found to have a 70% risk of postoperative adhesions, compared with a 90% risk after laparotomy. It is unclear whether peritoneal closure at laparotomy reduces or increases adhesions, but parietal peritoneal closure at primary cesarean delivery results in fewer dense and filmy adhesions.

Related Article: How to avoid intestinal and urinary tract injuries during gynecologic laparoscopy Michael Baggish, MD (Second of a 2-part series on laparoscopic complications, October 2012)

Adjuncts to surgical technique
SRM and SRS reported on three adjuncts to surgical technique that have been proposed to reduce the risk of postoperative adhesions: anti-inflammatory agents, peritoneal instillates, and adhesion barriers.

Dexamethasone, promethazine, and other local and systemic anti-inflammatory drugs and adhesion-reducing substances have not been found effective for reducing postoperative adhesions.

Peritoneal instillates—which create “hydroflotation” and include antibiotic solutions, 32% dextran 70, and crystalloid solutions such as normal saline and Ringer’s lactate with or without heparin or corticosteroids—have not been found effective.⁸ Icodextrin 4% (Adept Adhesion Reduction Solution, Baxter Healthcare) is FDA approved as an adjunct to good surgical technique for the reduction of postoperative adhesions in patients undergoing gynecologic laparoscopic adhesiolysis. However, a systematic review concluded that there is insufficient evidence for its use as an adhesion-preventing agent.⁸

Adhesion barriers may help reduce postoperative adhesions but cannot compensate for poor surgical technique. Although the bioresorbable membrane sodium hyaluronic acid and carboxymethyl cellulose (Seprafilm, Genzyme Corp) is FDA-approved, there is limited evidence that it prevents adhesions after myomectomy.⁹ Because it fragments easily, it is mostly used at laparotomy.

Oxidized regenerated cellulose (Interceed, Ethicon Women’s Health and Urology) is an FDA-approved absorbable adhesion barrier for use at laparotomy that requires no suturing and has been shown to reduce the incidence and extent of new and recurrent adhesions at both laparoscopy and laparotomy by 40% to 50%, although there is little evidence that this improves fertility.⁹ Complete hemostasis must be achieved to use Interceed, and the addition of heparin confers no benefit.

Another product is expanded polytetrafluoroethylene (ePTFE, Gore-Tex Surgical Membrane, WL Gore and Associates), a nonabsorbable adhesion barrier produced in thin sheets and approved by the FDA for peritoneal repair. ePTFE must be sutured to tissue and helps prevent adhesion formation and reformation regardless of the type of injury or whether complete hemostasis has been achieved. In a small trial, it decreased postmyomectomy adhesions.¹⁰ ePTFE also was more effective than oxidized regenerated cellulose in preventing adhesions after adnexal surgery.¹¹ Its use has been limited by the need for suturing and later reoperation for removal, although it probably does not have to be removed if it will not interfere with normal organ function since it has been used as a pericardial graft for many years.¹²

Hyaluronic acid (HA) solution (Sepracoat, Genzyme) is a natural bioabsorbable component of the extracellular matrix. Women undergoing laparotomy have fewer new adhesions with HA solution, but it is not approved for use in the United States.¹³ Polyethylene glycol (PEG; SprayGel, Confluent Surgical) was effective in early clinical trials but is not FDA-approved.¹² Fibrin sealant (Tisseel VH, Baxter Healthcare) has been reported to decrease the formation of adhesions after salpingostomy, salpingolysis, and ovariolysis. Because it is a biologic product derived from human blood donors, it poses a risk for transmission of infectious agents. It is FDA-approved for use in cardiothoracic surgery, splenic injuries, and colostomy closure for hemostasis.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Adhesions are the most common complication following gynecologic surgery, and they pose potential longstanding consequences to patients. There is no evidence that anti-inflammatory agents reduce postoperative adhesions and insufficient evidence to recommend peritoneal instillates. FDA-approved surgical barriers reduce postoperative adhesions but there is not substantial evidence that their use improves fertility, decreases pain, or reduces the incidence of postoperative bowel obstruction. All gynecologists need to understand the importance of using microsurgical principles rather than relying on adhesion barriers to reduce postoperative adhesions.

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: obg@frontlinemedcom.com

These experts discuss three recent American Society for Reproductive Medicine Committee Opinions. The first is on the optimal use of the most widely prescribed medication for fertility, clomiphene citrate. The second highlights the currently recommended vaccinations for women who are of reproductive age. And the third is on the current evidence for prevention of postsurgical adhesions, which have the potential to cause infertility. Their discussions could affect how you approach your infertile patients. 

SAFE, EFFECTIVE USE OF CLOMIPHENE

Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in infertile women: A committee opinion. Fertil Steril. 2013;100(2):341–348.

Clomiphene citrate (CC) is the fertility medication most commonly used by gynecologists. However, important principles in its use often are not followed, resulting in suboptimal patient care. The American Society for Reproductive Medicine published a recent Committee Opinion on CC’s indications, use, and alternative treatments. We summarize the essential aspects of CC use.

Who should be treated?
CC can be used to treat both anovulation/oligo-ovulation and unexplained infertility, but it is not effective in hypothalamic amenorrhea or hypergonadotropic hypogonadism (usually premature ovarian insufficiency). Anovulation/oligo-ovulation may be due to polycystic ovary syndrome (PCOS), obesity, hypothalamic dysfunction related to eating disorders, weight, exercise, stress, hyper­prolactinemia, pituitary tumors, or thyroid disease. The exact cause is often indeterminable, however.

Related Article: Polycystic ovary syndrome: Where we stand with diagnosis and treatment and where we're going Steven R. Lindheim, MD, MMM, and Leah Whigham, PhD (First of a 4-part series, September 2012)

There is no evidence CC is effective treatment for “luteal phase defect.” ­Unexplained infertility also can be treated with CC with intrauterine insemination (IUI).¹

Pretreatment evaluation
Diagnosis of ovulatory dysfunction is usually made by menstrual history alone (normal menses, ≥24 and ≥35 days). Testing with luteal phase serum progesterone or serial transvaginal ultrasound generally is unnecessary.

Use the history, physical examination, and other testing, as necessary, to rule out other endocrinopathies, including diabetes mellitus (screening for impaired glucose tolerance), thyroid disorders (measurement of thyroid-stimulating hormone, or TSH), hyperprolactinemia (prolactin assessment), congenital adrenal hyperplasia (measurement of 17-alpha hydroxyprogesterone acetate), and virilization (assessment of testosterone and dehydroepiandrosterone sulfate, or DHEA-S).

If disease-specific treatment does not result in normal ovulation, then CC can be used. Although it may be difficult for them, obese women should be encouraged to lose weight. In infertile couples with a normal menstrual cycle and no other identifiable infertility factors, if hysterosalpingogram and semen analysis are normal, treatment of their unexplained infertility with CC and IUI may be effective. Ovulation induction or ovarian stimulation has little benefit when severe male, uterine, or tubal factors are present.

Treatment regimens
CC is usually given 50 mg/day orally for 5 days starting on the second to fifth spontaneous or progestin-induced menstrual cycle day, with equivalent treatment outcomes regardless of start day 2, 3, 4, or 5. If the patient’s response to this dose is inadequate, treatment can be increased 50 mg/day in each subsequent cycle, to a maximum of 250 mg/day. However, the maximum FDA-approved dose is 100 mg/day, and only 20% of patients respond when given doses higher than this. Obese patients may respond at the higher doses.

The luteinizing hormone (LH) surge occurs 5 to 12 days after the last CC dose is taken. There is no benefit to giving human chorionic gonadotropin (hCG) if the patient has a spontaneous LH surge. The pregnancy rate might actually be reduced by 25% when hCG is given unnecessarily.²

In anovulatory/oligo-ovulatory women, there is no benefit of IUI over timed intercourse for achieving pregnancy. For unexplained infertility, however, CC with timed intercourse does not appear effective, but CC combined with IUI is effective.³ Timed intercourse should occur approximately every 2 days (1–3 days) starting about 3 to 4 days before expected ovulation.

Treatment should continue 3 to 4 months. Younger patients (<35 years) with a short duration of infertility (<2 years) who respond to CC can receive up to 6 months of treatment. Treatment beyond 6 months is not recommended.

Ovulation and pregnancy rates
Half of anovulatory/oligo-ovulatory women will ovulate with a 50-mg dose of CC and half of the remaining will ovulate with a 100-mg dose. Among women who ovulate with CC, cumulative pregnancy rates for 50 mg/day, 100 mg/day, or 150 mg/day at 3 months are 50%, 45%, and 33%, respectively, and at 6 months are 62%, 66%, and 38%, respectively. In general, a 55% to 73% pregnancy rate can be expected.⁴ Increasing age, duration of infertility, and obesity are associated with lower pregnancy rates and treatment failure.

Alternative and adjunctive regimens
For patients who are not using progestin to induce menses and who have not responded with ovulation by day 14 to 21, longer courses of CC treatment (7 to 8 days) and a step-up protocol to the next highest CC dose are alternative regimens that may work in some cases.

Some anovulatory or oligo-ovulatory women with PCOS who do not respond to CC alone may respond to CC combined with metformin at 1,500 to 1,700 mg/day. Metformin combined with diet and exercise for weight loss is recommended. Metformin is associated with gastrointestinal side effects and rare hepatic toxicity or lactic acidosis; therefore, liver and renal functions should be assessed prior to treatment and monitored afterward.

Women with DHEA-S serum concentrations of 200 µg/dL or greater, and even some women with normal DHEA-S levels, may be more responsive to CC and achieve higher pregnancy rates when given dexamethasone 0.5 mg/daily on cycle days 3 to 12. Glucocorticoids have significant side effects and should be discontinued if treatment is unsuccessful or when pregnancy occurs.

Related Article: Clomiphene failure? Try adding dexamethasone to your clomiphene infertility regimen Robert L. Barbieri, MD (Editorial, May 2012)

Some CC-resistant anovulatory women and women with unexplained infertility may benefit from a trial of sequential CC/gonadotropin treatment consisting of standard CC treatment followed by human menopausal gonadotropins (hMG) or follicle-stimulating hormone (FSH) 75 to 150 IU/day for 3 days. Some, but not all, studies show pregnancy rates in these patients equivalent to those undergoing gonadotropin treatment alone (at a reduced cost). There are no studies directly comparing the treatment regimens, however, and risks of multiple pregnancy might be increased for patients taking both CC and gonadotropin, so this treatment should only be provided by clinicians with requisite training and experience.

Other alternatives to CC therapy in CC-resistant patients include aromatase inhibitors, tamoxifen, insulin-sensitizing agents, ovarian drilling, gonadotropins, and in vitro fertilization.

Monitoring of CC cycles
Objective evidence of ovulation is key to successful treatment. Ovulation predictor kits are more than 90% successful, if used properly, in identifying the LH surge 5 to 12 days after CC is finished (usually around cycle day 16 or 17). Ovulation occurs about one-half day to 2 days after the LH surge. Serum progesterone is the most certain test of prior ovulation (other than pregnancy) but cannot predict time of ovulation. Serial ultrasound shows the size and number of follicles and presumptive ovulation with follicle collapse, as well as echogenic corpus luteum and cul de sac fluid, but it is expensive and often not cost-effective.

It is prudent to postpone further treatment if the patient has large ovaries or a cyst, but routine baseline ultrasound monitoring is no longer considered necessary. However, regular contact with the patient should be maintained to review response to treatment and to ensure that any additional or alternative treatments are not delayed.

Side effects of CC treatment
Mood swings, visual disturbances, breast tenderness, pelvic discomfort, and nausea are reported in less than 10% of patients. Mild ovarian hyperstimulation syndrome (OHSS) is not uncommon, but severe OHSS is rare.

Related Article: Avoiding ovarian hyperstimulation syndrome G. David Adamson, MD (Audiocast, February 2011)

The major risk to CC treatment is twin (8% risk) and triplet (0.5% risk) pregnancies. There is no evidence of increased risk of congenital anomalies, miscarriage, or ovarian cancer.^1,5,6

WHAT THIS EVIDENCE MEANS FOR PRACTICE
All gynecologists should be able to diagnose and treat infertility with clomiphene. It is effective for many patients with anovulatory/oligo-ovulatory infertility, and also for unexplained infertility when combined with IUI. Careful evaluation of fertility and endocrinologic status is necessary before treatment, as is monitoring during treatment. Although this treatment may appear to be simple, there are many important principles that need to be followed if treatment is to be effective and safe, and if the patient is to receive quality infertility care. Treatment is safe, (the major risk is multiple pregnancy) but should not be continued for more than 3 to 6 months.

STRIVE FOR PREPREGNANCY VACCINATION

Practice Committee of American Society for Reproductive Medicine. Vaccination guidelines for female infertility patients: A committee opinion. Fertil Steril. 2013;99(2):337–339.

Patients presenting for fertility treatment may have incomplete or unknown immunization status. Encounters with women who desire conception offer an opportunity for providers to optimize their patients’ health prior to pregnancy. Vaccination before or, when appropriate, during pregnancy protects women from preventable disease, decreases the risk for vertical fetal transmission, and enables the passage of maternal immunoglobulins to the fetus, conferring passive immunity to the newborn.

National standards for vaccination have been established by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC). This yearly updated vaccination schedule is available at the CDC’s Web site (http://www.cdc.gov/vaccines/schedules/hcp/adult.html).⁷ Ideally, a woman’s immunization status should be evaluated and made complete prior to pregnancy. Some vaccines are safe and appropriate for administration during pregnancy, provided the benefits clearly outweigh the risks. The recommended vaccines during pregnancy include inactivated influenza (seasonal and H1N1) and the combined tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap).

Related Article: CDC urges flu vaccination for all, especially pregnant women (News for Your Practice, October 2013)

Many physicians avoid giving vaccinations during pregnancy because of the concern that a spontaneous abortion or congenital anomaly might be incorrectly attributed to vaccine administration, but few vaccines are contradicted during pregnancy. Those that are contraindicated are those containing live virus, including measles, mumps, and rubella (MMR); varicella; and herpes zoster. Concerns also have been raised regarding the safety of administering influenza vaccines containing the mercury-based preservative thimerosol. However, no scientific evidence has conclusively linked adverse effects on offspring with thimerosol-containing vaccines administered during pregnancy.

Immunizations recommended for women of reproductive age
Measles, mumps, rubella (MMR). This vaccine is recommended for all women lacking confirmed immunity to rubella. The vaccine contains live, attenuated virus and is given as a single dose. Women should avoid pregnancy for 1 month after vaccination.

Varicella. This vaccine is for all women lacking confirmed immunity to varicella. It also contains a live, attenuated virus. It is administered in two doses, 1 month apart, and women should avoid pregnancy for 1 month after vaccination.

Influenza. The flu vaccine is recommended annually for individuals 6 months of age and older. The injectable vaccine contains inactivated virus and may be administered during pregnancy—at any time but optimally in October or November because the flu season occurs January through March. (The intranasal influenza vaccine contains live, attenuated virus and should be avoided in pregnancy.) Either method is administered as a single dose. 

Thimerosal is a mercury-based preservative used in vaccines, including the influenza vaccine, and is appropriate for use in pregnant women; studies have not shown an association between vaccines containing thimerosal and adverse effects in pregnant women or their offspring.

Tetanus-diptheria-pertussis (Tdap) and tetanus-diphtheria (Td). Tdap or Td is recommended for adults aged 19 to 64 years who have or anticipate having close contact with an infant less than 12 months of age. Due to the recent increase in pertussis infection, Tdap should be given to all women who have not previously received the vaccine and who are pregnant or might become pregnant. It can be given anytime during pregnancy, but optimal administration is during the third trimester or late second trimester (after 20 weeks’ gestation) to confer the greatest amount of fetal protection.

If the vaccine is not being administered during pregnancy, it should be given in the immediate postpartum period to ensure pertussis immunity and to reduce transmission to the newborn. Tdap is administered as a single dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis. 

Non-routine vaccines include pneumococcus, hepatitis A, hepatitis B, and meningococcus (TABLE). These vaccines should be administered as indicated in high-risk patients.

