Reviews

In the last few decades, the survival rates have improved in many of the malignancies that affect young adults. This progress has made fertility preservation and quality of life after cancer treatment important, most of all in survivors of childhood cancers.

Men who are about to undergo cancer treatment can bank their sperm, but as yet no analogous noninvasive option is available for women. The most studied methods are often invasive and require the woman to take large doses of hormones. They may also necessitate a delay in starting cancer treatment.

Which method of fertility preservation a woman should choose depends on several factors, including the type of disease, the treatment required, the age of the patient, whether she has a long-term partner, and whether treatment can be delayed.

Chemotherapy and radiotherapy have well-known deleterious effects on female reproductive function. Many studies have shown that acute loss of growing follicles within the ovary and resultant premature ovarian failure often follow chemotherapy. This ovarian damage has long-term consequences, such as shortened reproductive life span and hormone deficiency.¹

Fertility preservation requires a team effort. It should be managed by an oncology center that has built a close collaboration between oncologists, fertility specialists, psychologists, and primary care physicians to allow early discussion and to offer a full range of options to these patients.

The aim of this paper is to discuss the current options for preserving fertility in female cancer patients who have to undergo gonadotoxic cancer treatment.

FEMALE FERTILITY AND ASSESSMENT OF OVARIAN RESERVE

At birth, baby girls have about 1 million primordial ovarian follicles, which is the most they will ever have. By the time they reach menarche, this number has declined to 180,000, and at menopause only about 1,000 remain.²

Throughout a woman’s reproductive life, the number of oocytes remaining—both primordial follicles and the relatively small number of maturing, growing follicles—is called her ovarian reserve. When cancer is diagnosed, we need to assess the patient’s ovarian reserve to direct the discussion about the need for fertility preservation.

In search of markers of ovarian reserve

Fertility experts have been looking for clinical biomarkers that could give us an estimate of the number of nongrowing follicles and, consequently, of the ovarian reserve.

All methods used for the assessment of ovarian reserve actually provide an indirect determination of the remaining pool of oocytes. In clinical practice, a high blood level of follicle-stimulating hormone (FSH) on cycle day 3 (>15 mU/mL) or a low level of anti-Müllerian hormone (AMH) (<1 ng/mL) is generally associated with a low ovarian reserve.

The serum FSH level is the marker most commonly used, but it varies widely at different times in the menstrual cycle.

The FSH test is usually performed on day 3 of the menstrual cycle, when the estrogen level is expected to be low due to negative feedback. The FSH result needs to be combined with the estradiol level, especially in those patients with irregular menstruation or in cases of amenorrhea. A random FSH test is considered valid if the detected estrogen level is low. Women undergoing in vitro fertilization with a day 3 FSH lower than 15 mIU/mL are more likely to conceive than women with a higher FSH level.

AMH and antral follicles. Recently, two other variables have been introduced in clinical practice: the AMH concentration and the antral follicle count (the number of small antral follicles within the ovary) as assessed by transvaginal ultrasonography.

AMH is released by the granulosa cells of small, growing follicles. Because its level is much more stable over the menstrual cycle than the FSH level, it can be measured on any day of the cycle.³ In cancer survivors, AMH is particularly useful in demonstrating the degree of ovarian tissue damage induced by radiotherapy and chemotherapy and in evaluating the ovarian reserve.⁴

A reduced number of antral follicles causes a diminished AMH production, which becomes undetectable with menopause. The AMH level is strongly associated with the basal antral follicle count. Various threshold values (0.2–1.26 ng/mL) have been used to identify women with low ovarian reserve.

HOW CANCER TREATMENT DAMAGES THE OVARIES

Advances in surgery, radiotherapy, and chemotherapy have significantly improved the prognosis for young cancer patients. However, cancer treatments often result in ovarian dysfunction, and premature menopause and irreversible sterility are the most dramatic outcomes. The resulting low estrogen levels, in addition to their physiologic consequences, also worsen quality of life through psychological effects, which can as well influence the patient’s compliance with treatment.

Chemotherapy: Alkylating agents are the most gonadotoxic

The mechanism by which chemotherapy affects ovarian function is poorly understood. Histologically, chemotherapeutic drugs could lead to ovarian atrophy and stromal fibrosis, to depletion of the primordial follicle stockpile, and to reduced ovarian weight, resulting in ovarian dysfunction.⁵

The patient's age correlates with the probability of ovarian damage or, inversely, ovarian resistance to chemotherapy. Young women have more primordial oocytes, and after chemotherapy they face a sharp reduction of their ovarian reserve. Still, younger patients show a lower rate of ovarian toxicity than older women.⁶

The type and the cumulative dose of cytotoxic agents used are other important variables.⁷ There are six main classes of chemotherapeutic drugs: alkylating agents, platinum derivatives, antibiotics, antimetabolites, plant alkaloids, and taxanes. They all affect ovarian function, but alkylating agents are the most gonadotoxic.

Alkylating agents covalently bind an alkyl group to the DNA molecule and inhibit it from replicating. In the ovaries they directly injure primordial oocytes and deplete follicles. ⁸ They also seriously damage the ovarian vasculature so that the follicles cannot grow.⁹ Their destructive effect on the primordial follicles is dose-dependent and varies with the age and developmental maturity of the patient at the time of the therapy, with older women more likely to be left infertile afterward.¹⁰

Cyclophosphamide is an alkylating agent often used to treat severe manifestations of autoimmune diseases such as systemic lupus erythematosus, BehÇet disease, steroid-resistant glomerulonephritis, inflammatory bowel disease, pemphigus vulgaris, and others. Because it can lead to premature ovarian failure and infertility, women receiving cyclophosphamide for autoimmune conditions may also need treatment to preserve fertility.¹¹

Radiotherapy

Ovarian follicles are remarkably vulnerable to damage from ionizing radiation, which results in ovarian atrophy and reduced follicle stores.¹

The risk of radiotherapy-induced infertility is closely related to the patient’s age and developmental maturity at the time of therapy and to dose fractionation and the extent of the irradiation field. Every patient has a different sensitivity to radiation damage that is probably genetically predetermined, but age seems to be the most important variable. Wo and Viswanathan¹² used a mathematical model devised by Wallace et al¹³ to show that the older the patient, the lower the radiation dose necessary to impair ovarian function.

The irradiation field is another aspect to consider. Pelvic radiation can be necessary in rectal cancer, cervical cancer, and lymphoma. In these cases, surgically moving the ovaries to a region outside the radiation field could be an option to minimize radiotherapy-induced ovarian damage.¹⁴

Radiotherapy can also damage the uterus. Pelvic irradiation can reduce uterine volume, alter uterine elasticity through myometrial fibrosis, and modify vascularization and endometrial thickness.^15,16 These alterations are closely correlated with the total radiation dose, the site of irradiation, and the patient’s age at the time of the treatment, the prepubertal uterus being more susceptible to damage. ^15,17 Larsen et al¹⁵ found that girls who received uterine irradiation before puberty had lower uterine volumes in adulthood than girls who received chemotherapy alone or radiation to other parts of the body, and that the younger the patient at the time of radiotherapy, the smaller the uterus later. These effects could result in adverse pregnancy outcomes.

Furthermore, radiation could also damage the uterine vasculature. Holm et al¹⁶ used ultrasonography to evaluate the effect of total-body irradiation and found that uterine volume and uterine blood flow were both impaired.¹⁵

All these possible alterations could lead to a reduced uterine response to cytotrophoblast invasion and to decreased fetoplacental blood flow, which could impair embryonic and fetal growth. In that case, a surrogate pregnancy would be the only method to achieve parenthood using the couple’s gametes.

OPTIONS FOR FERTILITY PRESERVATION

Assisted reproductive technology

Young women diagnosed with an oncologic disease may wish to use assisted reproductive technology (Table 1) to keep open the possibility of having children at a later date. One approach is to harvest oocytes, fertilize them in vitro, and deep-freeze (cryopreserve) the resulting embryos to be thawed and implanted later. Alternatively, oocytes can be frozen directly, although success rates are lower with this method. And another approach is to obtain and cryopreserve ovarian tissue. If none of these is possible, oocytes may be obtained from a donor.

Controlled ovarian stimulation

If oocytes are to be harvested, a number of them should be harvested at one time.

There is not an optimal number of oocytes that should be retrieved, but cryopreservation of a large number of oocytes allows us to perform multiple attempts at in vitro fertilization, improving the chances of pregnancy. The fertilization rate (defined as the total number of zygotes at the 2-pronucleus stage divided by the number of fertilized oocytes) with intracytoplasmic sperm injection is 70% to 80%. On average, for every 10 eggs, 7 to 8 eggs will normally be fertilized. The implantation rate (defined as the total number of pregnancies divided by the total number of embryo transferred) with intracytoplasmic sperm injection is 40% to 50%—ie, only half of the transferred embryos will successfully implant and result in a pregnancy.

So that more than one ripe egg can be obtained at a time, the patient must undergo a regimen of controlled ovarian stimulation to achieve multifollicular growth. Stimulation protocols are based on giving pituitary hormones, ie, analogues of gonadotropin-releasing hormone (GnRH) (both agonists and antagonists), followed by recombinant FSH or human menopausal gonadotropin to promote follicular development. A single dose of human chorionic gonadotropin (hCG) is given to induce ovulation when the lead follicles have reached 18 to 20 mm in size.¹⁸

Many oncologists consider controlled ovarian stimulation dangerous for cancer patients because it takes time and thus delays cancer treatment. Furthermore, the regimen boosts the levels of circulating estrogens, which could be harmful in patients with hormone-dependent tumors.¹⁹

Oocytes can also be retrieved during unstimulated cycles. This avoids increasing estrogen concentrations above the physiologic level, but no more than a single oocyte is collected per cycle. The patient could undergo multiple oocyte harvestings, one per cycle, but this would delay her cancer treatment even more—by months—which is not recommended.

Serious efforts to minimize estrogen production during controlled ovarian stimulation have been made, although further studies are needed. Research is under way to develop appropriate ovarian stimulation protocols based on drugs with antiestrogenic effects.

Tamoxifen, an antagonist of the estrogen receptor, is widely used in breast cancer treatment. ²⁰ It can also be given during controlled ovarian stimulation because it promotes follicular growth and induces ovulation.²¹ Oktay et al²² found that the embryo yield was 2.5 times higher in women with breast cancer treated with tamoxifen than in a retrospective control group consisting of breast cancer patients attempting natural-cycle oocyte retrieval.

Letrozole, an aromatase inhibitor, is also commonly used in treating breast and ovarian cancer. Aromatase is an enzyme that catalyzes the conversion of androgenic precursors to estrogens, and it is found in many tissues, including granulosa cells. Several studies report the use of letrozole, alone or in combination with low doses of recombinant FSH, in ovarian stimulation protocols in cancer patients, with positive clinical outcomes.²³

Tamoxifen or letrozole, combined with recombinant FSH, is an attractive option in a controlled ovarian stimulation protocol for cancer patients,²⁴ although further investigation is needed.

Two main protocols are currently used to freeze oocytes, embryos, and ovarian tissue: slow freezing and vitrification.

In the slow-freezing method, cryoprotectant agents are used to draw water out of the cells, raising intracellular viscosity without (or with minimal) intracellular ice crystal formation, while the sample is cooled slowly in a controlled manner. These cryoprotectant chemicals lower the freezing point of the solution, allowing greater cellular dehydration during the slow freezing. They also protect the plasmatic cell membrane by changing its physical state from liquid to partially dry. To avoid excessive deformation that could damage the cytoplasmic structures, cryoprotectant agents are added in successive stages.²⁵

Vitrification is a newer method that uses higher concentrations of cryoprotectants and flash freezing. The instant drop in temperature converts this highly concentrated solution from an aqueous state to a semisolid, amorphous state that does not contain ice crystals, which are the main cause of damage during the freezing process.²⁶ Since most cryoprotectant agents are extremely toxic, it is necessary to minimize the time that oocytes, embryos, and ovarian tissue are exposed to them.

Cryopreservation of embryos

According to the American Society of Clinical Oncology and the American Society of Reproductive Medicine, embryo freezing is the most established method for fertility preservation, with tangible and widely reported success.²⁷ In normal practice, oocytes are retrieved after a controlled ovarian stimulation and then fertilized in vitro. Then they are treated with cryoprotectant agents, frozen, and stored. Upon demand, embryos can be thawed and implanted.

The Society for Assisted Reproductive Technology reports that the current live birth rate per transfer using thawed embryos from nondonor oocytes in US women under age 35 is 38.7%; at age 35 to 37 it is 35.1%.²⁸ In women with cancer, storing as many embryos as possible could help improve embryo survival and the implantation rate. The optimal time to perform embryo cryopreservation is still being discussed,²⁹ but, as in women without cancer, it is commonly done 3 to 5 days after fertilization.

In the past few years, the use of vitrification has greatly increased, as the post-thawing survival rates and pregnancy rates are higher with this method than with slow freezing.³⁰

Despite its success, embryo cryopreservation has important drawbacks. First, the patient must be of reproductive age and have a partner or accept the use of donor sperm. Second, most patients undergo controlled ovarian stimulation before oocyte retrieval, causing a delay in starting cancer treatment, which is not acceptable in many cases. Moreover, the high serum estrogen levels caused by ovarian stimulation may be contraindicated in women with estrogen-sensitive malignancies.¹⁹

Oocyte cryopreservation

Cryopreservation of oocytes avoids the need for sperm and, thus, may be offered to more patients than embryo cryopreservation. In addition, it may circumvent ethical or legal considerations associated with embryo freezing, such as ownership of reproductive material.

However, oocytes are more difficult to cryopreserve than embryos. Indeed, ice crystals frequently form inside and outside the cells, damaging the cell membrane and the meiotic spindle. In routine practice, mature oocytes in metaphase II are used for cryopreservation. Metaphase II oocytes are large cells that contain a delicate meiotic spindle. Moreover, their cytoplasm contains a higher proportion of water than other cells, which could affect their viability after freezing and thawing due to ice crystal formation. In addition, cryopreservation could be responsible for hardening of the zona pellucida (through diffuse thickening of the cell membrane), adversely affecting fertilization rates.³¹

Significant improvements were achieved in fertilization of cryopreserved oocytes with intracytoplasmic sperm injection. Nevertheless, there are still concerns regarding oocyte cryopreservation. Further studies are needed to determine the risk of aneuploidy caused by damage to the meiotic spindle after oocyte cryopreservation. The potentially detrimental effects of high cryopreservant concentrations used in vitrification also need to be investigated.

In vitro maturation

A novel fertility preservation strategy involves collecting immature oocytes from primordial follicles in unstimulated cycles and then letting them mature in vitro.

To date, immature oocytes retrieved at the germinal vesicle stage can be cryopreserved with vitrification followed by in vitro maturation after thawing, but several studies have demonstrated that better results are obtained when vitrification follows the in vitro maturation process.³²

Compared with mature oocytes, immature oocytes are less susceptible to damage during cryopreservation and thus have a better chance of surviving freezing and thawing, thanks to some peculiar characteristics: they are small, have few organelles, lack a zona pellucida, have low metabolic activity, and are in a state of relative quiescence.³³ Controlled ovarian stimulation is not necessary, so this procedure preserves fertility without delaying the start of cancer treatment.

Patients are usually evaluated with transvaginal ultrasonography in the early follicular phase of the menstrual cycle (between day 2 and day 4) to count and measure the antral follicles. Immature oocytes are collected when the leading follicle has reached 10 to 12 mm in size and 36 hours after a subcutaneous injection of hCG.³⁴ The retrieved oocytes are then incubated for 24 to 48 hours in a special medium supplemented with FSH and luteinizing hormone (LH). Immature oocytes can also be collected in the luteal phase.

This option could be considered when cancer treatment cannot be delayed for conventional follicular-phase retrieval³⁵ or in case of a premature LH surge during ovarian stimulation. ³⁶ It should be offered to patients facing infertility related to cancer treatment only after appropriate counseling and as a part of a clinical study.

Ovarian tissue cryopreservation

Cryopreservation of ovarian tissue is an experimental but highly promising technique for preserving fertility. Like oocyte cryopreservation, it avoids the need for hormonal stimulation and the need to delay cancer treatment. It may also be the only possible option for prepubertal girls, as well as for women who cannot postpone their cancer treatment. Although it is still experimental, it has obtained progressively better results: after having ovarian tissue preserved, thawed, and subsequently reimplanted in the same position or in a different part of the body, some patients transiently resumed having menstrual cycles and endocrine activity and in a very few cases achieved pregnancy.³⁷

Ovarian tissue for cryopreservation is usually taken via laparoscopic surgery, unless the patient has to undergo open laparotomy for another indication. Laparoscopic surgery offers significant advantages, such as the possibility of performing it on short notice without delaying oncologic therapy. Considering that women at age 30 have about 35 primordial follicles per square millimeter of ovarian tissue, 5 cubic fragments 5 mm wide may be sufficient to obtain more than 4,000 primordial follicles.³⁸ In cases in which complete ovariectomy is necessary, it is possible to remove and cryopreserve fragments of normal ovarian tissue located at the margins of the surgical specimen. Ovarian tissue withdrawal can also be performed in pediatric patients and during other surgical procedures.

The most studied method of cryopreserving ovarian tissue is slow freezing, but the use of vitrification is increasing. This technique was initially carried out in order to preserve the largest number of primordial follicles, but in recent years the possibility of cryopreserving the whole ovary with or without its vascular pedicle has also been studied. Martinez-Madrid et al³⁹ described a protocol of cryopreserving the entire ovary with its stem and found it possible to reach a follicular survival rate of 75%, preserving vessels and stromal structure.³⁹

Currently, the most promising approach seems to be the transplantation of the ovarian tissue back into the donor, ie, autotransplantation. This avoids the need for immunosuppression.

The location can be either orthotopic or heterotopic. In orthotopic transplantation the tissue is placed back in its original location. In theory, the patient could then become pregnant in the usual way if the rest of the reproductive system is not damaged.

In heterotopic transplantation the tissue is placed in a different location, usually easily accessible, like the forearm or the subcutaneous abdominal area. Heterotopic transplants have been shown to be able to restore ovarian function, but not to give pregnancies after oocyte collection.⁴⁰ Indeed, the pregnancies obtained after transplantation came from autografts of ovarian cortex in orthotopic sites like the fossa ovarica or the remnant ovary.

With autotransplantation, there is a high risk of transmission of metastatic cancer cells. Blood-bone cancers such as leukemia and lymphomas are likely to be associated with the highest risk of ovarian metastasis through transplantation of thawed cryopreserved ovarian tissue. Neuroblastoma and breast cancer are associated with a moderate risk of metastasis to the ovaries. Ovarian involvement is extremely rare in Wilms tumor, lymphomas (except for Burkitt lymphoma), osteosarcomas, Ewing sarcoma, and extragenital rhabdomyosarcoma. Squamous cell cervical cancer metastasizes to the ovaries in fewer than 0.2% of cases, even in the most advanced stages. Histologic evaluation of ovarian samples before transplantation has been proposed to prevent cancer transmission, although it is not possible to completely abolish this risk.^41,42 This jeopardy could potentially be eliminated by in vitro maturation of immature oocytes collected from cryopreserved ovarian tissue.

