OBG Management

How common is IUD perforation, expulsion, and malposition?

ROBERT L. BARBIERI, MD (APRIL 2022)

The seriousness of IUD embedment

I appreciated Dr. Barbieri’s comprehensive review of clinical problems regarding the intrauterine device (IUD). It is interesting that, in spite of your mention of IUD embedment in the myometrium, other publications regarding this phenomenon are seemingly absent (except for ours).¹ Whether or not there is associated pain (and sometimes there is not), in our experience its removal can result in IUD fracture. As you stated, it is true that 3D transvaginal sonography perfectly enables this visualization, yet it is surprising that others have not experienced what we have. Nonetheless, it is encouraging to see that IUD embedment is seriously mentioned. 

1. Fernandez CM, Levine EM, Cabiya M, et al. Intrauterine device embedment resulting in its fracture: a case series. Arch Obstet Gynecol. 2021;2:1-4.

Elliot Levine, MD

Chicago, Illinois

Dr. Barbieri responds

I thank Dr. Levine for highlighting the important issue of IUD fracture and providing a reference to a case series of IUD fractures. Although such fracture is not common, when it does occur it may require a hysteroscopic procedure to remove all pieces of the IUD. In the cited case series, fracture was more commonly observed with the copper IUD than with the LNG-IUD. With regard to IUD malposition, 4 publications reviewed in my recent editorial describe the problem of an IUD arm embedded in the myometrium.^1-4

References

1. Benacerraf BR, Shipp TD, Bromley B. Three-dimensional ultrasound detection of abnormally located intrauterine contraceptive devices which are a source of pelvic pain and abnormal bleeding. Ultrasound Obstet Gynecol. 2009;34:110-115.
2. Braaten KP, Benson CB, Maurer R, et al. Malpositioned intrauterine contraceptive devices: risk factors, outcomes and future pregnancies. Obstet Gynecol. 2011;118:1014-1020.
3. Gerkowicz SA, Fiorentino DG, Kovacs AP, et al. Uterine structural abnormality and intrauterine device malposition: analysis of ultrasonographic and demographic variables of 517 patients. Am J Obstet Gynecol. 2019;220:183.e1-e8.
4. Connolly CT, Fox NS. Incidence and risk factors for a malpositioned intrauterine device detected on three-dimensional ultrasound within eight weeks of placement. J Ultrasound Med. September 27, 2021.

Will NAAT replace microscopy for the identification of organisms causing vaginitis?

ROBERT L. BARBIERI, MD (MARCH 2022)

Follow-up questions on NAAT testing

The sensitivity of NAAT testing, as outlined in Dr. Barbieri’s editorial, is undoubtedly better than the clinical methods most clinicians are using. I appreciate the frustration we providers often experience in drawing conclusions for patients based on the Amsel criteria for bacterial vaginitis (BV). I am surprised by the low sensitivity of microscopy for yeast vaginitis. My follow-up questions are:

• Have the NAATs referenced been validated in clinical trials and proven to improve patient outcomes?
• Will the proposal to begin empiric therapy for both yeast vaginitis and BV in combination while waiting for NAAT results lead to an increase of resistant strains?
• What is the cost of NAAT for vaginitis, and is this cost effective in routine practice?
• Can NAATs be utilized to detect resistant strains of yeast or Gardnerella sp?

Alan Paul Gehrich, MD (COL, MC ret.)

Bethesda, Maryland

Dr. Barbieri responds

I thank Dr. Gehrich for raising the important issue of what is the optimal endpoint to assess the clinical utility of NAAT testing for vaginitis. Most studies of the use of NAAT to diagnose the cause of vaginitis focus on comparing NAAT results to standard clinical practice (microscopy and pH), and to a “gold standard.” In most studies the gold standards are Nugent scoring with Amsel criteria to resolve intermediate Nugent scores for bacterial vaginosis, culture for Candida, and culture for Trichomonas vaginalis. It is clear from multiple studies that NAAT provides superior sensitivity and specificity compared with standard clinical practice.^1-3 As noted in the editorial, in a study of 466 patients with symptoms of vaginitis, standard office approaches to the diagnosis of vaginitis resulted in the failure to identify the correct infection in a large number of cases.⁴ For the diagnosis of BV, clinicians missed 42% of the cases identified by NAAT. For the diagnosis of Candida, clinicians missed 46% of the cases identified by NAAT. For the diagnosis of T vaginalis, clinicians missed 72% of the cases identified by NAAT. This resulted in clinicians not appropriately treating many infections detected by NAAT.

NAAT does provide information about the presence of Candida glabrata and Candida krusei, organisms which may be resistant to fluconazole. I agree with Dr. Gehrich that the optimal use of NAAT testing in practice is poorly studied with regard to treatment between sample collection and NAAT results. Cost of testing is a complex issue. Standard microscopy is relatively inexpensive, but performs poorly in clinical practice, resulting in misdiagnosis. NAAT testing is expensive but correctly identifies causes of vaginitis.

References 

1. Schwebke JR, Gaydos CA, Hyirjesy P, et al. Diagnostic performance of a molecular test versus clinician assessment of vaginitis. J Clin Microbiol. 2018;56:e00252-18.
2. Broache M, Cammarata CL, Stonebraker E, et al. Performance of vaginal panel assay compared with clinical diagnosis of vaginitis. Obstet Gynecol. 2021;138:853-859.
3. Schwebke JR, Taylor SN, Ackerman N, et al. Clinical validation of the Aptima bacterial vaginosis and Aptima Candida/Trichomonas vaginalis assays: results from a prospective multi-center study. J Clin Microbiol. 2020;58:e01643-19. 4
4. Gaydos CA, Beqaj S, Schwebke JR, et al. Clinical validation of a test for the diagnosis of vaginitis. Obstet Gynecol. 2017;130:181-189.

How common is IUD perforation, expulsion, and malposition?

ROBERT L. BARBIERI, MD (APRIL 2022)

The seriousness of IUD embedment

I appreciated Dr. Barbieri’s comprehensive review of clinical problems regarding the intrauterine device (IUD). It is interesting that, in spite of your mention of IUD embedment in the myometrium, other publications regarding this phenomenon are seemingly absent (except for ours).¹ Whether or not there is associated pain (and sometimes there is not), in our experience its removal can result in IUD fracture. As you stated, it is true that 3D transvaginal sonography perfectly enables this visualization, yet it is surprising that others have not experienced what we have. Nonetheless, it is encouraging to see that IUD embedment is seriously mentioned. 

1. Fernandez CM, Levine EM, Cabiya M, et al. Intrauterine device embedment resulting in its fracture: a case series. Arch Obstet Gynecol. 2021;2:1-4.

Elliot Levine, MD

Chicago, Illinois

Dr. Barbieri responds

I thank Dr. Levine for highlighting the important issue of IUD fracture and providing a reference to a case series of IUD fractures. Although such fracture is not common, when it does occur it may require a hysteroscopic procedure to remove all pieces of the IUD. In the cited case series, fracture was more commonly observed with the copper IUD than with the LNG-IUD. With regard to IUD malposition, 4 publications reviewed in my recent editorial describe the problem of an IUD arm embedded in the myometrium.^1-4

References

1. Benacerraf BR, Shipp TD, Bromley B. Three-dimensional ultrasound detection of abnormally located intrauterine contraceptive devices which are a source of pelvic pain and abnormal bleeding. Ultrasound Obstet Gynecol. 2009;34:110-115.
2. Braaten KP, Benson CB, Maurer R, et al. Malpositioned intrauterine contraceptive devices: risk factors, outcomes and future pregnancies. Obstet Gynecol. 2011;118:1014-1020.
3. Gerkowicz SA, Fiorentino DG, Kovacs AP, et al. Uterine structural abnormality and intrauterine device malposition: analysis of ultrasonographic and demographic variables of 517 patients. Am J Obstet Gynecol. 2019;220:183.e1-e8.
4. Connolly CT, Fox NS. Incidence and risk factors for a malpositioned intrauterine device detected on three-dimensional ultrasound within eight weeks of placement. J Ultrasound Med. September 27, 2021.

Will NAAT replace microscopy for the identification of organisms causing vaginitis?

ROBERT L. BARBIERI, MD (MARCH 2022)

Follow-up questions on NAAT testing

The sensitivity of NAAT testing, as outlined in Dr. Barbieri’s editorial, is undoubtedly better than the clinical methods most clinicians are using. I appreciate the frustration we providers often experience in drawing conclusions for patients based on the Amsel criteria for bacterial vaginitis (BV). I am surprised by the low sensitivity of microscopy for yeast vaginitis. My follow-up questions are:

• Have the NAATs referenced been validated in clinical trials and proven to improve patient outcomes?
• Will the proposal to begin empiric therapy for both yeast vaginitis and BV in combination while waiting for NAAT results lead to an increase of resistant strains?
• What is the cost of NAAT for vaginitis, and is this cost effective in routine practice?
• Can NAATs be utilized to detect resistant strains of yeast or Gardnerella sp?

Alan Paul Gehrich, MD (COL, MC ret.)

Bethesda, Maryland

Dr. Barbieri responds

I thank Dr. Gehrich for raising the important issue of what is the optimal endpoint to assess the clinical utility of NAAT testing for vaginitis. Most studies of the use of NAAT to diagnose the cause of vaginitis focus on comparing NAAT results to standard clinical practice (microscopy and pH), and to a “gold standard.” In most studies the gold standards are Nugent scoring with Amsel criteria to resolve intermediate Nugent scores for bacterial vaginosis, culture for Candida, and culture for Trichomonas vaginalis. It is clear from multiple studies that NAAT provides superior sensitivity and specificity compared with standard clinical practice.^1-3 As noted in the editorial, in a study of 466 patients with symptoms of vaginitis, standard office approaches to the diagnosis of vaginitis resulted in the failure to identify the correct infection in a large number of cases.⁴ For the diagnosis of BV, clinicians missed 42% of the cases identified by NAAT. For the diagnosis of Candida, clinicians missed 46% of the cases identified by NAAT. For the diagnosis of T vaginalis, clinicians missed 72% of the cases identified by NAAT. This resulted in clinicians not appropriately treating many infections detected by NAAT.

NAAT does provide information about the presence of Candida glabrata and Candida krusei, organisms which may be resistant to fluconazole. I agree with Dr. Gehrich that the optimal use of NAAT testing in practice is poorly studied with regard to treatment between sample collection and NAAT results. Cost of testing is a complex issue. Standard microscopy is relatively inexpensive, but performs poorly in clinical practice, resulting in misdiagnosis. NAAT testing is expensive but correctly identifies causes of vaginitis.