Health-care providers caring for women with infertility are urged to assess patients’ immunization status prior to attempting pregnancy, to counsel patients about the importance of protecting them and their potential offspring from preventable disease, and to facilitate vaccination prior to conception attempts. 

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Vaccination is a very important aspect of pre-pregnancy care but is especially important for infertile women who desire pregnancy. Planning of infertility treatment should include assessment of the patient’s vaccination status and completion of appropriate vaccinations before infertility treatment is initiated.

DO CURRENT OPTIONS EFFECTIVELY PREVENT POSTSURGICAL ADHESIONS?

Practice Committee of American Society for Reproductive Medicine in collaboration with Society of Reproductive Surgeons. Pathogenesis, consequences, and control of peritoneal adhesions in gynecologic surgery: A committee opinion. Fertil Steril. 2013;99(6):1550–1555.

Postoperative adhesions are a natural consequence of surgery and a major problem in gynecology. They may cause postsurgical infertility, abdominal/pelvic pain, or bowel obstruction as well as complicate subsequent surgeries by increasing operative times and the risk of bowel injury. The American Society for Reproductive Medicine (ASRM) and the Society of Reproductive Surgeons (SRS) recently evaluated the epidemiology, pathogenesis, and clinical consequences of adhesion formation and the evidence behind strategies for reducing adhesion formation.

In their joint Committee Opinion, they noted that open and laparoscopic approaches to surgery carry comparable levels of risk for adhesion-related hospital readmission. Ovarian surgery has the highest risk for adhesion-related readmission, at 7.5 per 100 initial operations, and the incidence of small bowel obstruction after hysterectomy was found to be 1.6 per 100 procedures. Adhesion-related US health-care costs are estimated at approximately $1 billion annually.

The Societies noted that more severe adnexal adhesions are associated with lower pregnancy rates, and treatment of adnexal adhesions appears to improve pregnancy rates. Investigators found adhesions to cause about three-quarters of postoperative small bowel obstructions; however, the relationship between adhesions and pelvic pain remains unclear. It is thought that adhesions may cause visceral pain by impairing organ mobility, but there is no relationship between the extent of adhesions and the severity of pain. It appears that only dense adhesions ­involving the bowel are associated with chronic pelvic pain. Predicting the outcome of lysis of adnexal or bowel adhesions is difficult.

Reduction of adhesion formation
Theoretically, adhesions may be reduced by minimizing peritoneal injury during surgery, avoiding intraoperative reactive foreign bodies, reducing local inflammatory response, inhibiting the coagulation cascade and promoting fibrinolysis, or by placing barriers between damaged tissues.

Related Article: Update on Fertility G. David Adamson, MD (February 2008)

Careful surgical technique includes gentle tissue handling, meticulous hemostasis, excision of necrotic tissue, minimizing ischemia and desiccation, using fine and nonreactive suture, and preventing foreign-body reaction and infection, all “microsurgical principles.”

ASRM and SRS reported that the surgical approach (laparoscopy vs laparotomy) is much less important than the extent of tissue injury. However, laparoscopy may result in less tissue and organ handling and trauma, avoid contamination with foreign bodies, enable more precise tissue handling, and result in less postoperative infection. The pneumoperitoneum has a tamponade effect that facilitates hemostasis during laparoscopy, but the process also can be associated with peritoneal desiccation and reduced temperatures that can increase injury.

Laparoscopic myomectomy was found to have a 70% risk of postoperative adhesions, compared with a 90% risk after laparotomy. It is unclear whether peritoneal closure at laparotomy reduces or increases adhesions, but parietal peritoneal closure at primary cesarean delivery results in fewer dense and filmy adhesions.

Related Article: How to avoid intestinal and urinary tract injuries during gynecologic laparoscopy Michael Baggish, MD (Second of a 2-part series on laparoscopic complications, October 2012)

Adjuncts to surgical technique
SRM and SRS reported on three adjuncts to surgical technique that have been proposed to reduce the risk of postoperative adhesions: anti-inflammatory agents, peritoneal instillates, and adhesion barriers.

Dexamethasone, promethazine, and other local and systemic anti-inflammatory drugs and adhesion-reducing substances have not been found effective for reducing postoperative adhesions.

Peritoneal instillates—which create “hydroflotation” and include antibiotic solutions, 32% dextran 70, and crystalloid solutions such as normal saline and Ringer’s lactate with or without heparin or corticosteroids—have not been found effective.⁸ Icodextrin 4% (Adept Adhesion Reduction Solution, Baxter Healthcare) is FDA approved as an adjunct to good surgical technique for the reduction of postoperative adhesions in patients undergoing gynecologic laparoscopic adhesiolysis. However, a systematic review concluded that there is insufficient evidence for its use as an adhesion-preventing agent.⁸

Adhesion barriers may help reduce postoperative adhesions but cannot compensate for poor surgical technique. Although the bioresorbable membrane sodium hyaluronic acid and carboxymethyl cellulose (Seprafilm, Genzyme Corp) is FDA-approved, there is limited evidence that it prevents adhesions after myomectomy.⁹ Because it fragments easily, it is mostly used at laparotomy.

Oxidized regenerated cellulose (Interceed, Ethicon Women’s Health and Urology) is an FDA-approved absorbable adhesion barrier for use at laparotomy that requires no suturing and has been shown to reduce the incidence and extent of new and recurrent adhesions at both laparoscopy and laparotomy by 40% to 50%, although there is little evidence that this improves fertility.⁹ Complete hemostasis must be achieved to use Interceed, and the addition of heparin confers no benefit.

Another product is expanded polytetrafluoroethylene (ePTFE, Gore-Tex Surgical Membrane, WL Gore and Associates), a nonabsorbable adhesion barrier produced in thin sheets and approved by the FDA for peritoneal repair. ePTFE must be sutured to tissue and helps prevent adhesion formation and reformation regardless of the type of injury or whether complete hemostasis has been achieved. In a small trial, it decreased postmyomectomy adhesions.¹⁰ ePTFE also was more effective than oxidized regenerated cellulose in preventing adhesions after adnexal surgery.¹¹ Its use has been limited by the need for suturing and later reoperation for removal, although it probably does not have to be removed if it will not interfere with normal organ function since it has been used as a pericardial graft for many years.¹²

Hyaluronic acid (HA) solution (Sepracoat, Genzyme) is a natural bioabsorbable component of the extracellular matrix. Women undergoing laparotomy have fewer new adhesions with HA solution, but it is not approved for use in the United States.¹³ Polyethylene glycol (PEG; SprayGel, Confluent Surgical) was effective in early clinical trials but is not FDA-approved.¹² Fibrin sealant (Tisseel VH, Baxter Healthcare) has been reported to decrease the formation of adhesions after salpingostomy, salpingolysis, and ovariolysis. Because it is a biologic product derived from human blood donors, it poses a risk for transmission of infectious agents. It is FDA-approved for use in cardiothoracic surgery, splenic injuries, and colostomy closure for hemostasis.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Adhesions are the most common complication following gynecologic surgery, and they pose potential longstanding consequences to patients. There is no evidence that anti-inflammatory agents reduce postoperative adhesions and insufficient evidence to recommend peritoneal instillates. FDA-approved surgical barriers reduce postoperative adhesions but there is not substantial evidence that their use improves fertility, decreases pain, or reduces the incidence of postoperative bowel obstruction. All gynecologists need to understand the importance of using microsurgical principles rather than relying on adhesion barriers to reduce postoperative adhesions.

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: obg@frontlinemedcom.com

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

Infertility is not just a woman’s issue; it is a couple’s issue. According to the Centers for Disease Control and Prevention, one-third of cases of infertility are caused by a reproductive problem for the woman, one-third are caused by a problem for the man, and one-third are due to problems for both partners or to unknown causes.¹

Here, we discuss three developments within the past 12 months related to the treatment of infertility:

• The International Federation of Gynecology and Obstetrics (FIGO) Committee on Reproductive Medicine—charged with developing evidence-based, cost-effective guidelines that would be accepted as standards for increasing access to quality reproductive medical care in all countries of the world—has developed The FIGO Fertility Tool Box™.
• Smoking cigarettes negatively affects a man’s and woman’s fertility, yet smoking’s contribution to infertility is under-recognized. The Practice Committee of the American Society for Reproductive Medicine culled the evidence, and published its review on the effects of smoking on fertility.
• Results of a large, population-wide cohort study shed light on the association of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with birth defects and whether underlying factors present in patients with infertility also may play a role.

FIGO offers Tools for managing infertility

Adamson GD. A quick guide to the FIGO Fertility Tool Box. The FIGO Fertility Tool Box. The International Federation of Gynecology and Obstetrics Web site. http://www.arcfertility.com/figo. Published 2013. Accessed January 21, 2013.

FIGO has as members 125 national ObGyn societies. The FIGO Committee on Reproductive Medicine’s mission is to create access to quality reproductive medical care and is focused on helping infertile women become pregnant and/or on alleviating the burden of infertility. The Committee has just released The FIGO Fertility Tool Box™ to further this goal.

Who should use the Tool Box?

Anybody who wants to help infertile people! It is designed for health-care workers and others who want to make a difference in the lives of infertile people. The Tool Box can be accessed electronically on both computers and cell phones at http://www.figo.org/news/resources/FIGO_Fertility_Tool_Box.

What’s in the Tool Box?

Seven Tools help you tackle the disease/ disability of infertility. Each Tool provides information on how to manage a particular aspect of infertility:

• Tool 1: The FIGO Fertility Daisy—why we should care about infertility
• Tool 2: Overcome personal barriers
• Tool 3: Overcome societal barriers
• Tool 4: Diagnose infertility
• Tool 5: Treat infertility
• Tool 6: Refer/resolve infertility
• Tool 7: Prevent infertility.

The Tools Pyramid ( FIGURE 1 ) contains these seven Tools.

FIGURE 1 The Tools Pyramid^™

How do the Tools work?

Each of the seven Tools consists of three levels:

Level 1: Basic Tools. The first level consists of 7 Basic Tools™, which contain information that is brief and succinct—just a simple statement or summary of the Daisy and each of the six Pyramids of Action. The Basic Tools are colored orange.

Level 2: Support Tools. The second level is Support Tools™, which provide more information and detail—enough so that you know what to do to take action. Support Tools are colored green.

Level 3: Reference Tools. The third level is Reference Tools™, which are lists of references that provide evidence for the information and recommended actions in the Basic and Support Tools. Reference Tools are colored white.

The Glossary provides definitions and explanations of abbreviations and acronyms and is colored white like the References. By coloring the levels icons this way, you can always tell whether you are using a Basic Tool, Support Tool, or Reference Tool.

The Levels Pyramid (FIGURE 2 ) shows how the Basic Tools, Support Tools, and Reference Tools relate to each other. You can choose your Tool and level by clicking on the icons from your computer or cellphone.

FIGURE 2 The Levels Pyramid^™

How do I know what to do?—The Actions Pyramids^™

With the exception of the Daisy (Tool 1), all Tools have the shape of a pyramid ( FIGURE 3 ). At the base of each pyramid are actions that can be taken in low-resource settings; that is, they are often simpler, elementary, involve fewer people and are low-cost interventions or opportunities. Overall, there are 64 total actions described in the seven Tools.

As you move higher in the pyramid, generally more resources are required to take actions that are usually more complex. You can think of it as a kind of ladder—as you climb higher it usually gets a bit more complex or complicated. Sometimes, however, it might also be easier higher up on the ladder, and the elementary aspects might be those most challenging.

If you are interested in helping a patient with infertility, you are encouraged to do whatever you can do at any level in any of the Tools in The Actions Pyramid. In the online version, you can click on the actions arrow or icons to click immediately to the action you wish to learn about and do.

FIGURE 3 The Actions Pyramid^™

Which Tool should I use?

The one you think will work best for you and will give you some results quickly. Doing something is better than doing nothing. There is no right or wrong way to make a start. Then, if you want to do more you can choose other Tools or individual aspects of other Tools to build on what you have already achieved. Or, if you want to be very systematic and are very committed you can start with Tool 1 and work your way through the entire Tool Box.

What if I can’t implement some of the recommendations?

Then drop it and move onto something that you can do or implement. No single component of the Tool Box is so essential to helping infertile couples that your efforts will fail if you can’t apply it. Using even one or two actions in one or two Tools will empower you to help many infertile individuals.

What if I want to change a Tool?

Just do it. The Tool Box is made to be changed so that it can be adapted to work in any type of health-care setting anywhere in the world. You know what works best in your situation. Just never stop caring and trying to help infertile people.

Does the Tool Box have a compliments and complaints section?

Yes, it is called the FIGO Committee on Reproductive Medicine. E-mail us at fertilitytool box@figo.org. We would love to hear from you about what you like and what works in the Tool Box and what doesn’t. We hope to constantly improve The FIGO Fertility Tool Box to make it a better Tool to help you tackle the disease/disability of infertility.

Smoking, by either partner, active or passive, negatively affects reproductive health

Pfeifer S, Fritz M, Goldberg J, et al; the Practice Committee of the American Society for Reproductive Medicine. Smoking and infertility: a committee opinion. Fertil Steril. 2012;98(6):1400–1406.

Approximately 30% of reproductive-age women and 35% of reproductive-age men smoke cigarettes. Although smoking has been linked to many adverse health effects, the substantial detrimental effects of cigarette smoking on fecundity and reproduction are under-recognized. In a recent publication, the Practice Committee of the American Society for Reproductive Medicine reviewed the effects of smoking on fertility.

Smoking’s ill effects on fertility

Conception delay

Smokers are at an increased risk for infertility and conception delay. Independent of other factors, smoking has a negative impact on fecundity, with a trend toward increased time to conception with increased number of cigarettes smoked.^2,3 The percentage of women experiencing conception delay for more than 12 months was shown to be 54% higher in smoking versus nonsmoking women in one study.³ These authors found that active smoking by either partner had an adverse effect on conception. Furthermore, the impact of passive smoking by either partner was found to be only slightly less than the impact found for active smoking by either partner.³

Ovarian follicular depletion

Basal levels of follicle-stimulating hormone (FSH) are significantly higher in smokers, with one study demonstrating a 66% increase in smoking versus nonsmoking women and a 39% increase in passive versus nonsmoking women.⁴ Chemicals in cigarette smoke appear to accelerate follicular depletion and loss of reproductive function, and menopause has been found to occur 1 to 4 years earlier in smoking versus nonsmoking women.²

Effects on sperm parameters

Poor function. Smoking has been found to reduce sperm density, motility, and possibly morphology. Sperm function tests appear to be 22% poorer in smokers versus nonsmokers, and the effects are dose-dependent.