Despite significant advances, to date there have been fewer than 20 babies born worldwide through this method.⁴³

Oocyte donation

Assisted reproduction techniques also include in vitro fertilization using a sperm sample from the partner and oocytes from a donor. The embryos obtained are then transferred, saving the woman from ovarian stimulation without any delay in starting the cancer treatment. Although this method has a high success rate, it inevitably raises personal considerations.

OVARIAN TRANSPOSITION

When a woman of childbearing age needs radiation treatment for a pelvic malignancy, transposition of the ovaries above the pelvic brim outside the radiation field (oophoropexy) should be considered before starting therapy. It is indicated in patients diagnosed with malignancies that require pelvic radiation but not the removal of the ovaries. It can be performed during surgical treatment of the tumor or as a separate laparoscopic procedure. The radiation dose that the transposed ovaries receive is considerably less than that in ovaries left in place.

Laparoscopic ovarian transposition is highly effective. However, the risk involved in the surgical procedure should not be underestimated. The most important complications are vascular injury, infarction of the fallopian tube, and ovarian cyst formation.⁴⁴

PHARMACOLOGIC PROTECTION

Some drugs induce a state of ovarian quiescence similar to menopause. Can they be used during chemotherapy to protect the ovaries, allowing restoration of normal ovarian function and natural fertility after cancer treatment and preventing premature ovarian failure?

GnRH analogues slow the cellular activity of the gonads, in theory making them less sensitive to damage by cytotoxic agents. Initially, the release of gonadotropins is stimulated (flare-up effect), but after 10 to 15 days pituitary GnRH receptors are down-regulated by internalization of receptors. Since chemotherapy affects mainly actively dividing cells such as mature ovarian follicles, the use of the analogues is based on the assumption that by reducing FSH levels, follicles will remain quiescent, decreasing their sensitivity to the gonadotoxic effect of chemotherapy.

In a randomized study of 281 patients with early breast cancer, Del Mastro et al⁴⁵ reported a reduction in the occurrence of early menopause in those treated with a GnRH analogue during chemotherapy after 1 year of follow-up. However, the debate regarding the effect of GnRH analogues on the fertility of cancer patients is still open and needs further investigation.

In recent years, research has focused on imatinib, a new, potentially protective drug,⁴⁶ but a lot of work still needs to be done. To date, the use of GnRH analogues is not recommended outside of clinical studies, and it should be offered only after careful counseling about other options to preserve fertility.

In the last few decades, the survival rates have improved in many of the malignancies that affect young adults. This progress has made fertility preservation and quality of life after cancer treatment important, most of all in survivors of childhood cancers.

Men who are about to undergo cancer treatment can bank their sperm, but as yet no analogous noninvasive option is available for women. The most studied methods are often invasive and require the woman to take large doses of hormones. They may also necessitate a delay in starting cancer treatment.

Which method of fertility preservation a woman should choose depends on several factors, including the type of disease, the treatment required, the age of the patient, whether she has a long-term partner, and whether treatment can be delayed.

Chemotherapy and radiotherapy have well-known deleterious effects on female reproductive function. Many studies have shown that acute loss of growing follicles within the ovary and resultant premature ovarian failure often follow chemotherapy. This ovarian damage has long-term consequences, such as shortened reproductive life span and hormone deficiency.¹

Fertility preservation requires a team effort. It should be managed by an oncology center that has built a close collaboration between oncologists, fertility specialists, psychologists, and primary care physicians to allow early discussion and to offer a full range of options to these patients.

The aim of this paper is to discuss the current options for preserving fertility in female cancer patients who have to undergo gonadotoxic cancer treatment.

FEMALE FERTILITY AND ASSESSMENT OF OVARIAN RESERVE

At birth, baby girls have about 1 million primordial ovarian follicles, which is the most they will ever have. By the time they reach menarche, this number has declined to 180,000, and at menopause only about 1,000 remain.²

Throughout a woman’s reproductive life, the number of oocytes remaining—both primordial follicles and the relatively small number of maturing, growing follicles—is called her ovarian reserve. When cancer is diagnosed, we need to assess the patient’s ovarian reserve to direct the discussion about the need for fertility preservation.

In search of markers of ovarian reserve

Fertility experts have been looking for clinical biomarkers that could give us an estimate of the number of nongrowing follicles and, consequently, of the ovarian reserve.

All methods used for the assessment of ovarian reserve actually provide an indirect determination of the remaining pool of oocytes. In clinical practice, a high blood level of follicle-stimulating hormone (FSH) on cycle day 3 (>15 mU/mL) or a low level of anti-Müllerian hormone (AMH) (<1 ng/mL) is generally associated with a low ovarian reserve.

The serum FSH level is the marker most commonly used, but it varies widely at different times in the menstrual cycle.

The FSH test is usually performed on day 3 of the menstrual cycle, when the estrogen level is expected to be low due to negative feedback. The FSH result needs to be combined with the estradiol level, especially in those patients with irregular menstruation or in cases of amenorrhea. A random FSH test is considered valid if the detected estrogen level is low. Women undergoing in vitro fertilization with a day 3 FSH lower than 15 mIU/mL are more likely to conceive than women with a higher FSH level.

AMH and antral follicles. Recently, two other variables have been introduced in clinical practice: the AMH concentration and the antral follicle count (the number of small antral follicles within the ovary) as assessed by transvaginal ultrasonography.

AMH is released by the granulosa cells of small, growing follicles. Because its level is much more stable over the menstrual cycle than the FSH level, it can be measured on any day of the cycle.³ In cancer survivors, AMH is particularly useful in demonstrating the degree of ovarian tissue damage induced by radiotherapy and chemotherapy and in evaluating the ovarian reserve.⁴

A reduced number of antral follicles causes a diminished AMH production, which becomes undetectable with menopause. The AMH level is strongly associated with the basal antral follicle count. Various threshold values (0.2–1.26 ng/mL) have been used to identify women with low ovarian reserve.

HOW CANCER TREATMENT DAMAGES THE OVARIES

Advances in surgery, radiotherapy, and chemotherapy have significantly improved the prognosis for young cancer patients. However, cancer treatments often result in ovarian dysfunction, and premature menopause and irreversible sterility are the most dramatic outcomes. The resulting low estrogen levels, in addition to their physiologic consequences, also worsen quality of life through psychological effects, which can as well influence the patient’s compliance with treatment.

Chemotherapy: Alkylating agents are the most gonadotoxic

The mechanism by which chemotherapy affects ovarian function is poorly understood. Histologically, chemotherapeutic drugs could lead to ovarian atrophy and stromal fibrosis, to depletion of the primordial follicle stockpile, and to reduced ovarian weight, resulting in ovarian dysfunction.⁵

The patient's age correlates with the probability of ovarian damage or, inversely, ovarian resistance to chemotherapy. Young women have more primordial oocytes, and after chemotherapy they face a sharp reduction of their ovarian reserve. Still, younger patients show a lower rate of ovarian toxicity than older women.⁶

The type and the cumulative dose of cytotoxic agents used are other important variables.⁷ There are six main classes of chemotherapeutic drugs: alkylating agents, platinum derivatives, antibiotics, antimetabolites, plant alkaloids, and taxanes. They all affect ovarian function, but alkylating agents are the most gonadotoxic.

Alkylating agents covalently bind an alkyl group to the DNA molecule and inhibit it from replicating. In the ovaries they directly injure primordial oocytes and deplete follicles. ⁸ They also seriously damage the ovarian vasculature so that the follicles cannot grow.⁹ Their destructive effect on the primordial follicles is dose-dependent and varies with the age and developmental maturity of the patient at the time of the therapy, with older women more likely to be left infertile afterward.¹⁰

Cyclophosphamide is an alkylating agent often used to treat severe manifestations of autoimmune diseases such as systemic lupus erythematosus, BehÇet disease, steroid-resistant glomerulonephritis, inflammatory bowel disease, pemphigus vulgaris, and others. Because it can lead to premature ovarian failure and infertility, women receiving cyclophosphamide for autoimmune conditions may also need treatment to preserve fertility.¹¹

Radiotherapy

Ovarian follicles are remarkably vulnerable to damage from ionizing radiation, which results in ovarian atrophy and reduced follicle stores.¹

The risk of radiotherapy-induced infertility is closely related to the patient’s age and developmental maturity at the time of therapy and to dose fractionation and the extent of the irradiation field. Every patient has a different sensitivity to radiation damage that is probably genetically predetermined, but age seems to be the most important variable. Wo and Viswanathan¹² used a mathematical model devised by Wallace et al¹³ to show that the older the patient, the lower the radiation dose necessary to impair ovarian function.

The irradiation field is another aspect to consider. Pelvic radiation can be necessary in rectal cancer, cervical cancer, and lymphoma. In these cases, surgically moving the ovaries to a region outside the radiation field could be an option to minimize radiotherapy-induced ovarian damage.¹⁴

Radiotherapy can also damage the uterus. Pelvic irradiation can reduce uterine volume, alter uterine elasticity through myometrial fibrosis, and modify vascularization and endometrial thickness.^15,16 These alterations are closely correlated with the total radiation dose, the site of irradiation, and the patient’s age at the time of the treatment, the prepubertal uterus being more susceptible to damage. ^15,17 Larsen et al¹⁵ found that girls who received uterine irradiation before puberty had lower uterine volumes in adulthood than girls who received chemotherapy alone or radiation to other parts of the body, and that the younger the patient at the time of radiotherapy, the smaller the uterus later. These effects could result in adverse pregnancy outcomes.

Furthermore, radiation could also damage the uterine vasculature. Holm et al¹⁶ used ultrasonography to evaluate the effect of total-body irradiation and found that uterine volume and uterine blood flow were both impaired.¹⁵

All these possible alterations could lead to a reduced uterine response to cytotrophoblast invasion and to decreased fetoplacental blood flow, which could impair embryonic and fetal growth. In that case, a surrogate pregnancy would be the only method to achieve parenthood using the couple’s gametes.

OPTIONS FOR FERTILITY PRESERVATION

Assisted reproductive technology

Young women diagnosed with an oncologic disease may wish to use assisted reproductive technology (Table 1) to keep open the possibility of having children at a later date. One approach is to harvest oocytes, fertilize them in vitro, and deep-freeze (cryopreserve) the resulting embryos to be thawed and implanted later. Alternatively, oocytes can be frozen directly, although success rates are lower with this method. And another approach is to obtain and cryopreserve ovarian tissue. If none of these is possible, oocytes may be obtained from a donor.

Controlled ovarian stimulation

If oocytes are to be harvested, a number of them should be harvested at one time.

There is not an optimal number of oocytes that should be retrieved, but cryopreservation of a large number of oocytes allows us to perform multiple attempts at in vitro fertilization, improving the chances of pregnancy. The fertilization rate (defined as the total number of zygotes at the 2-pronucleus stage divided by the number of fertilized oocytes) with intracytoplasmic sperm injection is 70% to 80%. On average, for every 10 eggs, 7 to 8 eggs will normally be fertilized. The implantation rate (defined as the total number of pregnancies divided by the total number of embryo transferred) with intracytoplasmic sperm injection is 40% to 50%—ie, only half of the transferred embryos will successfully implant and result in a pregnancy.

So that more than one ripe egg can be obtained at a time, the patient must undergo a regimen of controlled ovarian stimulation to achieve multifollicular growth. Stimulation protocols are based on giving pituitary hormones, ie, analogues of gonadotropin-releasing hormone (GnRH) (both agonists and antagonists), followed by recombinant FSH or human menopausal gonadotropin to promote follicular development. A single dose of human chorionic gonadotropin (hCG) is given to induce ovulation when the lead follicles have reached 18 to 20 mm in size.¹⁸

Many oncologists consider controlled ovarian stimulation dangerous for cancer patients because it takes time and thus delays cancer treatment. Furthermore, the regimen boosts the levels of circulating estrogens, which could be harmful in patients with hormone-dependent tumors.¹⁹

Oocytes can also be retrieved during unstimulated cycles. This avoids increasing estrogen concentrations above the physiologic level, but no more than a single oocyte is collected per cycle. The patient could undergo multiple oocyte harvestings, one per cycle, but this would delay her cancer treatment even more—by months—which is not recommended.

Serious efforts to minimize estrogen production during controlled ovarian stimulation have been made, although further studies are needed. Research is under way to develop appropriate ovarian stimulation protocols based on drugs with antiestrogenic effects.

Tamoxifen, an antagonist of the estrogen receptor, is widely used in breast cancer treatment. ²⁰ It can also be given during controlled ovarian stimulation because it promotes follicular growth and induces ovulation.²¹ Oktay et al²² found that the embryo yield was 2.5 times higher in women with breast cancer treated with tamoxifen than in a retrospective control group consisting of breast cancer patients attempting natural-cycle oocyte retrieval.

Letrozole, an aromatase inhibitor, is also commonly used in treating breast and ovarian cancer. Aromatase is an enzyme that catalyzes the conversion of androgenic precursors to estrogens, and it is found in many tissues, including granulosa cells. Several studies report the use of letrozole, alone or in combination with low doses of recombinant FSH, in ovarian stimulation protocols in cancer patients, with positive clinical outcomes.²³

Tamoxifen or letrozole, combined with recombinant FSH, is an attractive option in a controlled ovarian stimulation protocol for cancer patients,²⁴ although further investigation is needed.

Two main protocols are currently used to freeze oocytes, embryos, and ovarian tissue: slow freezing and vitrification.

In the slow-freezing method, cryoprotectant agents are used to draw water out of the cells, raising intracellular viscosity without (or with minimal) intracellular ice crystal formation, while the sample is cooled slowly in a controlled manner. These cryoprotectant chemicals lower the freezing point of the solution, allowing greater cellular dehydration during the slow freezing. They also protect the plasmatic cell membrane by changing its physical state from liquid to partially dry. To avoid excessive deformation that could damage the cytoplasmic structures, cryoprotectant agents are added in successive stages.²⁵

Vitrification is a newer method that uses higher concentrations of cryoprotectants and flash freezing. The instant drop in temperature converts this highly concentrated solution from an aqueous state to a semisolid, amorphous state that does not contain ice crystals, which are the main cause of damage during the freezing process.²⁶ Since most cryoprotectant agents are extremely toxic, it is necessary to minimize the time that oocytes, embryos, and ovarian tissue are exposed to them.

Cryopreservation of embryos

According to the American Society of Clinical Oncology and the American Society of Reproductive Medicine, embryo freezing is the most established method for fertility preservation, with tangible and widely reported success.²⁷ In normal practice, oocytes are retrieved after a controlled ovarian stimulation and then fertilized in vitro. Then they are treated with cryoprotectant agents, frozen, and stored. Upon demand, embryos can be thawed and implanted.

The Society for Assisted Reproductive Technology reports that the current live birth rate per transfer using thawed embryos from nondonor oocytes in US women under age 35 is 38.7%; at age 35 to 37 it is 35.1%.²⁸ In women with cancer, storing as many embryos as possible could help improve embryo survival and the implantation rate. The optimal time to perform embryo cryopreservation is still being discussed,²⁹ but, as in women without cancer, it is commonly done 3 to 5 days after fertilization.

In the past few years, the use of vitrification has greatly increased, as the post-thawing survival rates and pregnancy rates are higher with this method than with slow freezing.³⁰

Despite its success, embryo cryopreservation has important drawbacks. First, the patient must be of reproductive age and have a partner or accept the use of donor sperm. Second, most patients undergo controlled ovarian stimulation before oocyte retrieval, causing a delay in starting cancer treatment, which is not acceptable in many cases. Moreover, the high serum estrogen levels caused by ovarian stimulation may be contraindicated in women with estrogen-sensitive malignancies.¹⁹

Oocyte cryopreservation

Cryopreservation of oocytes avoids the need for sperm and, thus, may be offered to more patients than embryo cryopreservation. In addition, it may circumvent ethical or legal considerations associated with embryo freezing, such as ownership of reproductive material.

However, oocytes are more difficult to cryopreserve than embryos. Indeed, ice crystals frequently form inside and outside the cells, damaging the cell membrane and the meiotic spindle. In routine practice, mature oocytes in metaphase II are used for cryopreservation. Metaphase II oocytes are large cells that contain a delicate meiotic spindle. Moreover, their cytoplasm contains a higher proportion of water than other cells, which could affect their viability after freezing and thawing due to ice crystal formation. In addition, cryopreservation could be responsible for hardening of the zona pellucida (through diffuse thickening of the cell membrane), adversely affecting fertilization rates.³¹

Significant improvements were achieved in fertilization of cryopreserved oocytes with intracytoplasmic sperm injection. Nevertheless, there are still concerns regarding oocyte cryopreservation. Further studies are needed to determine the risk of aneuploidy caused by damage to the meiotic spindle after oocyte cryopreservation. The potentially detrimental effects of high cryopreservant concentrations used in vitrification also need to be investigated.

In vitro maturation

A novel fertility preservation strategy involves collecting immature oocytes from primordial follicles in unstimulated cycles and then letting them mature in vitro.

To date, immature oocytes retrieved at the germinal vesicle stage can be cryopreserved with vitrification followed by in vitro maturation after thawing, but several studies have demonstrated that better results are obtained when vitrification follows the in vitro maturation process.³²

Compared with mature oocytes, immature oocytes are less susceptible to damage during cryopreservation and thus have a better chance of surviving freezing and thawing, thanks to some peculiar characteristics: they are small, have few organelles, lack a zona pellucida, have low metabolic activity, and are in a state of relative quiescence.³³ Controlled ovarian stimulation is not necessary, so this procedure preserves fertility without delaying the start of cancer treatment.

Patients are usually evaluated with transvaginal ultrasonography in the early follicular phase of the menstrual cycle (between day 2 and day 4) to count and measure the antral follicles. Immature oocytes are collected when the leading follicle has reached 10 to 12 mm in size and 36 hours after a subcutaneous injection of hCG.³⁴ The retrieved oocytes are then incubated for 24 to 48 hours in a special medium supplemented with FSH and luteinizing hormone (LH). Immature oocytes can also be collected in the luteal phase.

This option could be considered when cancer treatment cannot be delayed for conventional follicular-phase retrieval³⁵ or in case of a premature LH surge during ovarian stimulation. ³⁶ It should be offered to patients facing infertility related to cancer treatment only after appropriate counseling and as a part of a clinical study.