References 

1. Schwebke JR, Gaydos CA, Hyirjesy P, et al. Diagnostic performance of a molecular test versus clinician assessment of vaginitis. J Clin Microbiol. 2018;56:e00252-18.
2. Broache M, Cammarata CL, Stonebraker E, et al. Performance of vaginal panel assay compared with clinical diagnosis of vaginitis. Obstet Gynecol. 2021;138:853-859.
3. Schwebke JR, Taylor SN, Ackerman N, et al. Clinical validation of the Aptima bacterial vaginosis and Aptima Candida/Trichomonas vaginalis assays: results from a prospective multi-center study. J Clin Microbiol. 2020;58:e01643-19. 4
4. Gaydos CA, Beqaj S, Schwebke JR, et al. Clinical validation of a test for the diagnosis of vaginitis. Obstet Gynecol. 2017;130:181-189.

How common is IUD perforation, expulsion, and malposition?

ROBERT L. BARBIERI, MD (APRIL 2022)

The seriousness of IUD embedment

I appreciated Dr. Barbieri’s comprehensive review of clinical problems regarding the intrauterine device (IUD). It is interesting that, in spite of your mention of IUD embedment in the myometrium, other publications regarding this phenomenon are seemingly absent (except for ours).¹ Whether or not there is associated pain (and sometimes there is not), in our experience its removal can result in IUD fracture. As you stated, it is true that 3D transvaginal sonography perfectly enables this visualization, yet it is surprising that others have not experienced what we have. Nonetheless, it is encouraging to see that IUD embedment is seriously mentioned. 

1. Fernandez CM, Levine EM, Cabiya M, et al. Intrauterine device embedment resulting in its fracture: a case series. Arch Obstet Gynecol. 2021;2:1-4.

Elliot Levine, MD

Chicago, Illinois

Dr. Barbieri responds

I thank Dr. Levine for highlighting the important issue of IUD fracture and providing a reference to a case series of IUD fractures. Although such fracture is not common, when it does occur it may require a hysteroscopic procedure to remove all pieces of the IUD. In the cited case series, fracture was more commonly observed with the copper IUD than with the LNG-IUD. With regard to IUD malposition, 4 publications reviewed in my recent editorial describe the problem of an IUD arm embedded in the myometrium.^1-4

References

1. Benacerraf BR, Shipp TD, Bromley B. Three-dimensional ultrasound detection of abnormally located intrauterine contraceptive devices which are a source of pelvic pain and abnormal bleeding. Ultrasound Obstet Gynecol. 2009;34:110-115.
2. Braaten KP, Benson CB, Maurer R, et al. Malpositioned intrauterine contraceptive devices: risk factors, outcomes and future pregnancies. Obstet Gynecol. 2011;118:1014-1020.
3. Gerkowicz SA, Fiorentino DG, Kovacs AP, et al. Uterine structural abnormality and intrauterine device malposition: analysis of ultrasonographic and demographic variables of 517 patients. Am J Obstet Gynecol. 2019;220:183.e1-e8.
4. Connolly CT, Fox NS. Incidence and risk factors for a malpositioned intrauterine device detected on three-dimensional ultrasound within eight weeks of placement. J Ultrasound Med. September 27, 2021.

Will NAAT replace microscopy for the identification of organisms causing vaginitis?

ROBERT L. BARBIERI, MD (MARCH 2022)

Follow-up questions on NAAT testing

The sensitivity of NAAT testing, as outlined in Dr. Barbieri’s editorial, is undoubtedly better than the clinical methods most clinicians are using. I appreciate the frustration we providers often experience in drawing conclusions for patients based on the Amsel criteria for bacterial vaginitis (BV). I am surprised by the low sensitivity of microscopy for yeast vaginitis. My follow-up questions are:

• Have the NAATs referenced been validated in clinical trials and proven to improve patient outcomes?
• Will the proposal to begin empiric therapy for both yeast vaginitis and BV in combination while waiting for NAAT results lead to an increase of resistant strains?
• What is the cost of NAAT for vaginitis, and is this cost effective in routine practice?
• Can NAATs be utilized to detect resistant strains of yeast or Gardnerella sp?

Alan Paul Gehrich, MD (COL, MC ret.)

Bethesda, Maryland

Dr. Barbieri responds

I thank Dr. Gehrich for raising the important issue of what is the optimal endpoint to assess the clinical utility of NAAT testing for vaginitis. Most studies of the use of NAAT to diagnose the cause of vaginitis focus on comparing NAAT results to standard clinical practice (microscopy and pH), and to a “gold standard.” In most studies the gold standards are Nugent scoring with Amsel criteria to resolve intermediate Nugent scores for bacterial vaginosis, culture for Candida, and culture for Trichomonas vaginalis. It is clear from multiple studies that NAAT provides superior sensitivity and specificity compared with standard clinical practice.^1-3 As noted in the editorial, in a study of 466 patients with symptoms of vaginitis, standard office approaches to the diagnosis of vaginitis resulted in the failure to identify the correct infection in a large number of cases.⁴ For the diagnosis of BV, clinicians missed 42% of the cases identified by NAAT. For the diagnosis of Candida, clinicians missed 46% of the cases identified by NAAT. For the diagnosis of T vaginalis, clinicians missed 72% of the cases identified by NAAT. This resulted in clinicians not appropriately treating many infections detected by NAAT.

NAAT does provide information about the presence of Candida glabrata and Candida krusei, organisms which may be resistant to fluconazole. I agree with Dr. Gehrich that the optimal use of NAAT testing in practice is poorly studied with regard to treatment between sample collection and NAAT results. Cost of testing is a complex issue. Standard microscopy is relatively inexpensive, but performs poorly in clinical practice, resulting in misdiagnosis. NAAT testing is expensive but correctly identifies causes of vaginitis.

References 

1. Schwebke JR, Gaydos CA, Hyirjesy P, et al. Diagnostic performance of a molecular test versus clinician assessment of vaginitis. J Clin Microbiol. 2018;56:e00252-18.
2. Broache M, Cammarata CL, Stonebraker E, et al. Performance of vaginal panel assay compared with clinical diagnosis of vaginitis. Obstet Gynecol. 2021;138:853-859.
3. Schwebke JR, Taylor SN, Ackerman N, et al. Clinical validation of the Aptima bacterial vaginosis and Aptima Candida/Trichomonas vaginalis assays: results from a prospective multi-center study. J Clin Microbiol. 2020;58:e01643-19. 4
4. Gaydos CA, Beqaj S, Schwebke JR, et al. Clinical validation of a test for the diagnosis of vaginitis. Obstet Gynecol. 2017;130:181-189.

In their peer-to-peer interview, “Cervical cancer: A path to eradication,” (OBG Manag. May 2022;34:30-34.) David G. Mutch, MD, and Warner Huh, MD, discussed the varying guidelines for cervical cancer screening. Dr. Huh pointed out that the 2020 guidelines for the American Cancer Society recommend cervical cancer screening to begin at age 25 years, although the current guidelines for the American College of Obstetricians and Gynecologists continue to recommend age 21. He noted that “the rate of cervical cancer is extremely low under age 25, and other countries like the United Kingdom already” screen beginning at age 25. OBG Management followed up with a poll for readers to ask: “Guidelines vary on what age to begin screening for cervical cancer. What age do you typically recommend for patients?”

In their peer-to-peer interview, “Cervical cancer: A path to eradication,” (OBG Manag. May 2022;34:30-34.) David G. Mutch, MD, and Warner Huh, MD, discussed the varying guidelines for cervical cancer screening. Dr. Huh pointed out that the 2020 guidelines for the American Cancer Society recommend cervical cancer screening to begin at age 25 years, although the current guidelines for the American College of Obstetricians and Gynecologists continue to recommend age 21. He noted that “the rate of cervical cancer is extremely low under age 25, and other countries like the United Kingdom already” screen beginning at age 25. OBG Management followed up with a poll for readers to ask: “Guidelines vary on what age to begin screening for cervical cancer. What age do you typically recommend for patients?”

In their peer-to-peer interview, “Cervical cancer: A path to eradication,” (OBG Manag. May 2022;34:30-34.) David G. Mutch, MD, and Warner Huh, MD, discussed the varying guidelines for cervical cancer screening. Dr. Huh pointed out that the 2020 guidelines for the American Cancer Society recommend cervical cancer screening to begin at age 25 years, although the current guidelines for the American College of Obstetricians and Gynecologists continue to recommend age 21. He noted that “the rate of cervical cancer is extremely low under age 25, and other countries like the United Kingdom already” screen beginning at age 25. OBG Management followed up with a poll for readers to ask: “Guidelines vary on what age to begin screening for cervical cancer. What age do you typically recommend for patients?”

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Many authors have commented on the lack of research into female sexual dysfunction, especially when compared with the hundreds of research publications related to male sexual health and dysfunction. Not surprisingly, very little has been published in the past year on the subject of female sexual health.

Recently, the International Society for the Study of Women’s Sexual Health (ISSWSH) published 2 important papers: a guideline on the use of testosterone for hypoactive sexual desire disorder (HSDD) in women and a consensus document on the management of persistent genital arousal disorder (PGAD). The lack of funding and support for female sexual health leaves women’s health professionals with little education or guidance on how to identify and treat conditions that are likely as common in women as erectile dysfunction is in men. While we would like to rely on randomized trials to inform our clinical care, the very limited literature on female sexual health makes this difficult. Bringing together experienced clinicians who focus their practices on sexual health, ISSWSH has provided some much-needed recommendations for the management of difficult conditions.

ISSWSH provides clinical guidance on testosterone therapy for women with HSDD

Parish S, Simon J, Davis S, et al. International Society for the Study of Women’s Sexual Health clinical practice guideline for the use of systemic testosterone for hypoactive sexual desire disorder in women. J Sex Med. 2021;18:849-867.

For development of the ISSWSH clinical practice guideline on testosterone therapy for women with HSDD, 16 international researchers and clinicians were convened. A modified Delphi method was used to establish consensus at the meeting on the recommended indications for testosterone treatment, formulations, and when measurement of testosterone levels is appropriate.

An extensive evidence-based literature review was performed, which included original research, meta-analyses, reviews, and clinical practice guidelines, to address the use of testosterone in women for management of HSDD. Notably, in 2019, representatives of  10 medical societies published a Global Consensus Position Statement on the Use of Testosterone Therapy for Women that reviewed the existing literature on testosterone’s effects on sexual dysfunction, mood, cognition, musculoskeletal, cardiovascular, and breast health as well as androgenic side effects and adverse events.¹ Based on their review, the only evidence-based indication for testosterone use is for the treatment of HSDD.