No link to male infertility, yet. While evidence suggests an adverse effect on sperm function from smoking, available data do not conclusively demonstrate a reduction in male fertility due to smoking. This could be due to secondary confounding effects of partner status.²

Maternal smoking may decrease sperm counts in offspring, according to Storgaard and colleagues, who found that men whose mothers had smoked more than 10 cigarettes per day had lower sperm densities than men with nonsmoking mothers.⁵

Mutagenic potential

Tobacco smoke exposure may harm gametogenesis by adversely affecting chromosomes and damaging the meiotic spindle and has been associated with an increased risk of trisomy 21 offspring resulting from maternal nondisjunction.^6,7 Gene damage in sperm may be secondary to direct binding of tobacco smoke constituents or chemical byproducts to DNA, creating premutational lesions or “adducts.” These mutagenic adducts have been found in greater numbers in embryos from smokers versus nonsmokers, suggesting a mechanism for the transmission of adversely modified DNA from parental smoking.²

Early pregnancy effects

Smoking increases the risk of spontaneous miscarriage in both natural and assisted conceptions and has been linked to an increased risk for bacterial vaginosis, which in turn increases the risk for second trimester miscarriage and preterm labor.² Studies also have identified an increased risk of ectopic pregnancy in smokers, including one study demonstrating an odds ratio (OR) for ectopic pregnancy of 3.5 (95% confidence interval [CI], 1.4–8.6) in women who smoked more than 20 cigarettes per day versus nonsmokers.⁶

Assisted reproductive therapies rendered less effective

Studies of IVF have demonstrated that smokers versus nonsmokers have an increased gonadotropin requirement for ovarian stimulation, lower peak estradiol levels, elevated testosterone levels, fewer oocytes retrieved, higher numbers of cancelled cycles, thicker zone pellucida, lower implantation rates, and an increased rate of failed fertilization.² In order to achieve conception, smokers require nearly twice the number of IVF cycles versus nonsmokers.² Authors of a 5-year, prospective study controlling for potential confounders found that if a woman ever smoked in her lifetime, her risk of failing to conceive with assisted reproductive technologies (ART) more than doubled (relative risk, 2.5; 95% CI, 1.38–4.55). Each year of smoking was associated with a 9% increase in the risk of unsuccessful ART cycles (95% CI, 1.02–1.15;
P <.01).⁸

We have an important role in helping patients quit

A study involving smoking cessation in infertile women found that simple interventions, such as counseling, education, and encouragement during each clinic visit, were more successful than merely providing educational materials and Web site addresses. The rates of smoking cessation increased from 4% at baseline to 24% after 12 months.⁹

The Public Health Service and National Cancer Institute offer validated, office-based intervention guidelines for smoking cessation, including a five-step approach² :

1. Ask about smoking at every opportunity
2. Advise all smokers to stop
3. Assist willingness to stop
4. Assist patients in stopping (including through the use of pharmaceuticals and carbon monoxide handheld monitors)
5. Arrange follow-up visits.

The use of adjunctive medical therapies, including nicotine replacement therapy and/or buproprion, has resulted in a twofold increase in the proportion of nonpregnant women who quit smoking.² These medical therapies may be useful if behavioral approaches alone fail—although their use has not been studied in infertile women. Smoking cessation rates appear to be higher in infertile versus pregnant women, yet only 18% of women referred for infertility care have received advice on smoking cessation from their referring provider.⁹

The safety of assisted reproductive technologies

Davies ML, Moore VM, Willson KJ, et al. Reproductive technologies and the risk of birth defects. N Engl J Med. 2012;366(19):1803–1813.

Since the birth of Louise Brown, the first baby born after being conceived with in vitro fertilization (IVF) in 1978, IVF has become a pillar in the treatment of infertility. Although recognized as a highly effective treatment, the safety of IVF and its related technologies, such as intracytoplasmic sperm injection (ICSI), has been questioned. Studies have linked the use of assisted reproduction, including IVF and ICSI, with an increased risk of birth defects.^10-15 Findings, however, were limited by small sample sizes and lack of appropriate controls. Furthermore, it has been unclear if this increased risk is due to factors related to treatment or to an underlying factor present in patients with infertility. It also has been unclear whether there is a differential in risk according to the type of ART used. In a large population-wide cohort study, Davies and colleagues linked a census of treatment with ART in South Australia to a registry of births and terminations with a gestation period of at least 20 weeks or a birth weight of 400 g and registries of birth defects.

The authors compared the risk of birth defects in pregnancies among women who had conceived with the use of ART, women with spontaneous pregnancies who had had a previous birth after ART treatment, women with a diagnosis of infertility who had conceived without ART, and pregnancies in women without infertility. Births and pregnancy terminations secondary to birth defects were studied to assess the birth defect risk from pregnancy to a child’s fifth birthday.

Details of the trial

A total of 308,974 births were included in the analysis. Births in women who conceived with the use of ART were associated with a significant increase in risk of birth defects (8.3%) compared with births conceived spontaneously in fertile women (8.3% vs 5.8%, respectively; unadjusted OR, 1.47; 95% CI, 1.33-1.62). This effect remained significant after multivariate adjustment (adjusted OR, 1.28; 95% CI, 1.16-1.41).

While there was no significant association between ART and the risk of specific syndromes such as Down’s, Turner’s, Edward’s, and others, there was a significantly increased adjusted OR for any defect and multiple defects in births conceived with ART versus those conceived spontaneously in fertile women.

The OR for birth defects associated with IVF was 1.26 (95% CI, 1.07-1.48) in unadjusted analyses and 1.07 (95% CI, 0.9-1.26) after multivariate adjustment. The OR for birth defects associated with IVF with ICSI were 1.77 (95% CI, 1.47-2.12) in unadjusted and 1.57 (95% CI, 1.30-1.90) after multivariate analysis. Compared with ICSI, IVF was associated with a reduced risk of any birth defect (OR, 0.68; 95% CI, 0.53-0.87).

Births after gamete intrafallopian transfer, intrauterine insemination, or the use of clomiphene citrate at home were associated with significantly increased risks of any birth defect in adjusted analyses. Births after conception with donor insemination and clinically supervised ovulation induction were not associated with an increased risk of birth defects. Births occurring after spontaneous conception in women with a history of a previous birth with ART were also associated with an increased risk of birth defects, even after adjustment for confounders (adjusted OR, 1.25; 95% CI, 1.01-1.56). Births occurring after spontaneous conception in women with a history of infertility without previous ART treatment were also significantly associated with a small increased risk in birth defects (OR, 1.29; 95% CI, 0.99-1.68).

ICSI and birth-defect association persisted

In this large observational study, the authors confirmed findings from previous studies^11,12,16-18 that the number of birth defects found in pregnancies conceived with ART are higher than the number found in pregnancies conceived spontaneously. In this study, after multivariate adjustment, the association between IVF and an increased risk of birth defects was found to be no longer significant, but the risk remained elevated after ART with ICSI. These findings are similar to results in previous studies.^18,19 The increased risk may be secondary to the ICSI procedure itself^19,20 or to underlying male infertility factors leading to the use of ICSI.¹⁴

Birth defects appeared to be highest in fresh embryo cycles of ICSI versus IVF and lowest in frozen-embryo cycles. A reduction in birth defects with cryopreservation may be secondary to a reduced likelihood that cryopreserved embryos would survive the thawing process as well as the temporal separation of the developing embryo from a hormonally stimulated cycle.^21-23 Treatment with ART was associated with an increased risk of cardiovascular, musculoskeletal, urogenital, and gastrointestinal defects, as well as cerebral palsy. The observation of an increased risk of cerebral palsy with ART treatment is consistent with findings from a previous study. Strömberg and colleagues found that the risk of cerebral palsy was increased by a factor of 3.7 among multiples conceived with IVF and 2.8 among singletons conceived with IVF.²⁴

Davies and colleagues also observed that the risk of a birth defect was increased among women with a history of infertility who were able to conceive without ART,²⁵ a finding observed in a previous large Danish registry.¹⁵

We want to hear from you!  Tell us what you think.

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

Infertility is not just a woman’s issue; it is a couple’s issue. According to the Centers for Disease Control and Prevention, one-third of cases of infertility are caused by a reproductive problem for the woman, one-third are caused by a problem for the man, and one-third are due to problems for both partners or to unknown causes.¹

Here, we discuss three developments within the past 12 months related to the treatment of infertility:

• The International Federation of Gynecology and Obstetrics (FIGO) Committee on Reproductive Medicine—charged with developing evidence-based, cost-effective guidelines that would be accepted as standards for increasing access to quality reproductive medical care in all countries of the world—has developed The FIGO Fertility Tool Box™.
• Smoking cigarettes negatively affects a man’s and woman’s fertility, yet smoking’s contribution to infertility is under-recognized. The Practice Committee of the American Society for Reproductive Medicine culled the evidence, and published its review on the effects of smoking on fertility.
• Results of a large, population-wide cohort study shed light on the association of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with birth defects and whether underlying factors present in patients with infertility also may play a role.

FIGO offers Tools for managing infertility

Adamson GD. A quick guide to the FIGO Fertility Tool Box. The FIGO Fertility Tool Box. The International Federation of Gynecology and Obstetrics Web site. http://www.arcfertility.com/figo. Published 2013. Accessed January 21, 2013.

FIGO has as members 125 national ObGyn societies. The FIGO Committee on Reproductive Medicine’s mission is to create access to quality reproductive medical care and is focused on helping infertile women become pregnant and/or on alleviating the burden of infertility. The Committee has just released The FIGO Fertility Tool Box™ to further this goal.

Who should use the Tool Box?

Anybody who wants to help infertile people! It is designed for health-care workers and others who want to make a difference in the lives of infertile people. The Tool Box can be accessed electronically on both computers and cell phones at http://www.figo.org/news/resources/FIGO_Fertility_Tool_Box.

What’s in the Tool Box?

Seven Tools help you tackle the disease/ disability of infertility. Each Tool provides information on how to manage a particular aspect of infertility:

• Tool 1: The FIGO Fertility Daisy—why we should care about infertility
• Tool 2: Overcome personal barriers
• Tool 3: Overcome societal barriers
• Tool 4: Diagnose infertility
• Tool 5: Treat infertility
• Tool 6: Refer/resolve infertility
• Tool 7: Prevent infertility.

The Tools Pyramid ( FIGURE 1 ) contains these seven Tools.

FIGURE 1 The Tools Pyramid^™

How do the Tools work?

Each of the seven Tools consists of three levels:

Level 1: Basic Tools. The first level consists of 7 Basic Tools™, which contain information that is brief and succinct—just a simple statement or summary of the Daisy and each of the six Pyramids of Action. The Basic Tools are colored orange.

Level 2: Support Tools. The second level is Support Tools™, which provide more information and detail—enough so that you know what to do to take action. Support Tools are colored green.

Level 3: Reference Tools. The third level is Reference Tools™, which are lists of references that provide evidence for the information and recommended actions in the Basic and Support Tools. Reference Tools are colored white.

The Glossary provides definitions and explanations of abbreviations and acronyms and is colored white like the References. By coloring the levels icons this way, you can always tell whether you are using a Basic Tool, Support Tool, or Reference Tool.

The Levels Pyramid (FIGURE 2 ) shows how the Basic Tools, Support Tools, and Reference Tools relate to each other. You can choose your Tool and level by clicking on the icons from your computer or cellphone.

FIGURE 2 The Levels Pyramid^™

How do I know what to do?—The Actions Pyramids^™

With the exception of the Daisy (Tool 1), all Tools have the shape of a pyramid ( FIGURE 3 ). At the base of each pyramid are actions that can be taken in low-resource settings; that is, they are often simpler, elementary, involve fewer people and are low-cost interventions or opportunities. Overall, there are 64 total actions described in the seven Tools.

As you move higher in the pyramid, generally more resources are required to take actions that are usually more complex. You can think of it as a kind of ladder—as you climb higher it usually gets a bit more complex or complicated. Sometimes, however, it might also be easier higher up on the ladder, and the elementary aspects might be those most challenging.

If you are interested in helping a patient with infertility, you are encouraged to do whatever you can do at any level in any of the Tools in The Actions Pyramid. In the online version, you can click on the actions arrow or icons to click immediately to the action you wish to learn about and do.

FIGURE 3 The Actions Pyramid^™

Which Tool should I use?

The one you think will work best for you and will give you some results quickly. Doing something is better than doing nothing. There is no right or wrong way to make a start. Then, if you want to do more you can choose other Tools or individual aspects of other Tools to build on what you have already achieved. Or, if you want to be very systematic and are very committed you can start with Tool 1 and work your way through the entire Tool Box.

What if I can’t implement some of the recommendations?

Then drop it and move onto something that you can do or implement. No single component of the Tool Box is so essential to helping infertile couples that your efforts will fail if you can’t apply it. Using even one or two actions in one or two Tools will empower you to help many infertile individuals.

What if I want to change a Tool?

Just do it. The Tool Box is made to be changed so that it can be adapted to work in any type of health-care setting anywhere in the world. You know what works best in your situation. Just never stop caring and trying to help infertile people.

Does the Tool Box have a compliments and complaints section?

Yes, it is called the FIGO Committee on Reproductive Medicine. E-mail us at fertilitytool box@figo.org. We would love to hear from you about what you like and what works in the Tool Box and what doesn’t. We hope to constantly improve The FIGO Fertility Tool Box to make it a better Tool to help you tackle the disease/disability of infertility.

Smoking, by either partner, active or passive, negatively affects reproductive health

Pfeifer S, Fritz M, Goldberg J, et al; the Practice Committee of the American Society for Reproductive Medicine. Smoking and infertility: a committee opinion. Fertil Steril. 2012;98(6):1400–1406.

Approximately 30% of reproductive-age women and 35% of reproductive-age men smoke cigarettes. Although smoking has been linked to many adverse health effects, the substantial detrimental effects of cigarette smoking on fecundity and reproduction are under-recognized. In a recent publication, the Practice Committee of the American Society for Reproductive Medicine reviewed the effects of smoking on fertility.

Smoking’s ill effects on fertility

Conception delay

Smokers are at an increased risk for infertility and conception delay. Independent of other factors, smoking has a negative impact on fecundity, with a trend toward increased time to conception with increased number of cigarettes smoked.^2,3 The percentage of women experiencing conception delay for more than 12 months was shown to be 54% higher in smoking versus nonsmoking women in one study.³ These authors found that active smoking by either partner had an adverse effect on conception. Furthermore, the impact of passive smoking by either partner was found to be only slightly less than the impact found for active smoking by either partner.³

Ovarian follicular depletion

Basal levels of follicle-stimulating hormone (FSH) are significantly higher in smokers, with one study demonstrating a 66% increase in smoking versus nonsmoking women and a 39% increase in passive versus nonsmoking women.⁴ Chemicals in cigarette smoke appear to accelerate follicular depletion and loss of reproductive function, and menopause has been found to occur 1 to 4 years earlier in smoking versus nonsmoking women.²

Effects on sperm parameters

Poor function. Smoking has been found to reduce sperm density, motility, and possibly morphology. Sperm function tests appear to be 22% poorer in smokers versus nonsmokers, and the effects are dose-dependent.

No link to male infertility, yet. While evidence suggests an adverse effect on sperm function from smoking, available data do not conclusively demonstrate a reduction in male fertility due to smoking. This could be due to secondary confounding effects of partner status.²

Maternal smoking may decrease sperm counts in offspring, according to Storgaard and colleagues, who found that men whose mothers had smoked more than 10 cigarettes per day had lower sperm densities than men with nonsmoking mothers.⁵

Mutagenic potential

Tobacco smoke exposure may harm gametogenesis by adversely affecting chromosomes and damaging the meiotic spindle and has been associated with an increased risk of trisomy 21 offspring resulting from maternal nondisjunction.^6,7 Gene damage in sperm may be secondary to direct binding of tobacco smoke constituents or chemical byproducts to DNA, creating premutational lesions or “adducts.” These mutagenic adducts have been found in greater numbers in embryos from smokers versus nonsmokers, suggesting a mechanism for the transmission of adversely modified DNA from parental smoking.²

Early pregnancy effects

Smoking increases the risk of spontaneous miscarriage in both natural and assisted conceptions and has been linked to an increased risk for bacterial vaginosis, which in turn increases the risk for second trimester miscarriage and preterm labor.² Studies also have identified an increased risk of ectopic pregnancy in smokers, including one study demonstrating an odds ratio (OR) for ectopic pregnancy of 3.5 (95% confidence interval [CI], 1.4–8.6) in women who smoked more than 20 cigarettes per day versus nonsmokers.⁶

Assisted reproductive therapies rendered less effective

Studies of IVF have demonstrated that smokers versus nonsmokers have an increased gonadotropin requirement for ovarian stimulation, lower peak estradiol levels, elevated testosterone levels, fewer oocytes retrieved, higher numbers of cancelled cycles, thicker zone pellucida, lower implantation rates, and an increased rate of failed fertilization.² In order to achieve conception, smokers require nearly twice the number of IVF cycles versus nonsmokers.² Authors of a 5-year, prospective study controlling for potential confounders found that if a woman ever smoked in her lifetime, her risk of failing to conceive with assisted reproductive technologies (ART) more than doubled (relative risk, 2.5; 95% CI, 1.38–4.55). Each year of smoking was associated with a 9% increase in the risk of unsuccessful ART cycles (95% CI, 1.02–1.15;
P <.01).⁸

We have an important role in helping patients quit

A study involving smoking cessation in infertile women found that simple interventions, such as counseling, education, and encouragement during each clinic visit, were more successful than merely providing educational materials and Web site addresses. The rates of smoking cessation increased from 4% at baseline to 24% after 12 months.⁹

The Public Health Service and National Cancer Institute offer validated, office-based intervention guidelines for smoking cessation, including a five-step approach² :

1. Ask about smoking at every opportunity
2. Advise all smokers to stop
3. Assist willingness to stop
4. Assist patients in stopping (including through the use of pharmaceuticals and carbon monoxide handheld monitors)
5. Arrange follow-up visits.