Ovarian tissue cryopreservation

Cryopreservation of ovarian tissue is an experimental but highly promising technique for preserving fertility. Like oocyte cryopreservation, it avoids the need for hormonal stimulation and the need to delay cancer treatment. It may also be the only possible option for prepubertal girls, as well as for women who cannot postpone their cancer treatment. Although it is still experimental, it has obtained progressively better results: after having ovarian tissue preserved, thawed, and subsequently reimplanted in the same position or in a different part of the body, some patients transiently resumed having menstrual cycles and endocrine activity and in a very few cases achieved pregnancy.³⁷

Ovarian tissue for cryopreservation is usually taken via laparoscopic surgery, unless the patient has to undergo open laparotomy for another indication. Laparoscopic surgery offers significant advantages, such as the possibility of performing it on short notice without delaying oncologic therapy. Considering that women at age 30 have about 35 primordial follicles per square millimeter of ovarian tissue, 5 cubic fragments 5 mm wide may be sufficient to obtain more than 4,000 primordial follicles.³⁸ In cases in which complete ovariectomy is necessary, it is possible to remove and cryopreserve fragments of normal ovarian tissue located at the margins of the surgical specimen. Ovarian tissue withdrawal can also be performed in pediatric patients and during other surgical procedures.

The most studied method of cryopreserving ovarian tissue is slow freezing, but the use of vitrification is increasing. This technique was initially carried out in order to preserve the largest number of primordial follicles, but in recent years the possibility of cryopreserving the whole ovary with or without its vascular pedicle has also been studied. Martinez-Madrid et al³⁹ described a protocol of cryopreserving the entire ovary with its stem and found it possible to reach a follicular survival rate of 75%, preserving vessels and stromal structure.³⁹

Currently, the most promising approach seems to be the transplantation of the ovarian tissue back into the donor, ie, autotransplantation. This avoids the need for immunosuppression.

The location can be either orthotopic or heterotopic. In orthotopic transplantation the tissue is placed back in its original location. In theory, the patient could then become pregnant in the usual way if the rest of the reproductive system is not damaged.

In heterotopic transplantation the tissue is placed in a different location, usually easily accessible, like the forearm or the subcutaneous abdominal area. Heterotopic transplants have been shown to be able to restore ovarian function, but not to give pregnancies after oocyte collection.⁴⁰ Indeed, the pregnancies obtained after transplantation came from autografts of ovarian cortex in orthotopic sites like the fossa ovarica or the remnant ovary.

With autotransplantation, there is a high risk of transmission of metastatic cancer cells. Blood-bone cancers such as leukemia and lymphomas are likely to be associated with the highest risk of ovarian metastasis through transplantation of thawed cryopreserved ovarian tissue. Neuroblastoma and breast cancer are associated with a moderate risk of metastasis to the ovaries. Ovarian involvement is extremely rare in Wilms tumor, lymphomas (except for Burkitt lymphoma), osteosarcomas, Ewing sarcoma, and extragenital rhabdomyosarcoma. Squamous cell cervical cancer metastasizes to the ovaries in fewer than 0.2% of cases, even in the most advanced stages. Histologic evaluation of ovarian samples before transplantation has been proposed to prevent cancer transmission, although it is not possible to completely abolish this risk.^41,42 This jeopardy could potentially be eliminated by in vitro maturation of immature oocytes collected from cryopreserved ovarian tissue.

Despite significant advances, to date there have been fewer than 20 babies born worldwide through this method.⁴³

Oocyte donation

Assisted reproduction techniques also include in vitro fertilization using a sperm sample from the partner and oocytes from a donor. The embryos obtained are then transferred, saving the woman from ovarian stimulation without any delay in starting the cancer treatment. Although this method has a high success rate, it inevitably raises personal considerations.

OVARIAN TRANSPOSITION

When a woman of childbearing age needs radiation treatment for a pelvic malignancy, transposition of the ovaries above the pelvic brim outside the radiation field (oophoropexy) should be considered before starting therapy. It is indicated in patients diagnosed with malignancies that require pelvic radiation but not the removal of the ovaries. It can be performed during surgical treatment of the tumor or as a separate laparoscopic procedure. The radiation dose that the transposed ovaries receive is considerably less than that in ovaries left in place.

Laparoscopic ovarian transposition is highly effective. However, the risk involved in the surgical procedure should not be underestimated. The most important complications are vascular injury, infarction of the fallopian tube, and ovarian cyst formation.⁴⁴

PHARMACOLOGIC PROTECTION

Some drugs induce a state of ovarian quiescence similar to menopause. Can they be used during chemotherapy to protect the ovaries, allowing restoration of normal ovarian function and natural fertility after cancer treatment and preventing premature ovarian failure?

GnRH analogues slow the cellular activity of the gonads, in theory making them less sensitive to damage by cytotoxic agents. Initially, the release of gonadotropins is stimulated (flare-up effect), but after 10 to 15 days pituitary GnRH receptors are down-regulated by internalization of receptors. Since chemotherapy affects mainly actively dividing cells such as mature ovarian follicles, the use of the analogues is based on the assumption that by reducing FSH levels, follicles will remain quiescent, decreasing their sensitivity to the gonadotoxic effect of chemotherapy.

In a randomized study of 281 patients with early breast cancer, Del Mastro et al⁴⁵ reported a reduction in the occurrence of early menopause in those treated with a GnRH analogue during chemotherapy after 1 year of follow-up. However, the debate regarding the effect of GnRH analogues on the fertility of cancer patients is still open and needs further investigation.

In recent years, research has focused on imatinib, a new, potentially protective drug,⁴⁶ but a lot of work still needs to be done. To date, the use of GnRH analogues is not recommended outside of clinical studies, and it should be offered only after careful counseling about other options to preserve fertility.

In the last few decades, the survival rates have improved in many of the malignancies that affect young adults. This progress has made fertility preservation and quality of life after cancer treatment important, most of all in survivors of childhood cancers.

Men who are about to undergo cancer treatment can bank their sperm, but as yet no analogous noninvasive option is available for women. The most studied methods are often invasive and require the woman to take large doses of hormones. They may also necessitate a delay in starting cancer treatment.

Which method of fertility preservation a woman should choose depends on several factors, including the type of disease, the treatment required, the age of the patient, whether she has a long-term partner, and whether treatment can be delayed.

Chemotherapy and radiotherapy have well-known deleterious effects on female reproductive function. Many studies have shown that acute loss of growing follicles within the ovary and resultant premature ovarian failure often follow chemotherapy. This ovarian damage has long-term consequences, such as shortened reproductive life span and hormone deficiency.¹

Fertility preservation requires a team effort. It should be managed by an oncology center that has built a close collaboration between oncologists, fertility specialists, psychologists, and primary care physicians to allow early discussion and to offer a full range of options to these patients.

The aim of this paper is to discuss the current options for preserving fertility in female cancer patients who have to undergo gonadotoxic cancer treatment.

FEMALE FERTILITY AND ASSESSMENT OF OVARIAN RESERVE

At birth, baby girls have about 1 million primordial ovarian follicles, which is the most they will ever have. By the time they reach menarche, this number has declined to 180,000, and at menopause only about 1,000 remain.²

Throughout a woman’s reproductive life, the number of oocytes remaining—both primordial follicles and the relatively small number of maturing, growing follicles—is called her ovarian reserve. When cancer is diagnosed, we need to assess the patient’s ovarian reserve to direct the discussion about the need for fertility preservation.

In search of markers of ovarian reserve

Fertility experts have been looking for clinical biomarkers that could give us an estimate of the number of nongrowing follicles and, consequently, of the ovarian reserve.

All methods used for the assessment of ovarian reserve actually provide an indirect determination of the remaining pool of oocytes. In clinical practice, a high blood level of follicle-stimulating hormone (FSH) on cycle day 3 (>15 mU/mL) or a low level of anti-Müllerian hormone (AMH) (<1 ng/mL) is generally associated with a low ovarian reserve.

The serum FSH level is the marker most commonly used, but it varies widely at different times in the menstrual cycle.

The FSH test is usually performed on day 3 of the menstrual cycle, when the estrogen level is expected to be low due to negative feedback. The FSH result needs to be combined with the estradiol level, especially in those patients with irregular menstruation or in cases of amenorrhea. A random FSH test is considered valid if the detected estrogen level is low. Women undergoing in vitro fertilization with a day 3 FSH lower than 15 mIU/mL are more likely to conceive than women with a higher FSH level.

AMH and antral follicles. Recently, two other variables have been introduced in clinical practice: the AMH concentration and the antral follicle count (the number of small antral follicles within the ovary) as assessed by transvaginal ultrasonography.

AMH is released by the granulosa cells of small, growing follicles. Because its level is much more stable over the menstrual cycle than the FSH level, it can be measured on any day of the cycle.³ In cancer survivors, AMH is particularly useful in demonstrating the degree of ovarian tissue damage induced by radiotherapy and chemotherapy and in evaluating the ovarian reserve.⁴

A reduced number of antral follicles causes a diminished AMH production, which becomes undetectable with menopause. The AMH level is strongly associated with the basal antral follicle count. Various threshold values (0.2–1.26 ng/mL) have been used to identify women with low ovarian reserve.

HOW CANCER TREATMENT DAMAGES THE OVARIES

Advances in surgery, radiotherapy, and chemotherapy have significantly improved the prognosis for young cancer patients. However, cancer treatments often result in ovarian dysfunction, and premature menopause and irreversible sterility are the most dramatic outcomes. The resulting low estrogen levels, in addition to their physiologic consequences, also worsen quality of life through psychological effects, which can as well influence the patient’s compliance with treatment.

Chemotherapy: Alkylating agents are the most gonadotoxic

The mechanism by which chemotherapy affects ovarian function is poorly understood. Histologically, chemotherapeutic drugs could lead to ovarian atrophy and stromal fibrosis, to depletion of the primordial follicle stockpile, and to reduced ovarian weight, resulting in ovarian dysfunction.⁵

The patient's age correlates with the probability of ovarian damage or, inversely, ovarian resistance to chemotherapy. Young women have more primordial oocytes, and after chemotherapy they face a sharp reduction of their ovarian reserve. Still, younger patients show a lower rate of ovarian toxicity than older women.⁶

The type and the cumulative dose of cytotoxic agents used are other important variables.⁷ There are six main classes of chemotherapeutic drugs: alkylating agents, platinum derivatives, antibiotics, antimetabolites, plant alkaloids, and taxanes. They all affect ovarian function, but alkylating agents are the most gonadotoxic.

Alkylating agents covalently bind an alkyl group to the DNA molecule and inhibit it from replicating. In the ovaries they directly injure primordial oocytes and deplete follicles. ⁸ They also seriously damage the ovarian vasculature so that the follicles cannot grow.⁹ Their destructive effect on the primordial follicles is dose-dependent and varies with the age and developmental maturity of the patient at the time of the therapy, with older women more likely to be left infertile afterward.¹⁰

Cyclophosphamide is an alkylating agent often used to treat severe manifestations of autoimmune diseases such as systemic lupus erythematosus, BehÇet disease, steroid-resistant glomerulonephritis, inflammatory bowel disease, pemphigus vulgaris, and others. Because it can lead to premature ovarian failure and infertility, women receiving cyclophosphamide for autoimmune conditions may also need treatment to preserve fertility.¹¹

Radiotherapy

Ovarian follicles are remarkably vulnerable to damage from ionizing radiation, which results in ovarian atrophy and reduced follicle stores.¹

The risk of radiotherapy-induced infertility is closely related to the patient’s age and developmental maturity at the time of therapy and to dose fractionation and the extent of the irradiation field. Every patient has a different sensitivity to radiation damage that is probably genetically predetermined, but age seems to be the most important variable. Wo and Viswanathan¹² used a mathematical model devised by Wallace et al¹³ to show that the older the patient, the lower the radiation dose necessary to impair ovarian function.

The irradiation field is another aspect to consider. Pelvic radiation can be necessary in rectal cancer, cervical cancer, and lymphoma. In these cases, surgically moving the ovaries to a region outside the radiation field could be an option to minimize radiotherapy-induced ovarian damage.¹⁴

Radiotherapy can also damage the uterus. Pelvic irradiation can reduce uterine volume, alter uterine elasticity through myometrial fibrosis, and modify vascularization and endometrial thickness.^15,16 These alterations are closely correlated with the total radiation dose, the site of irradiation, and the patient’s age at the time of the treatment, the prepubertal uterus being more susceptible to damage. ^15,17 Larsen et al¹⁵ found that girls who received uterine irradiation before puberty had lower uterine volumes in adulthood than girls who received chemotherapy alone or radiation to other parts of the body, and that the younger the patient at the time of radiotherapy, the smaller the uterus later. These effects could result in adverse pregnancy outcomes.

Furthermore, radiation could also damage the uterine vasculature. Holm et al¹⁶ used ultrasonography to evaluate the effect of total-body irradiation and found that uterine volume and uterine blood flow were both impaired.¹⁵

All these possible alterations could lead to a reduced uterine response to cytotrophoblast invasion and to decreased fetoplacental blood flow, which could impair embryonic and fetal growth. In that case, a surrogate pregnancy would be the only method to achieve parenthood using the couple’s gametes.

OPTIONS FOR FERTILITY PRESERVATION

Assisted reproductive technology

Young women diagnosed with an oncologic disease may wish to use assisted reproductive technology (Table 1) to keep open the possibility of having children at a later date. One approach is to harvest oocytes, fertilize them in vitro, and deep-freeze (cryopreserve) the resulting embryos to be thawed and implanted later. Alternatively, oocytes can be frozen directly, although success rates are lower with this method. And another approach is to obtain and cryopreserve ovarian tissue. If none of these is possible, oocytes may be obtained from a donor.

Controlled ovarian stimulation

If oocytes are to be harvested, a number of them should be harvested at one time.

There is not an optimal number of oocytes that should be retrieved, but cryopreservation of a large number of oocytes allows us to perform multiple attempts at in vitro fertilization, improving the chances of pregnancy. The fertilization rate (defined as the total number of zygotes at the 2-pronucleus stage divided by the number of fertilized oocytes) with intracytoplasmic sperm injection is 70% to 80%. On average, for every 10 eggs, 7 to 8 eggs will normally be fertilized. The implantation rate (defined as the total number of pregnancies divided by the total number of embryo transferred) with intracytoplasmic sperm injection is 40% to 50%—ie, only half of the transferred embryos will successfully implant and result in a pregnancy.

So that more than one ripe egg can be obtained at a time, the patient must undergo a regimen of controlled ovarian stimulation to achieve multifollicular growth. Stimulation protocols are based on giving pituitary hormones, ie, analogues of gonadotropin-releasing hormone (GnRH) (both agonists and antagonists), followed by recombinant FSH or human menopausal gonadotropin to promote follicular development. A single dose of human chorionic gonadotropin (hCG) is given to induce ovulation when the lead follicles have reached 18 to 20 mm in size.¹⁸

Many oncologists consider controlled ovarian stimulation dangerous for cancer patients because it takes time and thus delays cancer treatment. Furthermore, the regimen boosts the levels of circulating estrogens, which could be harmful in patients with hormone-dependent tumors.¹⁹

Oocytes can also be retrieved during unstimulated cycles. This avoids increasing estrogen concentrations above the physiologic level, but no more than a single oocyte is collected per cycle. The patient could undergo multiple oocyte harvestings, one per cycle, but this would delay her cancer treatment even more—by months—which is not recommended.

Serious efforts to minimize estrogen production during controlled ovarian stimulation have been made, although further studies are needed. Research is under way to develop appropriate ovarian stimulation protocols based on drugs with antiestrogenic effects.

Tamoxifen, an antagonist of the estrogen receptor, is widely used in breast cancer treatment. ²⁰ It can also be given during controlled ovarian stimulation because it promotes follicular growth and induces ovulation.²¹ Oktay et al²² found that the embryo yield was 2.5 times higher in women with breast cancer treated with tamoxifen than in a retrospective control group consisting of breast cancer patients attempting natural-cycle oocyte retrieval.

Letrozole, an aromatase inhibitor, is also commonly used in treating breast and ovarian cancer. Aromatase is an enzyme that catalyzes the conversion of androgenic precursors to estrogens, and it is found in many tissues, including granulosa cells. Several studies report the use of letrozole, alone or in combination with low doses of recombinant FSH, in ovarian stimulation protocols in cancer patients, with positive clinical outcomes.²³

Tamoxifen or letrozole, combined with recombinant FSH, is an attractive option in a controlled ovarian stimulation protocol for cancer patients,²⁴ although further investigation is needed.

Two main protocols are currently used to freeze oocytes, embryos, and ovarian tissue: slow freezing and vitrification.

In the slow-freezing method, cryoprotectant agents are used to draw water out of the cells, raising intracellular viscosity without (or with minimal) intracellular ice crystal formation, while the sample is cooled slowly in a controlled manner. These cryoprotectant chemicals lower the freezing point of the solution, allowing greater cellular dehydration during the slow freezing. They also protect the plasmatic cell membrane by changing its physical state from liquid to partially dry. To avoid excessive deformation that could damage the cytoplasmic structures, cryoprotectant agents are added in successive stages.²⁵

Vitrification is a newer method that uses higher concentrations of cryoprotectants and flash freezing. The instant drop in temperature converts this highly concentrated solution from an aqueous state to a semisolid, amorphous state that does not contain ice crystals, which are the main cause of damage during the freezing process.²⁶ Since most cryoprotectant agents are extremely toxic, it is necessary to minimize the time that oocytes, embryos, and ovarian tissue are exposed to them.

Cryopreservation of embryos

According to the American Society of Clinical Oncology and the American Society of Reproductive Medicine, embryo freezing is the most established method for fertility preservation, with tangible and widely reported success.²⁷ In normal practice, oocytes are retrieved after a controlled ovarian stimulation and then fertilized in vitro. Then they are treated with cryoprotectant agents, frozen, and stored. Upon demand, embryos can be thawed and implanted.

The Society for Assisted Reproductive Technology reports that the current live birth rate per transfer using thawed embryos from nondonor oocytes in US women under age 35 is 38.7%; at age 35 to 37 it is 35.1%.²⁸ In women with cancer, storing as many embryos as possible could help improve embryo survival and the implantation rate. The optimal time to perform embryo cryopreservation is still being discussed,²⁹ but, as in women without cancer, it is commonly done 3 to 5 days after fertilization.

In the past few years, the use of vitrification has greatly increased, as the post-thawing survival rates and pregnancy rates are higher with this method than with slow freezing.³⁰

Despite its success, embryo cryopreservation has important drawbacks. First, the patient must be of reproductive age and have a partner or accept the use of donor sperm. Second, most patients undergo controlled ovarian stimulation before oocyte retrieval, causing a delay in starting cancer treatment, which is not acceptable in many cases. Moreover, the high serum estrogen levels caused by ovarian stimulation may be contraindicated in women with estrogen-sensitive malignancies.¹⁹

Oocyte cryopreservation

Cryopreservation of oocytes avoids the need for sperm and, thus, may be offered to more patients than embryo cryopreservation. In addition, it may circumvent ethical or legal considerations associated with embryo freezing, such as ownership of reproductive material.