Testosterone formulations, HSDD diagnosis, and sex steroid physiology

More than 10 years ago, the US Food and Drug Administration (FDA) reviewed an application for the use of a transdermal testosterone patch (Intrinsa) in women for the treatment of HSDD. Efficacy of treatment was clearly demonstrated, and no safety signals were found in the placebo-controlled trial. Based, however, on the opinions of regulators who were “concerned” about the potential for cardiovascular adverse outcomes and worry that the peripheral conversion of testosterone to estradiol might lead to an increase in breast cancer—worry generated from the findings of the Women’s Health Initiative (which did not demonstrate an increase in breast cancer risk with estrogen alone but only when estrogen was combined with medroxyprogesterone acetate)—the FDA declined to approve the testosterone patch for women.

The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) defined HSDD as “persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity with marked distress or interpersonal difficulty.” The guideline authors noted that although the DSM-5 edition merged female arousal disorder with desire disorder into a single diagnosis, they used the DSM-IV definition as it had been the basis for the studies and literature reviewed. HSDD is a prevalent condition worldwide that affects between 12% and  53% of peri- and postmenopausal women.

The consensus guideline authors extensively reviewed the physiology and mechanism of action of sex steroids in women, particularly their impact on sexual function and the biologic alterations that occur during peri- and postmenopause.

Continue to: Consensus position  and recommendations...

Consensus position  and recommendations

The ISSWSH consensus guideline concluded that there is a moderate therapeutic benefit in adding testosterone therapy to achieve up to premenopausal levels in postmenopausal women with self-reported reduction in sexual desire that is causing distress as determined by a validated instrument.

The authors advise baseline hormone testing to rule out androgen excess and baseline renal, lipid, liver, and metabolic testing, even though transdermal testosterone therapy was not shown to alter these parameters in randomized trials of more than 3,000 women. Laboratory assays for both total and free testosterone are “highly unreliable” in the female range as they have been calibrated for male levels of hormone.

FDA-approved testosterone treatments for men with hypogonadism include transdermal gels, patches, intramuscular injection, and an oral formulation. Dosing for women is approximately one-tenth the dosage for treatment of men. Patients should be informed that this treatment is off-label and that long-term studies to establish safety are not available. The authors advised against the use of compounded formulations based on the National Academies of Science, Engineering, and Medicine guidelines, but they went on to say that if compounded products are used, the pharmacy should adhere to Good Manufacturing Practice and Active Pharmaceutical Ingredients standards.

Rare, complex sexual function disorder requires integrated biopsychosocial approach, says ISSWSH

Goldstein I, Komisaruk BR, Pukall CF, et al. International Society for the Study of Women’s Sexual Health (ISSWSH) review of epidemiology and pathophysiology, and a consensus nomenclature and process of care for the management of persistent genital arousal disorder/genito-pelvic dyesthesia (PGAD/GPD). J Sex Med. 2021;18:665-697.

Persistent genital arousal disorder is a poorly understood and relatively rare sexual dysfunction in women. The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin on Female Sexual Dysfunction does not mention this condition, leaving women’s health practitioners with little guidance as to diagnosis or management.² Prevalence for the condition is estimated at 1% to 3%. The symptoms may be intermittent or continuous.

In a recent ISSWSH review, a consensus panel defined 5 criteria for this disorder: the perception of genital arousal that is involuntary, unrelated to sexual desire, without any identified cause, not relieved with orgasm, and distressing to the patient. The panel made a clear distinction between PGAD/ genito-pelvic dysesthesia (GPD) and Compulsive Sexual Behavior Disorder (defined by the International Classification of Diseases revision 11 as “a persistent pattern of failure to control intense, repetitive sexual impulses or urges). Because there is considerable overlap with syndromes of genital dysesthesia—itching, burning, tingling, or pain— the consensus panel elected to expand the nomenclature to describe both persistent genital arousal and genito-pelvic dysesthesia as a single syndrome, namely, PGAD/GPD.

Continue to: Negative impact of PGAD/GPD...

Negative impact of PGAD/GPD

The consensus panel identified several contributors to the overall morbidity of this complex disorder, including end organ pathology, peripheral nerve, spinal cord and central sensory processing malfunction, and significant psychological issues. PGAD/GPD also may be associated with spinal cysts, cauda equina pathology, and withdrawal from selective serotonin reuptake inhibitors (SSRIs). Functional magnetic resonance imaging has identified specific brain regions (for example, the paracentral lobule) that are active during clitoral stimulation and that also activate during patients’ experience of persistent genital arousal.

PGAD/GPD negatively impacts sexual function, mental health, and ability to function in daily life. Of major importance is that a large proportion of people with this disorder have significant mental health disorders; in a survey, 54% of patients with PGAD reported suicidal ideation, compared with 25% of participants in a control group.

Evaluation and management recommendations

Diagnosis and management of PGAD/GPD are directed at the 5 areas of evaluation:

• end organ
• pelvis and perineum (assess for pelvic floor tension myalgia, pudendal neuropathy, pelvic congestion syndrome, or pelvic arteriovenous malformation)
• cauda equina (evaluate for neurologic deficits related to cysts compressing S2-S3 nerve roots)
• spinal cord (serotonin and norepinephrine pathways modulate nociceptive sensory activity; either SSRI/serotonin and norepinephrine reuptake inhibitor (SNRI) withdrawal or treatment could impact PGAD/ GPD based on their actions in the spinal cord)
• brain.

The consensus panel recommends an integrated biopsychosocial model for evaluation and treatment of PGAD/GPD. Comorbid mental health conditions, such as depression and anxiety, are common. Small studies suggest that a history of sexual trauma may contribute to catastrophizing and the experience of distressing persistent genital sensations, either arousal or dyesthesia, with 46.7% to 52.6% of patients reporting childhood sexual abuse.³

Future possibilities and current  actualities for patient care

Research dollars and investment in female sexual dysfunction remain inadequate to address the considerable gaps that exist in evidence-based clinical guidelines. ISSWSH is working to help clinicians approach these evidence gaps with guidelines and consensus statements to help women’s health professionals identify and manage our patients with sexual concerns and symptoms. An expert consensus guideline on the assessment and management of female orgasmic disorder is currently under development (personal communication, Dr. Sheryl Kingsberg). In addition, a phase 2b trial is underway to assess the impact of topical sildenafil cream for the treatment of female arousal disorder. Stay tuned for the results of these studies.

For now, women’s health professionals have 2 FDA-approved treatment options for premenopausal women with arousal disorder, flibanserin (a daily oral medication that requires abstinence from alcohol) and bremelanotide (an injectable medication that can be used just prior to a sexual encounter). For postmenopausal women, there are no FDA-approved therapies; however, based on the ISSWSH guideline summarized above, transdermal testosterone may be offered to postmenopausal women with distressing loss of sexual desire in doses approximately one-tenth those used to treat men with androgen deficiency. These small doses are challenging to achieve consistently with the delivery systems available for FDA-approved products sold for men.

The National Academies of Science, Engineering, and Medicine advise against the use of compounded hormonal products due to the potential for inconsistency and lack of FDA oversight in the manufacturing/compounding process. I have found and used some compounding pharmacies that are dedicated to safety, quality control, and compliance; test their products; and provide consistent, reliable compounded drugs for my patients. Consideration of compounded testosterone should be discussed with patients, and they should be informed of the current professional association guidelines. Testosterone creams may be compounded to a 1% product—20 mg/mL. Researchers in Australia have demonstrated that 5 mg of transdermal testosterone cream (one-quarter of a mL) results in typical premenopausal testosterone levels.⁴ When prescribing testosterone for postmenopausal women, check in with them after 6 weeks of treatment to assess impact and check blood levels to ensure that levels are not too high.

Testosterone pellets and intramuscular testosterone are not recommended and in fact should be actively avoided. These methods of administration are associated with extreme variation in hormone levels over time. There are typically supraphysiologic and quite high levels immediately after implantation or injection, followed by fairly significant drop-offs and rapid return of symptoms over time. This may lead to more and more frequent dosing and markedly elevated serum levels.

Management of PGAD/GPD is difficult, but knowing it exists as a valid syndrome will help clinicians validate patients’ symptoms and begin to approach appropriate evaluation and workup targeted to the 5 domains suggested by the ISSWSH expert panel. It is useful to understand the possible relationship to initiation or withdrawal from SSRIs or SNRIs and how aberrant norepinephrine signaling along the sensory pathways may contribute to genital dysesthesia or chronic sensations of arousal. Nonpharmacologic therapies, such as cognitive-behavioral therapy and others, are essential components of the multifaceted approach to treatment. Finally, many complex problems, such as chronic pelvic pain, vestibulodynia, vulvodynia, and chronic fatigue syndrome, are associated with childhood adverse experiences and sexual trauma. Approaching these patients with trauma-informed care is important to create the trust and therapeutic environment they need for successful multidisciplinary care. ●

Many authors have commented on the lack of research into female sexual dysfunction, especially when compared with the hundreds of research publications related to male sexual health and dysfunction. Not surprisingly, very little has been published in the past year on the subject of female sexual health.

Recently, the International Society for the Study of Women’s Sexual Health (ISSWSH) published 2 important papers: a guideline on the use of testosterone for hypoactive sexual desire disorder (HSDD) in women and a consensus document on the management of persistent genital arousal disorder (PGAD). The lack of funding and support for female sexual health leaves women’s health professionals with little education or guidance on how to identify and treat conditions that are likely as common in women as erectile dysfunction is in men. While we would like to rely on randomized trials to inform our clinical care, the very limited literature on female sexual health makes this difficult. Bringing together experienced clinicians who focus their practices on sexual health, ISSWSH has provided some much-needed recommendations for the management of difficult conditions.

ISSWSH provides clinical guidance on testosterone therapy for women with HSDD

Parish S, Simon J, Davis S, et al. International Society for the Study of Women’s Sexual Health clinical practice guideline for the use of systemic testosterone for hypoactive sexual desire disorder in women. J Sex Med. 2021;18:849-867.

For development of the ISSWSH clinical practice guideline on testosterone therapy for women with HSDD, 16 international researchers and clinicians were convened. A modified Delphi method was used to establish consensus at the meeting on the recommended indications for testosterone treatment, formulations, and when measurement of testosterone levels is appropriate.