The use of adjunctive medical therapies, including nicotine replacement therapy and/or buproprion, has resulted in a twofold increase in the proportion of nonpregnant women who quit smoking.² These medical therapies may be useful if behavioral approaches alone fail—although their use has not been studied in infertile women. Smoking cessation rates appear to be higher in infertile versus pregnant women, yet only 18% of women referred for infertility care have received advice on smoking cessation from their referring provider.⁹

The safety of assisted reproductive technologies

Davies ML, Moore VM, Willson KJ, et al. Reproductive technologies and the risk of birth defects. N Engl J Med. 2012;366(19):1803–1813.

Since the birth of Louise Brown, the first baby born after being conceived with in vitro fertilization (IVF) in 1978, IVF has become a pillar in the treatment of infertility. Although recognized as a highly effective treatment, the safety of IVF and its related technologies, such as intracytoplasmic sperm injection (ICSI), has been questioned. Studies have linked the use of assisted reproduction, including IVF and ICSI, with an increased risk of birth defects.^10-15 Findings, however, were limited by small sample sizes and lack of appropriate controls. Furthermore, it has been unclear if this increased risk is due to factors related to treatment or to an underlying factor present in patients with infertility. It also has been unclear whether there is a differential in risk according to the type of ART used. In a large population-wide cohort study, Davies and colleagues linked a census of treatment with ART in South Australia to a registry of births and terminations with a gestation period of at least 20 weeks or a birth weight of 400 g and registries of birth defects.

The authors compared the risk of birth defects in pregnancies among women who had conceived with the use of ART, women with spontaneous pregnancies who had had a previous birth after ART treatment, women with a diagnosis of infertility who had conceived without ART, and pregnancies in women without infertility. Births and pregnancy terminations secondary to birth defects were studied to assess the birth defect risk from pregnancy to a child’s fifth birthday.

Details of the trial

A total of 308,974 births were included in the analysis. Births in women who conceived with the use of ART were associated with a significant increase in risk of birth defects (8.3%) compared with births conceived spontaneously in fertile women (8.3% vs 5.8%, respectively; unadjusted OR, 1.47; 95% CI, 1.33-1.62). This effect remained significant after multivariate adjustment (adjusted OR, 1.28; 95% CI, 1.16-1.41).

While there was no significant association between ART and the risk of specific syndromes such as Down’s, Turner’s, Edward’s, and others, there was a significantly increased adjusted OR for any defect and multiple defects in births conceived with ART versus those conceived spontaneously in fertile women.

The OR for birth defects associated with IVF was 1.26 (95% CI, 1.07-1.48) in unadjusted analyses and 1.07 (95% CI, 0.9-1.26) after multivariate adjustment. The OR for birth defects associated with IVF with ICSI were 1.77 (95% CI, 1.47-2.12) in unadjusted and 1.57 (95% CI, 1.30-1.90) after multivariate analysis. Compared with ICSI, IVF was associated with a reduced risk of any birth defect (OR, 0.68; 95% CI, 0.53-0.87).

Births after gamete intrafallopian transfer, intrauterine insemination, or the use of clomiphene citrate at home were associated with significantly increased risks of any birth defect in adjusted analyses. Births after conception with donor insemination and clinically supervised ovulation induction were not associated with an increased risk of birth defects. Births occurring after spontaneous conception in women with a history of a previous birth with ART were also associated with an increased risk of birth defects, even after adjustment for confounders (adjusted OR, 1.25; 95% CI, 1.01-1.56). Births occurring after spontaneous conception in women with a history of infertility without previous ART treatment were also significantly associated with a small increased risk in birth defects (OR, 1.29; 95% CI, 0.99-1.68).

ICSI and birth-defect association persisted

In this large observational study, the authors confirmed findings from previous studies^11,12,16-18 that the number of birth defects found in pregnancies conceived with ART are higher than the number found in pregnancies conceived spontaneously. In this study, after multivariate adjustment, the association between IVF and an increased risk of birth defects was found to be no longer significant, but the risk remained elevated after ART with ICSI. These findings are similar to results in previous studies.^18,19 The increased risk may be secondary to the ICSI procedure itself^19,20 or to underlying male infertility factors leading to the use of ICSI.¹⁴

Birth defects appeared to be highest in fresh embryo cycles of ICSI versus IVF and lowest in frozen-embryo cycles. A reduction in birth defects with cryopreservation may be secondary to a reduced likelihood that cryopreserved embryos would survive the thawing process as well as the temporal separation of the developing embryo from a hormonally stimulated cycle.^21-23 Treatment with ART was associated with an increased risk of cardiovascular, musculoskeletal, urogenital, and gastrointestinal defects, as well as cerebral palsy. The observation of an increased risk of cerebral palsy with ART treatment is consistent with findings from a previous study. Strömberg and colleagues found that the risk of cerebral palsy was increased by a factor of 3.7 among multiples conceived with IVF and 2.8 among singletons conceived with IVF.²⁴

Davies and colleagues also observed that the risk of a birth defect was increased among women with a history of infertility who were able to conceive without ART,²⁵ a finding observed in a previous large Danish registry.¹⁵

We want to hear from you!  Tell us what you think.

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

Infertility is not just a woman’s issue; it is a couple’s issue. According to the Centers for Disease Control and Prevention, one-third of cases of infertility are caused by a reproductive problem for the woman, one-third are caused by a problem for the man, and one-third are due to problems for both partners or to unknown causes.¹

Here, we discuss three developments within the past 12 months related to the treatment of infertility:

• The International Federation of Gynecology and Obstetrics (FIGO) Committee on Reproductive Medicine—charged with developing evidence-based, cost-effective guidelines that would be accepted as standards for increasing access to quality reproductive medical care in all countries of the world—has developed The FIGO Fertility Tool Box™.
• Smoking cigarettes negatively affects a man’s and woman’s fertility, yet smoking’s contribution to infertility is under-recognized. The Practice Committee of the American Society for Reproductive Medicine culled the evidence, and published its review on the effects of smoking on fertility.
• Results of a large, population-wide cohort study shed light on the association of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with birth defects and whether underlying factors present in patients with infertility also may play a role.

FIGO offers Tools for managing infertility

Adamson GD. A quick guide to the FIGO Fertility Tool Box. The FIGO Fertility Tool Box. The International Federation of Gynecology and Obstetrics Web site. http://www.arcfertility.com/figo. Published 2013. Accessed January 21, 2013.

FIGO has as members 125 national ObGyn societies. The FIGO Committee on Reproductive Medicine’s mission is to create access to quality reproductive medical care and is focused on helping infertile women become pregnant and/or on alleviating the burden of infertility. The Committee has just released The FIGO Fertility Tool Box™ to further this goal.

Who should use the Tool Box?

Anybody who wants to help infertile people! It is designed for health-care workers and others who want to make a difference in the lives of infertile people. The Tool Box can be accessed electronically on both computers and cell phones at http://www.figo.org/news/resources/FIGO_Fertility_Tool_Box.

What’s in the Tool Box?

Seven Tools help you tackle the disease/ disability of infertility. Each Tool provides information on how to manage a particular aspect of infertility:

• Tool 1: The FIGO Fertility Daisy—why we should care about infertility
• Tool 2: Overcome personal barriers
• Tool 3: Overcome societal barriers
• Tool 4: Diagnose infertility
• Tool 5: Treat infertility
• Tool 6: Refer/resolve infertility
• Tool 7: Prevent infertility.

The Tools Pyramid ( FIGURE 1 ) contains these seven Tools.

FIGURE 1 The Tools Pyramid^™

How do the Tools work?

Each of the seven Tools consists of three levels:

Level 1: Basic Tools. The first level consists of 7 Basic Tools™, which contain information that is brief and succinct—just a simple statement or summary of the Daisy and each of the six Pyramids of Action. The Basic Tools are colored orange.

Level 2: Support Tools. The second level is Support Tools™, which provide more information and detail—enough so that you know what to do to take action. Support Tools are colored green.

Level 3: Reference Tools. The third level is Reference Tools™, which are lists of references that provide evidence for the information and recommended actions in the Basic and Support Tools. Reference Tools are colored white.

The Glossary provides definitions and explanations of abbreviations and acronyms and is colored white like the References. By coloring the levels icons this way, you can always tell whether you are using a Basic Tool, Support Tool, or Reference Tool.

The Levels Pyramid (FIGURE 2 ) shows how the Basic Tools, Support Tools, and Reference Tools relate to each other. You can choose your Tool and level by clicking on the icons from your computer or cellphone.

FIGURE 2 The Levels Pyramid^™

How do I know what to do?—The Actions Pyramids^™

With the exception of the Daisy (Tool 1), all Tools have the shape of a pyramid ( FIGURE 3 ). At the base of each pyramid are actions that can be taken in low-resource settings; that is, they are often simpler, elementary, involve fewer people and are low-cost interventions or opportunities. Overall, there are 64 total actions described in the seven Tools.

As you move higher in the pyramid, generally more resources are required to take actions that are usually more complex. You can think of it as a kind of ladder—as you climb higher it usually gets a bit more complex or complicated. Sometimes, however, it might also be easier higher up on the ladder, and the elementary aspects might be those most challenging.

If you are interested in helping a patient with infertility, you are encouraged to do whatever you can do at any level in any of the Tools in The Actions Pyramid. In the online version, you can click on the actions arrow or icons to click immediately to the action you wish to learn about and do.

FIGURE 3 The Actions Pyramid^™

Which Tool should I use?

The one you think will work best for you and will give you some results quickly. Doing something is better than doing nothing. There is no right or wrong way to make a start. Then, if you want to do more you can choose other Tools or individual aspects of other Tools to build on what you have already achieved. Or, if you want to be very systematic and are very committed you can start with Tool 1 and work your way through the entire Tool Box.

What if I can’t implement some of the recommendations?

Then drop it and move onto something that you can do or implement. No single component of the Tool Box is so essential to helping infertile couples that your efforts will fail if you can’t apply it. Using even one or two actions in one or two Tools will empower you to help many infertile individuals.

What if I want to change a Tool?

Just do it. The Tool Box is made to be changed so that it can be adapted to work in any type of health-care setting anywhere in the world. You know what works best in your situation. Just never stop caring and trying to help infertile people.

Does the Tool Box have a compliments and complaints section?

Yes, it is called the FIGO Committee on Reproductive Medicine. E-mail us at fertilitytool box@figo.org. We would love to hear from you about what you like and what works in the Tool Box and what doesn’t. We hope to constantly improve The FIGO Fertility Tool Box to make it a better Tool to help you tackle the disease/disability of infertility.

Smoking, by either partner, active or passive, negatively affects reproductive health

Pfeifer S, Fritz M, Goldberg J, et al; the Practice Committee of the American Society for Reproductive Medicine. Smoking and infertility: a committee opinion. Fertil Steril. 2012;98(6):1400–1406.

Approximately 30% of reproductive-age women and 35% of reproductive-age men smoke cigarettes. Although smoking has been linked to many adverse health effects, the substantial detrimental effects of cigarette smoking on fecundity and reproduction are under-recognized. In a recent publication, the Practice Committee of the American Society for Reproductive Medicine reviewed the effects of smoking on fertility.

Smoking’s ill effects on fertility

Conception delay

Smokers are at an increased risk for infertility and conception delay. Independent of other factors, smoking has a negative impact on fecundity, with a trend toward increased time to conception with increased number of cigarettes smoked.^2,3 The percentage of women experiencing conception delay for more than 12 months was shown to be 54% higher in smoking versus nonsmoking women in one study.³ These authors found that active smoking by either partner had an adverse effect on conception. Furthermore, the impact of passive smoking by either partner was found to be only slightly less than the impact found for active smoking by either partner.³

Ovarian follicular depletion

Basal levels of follicle-stimulating hormone (FSH) are significantly higher in smokers, with one study demonstrating a 66% increase in smoking versus nonsmoking women and a 39% increase in passive versus nonsmoking women.⁴ Chemicals in cigarette smoke appear to accelerate follicular depletion and loss of reproductive function, and menopause has been found to occur 1 to 4 years earlier in smoking versus nonsmoking women.²

Effects on sperm parameters

Poor function. Smoking has been found to reduce sperm density, motility, and possibly morphology. Sperm function tests appear to be 22% poorer in smokers versus nonsmokers, and the effects are dose-dependent.

No link to male infertility, yet. While evidence suggests an adverse effect on sperm function from smoking, available data do not conclusively demonstrate a reduction in male fertility due to smoking. This could be due to secondary confounding effects of partner status.²

Maternal smoking may decrease sperm counts in offspring, according to Storgaard and colleagues, who found that men whose mothers had smoked more than 10 cigarettes per day had lower sperm densities than men with nonsmoking mothers.⁵

Mutagenic potential

Tobacco smoke exposure may harm gametogenesis by adversely affecting chromosomes and damaging the meiotic spindle and has been associated with an increased risk of trisomy 21 offspring resulting from maternal nondisjunction.^6,7 Gene damage in sperm may be secondary to direct binding of tobacco smoke constituents or chemical byproducts to DNA, creating premutational lesions or “adducts.” These mutagenic adducts have been found in greater numbers in embryos from smokers versus nonsmokers, suggesting a mechanism for the transmission of adversely modified DNA from parental smoking.²

Early pregnancy effects

Smoking increases the risk of spontaneous miscarriage in both natural and assisted conceptions and has been linked to an increased risk for bacterial vaginosis, which in turn increases the risk for second trimester miscarriage and preterm labor.² Studies also have identified an increased risk of ectopic pregnancy in smokers, including one study demonstrating an odds ratio (OR) for ectopic pregnancy of 3.5 (95% confidence interval [CI], 1.4–8.6) in women who smoked more than 20 cigarettes per day versus nonsmokers.⁶

Assisted reproductive therapies rendered less effective

Studies of IVF have demonstrated that smokers versus nonsmokers have an increased gonadotropin requirement for ovarian stimulation, lower peak estradiol levels, elevated testosterone levels, fewer oocytes retrieved, higher numbers of cancelled cycles, thicker zone pellucida, lower implantation rates, and an increased rate of failed fertilization.² In order to achieve conception, smokers require nearly twice the number of IVF cycles versus nonsmokers.² Authors of a 5-year, prospective study controlling for potential confounders found that if a woman ever smoked in her lifetime, her risk of failing to conceive with assisted reproductive technologies (ART) more than doubled (relative risk, 2.5; 95% CI, 1.38–4.55). Each year of smoking was associated with a 9% increase in the risk of unsuccessful ART cycles (95% CI, 1.02–1.15;
P <.01).⁸

We have an important role in helping patients quit

A study involving smoking cessation in infertile women found that simple interventions, such as counseling, education, and encouragement during each clinic visit, were more successful than merely providing educational materials and Web site addresses. The rates of smoking cessation increased from 4% at baseline to 24% after 12 months.⁹

The Public Health Service and National Cancer Institute offer validated, office-based intervention guidelines for smoking cessation, including a five-step approach² :

1. Ask about smoking at every opportunity
2. Advise all smokers to stop
3. Assist willingness to stop
4. Assist patients in stopping (including through the use of pharmaceuticals and carbon monoxide handheld monitors)
5. Arrange follow-up visits.

The use of adjunctive medical therapies, including nicotine replacement therapy and/or buproprion, has resulted in a twofold increase in the proportion of nonpregnant women who quit smoking.² These medical therapies may be useful if behavioral approaches alone fail—although their use has not been studied in infertile women. Smoking cessation rates appear to be higher in infertile versus pregnant women, yet only 18% of women referred for infertility care have received advice on smoking cessation from their referring provider.⁹

The safety of assisted reproductive technologies

Davies ML, Moore VM, Willson KJ, et al. Reproductive technologies and the risk of birth defects. N Engl J Med. 2012;366(19):1803–1813.