However, oocytes are more difficult to cryopreserve than embryos. Indeed, ice crystals frequently form inside and outside the cells, damaging the cell membrane and the meiotic spindle. In routine practice, mature oocytes in metaphase II are used for cryopreservation. Metaphase II oocytes are large cells that contain a delicate meiotic spindle. Moreover, their cytoplasm contains a higher proportion of water than other cells, which could affect their viability after freezing and thawing due to ice crystal formation. In addition, cryopreservation could be responsible for hardening of the zona pellucida (through diffuse thickening of the cell membrane), adversely affecting fertilization rates.³¹

Significant improvements were achieved in fertilization of cryopreserved oocytes with intracytoplasmic sperm injection. Nevertheless, there are still concerns regarding oocyte cryopreservation. Further studies are needed to determine the risk of aneuploidy caused by damage to the meiotic spindle after oocyte cryopreservation. The potentially detrimental effects of high cryopreservant concentrations used in vitrification also need to be investigated.

In vitro maturation

A novel fertility preservation strategy involves collecting immature oocytes from primordial follicles in unstimulated cycles and then letting them mature in vitro.

To date, immature oocytes retrieved at the germinal vesicle stage can be cryopreserved with vitrification followed by in vitro maturation after thawing, but several studies have demonstrated that better results are obtained when vitrification follows the in vitro maturation process.³²

Compared with mature oocytes, immature oocytes are less susceptible to damage during cryopreservation and thus have a better chance of surviving freezing and thawing, thanks to some peculiar characteristics: they are small, have few organelles, lack a zona pellucida, have low metabolic activity, and are in a state of relative quiescence.³³ Controlled ovarian stimulation is not necessary, so this procedure preserves fertility without delaying the start of cancer treatment.

Patients are usually evaluated with transvaginal ultrasonography in the early follicular phase of the menstrual cycle (between day 2 and day 4) to count and measure the antral follicles. Immature oocytes are collected when the leading follicle has reached 10 to 12 mm in size and 36 hours after a subcutaneous injection of hCG.³⁴ The retrieved oocytes are then incubated for 24 to 48 hours in a special medium supplemented with FSH and luteinizing hormone (LH). Immature oocytes can also be collected in the luteal phase.

This option could be considered when cancer treatment cannot be delayed for conventional follicular-phase retrieval³⁵ or in case of a premature LH surge during ovarian stimulation. ³⁶ It should be offered to patients facing infertility related to cancer treatment only after appropriate counseling and as a part of a clinical study.

Ovarian tissue cryopreservation

Cryopreservation of ovarian tissue is an experimental but highly promising technique for preserving fertility. Like oocyte cryopreservation, it avoids the need for hormonal stimulation and the need to delay cancer treatment. It may also be the only possible option for prepubertal girls, as well as for women who cannot postpone their cancer treatment. Although it is still experimental, it has obtained progressively better results: after having ovarian tissue preserved, thawed, and subsequently reimplanted in the same position or in a different part of the body, some patients transiently resumed having menstrual cycles and endocrine activity and in a very few cases achieved pregnancy.³⁷

Ovarian tissue for cryopreservation is usually taken via laparoscopic surgery, unless the patient has to undergo open laparotomy for another indication. Laparoscopic surgery offers significant advantages, such as the possibility of performing it on short notice without delaying oncologic therapy. Considering that women at age 30 have about 35 primordial follicles per square millimeter of ovarian tissue, 5 cubic fragments 5 mm wide may be sufficient to obtain more than 4,000 primordial follicles.³⁸ In cases in which complete ovariectomy is necessary, it is possible to remove and cryopreserve fragments of normal ovarian tissue located at the margins of the surgical specimen. Ovarian tissue withdrawal can also be performed in pediatric patients and during other surgical procedures.

The most studied method of cryopreserving ovarian tissue is slow freezing, but the use of vitrification is increasing. This technique was initially carried out in order to preserve the largest number of primordial follicles, but in recent years the possibility of cryopreserving the whole ovary with or without its vascular pedicle has also been studied. Martinez-Madrid et al³⁹ described a protocol of cryopreserving the entire ovary with its stem and found it possible to reach a follicular survival rate of 75%, preserving vessels and stromal structure.³⁹

Currently, the most promising approach seems to be the transplantation of the ovarian tissue back into the donor, ie, autotransplantation. This avoids the need for immunosuppression.

The location can be either orthotopic or heterotopic. In orthotopic transplantation the tissue is placed back in its original location. In theory, the patient could then become pregnant in the usual way if the rest of the reproductive system is not damaged.

In heterotopic transplantation the tissue is placed in a different location, usually easily accessible, like the forearm or the subcutaneous abdominal area. Heterotopic transplants have been shown to be able to restore ovarian function, but not to give pregnancies after oocyte collection.⁴⁰ Indeed, the pregnancies obtained after transplantation came from autografts of ovarian cortex in orthotopic sites like the fossa ovarica or the remnant ovary.

With autotransplantation, there is a high risk of transmission of metastatic cancer cells. Blood-bone cancers such as leukemia and lymphomas are likely to be associated with the highest risk of ovarian metastasis through transplantation of thawed cryopreserved ovarian tissue. Neuroblastoma and breast cancer are associated with a moderate risk of metastasis to the ovaries. Ovarian involvement is extremely rare in Wilms tumor, lymphomas (except for Burkitt lymphoma), osteosarcomas, Ewing sarcoma, and extragenital rhabdomyosarcoma. Squamous cell cervical cancer metastasizes to the ovaries in fewer than 0.2% of cases, even in the most advanced stages. Histologic evaluation of ovarian samples before transplantation has been proposed to prevent cancer transmission, although it is not possible to completely abolish this risk.^41,42 This jeopardy could potentially be eliminated by in vitro maturation of immature oocytes collected from cryopreserved ovarian tissue.

Despite significant advances, to date there have been fewer than 20 babies born worldwide through this method.⁴³

Oocyte donation

Assisted reproduction techniques also include in vitro fertilization using a sperm sample from the partner and oocytes from a donor. The embryos obtained are then transferred, saving the woman from ovarian stimulation without any delay in starting the cancer treatment. Although this method has a high success rate, it inevitably raises personal considerations.

OVARIAN TRANSPOSITION

When a woman of childbearing age needs radiation treatment for a pelvic malignancy, transposition of the ovaries above the pelvic brim outside the radiation field (oophoropexy) should be considered before starting therapy. It is indicated in patients diagnosed with malignancies that require pelvic radiation but not the removal of the ovaries. It can be performed during surgical treatment of the tumor or as a separate laparoscopic procedure. The radiation dose that the transposed ovaries receive is considerably less than that in ovaries left in place.

Laparoscopic ovarian transposition is highly effective. However, the risk involved in the surgical procedure should not be underestimated. The most important complications are vascular injury, infarction of the fallopian tube, and ovarian cyst formation.⁴⁴

PHARMACOLOGIC PROTECTION

Some drugs induce a state of ovarian quiescence similar to menopause. Can they be used during chemotherapy to protect the ovaries, allowing restoration of normal ovarian function and natural fertility after cancer treatment and preventing premature ovarian failure?

GnRH analogues slow the cellular activity of the gonads, in theory making them less sensitive to damage by cytotoxic agents. Initially, the release of gonadotropins is stimulated (flare-up effect), but after 10 to 15 days pituitary GnRH receptors are down-regulated by internalization of receptors. Since chemotherapy affects mainly actively dividing cells such as mature ovarian follicles, the use of the analogues is based on the assumption that by reducing FSH levels, follicles will remain quiescent, decreasing their sensitivity to the gonadotoxic effect of chemotherapy.

In a randomized study of 281 patients with early breast cancer, Del Mastro et al⁴⁵ reported a reduction in the occurrence of early menopause in those treated with a GnRH analogue during chemotherapy after 1 year of follow-up. However, the debate regarding the effect of GnRH analogues on the fertility of cancer patients is still open and needs further investigation.

In recent years, research has focused on imatinib, a new, potentially protective drug,⁴⁶ but a lot of work still needs to be done. To date, the use of GnRH analogues is not recommended outside of clinical studies, and it should be offered only after careful counseling about other options to preserve fertility.

Hereditary angioedema due to deficiency of C1 inhibitor is a rare autosomal dominant disease that can be life-threatening. It affects about 1 in 50,000 people,¹ or about 6,000 people in the United States. There are no known differences in prevalence by ethnicity or sex. A form of hereditary angioedema with normal C1 inhibitor levels has also recently been identified.

Despite a growing awareness of hereditary angioedema in the medical community, repeated surveys have found an average gap of 10 years between the first appearance of symptoms and the correct diagnosis. In view of the risk of morbidity and death, recognizing this disease sooner is critical.

This article will discuss how to recognize hereditary angioedema and how to differentiate it from other forms of recurring angioedema. We will also review its acute and long-term management, with special attention to new therapies and clinical challenges.

EPISODES OF SWELLING WITHOUT HIVES

Hereditary angioedema involves recurrent episodes of nonpruritic, nonpitting, subcutaneous and submucosal edema that can affect the face, tongue, larynx, trunk, extremities, bowels, or genitals. Attacks typically follow a predictable course: swelling that increases slowly and continuously for 24 hours and then gradually subsides over the next 48 to 72 hours. Attacks that involve the oropharynx, larynx, or abdomen carry the highest risk of morbidity and death.¹

The frequency and severity of attacks are highly variable and unpredictable. A few patients have no attacks, a few have two attacks per week, and most fall in between.

Hives suggests an allergic or idiopathic rather than hereditary cause and will not be discussed here in detail. A history of angioedema that was rapidly aborted by antihistamines, corticosteroids, or epinephrine also suggests an allergic rather than hereditary cause.

UNCHECKED BRADYKININ PRODUCTION

Substantial evidence indicates that hereditary angioedema results from extravasation of plasma into deeper cutaneous or mucosal compartments as a result of overproduction of the vasoactive mediator bradykinin (Figure 1).

Activated factor XII cleaves plasma prekallikrein to generate active plasma kallikrein (which, in turn, activates more factor XII).² Once generated, plasma kallikrein cleaves high-molecular-weight kininogen, releasing bradykinin. Bradykinin binds to the B2 bradykinin receptor on endothelial cells, increasing the permeability of the endothelium.

Normally, C1 inhibitor helps control bradykinin production by inhibiting plasma kallikrein and activated factor XII. Without enough C1 inhibitor, the contact system is uninhibited and results in bradykinin being inappropriately generated.

Because the attacks of hereditary angioedema involve excessive bradykinin, they do not respond to the usual treatments for anaphylaxis and allergic angioedema (which involve mast cell degranulation), such as antihistamines, corticosteroids, and epinephrine.

TWO TYPES OF HEREDITARY ANGIOEDEMA

Figure 2 shows the evaluation of patients with suspected hereditary angioedema.

Hereditary angioedema due to C1 inhibitor deficiency

The classic forms of hereditary angioedema (types I and II) involve loss-of-function mutations in SERPING1—the gene that encodes for C1 inhibitor—resulting in low levels of functional C1 inhibitor.³ The mutation is inherited in an autosomal dominant pattern; however, in about 25% of cases, it appears to arise spontaneously,⁴ so a family history is not required for diagnosis.

Although C1 inhibitor deficiency is present from birth, the clinical disease most commonly presents for the first time when the patient is of school age. Half of patients have their first episode in the first decade of life, and another one-third first develop symptoms over the next 10 years.⁵

Clinically, types I and II are indistinguishable. Type I, accounting for 85% of cases,¹ results from low production of C1 inhibitor. Laboratory studies reveal low antigenic and functional levels of C1 inhibitor.

In type II, the mutant C1 inhibitor protein is present but dysfunctional and unable to inhibit target proteases. On laboratory testing, the functional level of C1 inhibitor is low but its antigenic level is normal (Table 1). Function can be tested by either chromogenic assay or enzyme-linked immunosorbent assay; the former is preferred because it is more sensitive.⁶

Because C1 inhibitor deficiency results in chronic activation of the complement system, patients with type I or II disease usually have low C4 levels regardless of disease activity, making measuring C4 the most economical screening test. When suspicion for hereditary angioedema is high, based on the presentation and family and clinical history, measuring antigenic and functional C1 inhibitor levels and C4 simultaneously is more efficient.

Hereditary angioedema with normal C1 inhibitor levels is also inherited in an autosomal dominant pattern. It is often estrogen-sensitive, making it more severe in women. Symptoms tend to develop slightly later in life than in type I or II disease.⁷

Angioedema with normal C1 inhibitor levels has been associated with factor XII mutations in a minority of cases, but most patients do not have a specific laboratory abnormality. Because there is no specific laboratory profile, the diagnosis is based on clinical criteria. Hereditary angioedema with normal C1 inhibitor levels should be considered in patients who have recurrent angioedema, normal C4, normal antigenic and functional C1 inhibitor levels, a lack of response to high-dose antihistamines, and either a family history of angioedema without hives or a known factor XII mutation.⁷ However, other forms of angioedema (allergic, drug-induced, and idiopathic) should also be considered, as C4 and C1 inhibitor levels are normal in these forms as well.

DIFFERENTIAL DIAGNOSIS: OTHER TYPES OF ANGIOEDEMA

Acquired C1 inhibitor deficiency

Symptoms of acquired C1 inhibitor deficiency resemble those of hereditary angioedema but typically do not emerge until the fourth decade of life or later, and patients have no family history of the condition. It is often associated with other diseases, most commonly B-cell lymphoproliferative disorders, which cause uncontrolled complement activation and consumption of C1 inhibitor.

In some patients, autoantibodies to C1 inhibitor develop, greatly reducing its effectiveness and resulting in enhanced consumption. The autoantibody is often associated with a monoclonal gammopathy of unknown significance. The presence of a C1 inhibitor autoantibody does not preclude the presence of an underlying disorder, and vice versa.

Laboratory studies reveal low C4, low C1-inhibitor antigenic and functional levels, and usually a low C1q level owing to consumption of complement. Autoantibodies to C1 inhibitor can be detected by laboratory testing.

Because of the association with autoimmune disease and malignant disorders (especially B-cell malignancy), a patient diagnosed with acquired C1 inhibitor deficiency should be further evaluated for underlying conditions.

Allergic angioedema

Allergic angioedema results from preformed antigen-specific immunoglobulin E (IgE) antibodies that stimulate mast cells to degranulate when patients are exposed to a particular allergen—most commonly food, insect venom, latex, or drugs. IgE-mediated histamine release causes swelling, as histamine is a potent vasodilator.

Symptoms often begin within 2 hours of exposure to the allergen and generally include concurrent urticaria and swelling that last less than 24 hours. Unlike in hereditary angioedema, the swelling responds to antihistamines and corticosteroids. When very severe, these symptoms may also be accompanied by bronchoconstriction and gastrointestinal symptoms, especially if the allergen is ingested.

Histamine-mediated angioedema may also be associated with exercise as part of a syndrome called exercise-induced anaphylaxis or angioedema.

Drug-induced angioedema

Drug-induced angioedema is typically associated with angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs).

Angioedema associated with ACE inhibitors is estimated to affect 0.1% to 6% of patients taking these medications, with African Americans being at significantly higher risk. Although 25% of affected patients develop symptoms of angioedema within the first month of taking the drugs, some tolerate them for as long as 10 years before the first episode.⁹ The swelling is not allergic or histamine-related. ACE normally degrades bradykinin; therefore, inhibiting ACE leads to accumulation of bradykinin. Because all ACE inhibitors have this effect, this class of drug should be discontinued in any patient who develops isolated angioedema.

NSAID-induced angioedema is often accompanied by other symptoms, including urticaria, rhinitis, cough, hoarseness, or breathlessness.¹⁰ The mechanism of NSAID-induced angioedema involves cyclooxygenase (COX) 1 (and to a lesser extent COX-2) inhibition. All NSAIDs (and aspirin) should be avoided in patients with recurrent angioedema. Specific COX-2 inhibitors, while theoretically capable of causing angioedema by the same mechanism, are generally well tolerated in patients who have had COX-1 inhibitor reactions.

Idiopathic angioedema

If no clear cause of recurrent angioedema (at least three episodes in a year) can be found, it is labeled idiopathic.¹¹ Some patients with idiopathic angioedema fail to benefit from high doses of antihistamines, suggesting that the cause is bradykinin-mediated.

CLINICAL MANIFESTATIONS OF HEREDITARY ANGIOEDEMA

Attacks may start at one site and progress to involve additional sites.

Prodromal symptoms may begin up to several days before an attack and include tingling, warmth, burning, or itching at the affected site; increased fatigue or malaise; nausea, abdominal distention, or gassiness; or increased hunger, particularly before an abdominal attack.⁵ The most characteristic prodromal symptom is erythema marginatum—a raised, serpiginous, nonpruritic rash on the trunk, arms, and legs but often sparing the face.

Abdominal attacks are easily confused with acute abdomen

Almost half of attacks involve the abdomen, and almost all patients with type I or II disease experience at least one such attack.¹² Symptoms can include severe abdominal pain, nausea, vomiting, and diarrhea. Abdominal attacks account for many emergency department visits, hospitalizations, and surgical procedures for acute abdomen; about one-third of patients with undiagnosed hereditary angioedema undergo an unnecessary surgery during an abdominal attack. Angioedema of the gastrointestinal tract can result in enough plasma extravasation and vasodilation to cause hypovolemic shock.

Eradicating Helicobacter pylori infection may alleviate abdominal attacks.¹³

Attacks of the extremities can be painful and disabling

Attacks of the extremities affect 96% of patients¹² and can be very disfiguring and disabling. Driving or using the phone is often difficult when the hands are affected. When feet are involved, walking and standing become painful. While these symptoms rarely result in a lengthy hospitalization, they interfere with work and school and require immediate medical attention because they can progress to other parts of the body.

Laryngeal attacks are life-threatening

About half of patients with hereditary angioedema have an attack of laryngeal edema at some point in their lives.¹² If not effectively managed, laryngeal angioedema can progress to asphyxiation. A survey of family history in 58 patients with hereditary angioedema suggested a 40% incidence of asphyxiation in untreated laryngeal attacks, and 25% to 30% of patients are estimated to have died of laryngeal edema before effective treatment became available.¹⁴

Symptoms of a laryngeal attack include change in voice, hoarseness, trouble swallowing, shortness of breath, and wheezing. Physicians must recognize these symptoms quickly and give effective treatment early in the attack to prevent morbidity and death.

Establishing an airway can be life-saving in the absence of effective therapy, but extensive swelling of the upper airway can make intubation extremely difficult.

Genitourinary attacks also occur

Attacks involving the scrotum and labia have been reported in up to two-thirds of patients with hereditary angioedema at some point in their lives. Attacks involving the bladder and kidneys have also been reported but are less common, affecting about 5% of patients.¹² Genitourinary attacks may be triggered by local trauma, such as horseback riding or sexual intercourse, although no trigger may be evident.