An extensive evidence-based literature review was performed, which included original research, meta-analyses, reviews, and clinical practice guidelines, to address the use of testosterone in women for management of HSDD. Notably, in 2019, representatives of  10 medical societies published a Global Consensus Position Statement on the Use of Testosterone Therapy for Women that reviewed the existing literature on testosterone’s effects on sexual dysfunction, mood, cognition, musculoskeletal, cardiovascular, and breast health as well as androgenic side effects and adverse events.¹ Based on their review, the only evidence-based indication for testosterone use is for the treatment of HSDD.

Testosterone formulations, HSDD diagnosis, and sex steroid physiology

More than 10 years ago, the US Food and Drug Administration (FDA) reviewed an application for the use of a transdermal testosterone patch (Intrinsa) in women for the treatment of HSDD. Efficacy of treatment was clearly demonstrated, and no safety signals were found in the placebo-controlled trial. Based, however, on the opinions of regulators who were “concerned” about the potential for cardiovascular adverse outcomes and worry that the peripheral conversion of testosterone to estradiol might lead to an increase in breast cancer—worry generated from the findings of the Women’s Health Initiative (which did not demonstrate an increase in breast cancer risk with estrogen alone but only when estrogen was combined with medroxyprogesterone acetate)—the FDA declined to approve the testosterone patch for women.

The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) defined HSDD as “persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity with marked distress or interpersonal difficulty.” The guideline authors noted that although the DSM-5 edition merged female arousal disorder with desire disorder into a single diagnosis, they used the DSM-IV definition as it had been the basis for the studies and literature reviewed. HSDD is a prevalent condition worldwide that affects between 12% and  53% of peri- and postmenopausal women.

The consensus guideline authors extensively reviewed the physiology and mechanism of action of sex steroids in women, particularly their impact on sexual function and the biologic alterations that occur during peri- and postmenopause.

Continue to: Consensus position  and recommendations...

Consensus position  and recommendations

The ISSWSH consensus guideline concluded that there is a moderate therapeutic benefit in adding testosterone therapy to achieve up to premenopausal levels in postmenopausal women with self-reported reduction in sexual desire that is causing distress as determined by a validated instrument.

The authors advise baseline hormone testing to rule out androgen excess and baseline renal, lipid, liver, and metabolic testing, even though transdermal testosterone therapy was not shown to alter these parameters in randomized trials of more than 3,000 women. Laboratory assays for both total and free testosterone are “highly unreliable” in the female range as they have been calibrated for male levels of hormone.

FDA-approved testosterone treatments for men with hypogonadism include transdermal gels, patches, intramuscular injection, and an oral formulation. Dosing for women is approximately one-tenth the dosage for treatment of men. Patients should be informed that this treatment is off-label and that long-term studies to establish safety are not available. The authors advised against the use of compounded formulations based on the National Academies of Science, Engineering, and Medicine guidelines, but they went on to say that if compounded products are used, the pharmacy should adhere to Good Manufacturing Practice and Active Pharmaceutical Ingredients standards.

Rare, complex sexual function disorder requires integrated biopsychosocial approach, says ISSWSH

Goldstein I, Komisaruk BR, Pukall CF, et al. International Society for the Study of Women’s Sexual Health (ISSWSH) review of epidemiology and pathophysiology, and a consensus nomenclature and process of care for the management of persistent genital arousal disorder/genito-pelvic dyesthesia (PGAD/GPD). J Sex Med. 2021;18:665-697.

Persistent genital arousal disorder is a poorly understood and relatively rare sexual dysfunction in women. The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin on Female Sexual Dysfunction does not mention this condition, leaving women’s health practitioners with little guidance as to diagnosis or management.² Prevalence for the condition is estimated at 1% to 3%. The symptoms may be intermittent or continuous.

In a recent ISSWSH review, a consensus panel defined 5 criteria for this disorder: the perception of genital arousal that is involuntary, unrelated to sexual desire, without any identified cause, not relieved with orgasm, and distressing to the patient. The panel made a clear distinction between PGAD/ genito-pelvic dysesthesia (GPD) and Compulsive Sexual Behavior Disorder (defined by the International Classification of Diseases revision 11 as “a persistent pattern of failure to control intense, repetitive sexual impulses or urges). Because there is considerable overlap with syndromes of genital dysesthesia—itching, burning, tingling, or pain— the consensus panel elected to expand the nomenclature to describe both persistent genital arousal and genito-pelvic dysesthesia as a single syndrome, namely, PGAD/GPD.

Continue to: Negative impact of PGAD/GPD...

Negative impact of PGAD/GPD

The consensus panel identified several contributors to the overall morbidity of this complex disorder, including end organ pathology, peripheral nerve, spinal cord and central sensory processing malfunction, and significant psychological issues. PGAD/GPD also may be associated with spinal cysts, cauda equina pathology, and withdrawal from selective serotonin reuptake inhibitors (SSRIs). Functional magnetic resonance imaging has identified specific brain regions (for example, the paracentral lobule) that are active during clitoral stimulation and that also activate during patients’ experience of persistent genital arousal.

PGAD/GPD negatively impacts sexual function, mental health, and ability to function in daily life. Of major importance is that a large proportion of people with this disorder have significant mental health disorders; in a survey, 54% of patients with PGAD reported suicidal ideation, compared with 25% of participants in a control group.

Evaluation and management recommendations

Diagnosis and management of PGAD/GPD are directed at the 5 areas of evaluation:

• end organ
• pelvis and perineum (assess for pelvic floor tension myalgia, pudendal neuropathy, pelvic congestion syndrome, or pelvic arteriovenous malformation)
• cauda equina (evaluate for neurologic deficits related to cysts compressing S2-S3 nerve roots)
• spinal cord (serotonin and norepinephrine pathways modulate nociceptive sensory activity; either SSRI/serotonin and norepinephrine reuptake inhibitor (SNRI) withdrawal or treatment could impact PGAD/ GPD based on their actions in the spinal cord)
• brain.

The consensus panel recommends an integrated biopsychosocial model for evaluation and treatment of PGAD/GPD. Comorbid mental health conditions, such as depression and anxiety, are common. Small studies suggest that a history of sexual trauma may contribute to catastrophizing and the experience of distressing persistent genital sensations, either arousal or dyesthesia, with 46.7% to 52.6% of patients reporting childhood sexual abuse.³

Future possibilities and current  actualities for patient care

Research dollars and investment in female sexual dysfunction remain inadequate to address the considerable gaps that exist in evidence-based clinical guidelines. ISSWSH is working to help clinicians approach these evidence gaps with guidelines and consensus statements to help women’s health professionals identify and manage our patients with sexual concerns and symptoms. An expert consensus guideline on the assessment and management of female orgasmic disorder is currently under development (personal communication, Dr. Sheryl Kingsberg). In addition, a phase 2b trial is underway to assess the impact of topical sildenafil cream for the treatment of female arousal disorder. Stay tuned for the results of these studies.

For now, women’s health professionals have 2 FDA-approved treatment options for premenopausal women with arousal disorder, flibanserin (a daily oral medication that requires abstinence from alcohol) and bremelanotide (an injectable medication that can be used just prior to a sexual encounter). For postmenopausal women, there are no FDA-approved therapies; however, based on the ISSWSH guideline summarized above, transdermal testosterone may be offered to postmenopausal women with distressing loss of sexual desire in doses approximately one-tenth those used to treat men with androgen deficiency. These small doses are challenging to achieve consistently with the delivery systems available for FDA-approved products sold for men.

The National Academies of Science, Engineering, and Medicine advise against the use of compounded hormonal products due to the potential for inconsistency and lack of FDA oversight in the manufacturing/compounding process. I have found and used some compounding pharmacies that are dedicated to safety, quality control, and compliance; test their products; and provide consistent, reliable compounded drugs for my patients. Consideration of compounded testosterone should be discussed with patients, and they should be informed of the current professional association guidelines. Testosterone creams may be compounded to a 1% product—20 mg/mL. Researchers in Australia have demonstrated that 5 mg of transdermal testosterone cream (one-quarter of a mL) results in typical premenopausal testosterone levels.⁴ When prescribing testosterone for postmenopausal women, check in with them after 6 weeks of treatment to assess impact and check blood levels to ensure that levels are not too high.

Testosterone pellets and intramuscular testosterone are not recommended and in fact should be actively avoided. These methods of administration are associated with extreme variation in hormone levels over time. There are typically supraphysiologic and quite high levels immediately after implantation or injection, followed by fairly significant drop-offs and rapid return of symptoms over time. This may lead to more and more frequent dosing and markedly elevated serum levels.

Management of PGAD/GPD is difficult, but knowing it exists as a valid syndrome will help clinicians validate patients’ symptoms and begin to approach appropriate evaluation and workup targeted to the 5 domains suggested by the ISSWSH expert panel. It is useful to understand the possible relationship to initiation or withdrawal from SSRIs or SNRIs and how aberrant norepinephrine signaling along the sensory pathways may contribute to genital dysesthesia or chronic sensations of arousal. Nonpharmacologic therapies, such as cognitive-behavioral therapy and others, are essential components of the multifaceted approach to treatment. Finally, many complex problems, such as chronic pelvic pain, vestibulodynia, vulvodynia, and chronic fatigue syndrome, are associated with childhood adverse experiences and sexual trauma. Approaching these patients with trauma-informed care is important to create the trust and therapeutic environment they need for successful multidisciplinary care. ●

Many authors have commented on the lack of research into female sexual dysfunction, especially when compared with the hundreds of research publications related to male sexual health and dysfunction. Not surprisingly, very little has been published in the past year on the subject of female sexual health.

Recently, the International Society for the Study of Women’s Sexual Health (ISSWSH) published 2 important papers: a guideline on the use of testosterone for hypoactive sexual desire disorder (HSDD) in women and a consensus document on the management of persistent genital arousal disorder (PGAD). The lack of funding and support for female sexual health leaves women’s health professionals with little education or guidance on how to identify and treat conditions that are likely as common in women as erectile dysfunction is in men. While we would like to rely on randomized trials to inform our clinical care, the very limited literature on female sexual health makes this difficult. Bringing together experienced clinicians who focus their practices on sexual health, ISSWSH has provided some much-needed recommendations for the management of difficult conditions.

ISSWSH provides clinical guidance on testosterone therapy for women with HSDD

Parish S, Simon J, Davis S, et al. International Society for the Study of Women’s Sexual Health clinical practice guideline for the use of systemic testosterone for hypoactive sexual desire disorder in women. J Sex Med. 2021;18:849-867.