Since the birth of Louise Brown, the first baby born after being conceived with in vitro fertilization (IVF) in 1978, IVF has become a pillar in the treatment of infertility. Although recognized as a highly effective treatment, the safety of IVF and its related technologies, such as intracytoplasmic sperm injection (ICSI), has been questioned. Studies have linked the use of assisted reproduction, including IVF and ICSI, with an increased risk of birth defects.^10-15 Findings, however, were limited by small sample sizes and lack of appropriate controls. Furthermore, it has been unclear if this increased risk is due to factors related to treatment or to an underlying factor present in patients with infertility. It also has been unclear whether there is a differential in risk according to the type of ART used. In a large population-wide cohort study, Davies and colleagues linked a census of treatment with ART in South Australia to a registry of births and terminations with a gestation period of at least 20 weeks or a birth weight of 400 g and registries of birth defects.

The authors compared the risk of birth defects in pregnancies among women who had conceived with the use of ART, women with spontaneous pregnancies who had had a previous birth after ART treatment, women with a diagnosis of infertility who had conceived without ART, and pregnancies in women without infertility. Births and pregnancy terminations secondary to birth defects were studied to assess the birth defect risk from pregnancy to a child’s fifth birthday.

Details of the trial

A total of 308,974 births were included in the analysis. Births in women who conceived with the use of ART were associated with a significant increase in risk of birth defects (8.3%) compared with births conceived spontaneously in fertile women (8.3% vs 5.8%, respectively; unadjusted OR, 1.47; 95% CI, 1.33-1.62). This effect remained significant after multivariate adjustment (adjusted OR, 1.28; 95% CI, 1.16-1.41).

While there was no significant association between ART and the risk of specific syndromes such as Down’s, Turner’s, Edward’s, and others, there was a significantly increased adjusted OR for any defect and multiple defects in births conceived with ART versus those conceived spontaneously in fertile women.

The OR for birth defects associated with IVF was 1.26 (95% CI, 1.07-1.48) in unadjusted analyses and 1.07 (95% CI, 0.9-1.26) after multivariate adjustment. The OR for birth defects associated with IVF with ICSI were 1.77 (95% CI, 1.47-2.12) in unadjusted and 1.57 (95% CI, 1.30-1.90) after multivariate analysis. Compared with ICSI, IVF was associated with a reduced risk of any birth defect (OR, 0.68; 95% CI, 0.53-0.87).

Births after gamete intrafallopian transfer, intrauterine insemination, or the use of clomiphene citrate at home were associated with significantly increased risks of any birth defect in adjusted analyses. Births after conception with donor insemination and clinically supervised ovulation induction were not associated with an increased risk of birth defects. Births occurring after spontaneous conception in women with a history of a previous birth with ART were also associated with an increased risk of birth defects, even after adjustment for confounders (adjusted OR, 1.25; 95% CI, 1.01-1.56). Births occurring after spontaneous conception in women with a history of infertility without previous ART treatment were also significantly associated with a small increased risk in birth defects (OR, 1.29; 95% CI, 0.99-1.68).

ICSI and birth-defect association persisted

In this large observational study, the authors confirmed findings from previous studies^11,12,16-18 that the number of birth defects found in pregnancies conceived with ART are higher than the number found in pregnancies conceived spontaneously. In this study, after multivariate adjustment, the association between IVF and an increased risk of birth defects was found to be no longer significant, but the risk remained elevated after ART with ICSI. These findings are similar to results in previous studies.^18,19 The increased risk may be secondary to the ICSI procedure itself^19,20 or to underlying male infertility factors leading to the use of ICSI.¹⁴

Birth defects appeared to be highest in fresh embryo cycles of ICSI versus IVF and lowest in frozen-embryo cycles. A reduction in birth defects with cryopreservation may be secondary to a reduced likelihood that cryopreserved embryos would survive the thawing process as well as the temporal separation of the developing embryo from a hormonally stimulated cycle.^21-23 Treatment with ART was associated with an increased risk of cardiovascular, musculoskeletal, urogenital, and gastrointestinal defects, as well as cerebral palsy. The observation of an increased risk of cerebral palsy with ART treatment is consistent with findings from a previous study. Strömberg and colleagues found that the risk of cerebral palsy was increased by a factor of 3.7 among multiples conceived with IVF and 2.8 among singletons conceived with IVF.²⁴

Davies and colleagues also observed that the risk of a birth defect was increased among women with a history of infertility who were able to conceive without ART,²⁵ a finding observed in a previous large Danish registry.¹⁵

We want to hear from you!  Tell us what you think.

Impaired fertility is no small problem. According to the Centers for Disease Control and Prevention (CDC), it affects 7.3 million women 15 to 44 years old in the United States alone, or approximately 10% of the female population of reproductive age.1

Not long ago, there was little to be done about the problem. Today, however, we have many tools and tactics at our disposal, and another CDC statistic demonstrates their efficacy: Fewer than one third of women who have received medical intervention for impaired fertility in the past year continue to experience the problem.¹

In this article, we highlight three recent developments in fertility:

• We know more about the effects of obesity on fecundity, and more about how to increase the likelihood of pregnancy and live birth in obese women
• The development of in vitro fertilization (IVF) more than 30 years ago represents a significant achievement and vast benefit to mankind, noted the Nobel Committee in awarding the 2010 prize for Physiology or Medicine to Robert Edwards, PhD
• Ovarian hyperstimulation syndrome after controlled ovarian stimulation cannot be avoided completely—but its likelihood can be reduced significantly through careful assessment of the patient and a cautious approach to ovarian stimulation.

Be mindful of the effects of obesity
on a woman’s reproductive function

Obese patients are almost three times as likely as women of normal weight to be infertile. Polycystic ovarian syndrome (PCOS) is generally unmasked or exacerbated, or both, by obesity, and the hyperandrogenicity associated with PCOS can cause ovulatory dysfunction. The hypothalamic-pituitary-ovarian (HPO) axis is also affected by overweight and obesity, resulting in oligo-ovulation in 30% to 47% of women.² Some studies suggest that fecundity may be reduced in ovulatory obese women as well as those with ovulatory dysfunction.² Most obese women are not infertile, however.

Once pregnancy is achieved, the risk of miscarriage is elevated in obese women (odds ratio [OR] ~1.67), and the live birth rate is lower (OR ~0.75), compared with women of normal weight.^2–4 Obese women also have an elevated risk of miscarriage after egg donation (OR ~1.52) and ovulation induction (OR ~5.11). There is no evidence that the rate of miscarriage is increased after IVF, compared with other treatments.

The diagnosis of infertility is difficult in obese patients because the pelvic examination is less informative, although ultrasonography (US) is usually helpful.⁵ In addition, obesity can blur the distinction between PCOS and HPO axis-related oligo-ovulation. Laparoscopy and other diagnostic interventions are performed less frequently in obese women, and complications of diagnostic laparoscopy are higher in this population.³

Take the initiative in recommending weight loss

As health-care providers, we need to be more proactive in recommending lifestyle changes for obese women so that they lose weight before pregnancy. Women who have infertility are usually very motivated to conceive; as a result, they may also be motivated to lose weight. Caloric restriction, increased physical activity, behavioral modification, and professional expertise are all essential for successful weight loss.² Even a reduction as small as 5% to 10% of body weight can have clinical benefit.^2,4,5

Metformin is an additional option. When combined with a low-calorie diet, metformin may lead to weight loss, restore ovulation, and improve fecundity in women who have PCOS.²

Bariatric surgery is now commonly reserved for women whose body weight is 45 kg or more above normal. Bariatric surgery can improve the altered hormone profile, including elevated thyroid-stimulating hormone (TSH), of obese women. It also appears to improve fecundity and reduce pregnancy-associated complications. However, it is not always successful and can have complications of its own.

What can you offer to obese patients who experience infertility?

• Clomiphene citrate is the most commonly used ovarian-stimulation agent for oligo-ovulation that arises from PCOS or HPO-axis disruption; it is most effective in patients of normal weight.^4,6 The protocols associated with clomiphene administration in obese patients are similar to those for women of normal weight; so are results, although the pregnancy rate is not as high in obese women.
• Gonadotropins are effective ovarian-stimulation drugs that are used in hypothalamic hypogonadal patients as well as after failed treatment with clomiphene citrate. Gonadotropins can be effective even in very obese patients; the dosage increases with body mass index (BMI).^4,6
• Metformin reduces insulin resistance in women who have PCOS. By itself, metformin is ineffective at inducing ovulation and has not proved to increase the pregnancy rate when it is added to clomiphene.⁵ Nevertheless, it is commonly given at a daily dosage of 1,000 to 2,000 mg to women who have hyperinsulinemia, and it may reduce the miscarriage rate in women who have PCOS.
• Other medications that have been used to enhance ovulation in obese women include dexamethasone to reduce elevated androgen levels, bromocryptine for elevated prolactin levels, and thyroid hormone for hypothyroidism.

FOR WOMEN WHO HAVE PCOS
In laparoscopic ovarian drilling, an insulated needle unipolar electrode is inserted in the ovary perpendicular to the surface to create 6 to 12 evenly spaced punctures using 40 watts of coagulating current for 2 seconds at each point. The mechanism of action is unclear, but it is thought that the destruction of androgen-producing stroma is responsible for the reduction in testosterone level, increase in follicle-stimulating hormone (FSH), and return to FSH cyclicity in 80% of cases.

• Among obese women who have oligo-ovulation, ovarian drilling (FIGURE) is generally reserved for patients who have not responded to clomiphene or gonadotropins. This procedure has proved to be as effective as clomiphene administration, with the advantage that it does not increase the risk of multiple gestation and leads to longstanding improvement in one third of patients.⁵ Ovarian drilling is a modification of ovarian wedge resection for women who have PCOS. The mechanism of action is not clear, but it is thought that destruction of adrogen-producing stroma causes an immediate reduction in testosterone, an increase in follicle-stimulating hormone (FSH), and a return to FSH cyclicity in 80% of cases. These effects can persist for several years, and a pregnancy rate of approximately 60% can be attained in less than 6 months. Clomiphene-resistant women may be more responsive to the drug after ovarian drilling, and the risk of ovarian hyperstimulation appears to be reduced. Ovarian drilling is less effective in obese women than in women of normal weight. Complications include adhesions around the ovary and reduced ovarian reserve.
• Assisted reproductive technology (ART) is sometimes used in this population, but it is less likely to lead to pregnancy and live birth, for unknown reasons.^2,3 We inform obese women that a BMI below 30 is desirable before ART.

IVF is cited by Nobel Committee for its “benefit to mankind”

On December 10, 2010, Robert Edwards, PhD, was awarded the Nobel Prize in Physiology or Medicine for his innovative and pioneering work to create IVF. In presenting the award, the Committee noted that Professor Edwards’ work “represents a monumental medical advance that can truly be said to confer the greatest benefit to mankind.”

Professor Edwards is the embryologist who performed the basic science and laboratory work, along with Dr. Patrick Steptoe, who provided clinical care, which led to the birth of the world’s first IVF baby, Louise Brown, on July 25, 1978. Since then, IVF has become the most successful treatment for infertility and is available in more than 100 countries. The delivery rate for each single IVF attempt is about 25% globally; it more than doubles in selected patients who have a good prognosis. In some countries, almost 5% of all births arise from IVF; in the United States, that figure is about 1%. The International Committee Monitoring ART (ICMART) estimates that more than 4 million babies have been born from IVF around the world.

Prof. Robert Edwards (left) holds the infant Louise Brown

Early road was rocky

Despite the broad and significant success of IVF, Professor Edwards struggled for years against scientific and social opposition. His research was opposed by some on ethical and religious grounds, and the United Kingdom refused to fund some of his early work. The initial lack of support for IVF has transformed into acceptance as infertility has been recognized as a disease by many governments and the World Health Organization (WHO). In addition, the Centers for Disease Control and Prevention (CDC) has recognized infertility as a public health issue.

Nevertheless, most insurers still provide inadequate IVF coverage because of misperceptions about infertility and lack of recognition that it is a disease that globally affects 9% of all women of reproductive age, with male-partner sperm problems contributing to the problem in about 50% of cases.

IVF technologies achieve many goals

Over the past 32 years, IVF has revolutionized reproductive medicine and the treatment of infertility and brought an entirely new science to human reproduction. Specific IVF technologies that have changed the face of medicine include:

• intracytoplasmic sperm injection (ICSI) to treat male factor infertility
• cryopreservation or vitrification of sperm, eggs, and embryos to allow optimal results from IVF and to help cancer patients have babies after treatment
• preimplantation genetic diagnosis (PGD) to prevent major genetic diseases. (For more on PGD, see the January 2009 “Update on Prenatal Counseling” in our archive at www.obgmanagement.com.)

Much scientific research is now directed toward assessing the quality of embryos so that the live birth rate can be increased at the same time that multiple births are reduced. Advances in PGD and stem cell research show great promise for the future of human reproduction and the management of diseases of all organ systems.

Ovarian hyperstimulation can be tempered
through strategic management

Controlled ovarian stimulation is pharmacotherapy of the ovaries to produce more than one oocyte in non-ART cycles or to produce multiple oocytes for retrieval at follicular aspiration.⁷ Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic, and potentially serious, complication of controlled ovarian stimulation. With vigilant management, however, its risks and sequelae can be reduced.

Best approach: Prevent OHSS

To reduce a woman’s risk of OHSS, identify her risk factors and employ the appropriate prevention strategies. The list of potential risk factors includes:

• age <33 years
• PCOS or its features
• high antral follicle count
• history of OHSS
• high basal anti-müllerian hormone level
• robust response to ovarian stimulation (≥18 follicles or estrogen level of 5,000 ng/dL, or both).

Once that patient’s risk is established, steps can be taken to judiciously manage her cycle and reduce the likelihood that she will develop OHSS.

Prevention strategies include:

• lowering the dosage of gonadotropin (consider a gonadotropin-releasing hormone [GnRH] antagonist protocol)
• coasting cycles until the estradiol level plateaus or decreases (reduce the dosage of human chorionic gonadotropin [hCG], use a GnRH agonist trigger for antagonist cycles, and avoid using hCG for luteal support)
• using an insulin-sensitizing agent such as metformin
• cryopreserving embryos for transfer at a later date (consider in vitro maturation instead of standard IVF [experimental]).⁸

Proposed clinical grading system for OHSS

Criteria	How would OHSS be graded?
	Mild	Moderate	Severe
Objective findings
Fluid in pouch of Douglas
Fluid around uterus (major pelvis)
Fluid around intestinal loops
Hematocrit >45%		*
White blood cells >15,000/mm3		±*
Low urine output <600 mL/24 h		±*
Creatinine >1.5 mg/dL		±*	±
Elevated transaminases		±*	±
Clotting disorder			±†
Pleural effusion			±†
Subjective findings
Abdominal distention
Pelvic discomfort
Breathing disorder	±**	±**
Acute pain	±**	±**	±**
Nausea and vomiting	±	±	±
Ovarian enlargement
Pregnancy occurrence	±	±
Note: ± indicates that the finding may or may not be present.
* If two of these are present, consider hospitalization
† If present, consider intensive care
** If present, consider hospitalization
SOURCE: Humaidan P, et al.8

OHSS has usually been classified according to the signs and symptoms present.⁹ However, Humaidan and colleagues recently presented a new classification system for OHSS that is also based on objective vaginal US and laboratory parameters, as well as volume of fluid shifts (TABLE).⁸

We want to hear from you! Tell us what you think.