MANAGING ACUTE ATTACKS

The goals of treatment are to alleviate acute exacerbations with on-demand treatment and to reduce the number of attacks with prophylaxis. Therapy should be individualized to each patient’s needs. Treatments have advanced greatly in the last several years, and new medications for treating acute attacks and preventing attacks have shown great promise (Figure 3, Table 2).

Patients tend to have recurrent symptoms interspersed with periods of health, suggesting that attacks ought to have identifiable triggers, although in most, no trigger is evident. The most commonly identified are local trauma (including medical and dental procedures), emotional stress, and acute infection. Disease severity may be worsened by menstruation, estrogen-containing oral contraceptives, hormone replacement therapy, ACE inhibitors, and NSAIDs.

It is critical that attacks be treated with an effective medication as soon as possible. Consensus guidelines state that all patients with hereditary angioedema due to C1 inhibitor deficiency, even if they are still asymptomatic, should have access to at least one of the drugs approved for on-demand treatment.¹⁵ The guidelines further state that whenever possible, “patients should have the on-demand medicine to treat acute attacks at home and should be trained to self-administer these medicines.”¹⁵

Several plasma-derived C1 inhibitors are available (Cinryze, Berinert, Cetor). They are prepared from fractionated plasma obtained from donors, then pasteurized and nanofiltered.

Berinert and Cinryze were each found to be superior to placebo in double-blind, placebo-controlled trials: attacks usually resolved 30 to 60 minutes after intravenous injection.^16,17 Berinert 20 U/kg is associated with the onset of symptom relief as early as half an hour after administration, compared with 1.5 hours with placebo. Early use (at the onset of symptoms) of a plasma-derived C1 inhibitor in a low dose (500 U) can also be effective.^18,19 Efficacy appears to be consistent at all sites of attack involvement, including laryngeal edema. Safety and efficacy have been demonstrated during pregnancy and lactation and in young children and babies.²⁰

Plasma-derived C1 inhibitors can be self-administered. The safety and efficacy of self-administration (under physician supervision) were demonstrated in a study of Cinryze and Cetor, in which attack duration, pain medication use, and graded attack severity were significantly less with self-administered therapy than with therapy in the clinic.²¹

A concern about plasma-derived products is the possibility of blood-borne infection, but this has not been confirmed by experience.²²

Recombinant human C1 inhibitor

A recombinant human C1 inhibitor (Rhucin) has been studied in two randomized placebo-controlled trials. Although this product has a shorter half-life than the plasma-derived C1 inhibitors (3 vs more than 24 hours), the two are equipotent: 1 U of recombinant human C1 inhibitor is equivalent to 1 U of plasma-derived C1 inhibitor. Because the supply of recombinant human C1 inhibitor is elastic, dosing has been higher, which may provide more efficacy.²³ Similar to plasma-derived C1 inhibitor products, the recombinant human C1 inhibitor resulted in more rapid symptom relief than with saline (66 vs 122 minutes) and in a shorter time to minimal symptoms (247−266 vs 1,210 minutes).²⁴

Allergy is of concern: in one study, a healthy volunteer with undisclosed rabbit allergy experienced an allergic reaction. Patients should be screened by a skin-prick test or serum testing for specific IgE to rabbit epithelium before being prescribed recombinant human C1 inhibitor. No data are available for use during pregnancy or breastfeeding.

Ecallantide

Ecallantide (Kalbitor) is a selective inhibitor of plasma kallikrein that is given in three subcutaneous injections. Ecallantide 30 mg was found superior to placebo during acute attacks.^25,26

Ecallantide is well tolerated, with the most common adverse effects being headache, nausea, fatigue, diarrhea, and local injection-site reactions. Antibodies to ecallantide can be found in patients with increasing drug exposure but do not appear to correlate with adverse events. Hypersensitivity reactions have been observed in 2% to 3% of patients receiving repeated doses. Because of anaphylaxis risk, ecallantide must be administered by a health care professional.

Icatibant

Icatibant (Firazyr) is a bradykinin receptor-2 antagonist that is given in a single subcutaneous injection. Icatibant 30 mg significantly shortened time to symptom relief and time to almost complete resolution compared with placebo.^27,28 Icatibant’s main adverse effect is transient local pain, swelling, and erythema at the injection site. Icatibant can be self-administered by patients.

Fresh-frozen plasma

Fresh-frozen plasma contains C1 inhibitor and was used before the newer products became available. Several noncontrolled studies reported benefit of its use in acute attacks.²⁹ However, its use is controversial because it also contains contact-system proteins that could provide additional substrate for the generation of bradykinin, which could exacerbate attacks in some patients.¹ This may be particularly dangerous in patients presenting with laryngeal edema: in such a situation, the physician should be ready to treat a sudden exacerbation with intubation. The risk of acquiring a blood-borne pathogen is also higher than with plasma-derived C1 inhibitor.

PROPHYLACTIC MANAGEMENT

Short-term and long-term prophylaxis have important roles in preventing attacks (Table 3).

Short-term prophylaxis before an anticipated attack

Short-term prophylaxis is used for patients whose disease is generally well controlled but who anticipate exposure to a potentially exacerbating situation, such as an invasive medical, surgical, or dental procedure. (Routine dental cleanings are generally considered safe and do not require prophylaxis.)

Prophylactic treatments include:

• Plasma-derived C1 inhibitor, 500 to 1,500 U 1 hour before the provoking event
• High-dose 17-alpha alkylated (attenuated) androgens (eg, danazol [Danocrine] 200 mg orally 3 times daily) for 5 to 10 days before the provoking event
• Fresh-frozen plasma, 2 U 1 to 12 hours before the event.¹

Yet even with short-term prophylaxis, on-demand treatment should be available.

Long-term prophylaxis

While many patients can be managed with on-demand treatment only, other patients (reflecting the severity of their attacks, as well as their individual needs) may benefit from a combination of on-demand treatment plus long-term prophylaxis. Several options are available (Table 3).

17-alpha alkylated androgens. Patients treated with danazol 600 mg/day were attack-free 90% of the time during a 28-day period compared with only 2.2% of the time in placebo-treated patients.³⁰ Use of anabolic androgens, however, is limited by their adverse effects, including weight gain, virilization, menstrual irregularities, headaches, depression, dyslipidemia, liver enzyme elevation, liver adenomas, and hepatocellular carcinoma. Arterial hypertension occurs in about 25% of treated patients.

Because adverse effects are dose-dependent, treatment should be empirically titrated to find the minimal effective dose, generally recommended to be no more than 200 mg per day of danazol or the equivalent.¹⁵

Contraindications include use by women during pregnancy or lactation and by children until growth is complete.

Regular follow-up is recommended every 6 months, with monitoring of liver enzymes, lipids, complete blood counts, alpha fetoprotein, and urinalysis. Abdominal ultrasonography (every 6 months if receiving 100 mg/day or more of danazol, every 12 months if less than 100 mg/day) is advisable for early diagnosis of liver tumors.

Antifibrinolytic drugs. Tranexamic acid (Lysteda) and aminocaproic acid (Amicar) have been found to be effective in reducing the number of attacks of hereditary angioedema compared with placebo but are considered to be less reliable than androgens. These drugs have been used in patients who do not tolerate anabolic androgens, and in children and pregnant women. Tranexamic acid is given at a dose of 20 to 50 mg/kg/day divided into two or three doses per day. The therapeutic dose of aminocaproic acid is 1 g orally three to four times per day.³¹ Patients with a personal or family history of thromboembolic disease may be at greater risk of venous or arterial thrombosis, but this has not occurred in clinical studies.

Plasma-derived C1 inhibitors. In a 24-week crossover study in 22 patients with hereditary angioedema, Cinryze 1,000 U every 3 to 4 days reduced the rate of attacks by 50% while also reducing their severity and duration.¹⁷ An open-label extension study in 146 patients for almost 3 years documented a 90% reduction in attack frequency with no evidence of tachyphylaxis.³²

New treatments are costlier

The newer on-demand and prophylactic drugs are substantially costlier than the older alternatives (androgens, antifibrinolytics, and fresh-frozen plasma); however, they have a substantially better benefit-to-risk ratio. Furthermore, the costs of care for an attack requiring emergency treatment are also high. Hereditary angioedema patients are often young, otherwise healthy, and capable of leading normal productive lives. While formal pharmacoeconomic studies of the optimal use of these newer drugs have not yet been done, it is important that the use of these drugs be well justified. Ideally, physicians who prescribe these drugs should be knowledgeable in the management of hereditary angioedema.

SPECIAL CHALLENGES IN WOMEN

Women with hereditary angioedema have more frequent attacks and generally a more severe disease course than men.¹² Optimizing care for women is challenging because hormonal changes often cause the disease to flare up in menarche, pregnancy, lactation, and menopause. Women also have a higher rate of discontinuing long-term androgen therapy because of side effects, including virilization and menstrual irregularities. Spironolactone (Aldactone) 100 to 200 mg daily can be used to control hirsutism.³³

Contraception

Because estrogen can trigger attacks, progesterone-only formulations, intrauterine devices, or barrier methods are recommended for contraception.³³ Progesterone-only pills are preferred and improve symptoms in more than 60% of women. Etonogestrel, another alternative, is available as an implant (Implanon) or vaginal ring (Nuvaring). Intrauterine devices are generally well tolerated, and no prophylaxis is needed during placement. The progesterone-eluting intrauterine device (Mirena) could be beneficial.³⁴

Pregnancy and lactation

Pregnancy and lactation pose particular challenges. Anabolic androgens are contraindicated during pregnancy as well as during breastfeeding because they can be passed on in breast milk. Women receiving androgen prophylaxis should understand that they can still ovulate and need contraception if they are sexually active.³⁴ Patients on attenuated androgens who desire pregnancy should discontinue them 2 months before trying to conceive.

Changes in attack patterns can be unpredictable during pregnancy. Attacks tend to be more severe during the first trimester and more frequent during the third. Due to its safety and efficacy, plasma-derived C1 inhibitor has become the treatment of choice for on-demand or prophylactic treatment during pregnancy and lactation. Antifibrinolytics are considered only when plasma-derived C1 inhibitor is not available.³¹ Ecallantide and icatibant have not been studied in pregnancy. If neither plasma-derived C1 inhibitor nor antifibrinolytics are available, fresh-frozen plasma or solvent-and-detergent-treated plasma can be used.

Short-term prophylaxis should be considered before amniocentesis, chorionic villous sampling, and dilation and curettage. Delivery should take place in a facility with rapid access to plasma-derived C1 inhibitor as well as consultants in obstetrics, anesthesiology, and perinatology. Although plasma-derived C1 inhibitor should be available at all times during labor and delivery, its prophylactic use is not required unless labor and delivery are particularly traumatic, the underlying hereditary angioedema is very severe, or if forceps, vacuum delivery, or cesarian section is performed. Close monitoring is recommended for at least 72 hours after routine vaginal delivery and for 1 week after cesarian section.

CONCLUSION

The goals of hereditary angioedema treatment are to alleviate morbidity and mortality associated with the disease and to improve the patient’s quality of life. Achieving these goals requires timely diagnosis, patient education, and careful selection of therapeutic modalities that are individualized to the needs of that patient. Treatments have advanced greatly in the last 4 years, and new medications for both the acute and chronic symptoms of hereditary angioedema have shown great promise.
 

 Acknowledgment: K.T. is funded by National Institutes of Health grant T32 AI 07469.

Hereditary angioedema due to deficiency of C1 inhibitor is a rare autosomal dominant disease that can be life-threatening. It affects about 1 in 50,000 people,¹ or about 6,000 people in the United States. There are no known differences in prevalence by ethnicity or sex. A form of hereditary angioedema with normal C1 inhibitor levels has also recently been identified.

Despite a growing awareness of hereditary angioedema in the medical community, repeated surveys have found an average gap of 10 years between the first appearance of symptoms and the correct diagnosis. In view of the risk of morbidity and death, recognizing this disease sooner is critical.

This article will discuss how to recognize hereditary angioedema and how to differentiate it from other forms of recurring angioedema. We will also review its acute and long-term management, with special attention to new therapies and clinical challenges.

EPISODES OF SWELLING WITHOUT HIVES

Hereditary angioedema involves recurrent episodes of nonpruritic, nonpitting, subcutaneous and submucosal edema that can affect the face, tongue, larynx, trunk, extremities, bowels, or genitals. Attacks typically follow a predictable course: swelling that increases slowly and continuously for 24 hours and then gradually subsides over the next 48 to 72 hours. Attacks that involve the oropharynx, larynx, or abdomen carry the highest risk of morbidity and death.¹

The frequency and severity of attacks are highly variable and unpredictable. A few patients have no attacks, a few have two attacks per week, and most fall in between.

Hives suggests an allergic or idiopathic rather than hereditary cause and will not be discussed here in detail. A history of angioedema that was rapidly aborted by antihistamines, corticosteroids, or epinephrine also suggests an allergic rather than hereditary cause.

UNCHECKED BRADYKININ PRODUCTION

Substantial evidence indicates that hereditary angioedema results from extravasation of plasma into deeper cutaneous or mucosal compartments as a result of overproduction of the vasoactive mediator bradykinin (Figure 1).

Activated factor XII cleaves plasma prekallikrein to generate active plasma kallikrein (which, in turn, activates more factor XII).² Once generated, plasma kallikrein cleaves high-molecular-weight kininogen, releasing bradykinin. Bradykinin binds to the B2 bradykinin receptor on endothelial cells, increasing the permeability of the endothelium.

Normally, C1 inhibitor helps control bradykinin production by inhibiting plasma kallikrein and activated factor XII. Without enough C1 inhibitor, the contact system is uninhibited and results in bradykinin being inappropriately generated.

Because the attacks of hereditary angioedema involve excessive bradykinin, they do not respond to the usual treatments for anaphylaxis and allergic angioedema (which involve mast cell degranulation), such as antihistamines, corticosteroids, and epinephrine.

TWO TYPES OF HEREDITARY ANGIOEDEMA

Figure 2 shows the evaluation of patients with suspected hereditary angioedema.

Hereditary angioedema due to C1 inhibitor deficiency

The classic forms of hereditary angioedema (types I and II) involve loss-of-function mutations in SERPING1—the gene that encodes for C1 inhibitor—resulting in low levels of functional C1 inhibitor.³ The mutation is inherited in an autosomal dominant pattern; however, in about 25% of cases, it appears to arise spontaneously,⁴ so a family history is not required for diagnosis.

Although C1 inhibitor deficiency is present from birth, the clinical disease most commonly presents for the first time when the patient is of school age. Half of patients have their first episode in the first decade of life, and another one-third first develop symptoms over the next 10 years.⁵

Clinically, types I and II are indistinguishable. Type I, accounting for 85% of cases,¹ results from low production of C1 inhibitor. Laboratory studies reveal low antigenic and functional levels of C1 inhibitor.

In type II, the mutant C1 inhibitor protein is present but dysfunctional and unable to inhibit target proteases. On laboratory testing, the functional level of C1 inhibitor is low but its antigenic level is normal (Table 1). Function can be tested by either chromogenic assay or enzyme-linked immunosorbent assay; the former is preferred because it is more sensitive.⁶

Because C1 inhibitor deficiency results in chronic activation of the complement system, patients with type I or II disease usually have low C4 levels regardless of disease activity, making measuring C4 the most economical screening test. When suspicion for hereditary angioedema is high, based on the presentation and family and clinical history, measuring antigenic and functional C1 inhibitor levels and C4 simultaneously is more efficient.

Hereditary angioedema with normal C1 inhibitor levels is also inherited in an autosomal dominant pattern. It is often estrogen-sensitive, making it more severe in women. Symptoms tend to develop slightly later in life than in type I or II disease.⁷

Angioedema with normal C1 inhibitor levels has been associated with factor XII mutations in a minority of cases, but most patients do not have a specific laboratory abnormality. Because there is no specific laboratory profile, the diagnosis is based on clinical criteria. Hereditary angioedema with normal C1 inhibitor levels should be considered in patients who have recurrent angioedema, normal C4, normal antigenic and functional C1 inhibitor levels, a lack of response to high-dose antihistamines, and either a family history of angioedema without hives or a known factor XII mutation.⁷ However, other forms of angioedema (allergic, drug-induced, and idiopathic) should also be considered, as C4 and C1 inhibitor levels are normal in these forms as well.

DIFFERENTIAL DIAGNOSIS: OTHER TYPES OF ANGIOEDEMA

Acquired C1 inhibitor deficiency

Symptoms of acquired C1 inhibitor deficiency resemble those of hereditary angioedema but typically do not emerge until the fourth decade of life or later, and patients have no family history of the condition. It is often associated with other diseases, most commonly B-cell lymphoproliferative disorders, which cause uncontrolled complement activation and consumption of C1 inhibitor.

In some patients, autoantibodies to C1 inhibitor develop, greatly reducing its effectiveness and resulting in enhanced consumption. The autoantibody is often associated with a monoclonal gammopathy of unknown significance. The presence of a C1 inhibitor autoantibody does not preclude the presence of an underlying disorder, and vice versa.

Laboratory studies reveal low C4, low C1-inhibitor antigenic and functional levels, and usually a low C1q level owing to consumption of complement. Autoantibodies to C1 inhibitor can be detected by laboratory testing.

Because of the association with autoimmune disease and malignant disorders (especially B-cell malignancy), a patient diagnosed with acquired C1 inhibitor deficiency should be further evaluated for underlying conditions.

Allergic angioedema

Allergic angioedema results from preformed antigen-specific immunoglobulin E (IgE) antibodies that stimulate mast cells to degranulate when patients are exposed to a particular allergen—most commonly food, insect venom, latex, or drugs. IgE-mediated histamine release causes swelling, as histamine is a potent vasodilator.

Symptoms often begin within 2 hours of exposure to the allergen and generally include concurrent urticaria and swelling that last less than 24 hours. Unlike in hereditary angioedema, the swelling responds to antihistamines and corticosteroids. When very severe, these symptoms may also be accompanied by bronchoconstriction and gastrointestinal symptoms, especially if the allergen is ingested.

Histamine-mediated angioedema may also be associated with exercise as part of a syndrome called exercise-induced anaphylaxis or angioedema.

Drug-induced angioedema

Drug-induced angioedema is typically associated with angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs).

Angioedema associated with ACE inhibitors is estimated to affect 0.1% to 6% of patients taking these medications, with African Americans being at significantly higher risk. Although 25% of affected patients develop symptoms of angioedema within the first month of taking the drugs, some tolerate them for as long as 10 years before the first episode.⁹ The swelling is not allergic or histamine-related. ACE normally degrades bradykinin; therefore, inhibiting ACE leads to accumulation of bradykinin. Because all ACE inhibitors have this effect, this class of drug should be discontinued in any patient who develops isolated angioedema.