For development of the ISSWSH clinical practice guideline on testosterone therapy for women with HSDD, 16 international researchers and clinicians were convened. A modified Delphi method was used to establish consensus at the meeting on the recommended indications for testosterone treatment, formulations, and when measurement of testosterone levels is appropriate.

An extensive evidence-based literature review was performed, which included original research, meta-analyses, reviews, and clinical practice guidelines, to address the use of testosterone in women for management of HSDD. Notably, in 2019, representatives of  10 medical societies published a Global Consensus Position Statement on the Use of Testosterone Therapy for Women that reviewed the existing literature on testosterone’s effects on sexual dysfunction, mood, cognition, musculoskeletal, cardiovascular, and breast health as well as androgenic side effects and adverse events.¹ Based on their review, the only evidence-based indication for testosterone use is for the treatment of HSDD.

Testosterone formulations, HSDD diagnosis, and sex steroid physiology

More than 10 years ago, the US Food and Drug Administration (FDA) reviewed an application for the use of a transdermal testosterone patch (Intrinsa) in women for the treatment of HSDD. Efficacy of treatment was clearly demonstrated, and no safety signals were found in the placebo-controlled trial. Based, however, on the opinions of regulators who were “concerned” about the potential for cardiovascular adverse outcomes and worry that the peripheral conversion of testosterone to estradiol might lead to an increase in breast cancer—worry generated from the findings of the Women’s Health Initiative (which did not demonstrate an increase in breast cancer risk with estrogen alone but only when estrogen was combined with medroxyprogesterone acetate)—the FDA declined to approve the testosterone patch for women.

The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) defined HSDD as “persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity with marked distress or interpersonal difficulty.” The guideline authors noted that although the DSM-5 edition merged female arousal disorder with desire disorder into a single diagnosis, they used the DSM-IV definition as it had been the basis for the studies and literature reviewed. HSDD is a prevalent condition worldwide that affects between 12% and  53% of peri- and postmenopausal women.

The consensus guideline authors extensively reviewed the physiology and mechanism of action of sex steroids in women, particularly their impact on sexual function and the biologic alterations that occur during peri- and postmenopause.

Continue to: Consensus position  and recommendations...

Consensus position  and recommendations

The ISSWSH consensus guideline concluded that there is a moderate therapeutic benefit in adding testosterone therapy to achieve up to premenopausal levels in postmenopausal women with self-reported reduction in sexual desire that is causing distress as determined by a validated instrument.

The authors advise baseline hormone testing to rule out androgen excess and baseline renal, lipid, liver, and metabolic testing, even though transdermal testosterone therapy was not shown to alter these parameters in randomized trials of more than 3,000 women. Laboratory assays for both total and free testosterone are “highly unreliable” in the female range as they have been calibrated for male levels of hormone.

FDA-approved testosterone treatments for men with hypogonadism include transdermal gels, patches, intramuscular injection, and an oral formulation. Dosing for women is approximately one-tenth the dosage for treatment of men. Patients should be informed that this treatment is off-label and that long-term studies to establish safety are not available. The authors advised against the use of compounded formulations based on the National Academies of Science, Engineering, and Medicine guidelines, but they went on to say that if compounded products are used, the pharmacy should adhere to Good Manufacturing Practice and Active Pharmaceutical Ingredients standards.

Rare, complex sexual function disorder requires integrated biopsychosocial approach, says ISSWSH

Goldstein I, Komisaruk BR, Pukall CF, et al. International Society for the Study of Women’s Sexual Health (ISSWSH) review of epidemiology and pathophysiology, and a consensus nomenclature and process of care for the management of persistent genital arousal disorder/genito-pelvic dyesthesia (PGAD/GPD). J Sex Med. 2021;18:665-697.

Persistent genital arousal disorder is a poorly understood and relatively rare sexual dysfunction in women. The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin on Female Sexual Dysfunction does not mention this condition, leaving women’s health practitioners with little guidance as to diagnosis or management.² Prevalence for the condition is estimated at 1% to 3%. The symptoms may be intermittent or continuous.

In a recent ISSWSH review, a consensus panel defined 5 criteria for this disorder: the perception of genital arousal that is involuntary, unrelated to sexual desire, without any identified cause, not relieved with orgasm, and distressing to the patient. The panel made a clear distinction between PGAD/ genito-pelvic dysesthesia (GPD) and Compulsive Sexual Behavior Disorder (defined by the International Classification of Diseases revision 11 as “a persistent pattern of failure to control intense, repetitive sexual impulses or urges). Because there is considerable overlap with syndromes of genital dysesthesia—itching, burning, tingling, or pain— the consensus panel elected to expand the nomenclature to describe both persistent genital arousal and genito-pelvic dysesthesia as a single syndrome, namely, PGAD/GPD.

Continue to: Negative impact of PGAD/GPD...

Negative impact of PGAD/GPD

The consensus panel identified several contributors to the overall morbidity of this complex disorder, including end organ pathology, peripheral nerve, spinal cord and central sensory processing malfunction, and significant psychological issues. PGAD/GPD also may be associated with spinal cysts, cauda equina pathology, and withdrawal from selective serotonin reuptake inhibitors (SSRIs). Functional magnetic resonance imaging has identified specific brain regions (for example, the paracentral lobule) that are active during clitoral stimulation and that also activate during patients’ experience of persistent genital arousal.

PGAD/GPD negatively impacts sexual function, mental health, and ability to function in daily life. Of major importance is that a large proportion of people with this disorder have significant mental health disorders; in a survey, 54% of patients with PGAD reported suicidal ideation, compared with 25% of participants in a control group.

Evaluation and management recommendations

Diagnosis and management of PGAD/GPD are directed at the 5 areas of evaluation:

• end organ
• pelvis and perineum (assess for pelvic floor tension myalgia, pudendal neuropathy, pelvic congestion syndrome, or pelvic arteriovenous malformation)
• cauda equina (evaluate for neurologic deficits related to cysts compressing S2-S3 nerve roots)
• spinal cord (serotonin and norepinephrine pathways modulate nociceptive sensory activity; either SSRI/serotonin and norepinephrine reuptake inhibitor (SNRI) withdrawal or treatment could impact PGAD/ GPD based on their actions in the spinal cord)
• brain.

The consensus panel recommends an integrated biopsychosocial model for evaluation and treatment of PGAD/GPD. Comorbid mental health conditions, such as depression and anxiety, are common. Small studies suggest that a history of sexual trauma may contribute to catastrophizing and the experience of distressing persistent genital sensations, either arousal or dyesthesia, with 46.7% to 52.6% of patients reporting childhood sexual abuse.³

Future possibilities and current  actualities for patient care

Research dollars and investment in female sexual dysfunction remain inadequate to address the considerable gaps that exist in evidence-based clinical guidelines. ISSWSH is working to help clinicians approach these evidence gaps with guidelines and consensus statements to help women’s health professionals identify and manage our patients with sexual concerns and symptoms. An expert consensus guideline on the assessment and management of female orgasmic disorder is currently under development (personal communication, Dr. Sheryl Kingsberg). In addition, a phase 2b trial is underway to assess the impact of topical sildenafil cream for the treatment of female arousal disorder. Stay tuned for the results of these studies.

For now, women’s health professionals have 2 FDA-approved treatment options for premenopausal women with arousal disorder, flibanserin (a daily oral medication that requires abstinence from alcohol) and bremelanotide (an injectable medication that can be used just prior to a sexual encounter). For postmenopausal women, there are no FDA-approved therapies; however, based on the ISSWSH guideline summarized above, transdermal testosterone may be offered to postmenopausal women with distressing loss of sexual desire in doses approximately one-tenth those used to treat men with androgen deficiency. These small doses are challenging to achieve consistently with the delivery systems available for FDA-approved products sold for men.

The National Academies of Science, Engineering, and Medicine advise against the use of compounded hormonal products due to the potential for inconsistency and lack of FDA oversight in the manufacturing/compounding process. I have found and used some compounding pharmacies that are dedicated to safety, quality control, and compliance; test their products; and provide consistent, reliable compounded drugs for my patients. Consideration of compounded testosterone should be discussed with patients, and they should be informed of the current professional association guidelines. Testosterone creams may be compounded to a 1% product—20 mg/mL. Researchers in Australia have demonstrated that 5 mg of transdermal testosterone cream (one-quarter of a mL) results in typical premenopausal testosterone levels.⁴ When prescribing testosterone for postmenopausal women, check in with them after 6 weeks of treatment to assess impact and check blood levels to ensure that levels are not too high.

Testosterone pellets and intramuscular testosterone are not recommended and in fact should be actively avoided. These methods of administration are associated with extreme variation in hormone levels over time. There are typically supraphysiologic and quite high levels immediately after implantation or injection, followed by fairly significant drop-offs and rapid return of symptoms over time. This may lead to more and more frequent dosing and markedly elevated serum levels.

Management of PGAD/GPD is difficult, but knowing it exists as a valid syndrome will help clinicians validate patients’ symptoms and begin to approach appropriate evaluation and workup targeted to the 5 domains suggested by the ISSWSH expert panel. It is useful to understand the possible relationship to initiation or withdrawal from SSRIs or SNRIs and how aberrant norepinephrine signaling along the sensory pathways may contribute to genital dysesthesia or chronic sensations of arousal. Nonpharmacologic therapies, such as cognitive-behavioral therapy and others, are essential components of the multifaceted approach to treatment. Finally, many complex problems, such as chronic pelvic pain, vestibulodynia, vulvodynia, and chronic fatigue syndrome, are associated with childhood adverse experiences and sexual trauma. Approaching these patients with trauma-informed care is important to create the trust and therapeutic environment they need for successful multidisciplinary care. ●

It is time to reconsider the recommendation for practicing fetal kick counts. A meta-analysis demonstrated no decrease in the outcome of stillbirth, but instead an increased risk of iatrogenic delivery.¹

CASE 1 8 vs 10 fetal movements in 2 hours

Ms. M is 38 weeks pregnant with an uncomplicated pregnancy. She calls your practice with concerns about fetal kick counts. During her prenatal care, she was counseled to ensure that the baby moved 10 times over a period of 2 hours. This morning, however, she only perceived 8 movements in 2 hours. She is scheduled for evaluation with a nonstress test (NST) on the labor and delivery unit. The NST reveals a reassuring, reactive tracing. Ultrasonography evaluation demonstrates a normal amniotic fluid index and normal fetal growth. The patient is reassured, returns home, and goes on to deliver a healthy baby at 39 weeks and 5 days.