Impaired fertility is no small problem. According to the Centers for Disease Control and Prevention (CDC), it affects 7.3 million women 15 to 44 years old in the United States alone, or approximately 10% of the female population of reproductive age.1

Not long ago, there was little to be done about the problem. Today, however, we have many tools and tactics at our disposal, and another CDC statistic demonstrates their efficacy: Fewer than one third of women who have received medical intervention for impaired fertility in the past year continue to experience the problem.¹

In this article, we highlight three recent developments in fertility:

• We know more about the effects of obesity on fecundity, and more about how to increase the likelihood of pregnancy and live birth in obese women
• The development of in vitro fertilization (IVF) more than 30 years ago represents a significant achievement and vast benefit to mankind, noted the Nobel Committee in awarding the 2010 prize for Physiology or Medicine to Robert Edwards, PhD
• Ovarian hyperstimulation syndrome after controlled ovarian stimulation cannot be avoided completely—but its likelihood can be reduced significantly through careful assessment of the patient and a cautious approach to ovarian stimulation.

Be mindful of the effects of obesity
on a woman’s reproductive function

Obese patients are almost three times as likely as women of normal weight to be infertile. Polycystic ovarian syndrome (PCOS) is generally unmasked or exacerbated, or both, by obesity, and the hyperandrogenicity associated with PCOS can cause ovulatory dysfunction. The hypothalamic-pituitary-ovarian (HPO) axis is also affected by overweight and obesity, resulting in oligo-ovulation in 30% to 47% of women.² Some studies suggest that fecundity may be reduced in ovulatory obese women as well as those with ovulatory dysfunction.² Most obese women are not infertile, however.

Once pregnancy is achieved, the risk of miscarriage is elevated in obese women (odds ratio [OR] ~1.67), and the live birth rate is lower (OR ~0.75), compared with women of normal weight.^2–4 Obese women also have an elevated risk of miscarriage after egg donation (OR ~1.52) and ovulation induction (OR ~5.11). There is no evidence that the rate of miscarriage is increased after IVF, compared with other treatments.

The diagnosis of infertility is difficult in obese patients because the pelvic examination is less informative, although ultrasonography (US) is usually helpful.⁵ In addition, obesity can blur the distinction between PCOS and HPO axis-related oligo-ovulation. Laparoscopy and other diagnostic interventions are performed less frequently in obese women, and complications of diagnostic laparoscopy are higher in this population.³

Take the initiative in recommending weight loss

As health-care providers, we need to be more proactive in recommending lifestyle changes for obese women so that they lose weight before pregnancy. Women who have infertility are usually very motivated to conceive; as a result, they may also be motivated to lose weight. Caloric restriction, increased physical activity, behavioral modification, and professional expertise are all essential for successful weight loss.² Even a reduction as small as 5% to 10% of body weight can have clinical benefit.^2,4,5

Metformin is an additional option. When combined with a low-calorie diet, metformin may lead to weight loss, restore ovulation, and improve fecundity in women who have PCOS.²

Bariatric surgery is now commonly reserved for women whose body weight is 45 kg or more above normal. Bariatric surgery can improve the altered hormone profile, including elevated thyroid-stimulating hormone (TSH), of obese women. It also appears to improve fecundity and reduce pregnancy-associated complications. However, it is not always successful and can have complications of its own.

What can you offer to obese patients who experience infertility?

• Clomiphene citrate is the most commonly used ovarian-stimulation agent for oligo-ovulation that arises from PCOS or HPO-axis disruption; it is most effective in patients of normal weight.^4,6 The protocols associated with clomiphene administration in obese patients are similar to those for women of normal weight; so are results, although the pregnancy rate is not as high in obese women.
• Gonadotropins are effective ovarian-stimulation drugs that are used in hypothalamic hypogonadal patients as well as after failed treatment with clomiphene citrate. Gonadotropins can be effective even in very obese patients; the dosage increases with body mass index (BMI).^4,6
• Metformin reduces insulin resistance in women who have PCOS. By itself, metformin is ineffective at inducing ovulation and has not proved to increase the pregnancy rate when it is added to clomiphene.⁵ Nevertheless, it is commonly given at a daily dosage of 1,000 to 2,000 mg to women who have hyperinsulinemia, and it may reduce the miscarriage rate in women who have PCOS.
• Other medications that have been used to enhance ovulation in obese women include dexamethasone to reduce elevated androgen levels, bromocryptine for elevated prolactin levels, and thyroid hormone for hypothyroidism.

FOR WOMEN WHO HAVE PCOS
In laparoscopic ovarian drilling, an insulated needle unipolar electrode is inserted in the ovary perpendicular to the surface to create 6 to 12 evenly spaced punctures using 40 watts of coagulating current for 2 seconds at each point. The mechanism of action is unclear, but it is thought that the destruction of androgen-producing stroma is responsible for the reduction in testosterone level, increase in follicle-stimulating hormone (FSH), and return to FSH cyclicity in 80% of cases.

• Among obese women who have oligo-ovulation, ovarian drilling (FIGURE) is generally reserved for patients who have not responded to clomiphene or gonadotropins. This procedure has proved to be as effective as clomiphene administration, with the advantage that it does not increase the risk of multiple gestation and leads to longstanding improvement in one third of patients.⁵ Ovarian drilling is a modification of ovarian wedge resection for women who have PCOS. The mechanism of action is not clear, but it is thought that destruction of adrogen-producing stroma causes an immediate reduction in testosterone, an increase in follicle-stimulating hormone (FSH), and a return to FSH cyclicity in 80% of cases. These effects can persist for several years, and a pregnancy rate of approximately 60% can be attained in less than 6 months. Clomiphene-resistant women may be more responsive to the drug after ovarian drilling, and the risk of ovarian hyperstimulation appears to be reduced. Ovarian drilling is less effective in obese women than in women of normal weight. Complications include adhesions around the ovary and reduced ovarian reserve.
• Assisted reproductive technology (ART) is sometimes used in this population, but it is less likely to lead to pregnancy and live birth, for unknown reasons.^2,3 We inform obese women that a BMI below 30 is desirable before ART.

IVF is cited by Nobel Committee for its “benefit to mankind”

On December 10, 2010, Robert Edwards, PhD, was awarded the Nobel Prize in Physiology or Medicine for his innovative and pioneering work to create IVF. In presenting the award, the Committee noted that Professor Edwards’ work “represents a monumental medical advance that can truly be said to confer the greatest benefit to mankind.”

Professor Edwards is the embryologist who performed the basic science and laboratory work, along with Dr. Patrick Steptoe, who provided clinical care, which led to the birth of the world’s first IVF baby, Louise Brown, on July 25, 1978. Since then, IVF has become the most successful treatment for infertility and is available in more than 100 countries. The delivery rate for each single IVF attempt is about 25% globally; it more than doubles in selected patients who have a good prognosis. In some countries, almost 5% of all births arise from IVF; in the United States, that figure is about 1%. The International Committee Monitoring ART (ICMART) estimates that more than 4 million babies have been born from IVF around the world.

Prof. Robert Edwards (left) holds the infant Louise Brown

Early road was rocky

Despite the broad and significant success of IVF, Professor Edwards struggled for years against scientific and social opposition. His research was opposed by some on ethical and religious grounds, and the United Kingdom refused to fund some of his early work. The initial lack of support for IVF has transformed into acceptance as infertility has been recognized as a disease by many governments and the World Health Organization (WHO). In addition, the Centers for Disease Control and Prevention (CDC) has recognized infertility as a public health issue.

Nevertheless, most insurers still provide inadequate IVF coverage because of misperceptions about infertility and lack of recognition that it is a disease that globally affects 9% of all women of reproductive age, with male-partner sperm problems contributing to the problem in about 50% of cases.

IVF technologies achieve many goals

Over the past 32 years, IVF has revolutionized reproductive medicine and the treatment of infertility and brought an entirely new science to human reproduction. Specific IVF technologies that have changed the face of medicine include:

• intracytoplasmic sperm injection (ICSI) to treat male factor infertility
• cryopreservation or vitrification of sperm, eggs, and embryos to allow optimal results from IVF and to help cancer patients have babies after treatment
• preimplantation genetic diagnosis (PGD) to prevent major genetic diseases. (For more on PGD, see the January 2009 “Update on Prenatal Counseling” in our archive at www.obgmanagement.com.)

Much scientific research is now directed toward assessing the quality of embryos so that the live birth rate can be increased at the same time that multiple births are reduced. Advances in PGD and stem cell research show great promise for the future of human reproduction and the management of diseases of all organ systems.

Ovarian hyperstimulation can be tempered
through strategic management

Controlled ovarian stimulation is pharmacotherapy of the ovaries to produce more than one oocyte in non-ART cycles or to produce multiple oocytes for retrieval at follicular aspiration.⁷ Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic, and potentially serious, complication of controlled ovarian stimulation. With vigilant management, however, its risks and sequelae can be reduced.

Best approach: Prevent OHSS

To reduce a woman’s risk of OHSS, identify her risk factors and employ the appropriate prevention strategies. The list of potential risk factors includes:

• age <33 years
• PCOS or its features
• high antral follicle count
• history of OHSS
• high basal anti-müllerian hormone level
• robust response to ovarian stimulation (≥18 follicles or estrogen level of 5,000 ng/dL, or both).

Once that patient’s risk is established, steps can be taken to judiciously manage her cycle and reduce the likelihood that she will develop OHSS.

Prevention strategies include:

• lowering the dosage of gonadotropin (consider a gonadotropin-releasing hormone [GnRH] antagonist protocol)
• coasting cycles until the estradiol level plateaus or decreases (reduce the dosage of human chorionic gonadotropin [hCG], use a GnRH agonist trigger for antagonist cycles, and avoid using hCG for luteal support)
• using an insulin-sensitizing agent such as metformin
• cryopreserving embryos for transfer at a later date (consider in vitro maturation instead of standard IVF [experimental]).⁸

Proposed clinical grading system for OHSS

OHSS has usually been classified according to the signs and symptoms present.⁹ However, Humaidan and colleagues recently presented a new classification system for OHSS that is also based on objective vaginal US and laboratory parameters, as well as volume of fluid shifts (TABLE).⁸

We want to hear from you! Tell us what you think.

Impaired fertility is no small problem. According to the Centers for Disease Control and Prevention (CDC), it affects 7.3 million women 15 to 44 years old in the United States alone, or approximately 10% of the female population of reproductive age.1

Not long ago, there was little to be done about the problem. Today, however, we have many tools and tactics at our disposal, and another CDC statistic demonstrates their efficacy: Fewer than one third of women who have received medical intervention for impaired fertility in the past year continue to experience the problem.¹

In this article, we highlight three recent developments in fertility:

• We know more about the effects of obesity on fecundity, and more about how to increase the likelihood of pregnancy and live birth in obese women
• The development of in vitro fertilization (IVF) more than 30 years ago represents a significant achievement and vast benefit to mankind, noted the Nobel Committee in awarding the 2010 prize for Physiology or Medicine to Robert Edwards, PhD
• Ovarian hyperstimulation syndrome after controlled ovarian stimulation cannot be avoided completely—but its likelihood can be reduced significantly through careful assessment of the patient and a cautious approach to ovarian stimulation.

Be mindful of the effects of obesity
on a woman’s reproductive function

Obese patients are almost three times as likely as women of normal weight to be infertile. Polycystic ovarian syndrome (PCOS) is generally unmasked or exacerbated, or both, by obesity, and the hyperandrogenicity associated with PCOS can cause ovulatory dysfunction. The hypothalamic-pituitary-ovarian (HPO) axis is also affected by overweight and obesity, resulting in oligo-ovulation in 30% to 47% of women.² Some studies suggest that fecundity may be reduced in ovulatory obese women as well as those with ovulatory dysfunction.² Most obese women are not infertile, however.

Once pregnancy is achieved, the risk of miscarriage is elevated in obese women (odds ratio [OR] ~1.67), and the live birth rate is lower (OR ~0.75), compared with women of normal weight.^2–4 Obese women also have an elevated risk of miscarriage after egg donation (OR ~1.52) and ovulation induction (OR ~5.11). There is no evidence that the rate of miscarriage is increased after IVF, compared with other treatments.

The diagnosis of infertility is difficult in obese patients because the pelvic examination is less informative, although ultrasonography (US) is usually helpful.⁵ In addition, obesity can blur the distinction between PCOS and HPO axis-related oligo-ovulation. Laparoscopy and other diagnostic interventions are performed less frequently in obese women, and complications of diagnostic laparoscopy are higher in this population.³

Take the initiative in recommending weight loss

As health-care providers, we need to be more proactive in recommending lifestyle changes for obese women so that they lose weight before pregnancy. Women who have infertility are usually very motivated to conceive; as a result, they may also be motivated to lose weight. Caloric restriction, increased physical activity, behavioral modification, and professional expertise are all essential for successful weight loss.² Even a reduction as small as 5% to 10% of body weight can have clinical benefit.^2,4,5

Metformin is an additional option. When combined with a low-calorie diet, metformin may lead to weight loss, restore ovulation, and improve fecundity in women who have PCOS.²

Bariatric surgery is now commonly reserved for women whose body weight is 45 kg or more above normal. Bariatric surgery can improve the altered hormone profile, including elevated thyroid-stimulating hormone (TSH), of obese women. It also appears to improve fecundity and reduce pregnancy-associated complications. However, it is not always successful and can have complications of its own.

What can you offer to obese patients who experience infertility?

• Clomiphene citrate is the most commonly used ovarian-stimulation agent for oligo-ovulation that arises from PCOS or HPO-axis disruption; it is most effective in patients of normal weight.^4,6 The protocols associated with clomiphene administration in obese patients are similar to those for women of normal weight; so are results, although the pregnancy rate is not as high in obese women.
• Gonadotropins are effective ovarian-stimulation drugs that are used in hypothalamic hypogonadal patients as well as after failed treatment with clomiphene citrate. Gonadotropins can be effective even in very obese patients; the dosage increases with body mass index (BMI).^4,6
• Metformin reduces insulin resistance in women who have PCOS. By itself, metformin is ineffective at inducing ovulation and has not proved to increase the pregnancy rate when it is added to clomiphene.⁵ Nevertheless, it is commonly given at a daily dosage of 1,000 to 2,000 mg to women who have hyperinsulinemia, and it may reduce the miscarriage rate in women who have PCOS.
• Other medications that have been used to enhance ovulation in obese women include dexamethasone to reduce elevated androgen levels, bromocryptine for elevated prolactin levels, and thyroid hormone for hypothyroidism.

FOR WOMEN WHO HAVE PCOS
In laparoscopic ovarian drilling, an insulated needle unipolar electrode is inserted in the ovary perpendicular to the surface to create 6 to 12 evenly spaced punctures using 40 watts of coagulating current for 2 seconds at each point. The mechanism of action is unclear, but it is thought that the destruction of androgen-producing stroma is responsible for the reduction in testosterone level, increase in follicle-stimulating hormone (FSH), and return to FSH cyclicity in 80% of cases.

• Among obese women who have oligo-ovulation, ovarian drilling (FIGURE) is generally reserved for patients who have not responded to clomiphene or gonadotropins. This procedure has proved to be as effective as clomiphene administration, with the advantage that it does not increase the risk of multiple gestation and leads to longstanding improvement in one third of patients.⁵ Ovarian drilling is a modification of ovarian wedge resection for women who have PCOS. The mechanism of action is not clear, but it is thought that destruction of adrogen-producing stroma causes an immediate reduction in testosterone, an increase in follicle-stimulating hormone (FSH), and a return to FSH cyclicity in 80% of cases. These effects can persist for several years, and a pregnancy rate of approximately 60% can be attained in less than 6 months. Clomiphene-resistant women may be more responsive to the drug after ovarian drilling, and the risk of ovarian hyperstimulation appears to be reduced. Ovarian drilling is less effective in obese women than in women of normal weight. Complications include adhesions around the ovary and reduced ovarian reserve.
• Assisted reproductive technology (ART) is sometimes used in this population, but it is less likely to lead to pregnancy and live birth, for unknown reasons.^2,3 We inform obese women that a BMI below 30 is desirable before ART.

IVF is cited by Nobel Committee for its “benefit to mankind”

On December 10, 2010, Robert Edwards, PhD, was awarded the Nobel Prize in Physiology or Medicine for his innovative and pioneering work to create IVF. In presenting the award, the Committee noted that Professor Edwards’ work “represents a monumental medical advance that can truly be said to confer the greatest benefit to mankind.”