NSAID-induced angioedema is often accompanied by other symptoms, including urticaria, rhinitis, cough, hoarseness, or breathlessness.¹⁰ The mechanism of NSAID-induced angioedema involves cyclooxygenase (COX) 1 (and to a lesser extent COX-2) inhibition. All NSAIDs (and aspirin) should be avoided in patients with recurrent angioedema. Specific COX-2 inhibitors, while theoretically capable of causing angioedema by the same mechanism, are generally well tolerated in patients who have had COX-1 inhibitor reactions.

Idiopathic angioedema

If no clear cause of recurrent angioedema (at least three episodes in a year) can be found, it is labeled idiopathic.¹¹ Some patients with idiopathic angioedema fail to benefit from high doses of antihistamines, suggesting that the cause is bradykinin-mediated.

CLINICAL MANIFESTATIONS OF HEREDITARY ANGIOEDEMA

Attacks may start at one site and progress to involve additional sites.

Prodromal symptoms may begin up to several days before an attack and include tingling, warmth, burning, or itching at the affected site; increased fatigue or malaise; nausea, abdominal distention, or gassiness; or increased hunger, particularly before an abdominal attack.⁵ The most characteristic prodromal symptom is erythema marginatum—a raised, serpiginous, nonpruritic rash on the trunk, arms, and legs but often sparing the face.

Abdominal attacks are easily confused with acute abdomen

Almost half of attacks involve the abdomen, and almost all patients with type I or II disease experience at least one such attack.¹² Symptoms can include severe abdominal pain, nausea, vomiting, and diarrhea. Abdominal attacks account for many emergency department visits, hospitalizations, and surgical procedures for acute abdomen; about one-third of patients with undiagnosed hereditary angioedema undergo an unnecessary surgery during an abdominal attack. Angioedema of the gastrointestinal tract can result in enough plasma extravasation and vasodilation to cause hypovolemic shock.

Eradicating Helicobacter pylori infection may alleviate abdominal attacks.¹³

Attacks of the extremities can be painful and disabling

Attacks of the extremities affect 96% of patients¹² and can be very disfiguring and disabling. Driving or using the phone is often difficult when the hands are affected. When feet are involved, walking and standing become painful. While these symptoms rarely result in a lengthy hospitalization, they interfere with work and school and require immediate medical attention because they can progress to other parts of the body.

Laryngeal attacks are life-threatening

About half of patients with hereditary angioedema have an attack of laryngeal edema at some point in their lives.¹² If not effectively managed, laryngeal angioedema can progress to asphyxiation. A survey of family history in 58 patients with hereditary angioedema suggested a 40% incidence of asphyxiation in untreated laryngeal attacks, and 25% to 30% of patients are estimated to have died of laryngeal edema before effective treatment became available.¹⁴

Symptoms of a laryngeal attack include change in voice, hoarseness, trouble swallowing, shortness of breath, and wheezing. Physicians must recognize these symptoms quickly and give effective treatment early in the attack to prevent morbidity and death.

Establishing an airway can be life-saving in the absence of effective therapy, but extensive swelling of the upper airway can make intubation extremely difficult.

Genitourinary attacks also occur

Attacks involving the scrotum and labia have been reported in up to two-thirds of patients with hereditary angioedema at some point in their lives. Attacks involving the bladder and kidneys have also been reported but are less common, affecting about 5% of patients.¹² Genitourinary attacks may be triggered by local trauma, such as horseback riding or sexual intercourse, although no trigger may be evident.

MANAGING ACUTE ATTACKS

The goals of treatment are to alleviate acute exacerbations with on-demand treatment and to reduce the number of attacks with prophylaxis. Therapy should be individualized to each patient’s needs. Treatments have advanced greatly in the last several years, and new medications for treating acute attacks and preventing attacks have shown great promise (Figure 3, Table 2).

Patients tend to have recurrent symptoms interspersed with periods of health, suggesting that attacks ought to have identifiable triggers, although in most, no trigger is evident. The most commonly identified are local trauma (including medical and dental procedures), emotional stress, and acute infection. Disease severity may be worsened by menstruation, estrogen-containing oral contraceptives, hormone replacement therapy, ACE inhibitors, and NSAIDs.

It is critical that attacks be treated with an effective medication as soon as possible. Consensus guidelines state that all patients with hereditary angioedema due to C1 inhibitor deficiency, even if they are still asymptomatic, should have access to at least one of the drugs approved for on-demand treatment.¹⁵ The guidelines further state that whenever possible, “patients should have the on-demand medicine to treat acute attacks at home and should be trained to self-administer these medicines.”¹⁵

Several plasma-derived C1 inhibitors are available (Cinryze, Berinert, Cetor). They are prepared from fractionated plasma obtained from donors, then pasteurized and nanofiltered.

Berinert and Cinryze were each found to be superior to placebo in double-blind, placebo-controlled trials: attacks usually resolved 30 to 60 minutes after intravenous injection.^16,17 Berinert 20 U/kg is associated with the onset of symptom relief as early as half an hour after administration, compared with 1.5 hours with placebo. Early use (at the onset of symptoms) of a plasma-derived C1 inhibitor in a low dose (500 U) can also be effective.^18,19 Efficacy appears to be consistent at all sites of attack involvement, including laryngeal edema. Safety and efficacy have been demonstrated during pregnancy and lactation and in young children and babies.²⁰

Plasma-derived C1 inhibitors can be self-administered. The safety and efficacy of self-administration (under physician supervision) were demonstrated in a study of Cinryze and Cetor, in which attack duration, pain medication use, and graded attack severity were significantly less with self-administered therapy than with therapy in the clinic.²¹

A concern about plasma-derived products is the possibility of blood-borne infection, but this has not been confirmed by experience.²²

Recombinant human C1 inhibitor

A recombinant human C1 inhibitor (Rhucin) has been studied in two randomized placebo-controlled trials. Although this product has a shorter half-life than the plasma-derived C1 inhibitors (3 vs more than 24 hours), the two are equipotent: 1 U of recombinant human C1 inhibitor is equivalent to 1 U of plasma-derived C1 inhibitor. Because the supply of recombinant human C1 inhibitor is elastic, dosing has been higher, which may provide more efficacy.²³ Similar to plasma-derived C1 inhibitor products, the recombinant human C1 inhibitor resulted in more rapid symptom relief than with saline (66 vs 122 minutes) and in a shorter time to minimal symptoms (247−266 vs 1,210 minutes).²⁴

Allergy is of concern: in one study, a healthy volunteer with undisclosed rabbit allergy experienced an allergic reaction. Patients should be screened by a skin-prick test or serum testing for specific IgE to rabbit epithelium before being prescribed recombinant human C1 inhibitor. No data are available for use during pregnancy or breastfeeding.

Ecallantide

Ecallantide (Kalbitor) is a selective inhibitor of plasma kallikrein that is given in three subcutaneous injections. Ecallantide 30 mg was found superior to placebo during acute attacks.^25,26

Ecallantide is well tolerated, with the most common adverse effects being headache, nausea, fatigue, diarrhea, and local injection-site reactions. Antibodies to ecallantide can be found in patients with increasing drug exposure but do not appear to correlate with adverse events. Hypersensitivity reactions have been observed in 2% to 3% of patients receiving repeated doses. Because of anaphylaxis risk, ecallantide must be administered by a health care professional.

Icatibant

Icatibant (Firazyr) is a bradykinin receptor-2 antagonist that is given in a single subcutaneous injection. Icatibant 30 mg significantly shortened time to symptom relief and time to almost complete resolution compared with placebo.^27,28 Icatibant’s main adverse effect is transient local pain, swelling, and erythema at the injection site. Icatibant can be self-administered by patients.

Fresh-frozen plasma

Fresh-frozen plasma contains C1 inhibitor and was used before the newer products became available. Several noncontrolled studies reported benefit of its use in acute attacks.²⁹ However, its use is controversial because it also contains contact-system proteins that could provide additional substrate for the generation of bradykinin, which could exacerbate attacks in some patients.¹ This may be particularly dangerous in patients presenting with laryngeal edema: in such a situation, the physician should be ready to treat a sudden exacerbation with intubation. The risk of acquiring a blood-borne pathogen is also higher than with plasma-derived C1 inhibitor.

PROPHYLACTIC MANAGEMENT

Short-term and long-term prophylaxis have important roles in preventing attacks (Table 3).

Short-term prophylaxis before an anticipated attack

Short-term prophylaxis is used for patients whose disease is generally well controlled but who anticipate exposure to a potentially exacerbating situation, such as an invasive medical, surgical, or dental procedure. (Routine dental cleanings are generally considered safe and do not require prophylaxis.)

Prophylactic treatments include:

• Plasma-derived C1 inhibitor, 500 to 1,500 U 1 hour before the provoking event
• High-dose 17-alpha alkylated (attenuated) androgens (eg, danazol [Danocrine] 200 mg orally 3 times daily) for 5 to 10 days before the provoking event
• Fresh-frozen plasma, 2 U 1 to 12 hours before the event.¹

Yet even with short-term prophylaxis, on-demand treatment should be available.

Long-term prophylaxis

While many patients can be managed with on-demand treatment only, other patients (reflecting the severity of their attacks, as well as their individual needs) may benefit from a combination of on-demand treatment plus long-term prophylaxis. Several options are available (Table 3).

17-alpha alkylated androgens. Patients treated with danazol 600 mg/day were attack-free 90% of the time during a 28-day period compared with only 2.2% of the time in placebo-treated patients.³⁰ Use of anabolic androgens, however, is limited by their adverse effects, including weight gain, virilization, menstrual irregularities, headaches, depression, dyslipidemia, liver enzyme elevation, liver adenomas, and hepatocellular carcinoma. Arterial hypertension occurs in about 25% of treated patients.

Because adverse effects are dose-dependent, treatment should be empirically titrated to find the minimal effective dose, generally recommended to be no more than 200 mg per day of danazol or the equivalent.¹⁵

Contraindications include use by women during pregnancy or lactation and by children until growth is complete.

Regular follow-up is recommended every 6 months, with monitoring of liver enzymes, lipids, complete blood counts, alpha fetoprotein, and urinalysis. Abdominal ultrasonography (every 6 months if receiving 100 mg/day or more of danazol, every 12 months if less than 100 mg/day) is advisable for early diagnosis of liver tumors.

Antifibrinolytic drugs. Tranexamic acid (Lysteda) and aminocaproic acid (Amicar) have been found to be effective in reducing the number of attacks of hereditary angioedema compared with placebo but are considered to be less reliable than androgens. These drugs have been used in patients who do not tolerate anabolic androgens, and in children and pregnant women. Tranexamic acid is given at a dose of 20 to 50 mg/kg/day divided into two or three doses per day. The therapeutic dose of aminocaproic acid is 1 g orally three to four times per day.³¹ Patients with a personal or family history of thromboembolic disease may be at greater risk of venous or arterial thrombosis, but this has not occurred in clinical studies.

Plasma-derived C1 inhibitors. In a 24-week crossover study in 22 patients with hereditary angioedema, Cinryze 1,000 U every 3 to 4 days reduced the rate of attacks by 50% while also reducing their severity and duration.¹⁷ An open-label extension study in 146 patients for almost 3 years documented a 90% reduction in attack frequency with no evidence of tachyphylaxis.³²

New treatments are costlier

The newer on-demand and prophylactic drugs are substantially costlier than the older alternatives (androgens, antifibrinolytics, and fresh-frozen plasma); however, they have a substantially better benefit-to-risk ratio. Furthermore, the costs of care for an attack requiring emergency treatment are also high. Hereditary angioedema patients are often young, otherwise healthy, and capable of leading normal productive lives. While formal pharmacoeconomic studies of the optimal use of these newer drugs have not yet been done, it is important that the use of these drugs be well justified. Ideally, physicians who prescribe these drugs should be knowledgeable in the management of hereditary angioedema.

SPECIAL CHALLENGES IN WOMEN

Women with hereditary angioedema have more frequent attacks and generally a more severe disease course than men.¹² Optimizing care for women is challenging because hormonal changes often cause the disease to flare up in menarche, pregnancy, lactation, and menopause. Women also have a higher rate of discontinuing long-term androgen therapy because of side effects, including virilization and menstrual irregularities. Spironolactone (Aldactone) 100 to 200 mg daily can be used to control hirsutism.³³

Contraception

Because estrogen can trigger attacks, progesterone-only formulations, intrauterine devices, or barrier methods are recommended for contraception.³³ Progesterone-only pills are preferred and improve symptoms in more than 60% of women. Etonogestrel, another alternative, is available as an implant (Implanon) or vaginal ring (Nuvaring). Intrauterine devices are generally well tolerated, and no prophylaxis is needed during placement. The progesterone-eluting intrauterine device (Mirena) could be beneficial.³⁴

Pregnancy and lactation

Pregnancy and lactation pose particular challenges. Anabolic androgens are contraindicated during pregnancy as well as during breastfeeding because they can be passed on in breast milk. Women receiving androgen prophylaxis should understand that they can still ovulate and need contraception if they are sexually active.³⁴ Patients on attenuated androgens who desire pregnancy should discontinue them 2 months before trying to conceive.

Changes in attack patterns can be unpredictable during pregnancy. Attacks tend to be more severe during the first trimester and more frequent during the third. Due to its safety and efficacy, plasma-derived C1 inhibitor has become the treatment of choice for on-demand or prophylactic treatment during pregnancy and lactation. Antifibrinolytics are considered only when plasma-derived C1 inhibitor is not available.³¹ Ecallantide and icatibant have not been studied in pregnancy. If neither plasma-derived C1 inhibitor nor antifibrinolytics are available, fresh-frozen plasma or solvent-and-detergent-treated plasma can be used.

Short-term prophylaxis should be considered before amniocentesis, chorionic villous sampling, and dilation and curettage. Delivery should take place in a facility with rapid access to plasma-derived C1 inhibitor as well as consultants in obstetrics, anesthesiology, and perinatology. Although plasma-derived C1 inhibitor should be available at all times during labor and delivery, its prophylactic use is not required unless labor and delivery are particularly traumatic, the underlying hereditary angioedema is very severe, or if forceps, vacuum delivery, or cesarian section is performed. Close monitoring is recommended for at least 72 hours after routine vaginal delivery and for 1 week after cesarian section.

CONCLUSION

The goals of hereditary angioedema treatment are to alleviate morbidity and mortality associated with the disease and to improve the patient’s quality of life. Achieving these goals requires timely diagnosis, patient education, and careful selection of therapeutic modalities that are individualized to the needs of that patient. Treatments have advanced greatly in the last 4 years, and new medications for both the acute and chronic symptoms of hereditary angioedema have shown great promise.
 

 Acknowledgment: K.T. is funded by National Institutes of Health grant T32 AI 07469.

Hereditary angioedema due to deficiency of C1 inhibitor is a rare autosomal dominant disease that can be life-threatening. It affects about 1 in 50,000 people,¹ or about 6,000 people in the United States. There are no known differences in prevalence by ethnicity or sex. A form of hereditary angioedema with normal C1 inhibitor levels has also recently been identified.

Despite a growing awareness of hereditary angioedema in the medical community, repeated surveys have found an average gap of 10 years between the first appearance of symptoms and the correct diagnosis. In view of the risk of morbidity and death, recognizing this disease sooner is critical.

This article will discuss how to recognize hereditary angioedema and how to differentiate it from other forms of recurring angioedema. We will also review its acute and long-term management, with special attention to new therapies and clinical challenges.

EPISODES OF SWELLING WITHOUT HIVES

Hereditary angioedema involves recurrent episodes of nonpruritic, nonpitting, subcutaneous and submucosal edema that can affect the face, tongue, larynx, trunk, extremities, bowels, or genitals. Attacks typically follow a predictable course: swelling that increases slowly and continuously for 24 hours and then gradually subsides over the next 48 to 72 hours. Attacks that involve the oropharynx, larynx, or abdomen carry the highest risk of morbidity and death.¹

The frequency and severity of attacks are highly variable and unpredictable. A few patients have no attacks, a few have two attacks per week, and most fall in between.

Hives suggests an allergic or idiopathic rather than hereditary cause and will not be discussed here in detail. A history of angioedema that was rapidly aborted by antihistamines, corticosteroids, or epinephrine also suggests an allergic rather than hereditary cause.

UNCHECKED BRADYKININ PRODUCTION

Substantial evidence indicates that hereditary angioedema results from extravasation of plasma into deeper cutaneous or mucosal compartments as a result of overproduction of the vasoactive mediator bradykinin (Figure 1).

Activated factor XII cleaves plasma prekallikrein to generate active plasma kallikrein (which, in turn, activates more factor XII).² Once generated, plasma kallikrein cleaves high-molecular-weight kininogen, releasing bradykinin. Bradykinin binds to the B2 bradykinin receptor on endothelial cells, increasing the permeability of the endothelium.

Normally, C1 inhibitor helps control bradykinin production by inhibiting plasma kallikrein and activated factor XII. Without enough C1 inhibitor, the contact system is uninhibited and results in bradykinin being inappropriately generated.

Because the attacks of hereditary angioedema involve excessive bradykinin, they do not respond to the usual treatments for anaphylaxis and allergic angioedema (which involve mast cell degranulation), such as antihistamines, corticosteroids, and epinephrine.

TWO TYPES OF HEREDITARY ANGIOEDEMA

Figure 2 shows the evaluation of patients with suspected hereditary angioedema.

Hereditary angioedema due to C1 inhibitor deficiency

The classic forms of hereditary angioedema (types I and II) involve loss-of-function mutations in SERPING1—the gene that encodes for C1 inhibitor—resulting in low levels of functional C1 inhibitor.³ The mutation is inherited in an autosomal dominant pattern; however, in about 25% of cases, it appears to arise spontaneously,⁴ so a family history is not required for diagnosis.

Although C1 inhibitor deficiency is present from birth, the clinical disease most commonly presents for the first time when the patient is of school age. Half of patients have their first episode in the first decade of life, and another one-third first develop symptoms over the next 10 years.⁵

Clinically, types I and II are indistinguishable. Type I, accounting for 85% of cases,¹ results from low production of C1 inhibitor. Laboratory studies reveal low antigenic and functional levels of C1 inhibitor.

In type II, the mutant C1 inhibitor protein is present but dysfunctional and unable to inhibit target proteases. On laboratory testing, the functional level of C1 inhibitor is low but its antigenic level is normal (Table 1). Function can be tested by either chromogenic assay or enzyme-linked immunosorbent assay; the former is preferred because it is more sensitive.⁶

Because C1 inhibitor deficiency results in chronic activation of the complement system, patients with type I or II disease usually have low C4 levels regardless of disease activity, making measuring C4 the most economical screening test. When suspicion for hereditary angioedema is high, based on the presentation and family and clinical history, measuring antigenic and functional C1 inhibitor levels and C4 simultaneously is more efficient.