Perception of decreased movement triggers evaluation and monitoring

Maternal perception of normal fetal movement has conceivably been used throughout history as a means of reassurance of fetal well-being; it is highly predictive of fetal viability.^2,3 When fetal movement is lacking or decreased, it can be an alarm sign and may result in concerns by the mother that her baby is unwell. Maternal perception of decreased fetal movements affects 5% to 15% of all pregnancies.^2,4 While decreased fetal movement can be associated with poor perinatal outcomes such as fetal growth restriction, oligohydramnios, and neuro-developmental disability, it also can be reflective of more benign issues such as anterior placenta, maternal activity, maternal caffeine or sugar consumption, or maternal position.^4,5

However, the definition of decreased fetal movement is subject to significant variation, from a total absence of movement over an entire day or what has commonly become accepted as the definition of fetal kick counts with Pearson’s Cardiff chart (which was defined in the 1970s as 10 movements within 12 hours).^6,7 Today, women in the United States are commonly recommended to monitor their baby over a 2-hour period and to look for 10 movements during that time.⁸ Anything less is considered reduced fetal movement and results in recommendations to undergo assessment of previously known high-risk conditions or any possible underlying conditions, such as hypertension, gestational diabetes, or fetal growth restriction. Further evaluation with more objective measures such as electronic fetal monitoring or ultrasonography with biophysical profile are often recommended concurrently.⁹

It is estimated that up to 15% of women present reporting decreased fetal movement in the third trimester and, as such, require additional monitoring and evaluation. This is not without cost of time and money to the health care system and pregnant patients.

It is uncertain that fetal kick counting prevents stillbirth

Intrauterine fetal demise is neither an uncommon nor completely preventable outcome, despite advances in antenatal care. Many cases occur without evidence of fetal abnormality or other risk factors, and 30% to 55% of women who experience intrauterine fetal demise experience decreased fetal movement in the preceding week.¹⁰ It makes physiologic sense that a fetus’ adaptive response to decreased oxygenation is reduced fetal movement, resulting from the prioritization of blood to the fetal brain and other organs over skeletal muscle.^4,9,11 Results of a 1976 small study of 61 low-risk pregnancies seemed to confirm that a decrease in fetal movement preceded intrauterine death by 3 to 4 days. Conversely, they found that a normal fetal movement count was generally associated with a good neonatal outcome.⁶ Thus, experts have long extrapolated that decreased fetal movement can be an indicator for utero-placental insufficiency and, in turn, chronic or acute hypoxia.

However, in larger studies, the ability of fetal movement counting to predict fetal death and fetal compromise appears limited.^8,10,11 A meta-analysis of studies, including 5 randomized controlled trials and 468,000 fetuses, compared the incidence of stillbirth in women receiving instructions for fetal movement counting versus women who did not. Rates of stillbirth were the same for each group, demonstrating no advantage to fetal kick counts to prevent a poor perinatal outcome, including stillbirth.¹

CASE 2 Reported reduced fetal movement over 4 weeks

Ms. E is a 20-year-old nullipara at 36 weeks’ and 6 days gestation who has come in to triage weekly for the last 4 weeks with concerns about decreased fetal movement. She states that she goes for several hours each day without feeling 10 movements in 2 hours. Recent fetal growth recorded 3 weeks ago was in the 45th percentile, and the amniotic fluid index has been above 10 cm on each weekly ultrasound. Her weekly NSTs have been reactive, and she has been normotensive. However, because she has had several weeks of persistent decreased fetal movement, the labor and delivery team opts to keep her for induction as she is “close to term.”

Decreased kick count frequency may increase unnecessary interventions

Women with fewer kick counts are more likely to present with concerns about the well-being of their baby. In a survey of obstetricians and midwives, a large proportion of providers were more apt to recommend delivery or admission to the hospital for women presenting with decreased fetal movements.² It stands to reason that recommendations for delivery or admission can lead to outcomes like preterm delivery or recommendations for cesarean delivery (CD). However, using fetal kick counts to portend stillbirth or other poor fetal and neonatal outcomes has been shown to be limited in its value with the AFFIRM trial.¹⁰ The results of this large study, which included more than 400,000 pregnancies from 37 hospitals, show the challenges of any study to address the use of management strategies for recent change in the frequency of fetal movements in the reduction of and cause of stillbirth. Additionally, the relatively low risk of stillbirth overall (4.06 stillbirths per 1,000 livebirths during the intervention period and 4.40 per 1,000 livebirths during the control period) but higher incidence of other outcomes, such as prolonged (>48 hours) antepartum admission (6.7% in the intervention period and 6.2% in the control period), induction of labor (40.7% in the intervention period and 35.9% in the control period), and CD (28.4% and 25.5%, respectively) may result in increased harm for many women rather than the intended benefit of preventing stillbirth.^10,12

Mindfetalness may be a viable and valuable alternative to kick counts

Alternatives have been proposed as a measure of fetal movement without using kick counts specifically. Mindfetalness has been a method studied in Sweden; its purpose is to strengthen the mother’s awareness of her baby through developing an understanding of the fetal-movement pattern. It is practiced starting at 28 weeks’ gestation for 15 minutes a day, with the woman instructed to lie on her left side and discern the intensity and character of the movements, as well as frequency, without overtly counting the movements.¹² In one small study, women felt more connected to their babies and felt less worried.¹² In a much larger study of 13,000 women, the authors found no evidence of harm from generalized awareness of fetal movements in a population of pregnant women at or beyond 32 weeks; in fact, they did see significant reductions in iatrogenic outcomes such as CDs and labor inductions.¹³

The case for movement awareness over kick counts

Stillbirth risk does not appear to be modified by the use of methods to detect fetal movement.^10,12 However, a perceived decrease in fetal kick counts has been shown to result in increased interventions and preterm deliveries. A more prudent approach appears to be educating mothers about general fetal movement, which appears to reduce potentially unnecessary visits and interventions without sacrificing the ability to reassure mothers about the well-being of their babies in utero. ●

It is time to reconsider the recommendation for practicing fetal kick counts. A meta-analysis demonstrated no decrease in the outcome of stillbirth, but instead an increased risk of iatrogenic delivery.¹

CASE 1 8 vs 10 fetal movements in 2 hours

Ms. M is 38 weeks pregnant with an uncomplicated pregnancy. She calls your practice with concerns about fetal kick counts. During her prenatal care, she was counseled to ensure that the baby moved 10 times over a period of 2 hours. This morning, however, she only perceived 8 movements in 2 hours. She is scheduled for evaluation with a nonstress test (NST) on the labor and delivery unit. The NST reveals a reassuring, reactive tracing. Ultrasonography evaluation demonstrates a normal amniotic fluid index and normal fetal growth. The patient is reassured, returns home, and goes on to deliver a healthy baby at 39 weeks and 5 days.

Perception of decreased movement triggers evaluation and monitoring

Maternal perception of normal fetal movement has conceivably been used throughout history as a means of reassurance of fetal well-being; it is highly predictive of fetal viability.^2,3 When fetal movement is lacking or decreased, it can be an alarm sign and may result in concerns by the mother that her baby is unwell. Maternal perception of decreased fetal movements affects 5% to 15% of all pregnancies.^2,4 While decreased fetal movement can be associated with poor perinatal outcomes such as fetal growth restriction, oligohydramnios, and neuro-developmental disability, it also can be reflective of more benign issues such as anterior placenta, maternal activity, maternal caffeine or sugar consumption, or maternal position.^4,5

However, the definition of decreased fetal movement is subject to significant variation, from a total absence of movement over an entire day or what has commonly become accepted as the definition of fetal kick counts with Pearson’s Cardiff chart (which was defined in the 1970s as 10 movements within 12 hours).^6,7 Today, women in the United States are commonly recommended to monitor their baby over a 2-hour period and to look for 10 movements during that time.⁸ Anything less is considered reduced fetal movement and results in recommendations to undergo assessment of previously known high-risk conditions or any possible underlying conditions, such as hypertension, gestational diabetes, or fetal growth restriction. Further evaluation with more objective measures such as electronic fetal monitoring or ultrasonography with biophysical profile are often recommended concurrently.⁹

It is estimated that up to 15% of women present reporting decreased fetal movement in the third trimester and, as such, require additional monitoring and evaluation. This is not without cost of time and money to the health care system and pregnant patients.

It is uncertain that fetal kick counting prevents stillbirth

Intrauterine fetal demise is neither an uncommon nor completely preventable outcome, despite advances in antenatal care. Many cases occur without evidence of fetal abnormality or other risk factors, and 30% to 55% of women who experience intrauterine fetal demise experience decreased fetal movement in the preceding week.¹⁰ It makes physiologic sense that a fetus’ adaptive response to decreased oxygenation is reduced fetal movement, resulting from the prioritization of blood to the fetal brain and other organs over skeletal muscle.^4,9,11 Results of a 1976 small study of 61 low-risk pregnancies seemed to confirm that a decrease in fetal movement preceded intrauterine death by 3 to 4 days. Conversely, they found that a normal fetal movement count was generally associated with a good neonatal outcome.⁶ Thus, experts have long extrapolated that decreased fetal movement can be an indicator for utero-placental insufficiency and, in turn, chronic or acute hypoxia.

However, in larger studies, the ability of fetal movement counting to predict fetal death and fetal compromise appears limited.^8,10,11 A meta-analysis of studies, including 5 randomized controlled trials and 468,000 fetuses, compared the incidence of stillbirth in women receiving instructions for fetal movement counting versus women who did not. Rates of stillbirth were the same for each group, demonstrating no advantage to fetal kick counts to prevent a poor perinatal outcome, including stillbirth.¹

CASE 2 Reported reduced fetal movement over 4 weeks

Ms. E is a 20-year-old nullipara at 36 weeks’ and 6 days gestation who has come in to triage weekly for the last 4 weeks with concerns about decreased fetal movement. She states that she goes for several hours each day without feeling 10 movements in 2 hours. Recent fetal growth recorded 3 weeks ago was in the 45th percentile, and the amniotic fluid index has been above 10 cm on each weekly ultrasound. Her weekly NSTs have been reactive, and she has been normotensive. However, because she has had several weeks of persistent decreased fetal movement, the labor and delivery team opts to keep her for induction as she is “close to term.”