Professor Edwards is the embryologist who performed the basic science and laboratory work, along with Dr. Patrick Steptoe, who provided clinical care, which led to the birth of the world’s first IVF baby, Louise Brown, on July 25, 1978. Since then, IVF has become the most successful treatment for infertility and is available in more than 100 countries. The delivery rate for each single IVF attempt is about 25% globally; it more than doubles in selected patients who have a good prognosis. In some countries, almost 5% of all births arise from IVF; in the United States, that figure is about 1%. The International Committee Monitoring ART (ICMART) estimates that more than 4 million babies have been born from IVF around the world.

Prof. Robert Edwards (left) holds the infant Louise Brown

Early road was rocky

Despite the broad and significant success of IVF, Professor Edwards struggled for years against scientific and social opposition. His research was opposed by some on ethical and religious grounds, and the United Kingdom refused to fund some of his early work. The initial lack of support for IVF has transformed into acceptance as infertility has been recognized as a disease by many governments and the World Health Organization (WHO). In addition, the Centers for Disease Control and Prevention (CDC) has recognized infertility as a public health issue.

Nevertheless, most insurers still provide inadequate IVF coverage because of misperceptions about infertility and lack of recognition that it is a disease that globally affects 9% of all women of reproductive age, with male-partner sperm problems contributing to the problem in about 50% of cases.

IVF technologies achieve many goals

Over the past 32 years, IVF has revolutionized reproductive medicine and the treatment of infertility and brought an entirely new science to human reproduction. Specific IVF technologies that have changed the face of medicine include:

• intracytoplasmic sperm injection (ICSI) to treat male factor infertility
• cryopreservation or vitrification of sperm, eggs, and embryos to allow optimal results from IVF and to help cancer patients have babies after treatment
• preimplantation genetic diagnosis (PGD) to prevent major genetic diseases. (For more on PGD, see the January 2009 “Update on Prenatal Counseling” in our archive at www.obgmanagement.com.)

Much scientific research is now directed toward assessing the quality of embryos so that the live birth rate can be increased at the same time that multiple births are reduced. Advances in PGD and stem cell research show great promise for the future of human reproduction and the management of diseases of all organ systems.

Ovarian hyperstimulation can be tempered
through strategic management

Controlled ovarian stimulation is pharmacotherapy of the ovaries to produce more than one oocyte in non-ART cycles or to produce multiple oocytes for retrieval at follicular aspiration.⁷ Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic, and potentially serious, complication of controlled ovarian stimulation. With vigilant management, however, its risks and sequelae can be reduced.

Best approach: Prevent OHSS

To reduce a woman’s risk of OHSS, identify her risk factors and employ the appropriate prevention strategies. The list of potential risk factors includes:

• age <33 years
• PCOS or its features
• high antral follicle count
• history of OHSS
• high basal anti-müllerian hormone level
• robust response to ovarian stimulation (≥18 follicles or estrogen level of 5,000 ng/dL, or both).

Once that patient’s risk is established, steps can be taken to judiciously manage her cycle and reduce the likelihood that she will develop OHSS.

Prevention strategies include:

• lowering the dosage of gonadotropin (consider a gonadotropin-releasing hormone [GnRH] antagonist protocol)
• coasting cycles until the estradiol level plateaus or decreases (reduce the dosage of human chorionic gonadotropin [hCG], use a GnRH agonist trigger for antagonist cycles, and avoid using hCG for luteal support)
• using an insulin-sensitizing agent such as metformin
• cryopreserving embryos for transfer at a later date (consider in vitro maturation instead of standard IVF [experimental]).⁸

Proposed clinical grading system for OHSS

OHSS has usually been classified according to the signs and symptoms present.⁹ However, Humaidan and colleagues recently presented a new classification system for OHSS that is also based on objective vaginal US and laboratory parameters, as well as volume of fluid shifts (TABLE).⁸

We want to hear from you! Tell us what you think.

Infertility and its treatment can be a roller-coaster ride for patient and physician. Amid the emotional stress that arises, the goal of treatment can inadvertently shift from achievement of a successful singleton pregnancy to pregnancy at any cost—even high-order multiple gestation.

Here’s an essential question: Can the rate of multiple gestation be reduced without seriously compromising the pregnancy rate? Several developments of the past year suggest that it can be. In this article, we discuss:

• new guidelines that limit the number of embryos to be transferred at in vitro fertilization (IVF)
• strategies to reduce the risk of multiple gestation after controlled ovarian stimulation or ovulation induction
• the need to address the patient’s emotional status during treatment
• a new index that helps predict the pregnancy rate after surgical staging of endometriosis.

Multiple gestation is known to have adverse effects on infants, including a significantly elevated risk of prematurity and related physical and developmental problems. It also greatly increases the need for resources. And the high cost of caring for infants affected by prematurity further burdens an already overwhelmed health-care system.

Not only is it essential that we reduce the rate of high-order multiple gestation (i.e., more than two fetuses), but we should also attempt to lower the rate of twin pregnancy. A healthy singleton pregnancy, with its diminished risks and more reasonable health-care cost, should be our goal.

New guidelines limit the number of embryos to be transferred at IVF

Practice Committee of the American Society for Reproductive Medicine, Practice Committee of the Society for Assisted Reproductive Technology. Guidelines on number of embryos transferred. Fertil Steril. 2009;92:1518–1519.

Since the birth of Louise Brown in 1978, assisted reproductive technology (ART) has enjoyed dramatic technological advances. Intracytoplasmic sperm injection (FIGURE 1), preimplantation genetic diagnosis, and improvements in cryopreservation have broadened the application of ART and increased the live birth rate to 30% for every cycle that is initiated. The cumulative live birth rate from additional fresh and frozen-thawed cycles can reach 50% to 80%.

These gains have not come without cost, however. Multiple emotional, financial, and other variables affecting the practice of IVF have produced a higher-than-natural rate of multiple gestation.

In November 2009, the Society for Assisted Reproductive Technology (SART) and the American Society for Reproductive Medicine (ASRM) issued new guidelines limiting the number of embryos that should be transferred in one IVF cycle. IVF clinics are required to report outcomes, and approximately 93% of US cycles are reported to SART. High-order multiple-pregnancy rates are audited by SART, and outlier clinics must implement remediation programs to lower their high rate or risk expulsion from SART.

The increasing emphasis on single-embryo transfer in young women who have a good prognosis reflects the societies’ commitment to help patients achieve a healthy singleton pregnancy and good birth outcome.

FIGURE 1 A wonder of technology

Intracytoplasmic sperm injection overcomes many barriers to fertilization, such as severe malefactor infertility. At some institutions, the technique yields a fertilization rate of 70% to 80%.

What makes a “good prognosis”?

Identification of patients who have a good prognosis is an essential component of these new guidelines. The patient is more likely to have a favorable outcome if one or more of the following is true:

• She is undergoing her first cycle of IVF
• The embryos have good morphology
• Excess embryos are available for cryopreservation
• She has had earlier success with IVF.

The TABLE details the recommended number of embryos to transfer, based on the age and prognosis of the patient. In cycles that involve a donor egg, base the number of embryos to be transferred on the age of the donor. In cycles that involve a frozen embryo, base the number of good-quality, thawed embryos to be transferred on the age of the patient at the time the embryos were created. One additional embryo may be transferred if the patient has a less favorable prognosis or a history of two failed, fresh IVF cycles.

Two important requisites: Careful counseling about the risk of high-order multiple gestation, and documentation of that counseling.

TABLE

SART and ASRM recommend limits on the number of embryos to be transferred at in vitro fertilization

Judicious management can reduce the rate of multiple gestation in ovulation stimulation

Dickey RP. Strategies to reduce multiple pregnancies due to ovulation stimulation. Fertil Steril. 2009;91:1–17.

Efforts to reduce the rate of multiple gestation should focus not only on patients undergoing IVF but on those undergoing controlled ovarian stimulation (COS) or ovulation induction. In COS, pharmacologic treatment is used to stimulate the production of more than one oocyte. In ovulation induction, pharmacologic therapy is used to induce normal cycles in anovulatory or oligo-ovulatory women.¹ A substantial majority of multiple gestations are conceived using ovarian stimulation and ovulation induction. These methods may be less difficult to manage than IVF because they are less dependent on technology. Like IVF, however, they carry a high risk of multiple gestation, especially high-order multiple gestation.²

Strategies to reduce multiple gestation

As Dickey points out in a comprehensive retrospective analysis, there are strategies that can help reduce multiple gestation during COS and ovulation induction. They include the following recommendations:

Be prepared to cancel a cycle. Initiate ovulation induction only if both patient and physician are prepared to cancel any cycle that involves an excessive number of preovulatory follicles. Singleton and twin births can be confidently expected only if the cycle is cancelled when there are more than two preovulatory follicles approximately 12 mm in diameter or larger. This may be psychologically difficult for some patients and doctors.

Preemptively identify risk factors for multiple gestation, including:

• seven or more preovulatory follicles
• an estradiol concentration of 1,000 pg/mL or higher
• early cycles of treatment (cycles 1–3)
• age younger than 32 years
• body mass index below 19 kg/m²
• use of donor sperm.

When any of these risk factors is present, consider starting the patient on a lower initial dosage of gonadotropin; perform more frequent monitoring; maintain a low threshold for cancellation; and consider performing IVF with single-embryo transfer rather than COS.

Use specific drugs. Increase the likelihood of monofollicular development and double-follicular recruitment and reduce the risk of high-order multiple gestation by using clomiphene citrate, a low dosage of gonadotropin, or pulsatile gonadotropin-releasing hormone (GnRH) in the initial three or four cycles.

Continue treatment for five or more cycles to achieve an overall pregnancy rate approaching 65% without high-order multiple gestation in patients younger than 38 years who develop one or two follicles in a cycle.

Don’t rely on multifetal pregnancy reduction

This strategy has been viewed by some as a way to control the outcome of multiple gestation. For example, this is a common approach in New York, New Jersey, and Connecticut. However, the procedure has pitfalls and should not be the primary means of reducing the rate of multiple gestation because:

• It is not an acceptable option for many patients
• All fetuses may be lost in some cases
• The risks associated with multiple gestation are not completely eliminated
• It may have adverse psychological consequences.^3,4

A registry is needed

Although a registry exists for IVF cycles and their outcomes and complications, none exists for cycles involving COS or ovulation induction. Despite many challenges to its development, we support the creation of such a registry.

Consider the patient’s emotional status when determining treatment for infertility

Domar AD, Smith K, Conboy L, Iannone M, Alper M. A prospective investigation into the reasons why insured United States patients drop out of in vitro fertilization treatment. Fertil Steril. 2009 Jul 8 [Epub ahead of print].

Most physicians have been trained to concentrate on the physiologic diagnosis and management of disease. Many fertility specialists also pay attention to economic barriers to treatment, such as lack of insurance and high cost, and attempt to help their patients gain access to quality care. One aspect of infertility that might be overlooked, however, is the patient’s emotional health—but it may be as important to the success of treatment as physiologic and economic variables.

A recent prospective investigation into the reasons insured patients drop out of IVF in the United States clearly demonstrated the psychological toll infertility can take. The study found that emotional distress is the number one reason that patients discontinue treatment.

How to lower the patient’s stress level

It can be challenging to counsel the patient to set realistic expectations for success yet enable her to maintain a sense of optimism. Stress management may be a key to success.

Physicians who treat patients with fertility problems should consider offering an in-practice counseling service aimed at reducing stress and improving coping mechanisms. At the very least, physicians should refer patients to outside resources that may be able to provide these services in a way that is meaningful and accessible.

Caring for a patient’s emotional well-being takes both time and skill. Besides offering direct emotional support to your patients, you can be a bridge to mental health and support services.

Patients who participate in a stress-reduction program while undergoing fertility treatment are 1) less likely to experience harmful emotional side effects and 2) more likely to continue treatment. Physicians who make such “mind-body” programs available are likely to reduce treatment dropout, improve the pregnancy rate, and increase the number of patients who take home babies.

New endometriosis fertility index predicts non-IVF success rate

Adamson GD, Pasta DJ. Endometriosis fertility index: the new, validated endometriosis staging system. Fertil Steril. 2009 Nov 18 [Epub ahead of print].

Endometriosis remains a frustrating disease for patients who have infertility, in part because no staging system has made it possible for physicians to predict the pregnancy rate with fertility treatment other than IVF. The new, validated endometriosis fertility index (EFI) changes that. This simple, robust clinical tool predicts the pregnancy rate after surgical staging of endometriosis. Using it can provide reassurance to patients who have a good prognosis and avoid cost and distress of treatment in patients who have a poor prognosis.

Among the variables the index utilizes to predict the likelihood of pregnancy are:

• age of the patient
• duration of infertility
• gravidity
• total revised American Fertility Society (R-AFS) score
• R-AFS lesion score
• the new “least function score” (capability of the tubes, fimbria, and ovaries to effect their reproductive function, as determined by the surgeon after operative treatment) (FIGURES 2 AND 3).

FIGURE 2 Estimated pregnancy rate, by EFI score

FIGURE 3 A look at the endometriosis fertility index (EFI)

The least-function (LF) score (A) is determined at the conclusion of surgery using this form. The endometriosis fertility index (EFI) (B) incorporates the LF score and other variables to determine the overall score.

Infertility and its treatment can be a roller-coaster ride for patient and physician. Amid the emotional stress that arises, the goal of treatment can inadvertently shift from achievement of a successful singleton pregnancy to pregnancy at any cost—even high-order multiple gestation.

Here’s an essential question: Can the rate of multiple gestation be reduced without seriously compromising the pregnancy rate? Several developments of the past year suggest that it can be. In this article, we discuss:

• new guidelines that limit the number of embryos to be transferred at in vitro fertilization (IVF)
• strategies to reduce the risk of multiple gestation after controlled ovarian stimulation or ovulation induction
• the need to address the patient’s emotional status during treatment
• a new index that helps predict the pregnancy rate after surgical staging of endometriosis.

Multiple gestation is known to have adverse effects on infants, including a significantly elevated risk of prematurity and related physical and developmental problems. It also greatly increases the need for resources. And the high cost of caring for infants affected by prematurity further burdens an already overwhelmed health-care system.

Not only is it essential that we reduce the rate of high-order multiple gestation (i.e., more than two fetuses), but we should also attempt to lower the rate of twin pregnancy. A healthy singleton pregnancy, with its diminished risks and more reasonable health-care cost, should be our goal.

New guidelines limit the number of embryos to be transferred at IVF

Practice Committee of the American Society for Reproductive Medicine, Practice Committee of the Society for Assisted Reproductive Technology. Guidelines on number of embryos transferred. Fertil Steril. 2009;92:1518–1519.

Since the birth of Louise Brown in 1978, assisted reproductive technology (ART) has enjoyed dramatic technological advances. Intracytoplasmic sperm injection (FIGURE 1), preimplantation genetic diagnosis, and improvements in cryopreservation have broadened the application of ART and increased the live birth rate to 30% for every cycle that is initiated. The cumulative live birth rate from additional fresh and frozen-thawed cycles can reach 50% to 80%.

These gains have not come without cost, however. Multiple emotional, financial, and other variables affecting the practice of IVF have produced a higher-than-natural rate of multiple gestation.

In November 2009, the Society for Assisted Reproductive Technology (SART) and the American Society for Reproductive Medicine (ASRM) issued new guidelines limiting the number of embryos that should be transferred in one IVF cycle. IVF clinics are required to report outcomes, and approximately 93% of US cycles are reported to SART. High-order multiple-pregnancy rates are audited by SART, and outlier clinics must implement remediation programs to lower their high rate or risk expulsion from SART.

The increasing emphasis on single-embryo transfer in young women who have a good prognosis reflects the societies’ commitment to help patients achieve a healthy singleton pregnancy and good birth outcome.

FIGURE 1 A wonder of technology

Intracytoplasmic sperm injection overcomes many barriers to fertilization, such as severe malefactor infertility. At some institutions, the technique yields a fertilization rate of 70% to 80%.

What makes a “good prognosis”?