Hereditary angioedema with normal C1 inhibitor levels is also inherited in an autosomal dominant pattern. It is often estrogen-sensitive, making it more severe in women. Symptoms tend to develop slightly later in life than in type I or II disease.⁷

Angioedema with normal C1 inhibitor levels has been associated with factor XII mutations in a minority of cases, but most patients do not have a specific laboratory abnormality. Because there is no specific laboratory profile, the diagnosis is based on clinical criteria. Hereditary angioedema with normal C1 inhibitor levels should be considered in patients who have recurrent angioedema, normal C4, normal antigenic and functional C1 inhibitor levels, a lack of response to high-dose antihistamines, and either a family history of angioedema without hives or a known factor XII mutation.⁷ However, other forms of angioedema (allergic, drug-induced, and idiopathic) should also be considered, as C4 and C1 inhibitor levels are normal in these forms as well.

DIFFERENTIAL DIAGNOSIS: OTHER TYPES OF ANGIOEDEMA

Acquired C1 inhibitor deficiency

Symptoms of acquired C1 inhibitor deficiency resemble those of hereditary angioedema but typically do not emerge until the fourth decade of life or later, and patients have no family history of the condition. It is often associated with other diseases, most commonly B-cell lymphoproliferative disorders, which cause uncontrolled complement activation and consumption of C1 inhibitor.

In some patients, autoantibodies to C1 inhibitor develop, greatly reducing its effectiveness and resulting in enhanced consumption. The autoantibody is often associated with a monoclonal gammopathy of unknown significance. The presence of a C1 inhibitor autoantibody does not preclude the presence of an underlying disorder, and vice versa.

Laboratory studies reveal low C4, low C1-inhibitor antigenic and functional levels, and usually a low C1q level owing to consumption of complement. Autoantibodies to C1 inhibitor can be detected by laboratory testing.

Because of the association with autoimmune disease and malignant disorders (especially B-cell malignancy), a patient diagnosed with acquired C1 inhibitor deficiency should be further evaluated for underlying conditions.

Allergic angioedema

Allergic angioedema results from preformed antigen-specific immunoglobulin E (IgE) antibodies that stimulate mast cells to degranulate when patients are exposed to a particular allergen—most commonly food, insect venom, latex, or drugs. IgE-mediated histamine release causes swelling, as histamine is a potent vasodilator.

Symptoms often begin within 2 hours of exposure to the allergen and generally include concurrent urticaria and swelling that last less than 24 hours. Unlike in hereditary angioedema, the swelling responds to antihistamines and corticosteroids. When very severe, these symptoms may also be accompanied by bronchoconstriction and gastrointestinal symptoms, especially if the allergen is ingested.

Histamine-mediated angioedema may also be associated with exercise as part of a syndrome called exercise-induced anaphylaxis or angioedema.

Drug-induced angioedema

Drug-induced angioedema is typically associated with angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs).

Angioedema associated with ACE inhibitors is estimated to affect 0.1% to 6% of patients taking these medications, with African Americans being at significantly higher risk. Although 25% of affected patients develop symptoms of angioedema within the first month of taking the drugs, some tolerate them for as long as 10 years before the first episode.⁹ The swelling is not allergic or histamine-related. ACE normally degrades bradykinin; therefore, inhibiting ACE leads to accumulation of bradykinin. Because all ACE inhibitors have this effect, this class of drug should be discontinued in any patient who develops isolated angioedema.

NSAID-induced angioedema is often accompanied by other symptoms, including urticaria, rhinitis, cough, hoarseness, or breathlessness.¹⁰ The mechanism of NSAID-induced angioedema involves cyclooxygenase (COX) 1 (and to a lesser extent COX-2) inhibition. All NSAIDs (and aspirin) should be avoided in patients with recurrent angioedema. Specific COX-2 inhibitors, while theoretically capable of causing angioedema by the same mechanism, are generally well tolerated in patients who have had COX-1 inhibitor reactions.

Idiopathic angioedema

If no clear cause of recurrent angioedema (at least three episodes in a year) can be found, it is labeled idiopathic.¹¹ Some patients with idiopathic angioedema fail to benefit from high doses of antihistamines, suggesting that the cause is bradykinin-mediated.

CLINICAL MANIFESTATIONS OF HEREDITARY ANGIOEDEMA

Attacks may start at one site and progress to involve additional sites.

Prodromal symptoms may begin up to several days before an attack and include tingling, warmth, burning, or itching at the affected site; increased fatigue or malaise; nausea, abdominal distention, or gassiness; or increased hunger, particularly before an abdominal attack.⁵ The most characteristic prodromal symptom is erythema marginatum—a raised, serpiginous, nonpruritic rash on the trunk, arms, and legs but often sparing the face.

Abdominal attacks are easily confused with acute abdomen

Almost half of attacks involve the abdomen, and almost all patients with type I or II disease experience at least one such attack.¹² Symptoms can include severe abdominal pain, nausea, vomiting, and diarrhea. Abdominal attacks account for many emergency department visits, hospitalizations, and surgical procedures for acute abdomen; about one-third of patients with undiagnosed hereditary angioedema undergo an unnecessary surgery during an abdominal attack. Angioedema of the gastrointestinal tract can result in enough plasma extravasation and vasodilation to cause hypovolemic shock.

Eradicating Helicobacter pylori infection may alleviate abdominal attacks.¹³

Attacks of the extremities can be painful and disabling

Attacks of the extremities affect 96% of patients¹² and can be very disfiguring and disabling. Driving or using the phone is often difficult when the hands are affected. When feet are involved, walking and standing become painful. While these symptoms rarely result in a lengthy hospitalization, they interfere with work and school and require immediate medical attention because they can progress to other parts of the body.

Laryngeal attacks are life-threatening

About half of patients with hereditary angioedema have an attack of laryngeal edema at some point in their lives.¹² If not effectively managed, laryngeal angioedema can progress to asphyxiation. A survey of family history in 58 patients with hereditary angioedema suggested a 40% incidence of asphyxiation in untreated laryngeal attacks, and 25% to 30% of patients are estimated to have died of laryngeal edema before effective treatment became available.¹⁴

Symptoms of a laryngeal attack include change in voice, hoarseness, trouble swallowing, shortness of breath, and wheezing. Physicians must recognize these symptoms quickly and give effective treatment early in the attack to prevent morbidity and death.

Establishing an airway can be life-saving in the absence of effective therapy, but extensive swelling of the upper airway can make intubation extremely difficult.

Genitourinary attacks also occur

Attacks involving the scrotum and labia have been reported in up to two-thirds of patients with hereditary angioedema at some point in their lives. Attacks involving the bladder and kidneys have also been reported but are less common, affecting about 5% of patients.¹² Genitourinary attacks may be triggered by local trauma, such as horseback riding or sexual intercourse, although no trigger may be evident.

MANAGING ACUTE ATTACKS

The goals of treatment are to alleviate acute exacerbations with on-demand treatment and to reduce the number of attacks with prophylaxis. Therapy should be individualized to each patient’s needs. Treatments have advanced greatly in the last several years, and new medications for treating acute attacks and preventing attacks have shown great promise (Figure 3, Table 2).

Patients tend to have recurrent symptoms interspersed with periods of health, suggesting that attacks ought to have identifiable triggers, although in most, no trigger is evident. The most commonly identified are local trauma (including medical and dental procedures), emotional stress, and acute infection. Disease severity may be worsened by menstruation, estrogen-containing oral contraceptives, hormone replacement therapy, ACE inhibitors, and NSAIDs.

It is critical that attacks be treated with an effective medication as soon as possible. Consensus guidelines state that all patients with hereditary angioedema due to C1 inhibitor deficiency, even if they are still asymptomatic, should have access to at least one of the drugs approved for on-demand treatment.¹⁵ The guidelines further state that whenever possible, “patients should have the on-demand medicine to treat acute attacks at home and should be trained to self-administer these medicines.”¹⁵

Several plasma-derived C1 inhibitors are available (Cinryze, Berinert, Cetor). They are prepared from fractionated plasma obtained from donors, then pasteurized and nanofiltered.

Berinert and Cinryze were each found to be superior to placebo in double-blind, placebo-controlled trials: attacks usually resolved 30 to 60 minutes after intravenous injection.^16,17 Berinert 20 U/kg is associated with the onset of symptom relief as early as half an hour after administration, compared with 1.5 hours with placebo. Early use (at the onset of symptoms) of a plasma-derived C1 inhibitor in a low dose (500 U) can also be effective.^18,19 Efficacy appears to be consistent at all sites of attack involvement, including laryngeal edema. Safety and efficacy have been demonstrated during pregnancy and lactation and in young children and babies.²⁰

Plasma-derived C1 inhibitors can be self-administered. The safety and efficacy of self-administration (under physician supervision) were demonstrated in a study of Cinryze and Cetor, in which attack duration, pain medication use, and graded attack severity were significantly less with self-administered therapy than with therapy in the clinic.²¹

A concern about plasma-derived products is the possibility of blood-borne infection, but this has not been confirmed by experience.²²

Recombinant human C1 inhibitor

A recombinant human C1 inhibitor (Rhucin) has been studied in two randomized placebo-controlled trials. Although this product has a shorter half-life than the plasma-derived C1 inhibitors (3 vs more than 24 hours), the two are equipotent: 1 U of recombinant human C1 inhibitor is equivalent to 1 U of plasma-derived C1 inhibitor. Because the supply of recombinant human C1 inhibitor is elastic, dosing has been higher, which may provide more efficacy.²³ Similar to plasma-derived C1 inhibitor products, the recombinant human C1 inhibitor resulted in more rapid symptom relief than with saline (66 vs 122 minutes) and in a shorter time to minimal symptoms (247−266 vs 1,210 minutes).²⁴

Allergy is of concern: in one study, a healthy volunteer with undisclosed rabbit allergy experienced an allergic reaction. Patients should be screened by a skin-prick test or serum testing for specific IgE to rabbit epithelium before being prescribed recombinant human C1 inhibitor. No data are available for use during pregnancy or breastfeeding.

Ecallantide

Ecallantide (Kalbitor) is a selective inhibitor of plasma kallikrein that is given in three subcutaneous injections. Ecallantide 30 mg was found superior to placebo during acute attacks.^25,26

Ecallantide is well tolerated, with the most common adverse effects being headache, nausea, fatigue, diarrhea, and local injection-site reactions. Antibodies to ecallantide can be found in patients with increasing drug exposure but do not appear to correlate with adverse events. Hypersensitivity reactions have been observed in 2% to 3% of patients receiving repeated doses. Because of anaphylaxis risk, ecallantide must be administered by a health care professional.

Icatibant

Icatibant (Firazyr) is a bradykinin receptor-2 antagonist that is given in a single subcutaneous injection. Icatibant 30 mg significantly shortened time to symptom relief and time to almost complete resolution compared with placebo.^27,28 Icatibant’s main adverse effect is transient local pain, swelling, and erythema at the injection site. Icatibant can be self-administered by patients.

Fresh-frozen plasma

Fresh-frozen plasma contains C1 inhibitor and was used before the newer products became available. Several noncontrolled studies reported benefit of its use in acute attacks.²⁹ However, its use is controversial because it also contains contact-system proteins that could provide additional substrate for the generation of bradykinin, which could exacerbate attacks in some patients.¹ This may be particularly dangerous in patients presenting with laryngeal edema: in such a situation, the physician should be ready to treat a sudden exacerbation with intubation. The risk of acquiring a blood-borne pathogen is also higher than with plasma-derived C1 inhibitor.

PROPHYLACTIC MANAGEMENT

Short-term and long-term prophylaxis have important roles in preventing attacks (Table 3).

Short-term prophylaxis before an anticipated attack

Short-term prophylaxis is used for patients whose disease is generally well controlled but who anticipate exposure to a potentially exacerbating situation, such as an invasive medical, surgical, or dental procedure. (Routine dental cleanings are generally considered safe and do not require prophylaxis.)

Prophylactic treatments include:

• Plasma-derived C1 inhibitor, 500 to 1,500 U 1 hour before the provoking event
• High-dose 17-alpha alkylated (attenuated) androgens (eg, danazol [Danocrine] 200 mg orally 3 times daily) for 5 to 10 days before the provoking event
• Fresh-frozen plasma, 2 U 1 to 12 hours before the event.¹

Yet even with short-term prophylaxis, on-demand treatment should be available.

Long-term prophylaxis

While many patients can be managed with on-demand treatment only, other patients (reflecting the severity of their attacks, as well as their individual needs) may benefit from a combination of on-demand treatment plus long-term prophylaxis. Several options are available (Table 3).

17-alpha alkylated androgens. Patients treated with danazol 600 mg/day were attack-free 90% of the time during a 28-day period compared with only 2.2% of the time in placebo-treated patients.³⁰ Use of anabolic androgens, however, is limited by their adverse effects, including weight gain, virilization, menstrual irregularities, headaches, depression, dyslipidemia, liver enzyme elevation, liver adenomas, and hepatocellular carcinoma. Arterial hypertension occurs in about 25% of treated patients.

Because adverse effects are dose-dependent, treatment should be empirically titrated to find the minimal effective dose, generally recommended to be no more than 200 mg per day of danazol or the equivalent.¹⁵

Contraindications include use by women during pregnancy or lactation and by children until growth is complete.

Regular follow-up is recommended every 6 months, with monitoring of liver enzymes, lipids, complete blood counts, alpha fetoprotein, and urinalysis. Abdominal ultrasonography (every 6 months if receiving 100 mg/day or more of danazol, every 12 months if less than 100 mg/day) is advisable for early diagnosis of liver tumors.

Antifibrinolytic drugs. Tranexamic acid (Lysteda) and aminocaproic acid (Amicar) have been found to be effective in reducing the number of attacks of hereditary angioedema compared with placebo but are considered to be less reliable than androgens. These drugs have been used in patients who do not tolerate anabolic androgens, and in children and pregnant women. Tranexamic acid is given at a dose of 20 to 50 mg/kg/day divided into two or three doses per day. The therapeutic dose of aminocaproic acid is 1 g orally three to four times per day.³¹ Patients with a personal or family history of thromboembolic disease may be at greater risk of venous or arterial thrombosis, but this has not occurred in clinical studies.

Plasma-derived C1 inhibitors. In a 24-week crossover study in 22 patients with hereditary angioedema, Cinryze 1,000 U every 3 to 4 days reduced the rate of attacks by 50% while also reducing their severity and duration.¹⁷ An open-label extension study in 146 patients for almost 3 years documented a 90% reduction in attack frequency with no evidence of tachyphylaxis.³²

New treatments are costlier

The newer on-demand and prophylactic drugs are substantially costlier than the older alternatives (androgens, antifibrinolytics, and fresh-frozen plasma); however, they have a substantially better benefit-to-risk ratio. Furthermore, the costs of care for an attack requiring emergency treatment are also high. Hereditary angioedema patients are often young, otherwise healthy, and capable of leading normal productive lives. While formal pharmacoeconomic studies of the optimal use of these newer drugs have not yet been done, it is important that the use of these drugs be well justified. Ideally, physicians who prescribe these drugs should be knowledgeable in the management of hereditary angioedema.

SPECIAL CHALLENGES IN WOMEN

Women with hereditary angioedema have more frequent attacks and generally a more severe disease course than men.¹² Optimizing care for women is challenging because hormonal changes often cause the disease to flare up in menarche, pregnancy, lactation, and menopause. Women also have a higher rate of discontinuing long-term androgen therapy because of side effects, including virilization and menstrual irregularities. Spironolactone (Aldactone) 100 to 200 mg daily can be used to control hirsutism.³³

Contraception

Because estrogen can trigger attacks, progesterone-only formulations, intrauterine devices, or barrier methods are recommended for contraception.³³ Progesterone-only pills are preferred and improve symptoms in more than 60% of women. Etonogestrel, another alternative, is available as an implant (Implanon) or vaginal ring (Nuvaring). Intrauterine devices are generally well tolerated, and no prophylaxis is needed during placement. The progesterone-eluting intrauterine device (Mirena) could be beneficial.³⁴

Pregnancy and lactation

Pregnancy and lactation pose particular challenges. Anabolic androgens are contraindicated during pregnancy as well as during breastfeeding because they can be passed on in breast milk. Women receiving androgen prophylaxis should understand that they can still ovulate and need contraception if they are sexually active.³⁴ Patients on attenuated androgens who desire pregnancy should discontinue them 2 months before trying to conceive.

Changes in attack patterns can be unpredictable during pregnancy. Attacks tend to be more severe during the first trimester and more frequent during the third. Due to its safety and efficacy, plasma-derived C1 inhibitor has become the treatment of choice for on-demand or prophylactic treatment during pregnancy and lactation. Antifibrinolytics are considered only when plasma-derived C1 inhibitor is not available.³¹ Ecallantide and icatibant have not been studied in pregnancy. If neither plasma-derived C1 inhibitor nor antifibrinolytics are available, fresh-frozen plasma or solvent-and-detergent-treated plasma can be used.

Short-term prophylaxis should be considered before amniocentesis, chorionic villous sampling, and dilation and curettage. Delivery should take place in a facility with rapid access to plasma-derived C1 inhibitor as well as consultants in obstetrics, anesthesiology, and perinatology. Although plasma-derived C1 inhibitor should be available at all times during labor and delivery, its prophylactic use is not required unless labor and delivery are particularly traumatic, the underlying hereditary angioedema is very severe, or if forceps, vacuum delivery, or cesarian section is performed. Close monitoring is recommended for at least 72 hours after routine vaginal delivery and for 1 week after cesarian section.

CONCLUSION

The goals of hereditary angioedema treatment are to alleviate morbidity and mortality associated with the disease and to improve the patient’s quality of life. Achieving these goals requires timely diagnosis, patient education, and careful selection of therapeutic modalities that are individualized to the needs of that patient. Treatments have advanced greatly in the last 4 years, and new medications for both the acute and chronic symptoms of hereditary angioedema have shown great promise.
 

 Acknowledgment: K.T. is funded by National Institutes of Health grant T32 AI 07469.

Child’s brain damage blamed on late cesarean

 A MOTHER WANTED A HOME BIRTH with a midwife. When  complications arose and labor stopped progressing, the midwife called an  ambulance. The emergency department (ED) physician ordered an urgent  cesarean delivery, but the procedure did not begin for another 2 hours.  The child was born with brain damage, multiple physical and mental  disabilities, complex seizure disorder, and cerebral palsy.

PARENTS’ CLAIM The child’s injuries occurred because cesarean delivery was delayed for 2 hours. Based on fetal heart-rate monitoring, the injuries most likely occurred in the last 18 minutes before birth, and were probably caused by compression of the umbilical cord. An earlier cesarean delivery would have avoided the injuries.

DEFENDANTS’ DEFENSE All of the injuries occurred prior to the mother’s arrival at the hospital, while she was under the care of the midwife. Fetal distress was present for an hour before the ambulance was called. When the mother arrived at the ED, she was an unknown patient, as the midwife did not have a collaborating physician. While the ED physician determined that a cesarean delivery was required, it was not considered an emergency. The mother was taken to the OR as soon as possible. Fetal monitoring strips at the hospital were reassuring.