Decreased kick count frequency may increase unnecessary interventions

Women with fewer kick counts are more likely to present with concerns about the well-being of their baby. In a survey of obstetricians and midwives, a large proportion of providers were more apt to recommend delivery or admission to the hospital for women presenting with decreased fetal movements.² It stands to reason that recommendations for delivery or admission can lead to outcomes like preterm delivery or recommendations for cesarean delivery (CD). However, using fetal kick counts to portend stillbirth or other poor fetal and neonatal outcomes has been shown to be limited in its value with the AFFIRM trial.¹⁰ The results of this large study, which included more than 400,000 pregnancies from 37 hospitals, show the challenges of any study to address the use of management strategies for recent change in the frequency of fetal movements in the reduction of and cause of stillbirth. Additionally, the relatively low risk of stillbirth overall (4.06 stillbirths per 1,000 livebirths during the intervention period and 4.40 per 1,000 livebirths during the control period) but higher incidence of other outcomes, such as prolonged (>48 hours) antepartum admission (6.7% in the intervention period and 6.2% in the control period), induction of labor (40.7% in the intervention period and 35.9% in the control period), and CD (28.4% and 25.5%, respectively) may result in increased harm for many women rather than the intended benefit of preventing stillbirth.^10,12

Mindfetalness may be a viable and valuable alternative to kick counts

Alternatives have been proposed as a measure of fetal movement without using kick counts specifically. Mindfetalness has been a method studied in Sweden; its purpose is to strengthen the mother’s awareness of her baby through developing an understanding of the fetal-movement pattern. It is practiced starting at 28 weeks’ gestation for 15 minutes a day, with the woman instructed to lie on her left side and discern the intensity and character of the movements, as well as frequency, without overtly counting the movements.¹² In one small study, women felt more connected to their babies and felt less worried.¹² In a much larger study of 13,000 women, the authors found no evidence of harm from generalized awareness of fetal movements in a population of pregnant women at or beyond 32 weeks; in fact, they did see significant reductions in iatrogenic outcomes such as CDs and labor inductions.¹³

The case for movement awareness over kick counts

Stillbirth risk does not appear to be modified by the use of methods to detect fetal movement.^10,12 However, a perceived decrease in fetal kick counts has been shown to result in increased interventions and preterm deliveries. A more prudent approach appears to be educating mothers about general fetal movement, which appears to reduce potentially unnecessary visits and interventions without sacrificing the ability to reassure mothers about the well-being of their babies in utero. ●

It is time to reconsider the recommendation for practicing fetal kick counts. A meta-analysis demonstrated no decrease in the outcome of stillbirth, but instead an increased risk of iatrogenic delivery.¹

CASE 1 8 vs 10 fetal movements in 2 hours

Ms. M is 38 weeks pregnant with an uncomplicated pregnancy. She calls your practice with concerns about fetal kick counts. During her prenatal care, she was counseled to ensure that the baby moved 10 times over a period of 2 hours. This morning, however, she only perceived 8 movements in 2 hours. She is scheduled for evaluation with a nonstress test (NST) on the labor and delivery unit. The NST reveals a reassuring, reactive tracing. Ultrasonography evaluation demonstrates a normal amniotic fluid index and normal fetal growth. The patient is reassured, returns home, and goes on to deliver a healthy baby at 39 weeks and 5 days.

Perception of decreased movement triggers evaluation and monitoring

Maternal perception of normal fetal movement has conceivably been used throughout history as a means of reassurance of fetal well-being; it is highly predictive of fetal viability.^2,3 When fetal movement is lacking or decreased, it can be an alarm sign and may result in concerns by the mother that her baby is unwell. Maternal perception of decreased fetal movements affects 5% to 15% of all pregnancies.^2,4 While decreased fetal movement can be associated with poor perinatal outcomes such as fetal growth restriction, oligohydramnios, and neuro-developmental disability, it also can be reflective of more benign issues such as anterior placenta, maternal activity, maternal caffeine or sugar consumption, or maternal position.^4,5

However, the definition of decreased fetal movement is subject to significant variation, from a total absence of movement over an entire day or what has commonly become accepted as the definition of fetal kick counts with Pearson’s Cardiff chart (which was defined in the 1970s as 10 movements within 12 hours).^6,7 Today, women in the United States are commonly recommended to monitor their baby over a 2-hour period and to look for 10 movements during that time.⁸ Anything less is considered reduced fetal movement and results in recommendations to undergo assessment of previously known high-risk conditions or any possible underlying conditions, such as hypertension, gestational diabetes, or fetal growth restriction. Further evaluation with more objective measures such as electronic fetal monitoring or ultrasonography with biophysical profile are often recommended concurrently.⁹

It is estimated that up to 15% of women present reporting decreased fetal movement in the third trimester and, as such, require additional monitoring and evaluation. This is not without cost of time and money to the health care system and pregnant patients.

It is uncertain that fetal kick counting prevents stillbirth

Intrauterine fetal demise is neither an uncommon nor completely preventable outcome, despite advances in antenatal care. Many cases occur without evidence of fetal abnormality or other risk factors, and 30% to 55% of women who experience intrauterine fetal demise experience decreased fetal movement in the preceding week.¹⁰ It makes physiologic sense that a fetus’ adaptive response to decreased oxygenation is reduced fetal movement, resulting from the prioritization of blood to the fetal brain and other organs over skeletal muscle.^4,9,11 Results of a 1976 small study of 61 low-risk pregnancies seemed to confirm that a decrease in fetal movement preceded intrauterine death by 3 to 4 days. Conversely, they found that a normal fetal movement count was generally associated with a good neonatal outcome.⁶ Thus, experts have long extrapolated that decreased fetal movement can be an indicator for utero-placental insufficiency and, in turn, chronic or acute hypoxia.

However, in larger studies, the ability of fetal movement counting to predict fetal death and fetal compromise appears limited.^8,10,11 A meta-analysis of studies, including 5 randomized controlled trials and 468,000 fetuses, compared the incidence of stillbirth in women receiving instructions for fetal movement counting versus women who did not. Rates of stillbirth were the same for each group, demonstrating no advantage to fetal kick counts to prevent a poor perinatal outcome, including stillbirth.¹

CASE 2 Reported reduced fetal movement over 4 weeks

Ms. E is a 20-year-old nullipara at 36 weeks’ and 6 days gestation who has come in to triage weekly for the last 4 weeks with concerns about decreased fetal movement. She states that she goes for several hours each day without feeling 10 movements in 2 hours. Recent fetal growth recorded 3 weeks ago was in the 45th percentile, and the amniotic fluid index has been above 10 cm on each weekly ultrasound. Her weekly NSTs have been reactive, and she has been normotensive. However, because she has had several weeks of persistent decreased fetal movement, the labor and delivery team opts to keep her for induction as she is “close to term.”

Decreased kick count frequency may increase unnecessary interventions

Women with fewer kick counts are more likely to present with concerns about the well-being of their baby. In a survey of obstetricians and midwives, a large proportion of providers were more apt to recommend delivery or admission to the hospital for women presenting with decreased fetal movements.² It stands to reason that recommendations for delivery or admission can lead to outcomes like preterm delivery or recommendations for cesarean delivery (CD). However, using fetal kick counts to portend stillbirth or other poor fetal and neonatal outcomes has been shown to be limited in its value with the AFFIRM trial.¹⁰ The results of this large study, which included more than 400,000 pregnancies from 37 hospitals, show the challenges of any study to address the use of management strategies for recent change in the frequency of fetal movements in the reduction of and cause of stillbirth. Additionally, the relatively low risk of stillbirth overall (4.06 stillbirths per 1,000 livebirths during the intervention period and 4.40 per 1,000 livebirths during the control period) but higher incidence of other outcomes, such as prolonged (>48 hours) antepartum admission (6.7% in the intervention period and 6.2% in the control period), induction of labor (40.7% in the intervention period and 35.9% in the control period), and CD (28.4% and 25.5%, respectively) may result in increased harm for many women rather than the intended benefit of preventing stillbirth.^10,12

Mindfetalness may be a viable and valuable alternative to kick counts

Alternatives have been proposed as a measure of fetal movement without using kick counts specifically. Mindfetalness has been a method studied in Sweden; its purpose is to strengthen the mother’s awareness of her baby through developing an understanding of the fetal-movement pattern. It is practiced starting at 28 weeks’ gestation for 15 minutes a day, with the woman instructed to lie on her left side and discern the intensity and character of the movements, as well as frequency, without overtly counting the movements.¹² In one small study, women felt more connected to their babies and felt less worried.¹² In a much larger study of 13,000 women, the authors found no evidence of harm from generalized awareness of fetal movements in a population of pregnant women at or beyond 32 weeks; in fact, they did see significant reductions in iatrogenic outcomes such as CDs and labor inductions.¹³

The case for movement awareness over kick counts

Stillbirth risk does not appear to be modified by the use of methods to detect fetal movement.^10,12 However, a perceived decrease in fetal kick counts has been shown to result in increased interventions and preterm deliveries. A more prudent approach appears to be educating mothers about general fetal movement, which appears to reduce potentially unnecessary visits and interventions without sacrificing the ability to reassure mothers about the well-being of their babies in utero. ●

CASE Healthy woman with hot flashes inquires about HT

A 54-year-old healthy woman with a history of hypothyroidism taking thyroid replacement medication comes in for her annual visit. Her last menstrual period was over 2 years ago and she reports severe hot flashes. They have greatly affected her quality of life and she must take frequent breaks at work. She wakes up frequently at night due to night sweats, which is impacting her sleep and, subsequently, her energy level. She has noted increased vaginal dryness so has been abstaining from sexual intercourse due to the discomfort. She has an intact uterus. Her family history is significant for heart disease, diagnosed in her mother at age 75.

On physical examination, she is normotensive and well-appearing. Her body mass index (BMI) is 21 kg/m². Labs obtained prior to her visit show normal renal and liver function. Her high-density lipid (HDL) level is 55 mg/dL, her low-density lipid (LDL) level is 80 mg/dL, and her triglyceride level is 100 mg/dL; HbA_1c is 5.5 mmol/mol.
 

She is interested in learning more about menopausal hormone therapy (HT) and whether or not she would be a candidate.

What information do you need to know to counsel and manage this patient?