Identification of patients who have a good prognosis is an essential component of these new guidelines. The patient is more likely to have a favorable outcome if one or more of the following is true:

• She is undergoing her first cycle of IVF
• The embryos have good morphology
• Excess embryos are available for cryopreservation
• She has had earlier success with IVF.

The TABLE details the recommended number of embryos to transfer, based on the age and prognosis of the patient. In cycles that involve a donor egg, base the number of embryos to be transferred on the age of the donor. In cycles that involve a frozen embryo, base the number of good-quality, thawed embryos to be transferred on the age of the patient at the time the embryos were created. One additional embryo may be transferred if the patient has a less favorable prognosis or a history of two failed, fresh IVF cycles.

Two important requisites: Careful counseling about the risk of high-order multiple gestation, and documentation of that counseling.

TABLE

SART and ASRM recommend limits on the number of embryos to be transferred at in vitro fertilization

Judicious management can reduce the rate of multiple gestation in ovulation stimulation

Dickey RP. Strategies to reduce multiple pregnancies due to ovulation stimulation. Fertil Steril. 2009;91:1–17.

Efforts to reduce the rate of multiple gestation should focus not only on patients undergoing IVF but on those undergoing controlled ovarian stimulation (COS) or ovulation induction. In COS, pharmacologic treatment is used to stimulate the production of more than one oocyte. In ovulation induction, pharmacologic therapy is used to induce normal cycles in anovulatory or oligo-ovulatory women.¹ A substantial majority of multiple gestations are conceived using ovarian stimulation and ovulation induction. These methods may be less difficult to manage than IVF because they are less dependent on technology. Like IVF, however, they carry a high risk of multiple gestation, especially high-order multiple gestation.²

Strategies to reduce multiple gestation

As Dickey points out in a comprehensive retrospective analysis, there are strategies that can help reduce multiple gestation during COS and ovulation induction. They include the following recommendations:

Be prepared to cancel a cycle. Initiate ovulation induction only if both patient and physician are prepared to cancel any cycle that involves an excessive number of preovulatory follicles. Singleton and twin births can be confidently expected only if the cycle is cancelled when there are more than two preovulatory follicles approximately 12 mm in diameter or larger. This may be psychologically difficult for some patients and doctors.

Preemptively identify risk factors for multiple gestation, including:

• seven or more preovulatory follicles
• an estradiol concentration of 1,000 pg/mL or higher
• early cycles of treatment (cycles 1–3)
• age younger than 32 years
• body mass index below 19 kg/m²
• use of donor sperm.

When any of these risk factors is present, consider starting the patient on a lower initial dosage of gonadotropin; perform more frequent monitoring; maintain a low threshold for cancellation; and consider performing IVF with single-embryo transfer rather than COS.

Use specific drugs. Increase the likelihood of monofollicular development and double-follicular recruitment and reduce the risk of high-order multiple gestation by using clomiphene citrate, a low dosage of gonadotropin, or pulsatile gonadotropin-releasing hormone (GnRH) in the initial three or four cycles.

Continue treatment for five or more cycles to achieve an overall pregnancy rate approaching 65% without high-order multiple gestation in patients younger than 38 years who develop one or two follicles in a cycle.

Don’t rely on multifetal pregnancy reduction

This strategy has been viewed by some as a way to control the outcome of multiple gestation. For example, this is a common approach in New York, New Jersey, and Connecticut. However, the procedure has pitfalls and should not be the primary means of reducing the rate of multiple gestation because:

• It is not an acceptable option for many patients
• All fetuses may be lost in some cases
• The risks associated with multiple gestation are not completely eliminated
• It may have adverse psychological consequences.^3,4

A registry is needed

Although a registry exists for IVF cycles and their outcomes and complications, none exists for cycles involving COS or ovulation induction. Despite many challenges to its development, we support the creation of such a registry.

Consider the patient’s emotional status when determining treatment for infertility

Domar AD, Smith K, Conboy L, Iannone M, Alper M. A prospective investigation into the reasons why insured United States patients drop out of in vitro fertilization treatment. Fertil Steril. 2009 Jul 8 [Epub ahead of print].

Most physicians have been trained to concentrate on the physiologic diagnosis and management of disease. Many fertility specialists also pay attention to economic barriers to treatment, such as lack of insurance and high cost, and attempt to help their patients gain access to quality care. One aspect of infertility that might be overlooked, however, is the patient’s emotional health—but it may be as important to the success of treatment as physiologic and economic variables.

A recent prospective investigation into the reasons insured patients drop out of IVF in the United States clearly demonstrated the psychological toll infertility can take. The study found that emotional distress is the number one reason that patients discontinue treatment.

How to lower the patient’s stress level

It can be challenging to counsel the patient to set realistic expectations for success yet enable her to maintain a sense of optimism. Stress management may be a key to success.

Physicians who treat patients with fertility problems should consider offering an in-practice counseling service aimed at reducing stress and improving coping mechanisms. At the very least, physicians should refer patients to outside resources that may be able to provide these services in a way that is meaningful and accessible.

Caring for a patient’s emotional well-being takes both time and skill. Besides offering direct emotional support to your patients, you can be a bridge to mental health and support services.

Patients who participate in a stress-reduction program while undergoing fertility treatment are 1) less likely to experience harmful emotional side effects and 2) more likely to continue treatment. Physicians who make such “mind-body” programs available are likely to reduce treatment dropout, improve the pregnancy rate, and increase the number of patients who take home babies.

New endometriosis fertility index predicts non-IVF success rate

Adamson GD, Pasta DJ. Endometriosis fertility index: the new, validated endometriosis staging system. Fertil Steril. 2009 Nov 18 [Epub ahead of print].

Endometriosis remains a frustrating disease for patients who have infertility, in part because no staging system has made it possible for physicians to predict the pregnancy rate with fertility treatment other than IVF. The new, validated endometriosis fertility index (EFI) changes that. This simple, robust clinical tool predicts the pregnancy rate after surgical staging of endometriosis. Using it can provide reassurance to patients who have a good prognosis and avoid cost and distress of treatment in patients who have a poor prognosis.

Among the variables the index utilizes to predict the likelihood of pregnancy are:

• age of the patient
• duration of infertility
• gravidity
• total revised American Fertility Society (R-AFS) score
• R-AFS lesion score
• the new “least function score” (capability of the tubes, fimbria, and ovaries to effect their reproductive function, as determined by the surgeon after operative treatment) (FIGURES 2 AND 3).

FIGURE 2 Estimated pregnancy rate, by EFI score

FIGURE 3 A look at the endometriosis fertility index (EFI)

The least-function (LF) score (A) is determined at the conclusion of surgery using this form. The endometriosis fertility index (EFI) (B) incorporates the LF score and other variables to determine the overall score.

Infertility and its treatment can be a roller-coaster ride for patient and physician. Amid the emotional stress that arises, the goal of treatment can inadvertently shift from achievement of a successful singleton pregnancy to pregnancy at any cost—even high-order multiple gestation.

Here’s an essential question: Can the rate of multiple gestation be reduced without seriously compromising the pregnancy rate? Several developments of the past year suggest that it can be. In this article, we discuss:

• new guidelines that limit the number of embryos to be transferred at in vitro fertilization (IVF)
• strategies to reduce the risk of multiple gestation after controlled ovarian stimulation or ovulation induction
• the need to address the patient’s emotional status during treatment
• a new index that helps predict the pregnancy rate after surgical staging of endometriosis.

Multiple gestation is known to have adverse effects on infants, including a significantly elevated risk of prematurity and related physical and developmental problems. It also greatly increases the need for resources. And the high cost of caring for infants affected by prematurity further burdens an already overwhelmed health-care system.

Not only is it essential that we reduce the rate of high-order multiple gestation (i.e., more than two fetuses), but we should also attempt to lower the rate of twin pregnancy. A healthy singleton pregnancy, with its diminished risks and more reasonable health-care cost, should be our goal.

New guidelines limit the number of embryos to be transferred at IVF

Practice Committee of the American Society for Reproductive Medicine, Practice Committee of the Society for Assisted Reproductive Technology. Guidelines on number of embryos transferred. Fertil Steril. 2009;92:1518–1519.

Since the birth of Louise Brown in 1978, assisted reproductive technology (ART) has enjoyed dramatic technological advances. Intracytoplasmic sperm injection (FIGURE 1), preimplantation genetic diagnosis, and improvements in cryopreservation have broadened the application of ART and increased the live birth rate to 30% for every cycle that is initiated. The cumulative live birth rate from additional fresh and frozen-thawed cycles can reach 50% to 80%.

These gains have not come without cost, however. Multiple emotional, financial, and other variables affecting the practice of IVF have produced a higher-than-natural rate of multiple gestation.

In November 2009, the Society for Assisted Reproductive Technology (SART) and the American Society for Reproductive Medicine (ASRM) issued new guidelines limiting the number of embryos that should be transferred in one IVF cycle. IVF clinics are required to report outcomes, and approximately 93% of US cycles are reported to SART. High-order multiple-pregnancy rates are audited by SART, and outlier clinics must implement remediation programs to lower their high rate or risk expulsion from SART.

The increasing emphasis on single-embryo transfer in young women who have a good prognosis reflects the societies’ commitment to help patients achieve a healthy singleton pregnancy and good birth outcome.

FIGURE 1 A wonder of technology

Intracytoplasmic sperm injection overcomes many barriers to fertilization, such as severe malefactor infertility. At some institutions, the technique yields a fertilization rate of 70% to 80%.

What makes a “good prognosis”?

Identification of patients who have a good prognosis is an essential component of these new guidelines. The patient is more likely to have a favorable outcome if one or more of the following is true:

• She is undergoing her first cycle of IVF
• The embryos have good morphology
• Excess embryos are available for cryopreservation
• She has had earlier success with IVF.

The TABLE details the recommended number of embryos to transfer, based on the age and prognosis of the patient. In cycles that involve a donor egg, base the number of embryos to be transferred on the age of the donor. In cycles that involve a frozen embryo, base the number of good-quality, thawed embryos to be transferred on the age of the patient at the time the embryos were created. One additional embryo may be transferred if the patient has a less favorable prognosis or a history of two failed, fresh IVF cycles.

Two important requisites: Careful counseling about the risk of high-order multiple gestation, and documentation of that counseling.

TABLE

SART and ASRM recommend limits on the number of embryos to be transferred at in vitro fertilization

Judicious management can reduce the rate of multiple gestation in ovulation stimulation

Dickey RP. Strategies to reduce multiple pregnancies due to ovulation stimulation. Fertil Steril. 2009;91:1–17.

Efforts to reduce the rate of multiple gestation should focus not only on patients undergoing IVF but on those undergoing controlled ovarian stimulation (COS) or ovulation induction. In COS, pharmacologic treatment is used to stimulate the production of more than one oocyte. In ovulation induction, pharmacologic therapy is used to induce normal cycles in anovulatory or oligo-ovulatory women.¹ A substantial majority of multiple gestations are conceived using ovarian stimulation and ovulation induction. These methods may be less difficult to manage than IVF because they are less dependent on technology. Like IVF, however, they carry a high risk of multiple gestation, especially high-order multiple gestation.²

Strategies to reduce multiple gestation

As Dickey points out in a comprehensive retrospective analysis, there are strategies that can help reduce multiple gestation during COS and ovulation induction. They include the following recommendations:

Be prepared to cancel a cycle. Initiate ovulation induction only if both patient and physician are prepared to cancel any cycle that involves an excessive number of preovulatory follicles. Singleton and twin births can be confidently expected only if the cycle is cancelled when there are more than two preovulatory follicles approximately 12 mm in diameter or larger. This may be psychologically difficult for some patients and doctors.

Preemptively identify risk factors for multiple gestation, including:

• seven or more preovulatory follicles
• an estradiol concentration of 1,000 pg/mL or higher
• early cycles of treatment (cycles 1–3)
• age younger than 32 years
• body mass index below 19 kg/m²
• use of donor sperm.

When any of these risk factors is present, consider starting the patient on a lower initial dosage of gonadotropin; perform more frequent monitoring; maintain a low threshold for cancellation; and consider performing IVF with single-embryo transfer rather than COS.

Use specific drugs. Increase the likelihood of monofollicular development and double-follicular recruitment and reduce the risk of high-order multiple gestation by using clomiphene citrate, a low dosage of gonadotropin, or pulsatile gonadotropin-releasing hormone (GnRH) in the initial three or four cycles.

Continue treatment for five or more cycles to achieve an overall pregnancy rate approaching 65% without high-order multiple gestation in patients younger than 38 years who develop one or two follicles in a cycle.

Don’t rely on multifetal pregnancy reduction

This strategy has been viewed by some as a way to control the outcome of multiple gestation. For example, this is a common approach in New York, New Jersey, and Connecticut. However, the procedure has pitfalls and should not be the primary means of reducing the rate of multiple gestation because:

• It is not an acceptable option for many patients
• All fetuses may be lost in some cases
• The risks associated with multiple gestation are not completely eliminated
• It may have adverse psychological consequences.^3,4

A registry is needed

Although a registry exists for IVF cycles and their outcomes and complications, none exists for cycles involving COS or ovulation induction. Despite many challenges to its development, we support the creation of such a registry.

Consider the patient’s emotional status when determining treatment for infertility

Domar AD, Smith K, Conboy L, Iannone M, Alper M. A prospective investigation into the reasons why insured United States patients drop out of in vitro fertilization treatment. Fertil Steril. 2009 Jul 8 [Epub ahead of print].

Most physicians have been trained to concentrate on the physiologic diagnosis and management of disease. Many fertility specialists also pay attention to economic barriers to treatment, such as lack of insurance and high cost, and attempt to help their patients gain access to quality care. One aspect of infertility that might be overlooked, however, is the patient’s emotional health—but it may be as important to the success of treatment as physiologic and economic variables.

A recent prospective investigation into the reasons insured patients drop out of IVF in the United States clearly demonstrated the psychological toll infertility can take. The study found that emotional distress is the number one reason that patients discontinue treatment.

How to lower the patient’s stress level

It can be challenging to counsel the patient to set realistic expectations for success yet enable her to maintain a sense of optimism. Stress management may be a key to success.

Physicians who treat patients with fertility problems should consider offering an in-practice counseling service aimed at reducing stress and improving coping mechanisms. At the very least, physicians should refer patients to outside resources that may be able to provide these services in a way that is meaningful and accessible.

Caring for a patient’s emotional well-being takes both time and skill. Besides offering direct emotional support to your patients, you can be a bridge to mental health and support services.

Patients who participate in a stress-reduction program while undergoing fertility treatment are 1) less likely to experience harmful emotional side effects and 2) more likely to continue treatment. Physicians who make such “mind-body” programs available are likely to reduce treatment dropout, improve the pregnancy rate, and increase the number of patients who take home babies.

New endometriosis fertility index predicts non-IVF success rate

Adamson GD, Pasta DJ. Endometriosis fertility index: the new, validated endometriosis staging system. Fertil Steril. 2009 Nov 18 [Epub ahead of print].

Endometriosis remains a frustrating disease for patients who have infertility, in part because no staging system has made it possible for physicians to predict the pregnancy rate with fertility treatment other than IVF. The new, validated endometriosis fertility index (EFI) changes that. This simple, robust clinical tool predicts the pregnancy rate after surgical staging of endometriosis. Using it can provide reassurance to patients who have a good prognosis and avoid cost and distress of treatment in patients who have a poor prognosis.

Among the variables the index utilizes to predict the likelihood of pregnancy are:

• age of the patient
• duration of infertility
• gravidity
• total revised American Fertility Society (R-AFS) score
• R-AFS lesion score
• the new “least function score” (capability of the tubes, fimbria, and ovaries to effect their reproductive function, as determined by the surgeon after operative treatment) (FIGURES 2 AND 3).

FIGURE 2 Estimated pregnancy rate, by EFI score

FIGURE 3 A look at the endometriosis fertility index (EFI)

The least-function (LF) score (A) is determined at the conclusion of surgery using this form. The endometriosis fertility index (EFI) (B) incorporates the LF score and other variables to determine the overall score.