VERDICT A $55 million Maryland verdict was returned against the hospital, including $26 million in noneconomic damages. After the court reduced noneconomic damages and future lost wages awards, the net verdict was $28 million.

ARDS after hysterectomy

A MORBIDLY OBESE WOMAN underwent a hysterectomy. The asthmatic, 38-year-old patient vomited after surgery. A pulmonologist undertook her care and determined that she had acute respiratory distress syndrome (ARDS). He prescribed the administration of oxygen. When she vomited again during the early morning hours of the second postsurgical day, he ordered intubation and went to the hospital immediately, but the patient quickly deteriorated. She died from cardiac arrest.

ESTATE’S CLAIM The patient’s death was due to failure to diagnose and treat ARDS in a timely manner. A bronchoscopy and frequent radiographs should have been performed. If the patient had been intubated earlier and steps had been taken to reduce the risk of vomiting, she would have had a better chance of survival. She should have been transferred to another facility when ARDS was diagnosed.

DEFENDANTS’ DEFENSE A bronchoscopy was not necessary. ARDS was diagnosed and treated in a timely manner. She was too unstable to transfer to another hospital.

VERDICT The hospital reached a confidential settlement, and the claim against the anesthesiologist was dismissed. The trial proceeded against the pulmonologist and his group. A New York defense verdict was returned.

Mother’s HELLP syndrome missed; fetus dies

DURING HER PREGNANCY, a 23-year-old woman was monitored for hypertension by her ObGyn and nurse midwife. At her 36-week prenatal visit, she was found to have preeclampsia, including proteinuria. She was sent directly to the ED, where the baby was monitored and laboratory tests were ordered by a nurse and nurse midwife. After 2 hours, she was told she had a urinary tract infection and discharged. Three days later, she returned to the ED in critical condition; she had suffered an intrauterine fetal demise.

PARENTS’ CLAIM Lab results showed critical values and confirmed that the patient had developed HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. The ED nurse and nurse midwife were negligent in their treatment: They never read the lab results or reported the results to the patient or an ObGyn.

DEFENDANTS’ DEFENSE The case was settled before trial.

VERDICT A $950,000 Virginia settlement was reached.

Was this pregnant prisoner in preterm labor ignored?

 A PREGNANT WOMAN WAS AWAITING TRIAL in County jail when she  went into preterm labor. She was taken to the ED but released 2 hours  later, although she was dilated 2–3 cm and having contractions. She was  returned to her locked cell and not monitored—no deputy or nurse was  within sight or sound of the patient. Her water broke and contractions  increased. Despite her screams, and those of other inmates, a nurse  didn’t arrive for 2 hours, when the baby’s head was crowning. EMS services were called and the baby was delivered in the jail cell. The child had no heartbeat or respiration. Mother and baby were transported to the hospital, where the child was resuscitated. She has severe mental impairment and cerebral palsy.

There is no documentation that the mother received any prenatal or postpartum care in jail. The mother is now serving a life sentence after a conviction for felony murder, kidnapping, and conspiracy.

CHILD’S CLAIM The case was brought on behalf of the child, and claimed that deliberate indifference and the failure to provide medical attention caused the child’s impairments.

DEFENDANTS’ DEFENSE The County claimed qualified immunity as a government entity and argued that, when the child was injured, she was still a fetus, and therefore not protected by the Constitution and civil rights laws.

VERDICT The US Circuit Court of Appeals rejected the County’s argument that the child was not protected by the Constitution. An $8 million Michigan settlement was reached.

Dermoid cyst still present after wrong-site surgery

A DERMOID CYST WAS DETECTED on the left ovary of a 28-year-old woman during prenatal ultrasonography (US). A year later, US confirmed the dermoid cyst, and the patient underwent outpatient cystectomy.

At the first postsurgical visit, the patient reported right pelvic pain. When she called the ObGyn’s office a few days later to again report right pelvic pain, her call was not returned.

She then went to the ED, where testing determined that the ObGyn had performed a right salpingo-oophorectomy and that her left ovary and cyst were still intact. She again attempted to contact the ObGyn, without response.

PATIENT’S CLAIM The ObGyn performed wrong-site surgery. The patient was not informed of the error during a postsurgical visit, nor were her attempts at contacting the physician returned. Still at risk for malignancy, she is facing a second surgical procedure to remove the cyst. Her fertility is diminished due to the surgical error, and she suffers anxiety and mental stress as a result of the situation.

At first, the ObGyn refused to provide medical records to the patient’s lawyer. When the records were obtained and compared with records obtained from another physician who treated the patient, it was evident that the ObGyn had altered the records to state that the patient had complained of right-side pain.

PHYSICIAN’S DEFENSE There was no negligence. The patient was properly treated for right-sided pain. The records were not altered.

VERDICT A $1.42 million Maryland verdict was returned. The state cap on noneconomic damages will reduce the verdict to $680,000.

Sponge left behind after vacuum-assisted closure

A WOMAN WENT TO THE ED with abdominal pain. It was determined that she had an abdominal abscess, and a surgeon assumed her care. After surgically draining the abdominal abscess, the surgeon placed a large black sponge into the abdominal cavity and then used vacuum-assisted closure. The patient was discharged 6 days later. She continued to receive treatment for a surgical-site infection that failed to heal. Two weeks later, the patient was readmitted to the hospital for exploratory surgery. The surgeon found and removed the sponge.

PATIENT’S CLAIM The surgeon was negligent for leaving the surgical sponge in the patient’s abdomen. She claimed pain, scarring, wound necrosis, infection, and the need for additional hospitalizations due to retention of the sponge.

PHYSICIAN’S DEFENSE A settlement was reached during the trial.

VERDICT A confidential Florida settlement was reached.

Child’s brain damage blamed on late cesarean

 A MOTHER WANTED A HOME BIRTH with a midwife. When  complications arose and labor stopped progressing, the midwife called an  ambulance. The emergency department (ED) physician ordered an urgent  cesarean delivery, but the procedure did not begin for another 2 hours.  The child was born with brain damage, multiple physical and mental  disabilities, complex seizure disorder, and cerebral palsy.

PARENTS’ CLAIM The child’s injuries occurred because cesarean delivery was delayed for 2 hours. Based on fetal heart-rate monitoring, the injuries most likely occurred in the last 18 minutes before birth, and were probably caused by compression of the umbilical cord. An earlier cesarean delivery would have avoided the injuries.

DEFENDANTS’ DEFENSE All of the injuries occurred prior to the mother’s arrival at the hospital, while she was under the care of the midwife. Fetal distress was present for an hour before the ambulance was called. When the mother arrived at the ED, she was an unknown patient, as the midwife did not have a collaborating physician. While the ED physician determined that a cesarean delivery was required, it was not considered an emergency. The mother was taken to the OR as soon as possible. Fetal monitoring strips at the hospital were reassuring.

VERDICT A $55 million Maryland verdict was returned against the hospital, including $26 million in noneconomic damages. After the court reduced noneconomic damages and future lost wages awards, the net verdict was $28 million.

ARDS after hysterectomy

A MORBIDLY OBESE WOMAN underwent a hysterectomy. The asthmatic, 38-year-old patient vomited after surgery. A pulmonologist undertook her care and determined that she had acute respiratory distress syndrome (ARDS). He prescribed the administration of oxygen. When she vomited again during the early morning hours of the second postsurgical day, he ordered intubation and went to the hospital immediately, but the patient quickly deteriorated. She died from cardiac arrest.

ESTATE’S CLAIM The patient’s death was due to failure to diagnose and treat ARDS in a timely manner. A bronchoscopy and frequent radiographs should have been performed. If the patient had been intubated earlier and steps had been taken to reduce the risk of vomiting, she would have had a better chance of survival. She should have been transferred to another facility when ARDS was diagnosed.

DEFENDANTS’ DEFENSE A bronchoscopy was not necessary. ARDS was diagnosed and treated in a timely manner. She was too unstable to transfer to another hospital.

VERDICT The hospital reached a confidential settlement, and the claim against the anesthesiologist was dismissed. The trial proceeded against the pulmonologist and his group. A New York defense verdict was returned.

Mother’s HELLP syndrome missed; fetus dies

DURING HER PREGNANCY, a 23-year-old woman was monitored for hypertension by her ObGyn and nurse midwife. At her 36-week prenatal visit, she was found to have preeclampsia, including proteinuria. She was sent directly to the ED, where the baby was monitored and laboratory tests were ordered by a nurse and nurse midwife. After 2 hours, she was told she had a urinary tract infection and discharged. Three days later, she returned to the ED in critical condition; she had suffered an intrauterine fetal demise.

PARENTS’ CLAIM Lab results showed critical values and confirmed that the patient had developed HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. The ED nurse and nurse midwife were negligent in their treatment: They never read the lab results or reported the results to the patient or an ObGyn.

DEFENDANTS’ DEFENSE The case was settled before trial.

VERDICT A $950,000 Virginia settlement was reached.

Was this pregnant prisoner in preterm labor ignored?

 A PREGNANT WOMAN WAS AWAITING TRIAL in County jail when she  went into preterm labor. She was taken to the ED but released 2 hours  later, although she was dilated 2–3 cm and having contractions. She was  returned to her locked cell and not monitored—no deputy or nurse was  within sight or sound of the patient. Her water broke and contractions  increased. Despite her screams, and those of other inmates, a nurse  didn’t arrive for 2 hours, when the baby’s head was crowning. EMS services were called and the baby was delivered in the jail cell. The child had no heartbeat or respiration. Mother and baby were transported to the hospital, where the child was resuscitated. She has severe mental impairment and cerebral palsy.

There is no documentation that the mother received any prenatal or postpartum care in jail. The mother is now serving a life sentence after a conviction for felony murder, kidnapping, and conspiracy.

CHILD’S CLAIM The case was brought on behalf of the child, and claimed that deliberate indifference and the failure to provide medical attention caused the child’s impairments.

DEFENDANTS’ DEFENSE The County claimed qualified immunity as a government entity and argued that, when the child was injured, she was still a fetus, and therefore not protected by the Constitution and civil rights laws.

VERDICT The US Circuit Court of Appeals rejected the County’s argument that the child was not protected by the Constitution. An $8 million Michigan settlement was reached.

Dermoid cyst still present after wrong-site surgery

A DERMOID CYST WAS DETECTED on the left ovary of a 28-year-old woman during prenatal ultrasonography (US). A year later, US confirmed the dermoid cyst, and the patient underwent outpatient cystectomy.

At the first postsurgical visit, the patient reported right pelvic pain. When she called the ObGyn’s office a few days later to again report right pelvic pain, her call was not returned.

She then went to the ED, where testing determined that the ObGyn had performed a right salpingo-oophorectomy and that her left ovary and cyst were still intact. She again attempted to contact the ObGyn, without response.

PATIENT’S CLAIM The ObGyn performed wrong-site surgery. The patient was not informed of the error during a postsurgical visit, nor were her attempts at contacting the physician returned. Still at risk for malignancy, she is facing a second surgical procedure to remove the cyst. Her fertility is diminished due to the surgical error, and she suffers anxiety and mental stress as a result of the situation.

At first, the ObGyn refused to provide medical records to the patient’s lawyer. When the records were obtained and compared with records obtained from another physician who treated the patient, it was evident that the ObGyn had altered the records to state that the patient had complained of right-side pain.

PHYSICIAN’S DEFENSE There was no negligence. The patient was properly treated for right-sided pain. The records were not altered.

VERDICT A $1.42 million Maryland verdict was returned. The state cap on noneconomic damages will reduce the verdict to $680,000.

Sponge left behind after vacuum-assisted closure

A WOMAN WENT TO THE ED with abdominal pain. It was determined that she had an abdominal abscess, and a surgeon assumed her care. After surgically draining the abdominal abscess, the surgeon placed a large black sponge into the abdominal cavity and then used vacuum-assisted closure. The patient was discharged 6 days later. She continued to receive treatment for a surgical-site infection that failed to heal. Two weeks later, the patient was readmitted to the hospital for exploratory surgery. The surgeon found and removed the sponge.

PATIENT’S CLAIM The surgeon was negligent for leaving the surgical sponge in the patient’s abdomen. She claimed pain, scarring, wound necrosis, infection, and the need for additional hospitalizations due to retention of the sponge.

PHYSICIAN’S DEFENSE A settlement was reached during the trial.

VERDICT A confidential Florida settlement was reached.

Child’s brain damage blamed on late cesarean

 A MOTHER WANTED A HOME BIRTH with a midwife. When  complications arose and labor stopped progressing, the midwife called an  ambulance. The emergency department (ED) physician ordered an urgent  cesarean delivery, but the procedure did not begin for another 2 hours.  The child was born with brain damage, multiple physical and mental  disabilities, complex seizure disorder, and cerebral palsy.

PARENTS’ CLAIM The child’s injuries occurred because cesarean delivery was delayed for 2 hours. Based on fetal heart-rate monitoring, the injuries most likely occurred in the last 18 minutes before birth, and were probably caused by compression of the umbilical cord. An earlier cesarean delivery would have avoided the injuries.

DEFENDANTS’ DEFENSE All of the injuries occurred prior to the mother’s arrival at the hospital, while she was under the care of the midwife. Fetal distress was present for an hour before the ambulance was called. When the mother arrived at the ED, she was an unknown patient, as the midwife did not have a collaborating physician. While the ED physician determined that a cesarean delivery was required, it was not considered an emergency. The mother was taken to the OR as soon as possible. Fetal monitoring strips at the hospital were reassuring.

VERDICT A $55 million Maryland verdict was returned against the hospital, including $26 million in noneconomic damages. After the court reduced noneconomic damages and future lost wages awards, the net verdict was $28 million.

ARDS after hysterectomy

A MORBIDLY OBESE WOMAN underwent a hysterectomy. The asthmatic, 38-year-old patient vomited after surgery. A pulmonologist undertook her care and determined that she had acute respiratory distress syndrome (ARDS). He prescribed the administration of oxygen. When she vomited again during the early morning hours of the second postsurgical day, he ordered intubation and went to the hospital immediately, but the patient quickly deteriorated. She died from cardiac arrest.

ESTATE’S CLAIM The patient’s death was due to failure to diagnose and treat ARDS in a timely manner. A bronchoscopy and frequent radiographs should have been performed. If the patient had been intubated earlier and steps had been taken to reduce the risk of vomiting, she would have had a better chance of survival. She should have been transferred to another facility when ARDS was diagnosed.

DEFENDANTS’ DEFENSE A bronchoscopy was not necessary. ARDS was diagnosed and treated in a timely manner. She was too unstable to transfer to another hospital.

VERDICT The hospital reached a confidential settlement, and the claim against the anesthesiologist was dismissed. The trial proceeded against the pulmonologist and his group. A New York defense verdict was returned.

Mother’s HELLP syndrome missed; fetus dies

DURING HER PREGNANCY, a 23-year-old woman was monitored for hypertension by her ObGyn and nurse midwife. At her 36-week prenatal visit, she was found to have preeclampsia, including proteinuria. She was sent directly to the ED, where the baby was monitored and laboratory tests were ordered by a nurse and nurse midwife. After 2 hours, she was told she had a urinary tract infection and discharged. Three days later, she returned to the ED in critical condition; she had suffered an intrauterine fetal demise.

PARENTS’ CLAIM Lab results showed critical values and confirmed that the patient had developed HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. The ED nurse and nurse midwife were negligent in their treatment: They never read the lab results or reported the results to the patient or an ObGyn.

DEFENDANTS’ DEFENSE The case was settled before trial.

VERDICT A $950,000 Virginia settlement was reached.

Was this pregnant prisoner in preterm labor ignored?

 A PREGNANT WOMAN WAS AWAITING TRIAL in County jail when she  went into preterm labor. She was taken to the ED but released 2 hours  later, although she was dilated 2–3 cm and having contractions. She was  returned to her locked cell and not monitored—no deputy or nurse was  within sight or sound of the patient. Her water broke and contractions  increased. Despite her screams, and those of other inmates, a nurse  didn’t arrive for 2 hours, when the baby’s head was crowning. EMS services were called and the baby was delivered in the jail cell. The child had no heartbeat or respiration. Mother and baby were transported to the hospital, where the child was resuscitated. She has severe mental impairment and cerebral palsy.

There is no documentation that the mother received any prenatal or postpartum care in jail. The mother is now serving a life sentence after a conviction for felony murder, kidnapping, and conspiracy.

CHILD’S CLAIM The case was brought on behalf of the child, and claimed that deliberate indifference and the failure to provide medical attention caused the child’s impairments.

DEFENDANTS’ DEFENSE The County claimed qualified immunity as a government entity and argued that, when the child was injured, she was still a fetus, and therefore not protected by the Constitution and civil rights laws.

VERDICT The US Circuit Court of Appeals rejected the County’s argument that the child was not protected by the Constitution. An $8 million Michigan settlement was reached.

Dermoid cyst still present after wrong-site surgery

A DERMOID CYST WAS DETECTED on the left ovary of a 28-year-old woman during prenatal ultrasonography (US). A year later, US confirmed the dermoid cyst, and the patient underwent outpatient cystectomy.

At the first postsurgical visit, the patient reported right pelvic pain. When she called the ObGyn’s office a few days later to again report right pelvic pain, her call was not returned.

She then went to the ED, where testing determined that the ObGyn had performed a right salpingo-oophorectomy and that her left ovary and cyst were still intact. She again attempted to contact the ObGyn, without response.

PATIENT’S CLAIM The ObGyn performed wrong-site surgery. The patient was not informed of the error during a postsurgical visit, nor were her attempts at contacting the physician returned. Still at risk for malignancy, she is facing a second surgical procedure to remove the cyst. Her fertility is diminished due to the surgical error, and she suffers anxiety and mental stress as a result of the situation.

At first, the ObGyn refused to provide medical records to the patient’s lawyer. When the records were obtained and compared with records obtained from another physician who treated the patient, it was evident that the ObGyn had altered the records to state that the patient had complained of right-side pain.

PHYSICIAN’S DEFENSE There was no negligence. The patient was properly treated for right-sided pain. The records were not altered.

VERDICT A $1.42 million Maryland verdict was returned. The state cap on noneconomic damages will reduce the verdict to $680,000.

Sponge left behind after vacuum-assisted closure

A WOMAN WENT TO THE ED with abdominal pain. It was determined that she had an abdominal abscess, and a surgeon assumed her care. After surgically draining the abdominal abscess, the surgeon placed a large black sponge into the abdominal cavity and then used vacuum-assisted closure. The patient was discharged 6 days later. She continued to receive treatment for a surgical-site infection that failed to heal. Two weeks later, the patient was readmitted to the hospital for exploratory surgery. The surgeon found and removed the sponge.

PATIENT’S CLAIM The surgeon was negligent for leaving the surgical sponge in the patient’s abdomen. She claimed pain, scarring, wound necrosis, infection, and the need for additional hospitalizations due to retention of the sponge.

PHYSICIAN’S DEFENSE A settlement was reached during the trial.

VERDICT A confidential Florida settlement was reached.