Menopausal HT prescribing practices have changed over the last few decades as a better understanding of the risks and benefits of treatment have emerged. Prior to 2002, HT was commonly used for treatment of symptoms associated with menopause and was thought to have beneficial effects for chronic disease prevention.^1-4 After data from the Women’s Health Initiative (WHI) was released, concerns arose around the effect of HT on cardiovascular health and risk of breast cancer. As a result, HT prescriptions fell precipitously after around 2002.⁵ Since then, postintervention analysis and cumulative 18-year follow-up of WHI data, along with results from subsequent randomized controlled trials, including the Kronos Early Estrogen Prevention Study (KEEPS) and the Early Versus Late Intervention Trial with Estradiol (ELITE), have demonstrated a favorable safety profile for healthy women starting HT early in menopause (less than age 60, or within 10 years from their final menstrual period).^5-11

There are many types, formulations, and routes of HT, and the effects and risks differ for each (TABLE). For example, oral estrogen therapy, such as conjugated equine estrogens, portend a higher risk of adverse effects compared with transdermal formulations. Topical and transdermal estrogens bypass first-pass hepatic metabolism and thus are associated with a lower risk of venous thromboembolism (VTE) compared with oral formulations.^12-14 A progestogen such as micronized progesterone is used in postmenopausal women with a uterus to protect the endometrium from unopposed estrogen therapy (ET). While it comes in oral and transdermal forms, the oral formulation is most widely used and studied in the United States; transdermal forms do not provide adequate endometrial protection and should not be used in combination therapy.^15,16

Risks and benefits

Cardiovascular risk

Over time, the benefits and risks of HT use in menopausal patients have been further elucidated and defined, although they remain complex and dependent on patient clinical characteristics. HT remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause.^17,18 In 2002, concerns for increased cardiovascular disease (CVD) and breast cancer risk resulted in early cessation of the WHI trial. Since that time the risk of CVD in postmenopausal women taking HT has been found to be more nuanced. In fact, updates in the literature have shown that HT results in a reduction of coronary heart disease if started in healthy women younger than age 60 years within 10 years of menopause.^7,9-11 With this updated information, the North American Menopause society (NAMS), American College of Obstetricians and Gynecologists and the Endocrine Society have published guidelines supporting the initiation of HT for symptomatic healthy women: under the age of 60, within 10 years of menopause, and without contraindications. After age 60 years and further from menopause, the benefits and risks become less known.^18-20

Risk stratification allows for more comprehensive counseling in use of HT for treatment of bothersome VMS. From a cardiovascular health standpoint, calculating an atherosclerotic CVD (ASCVD) risk score helps to evaluate appropriateness of HT prescribing:

• For those with low 10-year CVD risk (<5%), either oral or transdermal HT is appropriate.
• For those with moderate 10-year CVD risk (5%-10%), transdermal HT is recommended over oral HT.
• For those with high 10-year CVD risk (>10%), HT is not recommended.^19,21

Breast cancer risk

Follow up since the initial WHI publication have shown that breast cancer risk is largely dependent on the formulation and route of HT used. Oral estrogen combined with a progestogen has been shown to increase the risk of invasive breast cancer, though very rarely.²² To put it into context, the absolute risk of breast cancer based on follow-up studies from WHI showed less than 1 additional case per 1,000 person years of use; less risk than associated with drinking 2 glasses of wine per day and similar to that of obesity and/or sedentary lifestyle.^23,24 Studies have shown estrogen treatment alone for postmenopausal women does not appear to increase the risk of breast cancer. In fact, follow-up data from WHI showed a nonsignificant reduction in breast cancer risk for those taking ET alone.²⁵

Breast cancer risk stratification is helpful when determining appropriateness of HT in postmenopausal women. Generally, if using risk stratification models for breast cancer (ie, Gail Risk model or international breast cancer intervention study [IBIS] tool), a patient who is average to moderate risk, HT can be offered with appropriate counseling. By contrast, a patient who is high risk should have a more detailed discussion about their risk (surveillance and risk-reducing treatments), and they may consider nonhormonal options for treatment of VMS. Women with a history of breast cancer should not be prescribed systemic HT.

Continue to: Additional HT benefits...

Additional HT benefits

The benefits of HT in postmenopausal women include improved bone health and reduction of fractures; reduction of risk for type 2 diabetes mellitus (T2DM); improvement of insulin sensitivity; improvement of lipid profiles with increased HDL and decreased LDL levels; and reduction of colon cancer risk.²⁵ For women aged younger than 60 years who start HT within 10 years of their last menstrual period, HT has been shown to cause a reduction in all-cause mortality. Important risks to counsel patients on when starting HT include the low risk of stroke and venous thromboembolism (VTE) when using oral formulations.²⁶

CASE Resolved

Her ASCVD risk score, based on her history, estimates her 10-year CVD risk to be low (<5%). Thus, from a cardiovascular standpoint, either oral or transdermal HT would be an appropriate option. Her IBIS 10-year score is 1.5%, placing her in a low-risk category for breast cancer based on her personal and family history. Given that she is less than 60 years of age and within 10 years of menopause, along with her low-risk stratification for CVD and breast cancer, she would be an appropriate patient to begin combined HT with an estrogen plus an oral progesterone, such as an estradiol patch 0.0375 mg twice weekly, along with oral micronized progesterone 100 mg nightly. The dose could be increased over time based on symptoms and tolerability of the treatment.

ALTERNATE CASE 1 The patient has additional risk factors

Consider the patient case with the following additions to her history: the patient has a BMI of 34 kg/m², a history of well-controlled hypertension while taking amlodipine 5 mg, and an ASCVD risk score of 7.5%. She reports severe VMS that are greatly impacting her quality of life. How would your recommendations or counseling change?

Focus on healthy lifestyle

Obesity and hypertension, both common chronic conditions, pose additional risks to be accounted for when counseling on and approaching HT prescribing. Her alternate ASCVD risk score places her at moderate risk for CVD within 10 years, based on guidelines as discussed above. It would still be appropriate to offer her combined HT after a shared decision-making discussion that includes a focus on healthy lifestyle habits.

Consider transdermal HT in obese women

Longitudinal studies have found that weight gain is more a consequence of aging, regardless of menopausal status. Fat distribution and body composition changes are a menopause-related phenomenon driven by estrogen deficiency. HT has been shown to preserve lean body mass and reduce visceral adiposity, resulting in favorable effects of body composition. Still, obesity results in increased risk of CVD, VTE, and certain hormone-sensitive cancers.²⁷ When considering HT in obese patients, a transdermal estrogen route is preferred to reduce risks.

For women with hypertension, prescribe transdermal HT

Overall, studies have found that HT has a neutral effect on blood pressure.²⁵ When considering formulation of HT, micronized progesterone, dydrogesterone, and drospirenone seem to be most neutral and possibly even beneficial on blood pressure compared with synthetic progestins.²⁶ Oral estrogen is associated with increased vasoconstriction and/or increased sodium retention with resultant worsened regulation of blood pressure in women with hypertension, so transdermal estrogen is preferred for women with hypertension.²⁶ Hypertension is a component of the ASCVD risk score; factoring this into a patient’s clinical picture is important when discussing appropriateness of HT prescribing. To minimize risks, the transdermal route of estrogen is preferred for those with hypertension.

Continue to: ALTERNATE CASE 1 Resolved...

ALTERNATE CASE 1 Resolved

She has a moderate ASCVD risk score, is obese, and has a history of hypertension. Through shared decision making, you ultimately start her on transdermal estrogen and micronized progesterone to treat her quality-of-life-impacting VMS, a formulation that is most likely to mitigate the possible risks in her clinical case. You see her back in the clinic every 3-6 months to monitor her blood pressure.

ALTERNATE CASE 2 The patient has a high risk for breast cancer

The patient reveals further her significant family history of breast cancer in her maternal grandmother and mother, both diagnosed in their 50s. You calculate her risk of breast cancer with a model that incorporates family history. Her Tyrer Cuzick-IBIS 10-year risk score is >5% and lifetime risk is >20%, putting her at high risk for breast cancer. Since she has a uterus and would need concomitant progesterone therapy, her risk for breast cancer is higher than if she was taking ET alone. Ultimately, together you and the patient decide to trial nonhormonal options for her VMS.

What are nonhormonal options for treatment of VMS?

While HT remains the most effective treatment for VMS, there are multiple nonhormonal treatments for women who are either at too high a risk for HT or who favor other options, which are outlined in the NAMS 2015 nonhormonal management position statement.²⁷ Cognitive behavioral therapy (CBT) has been shown to decrease bother related to VMS but not frequency. Clinical hypnosis has been shown to reduce hot flash frequency and improve sleep. Paroxetine salt (7.5 mg/day) remains the only FDA nonhormonal-approved medication for treatment of moderate to severe vasomotor symptoms. Off label use of other selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors have been shown in studies to reduce VMS including paroxetine at slightly higher doses (10 mg/day–20 mg/day), citalopram (10 mg/day–20 mg/day), escitalopram (10 mg/day–20 mg/day), venlafaxine (37.5 mg/day–150 mg/day), and desvenlafaxine (50 mg/day–100 mg/day). Other treatments that could be considered include off-label use of gabapentin (900 mg/day–2,400 mg/day), oxybutynin (2.5–5 mg twice daily) or clonidine (0.1 mg/day–1 mg/day divided in doses) since they all have data demonstrating they are beneficial at reducing VMS.

Nonhormonal options that may be helpful but are recommended with caution due to lack of data include weight loss, mindfulness-based stress reduction, s-equol derivatives of soy isoflavones and a stellate ganglion block. Further evidence and studies are needed for the aforementioned options.²⁷

ALTERNATE CASE 2 Resolved

She may consider any of the nonhormonal options discussed. If she meets with a medical breast specialist to discuss her elevated risk of breast cancer and considers starting risk-reducing medications, particularly tamoxifen, you will want to avoid medications that have significant CPY 2D6 inhibition, such as paroxetine and fluoxetine. Safer choices would include venlafaxine, escitalopram, or citalopram.

The bottom line

In summary, the benefits and risks of HT in the treatment of VMS remain nuanced. For healthy women younger than 60 years of age and within 10 years from their last menstrual period, the benefits of HT largely outweigh the risks. Shared decision making, along with individualized and appropriate risk stratification specific for women, can guide appropriateness of HT prescribing. For those women who cannot take HT or choose not to, there are many nonhormonal options that will help manage their bothersome VMS. ●

CASE Healthy woman with hot flashes inquires about HT

A 54-year-old healthy woman with a history of hypothyroidism taking thyroid replacement medication comes in for her annual visit. Her last menstrual period was over 2 years ago and she reports severe hot flashes. They have greatly affected her quality of life and she must take frequent breaks at work. She wakes up frequently at night due to night sweats, which is impacting her sleep and, subsequently, her energy level. She has noted increased vaginal dryness so has been abstaining from sexual intercourse due to the discomfort. She has an intact uterus. Her family history is significant for heart disease, diagnosed in her mother at age 75.

On physical examination, she is normotensive and well-appearing. Her body mass index (BMI) is 21 kg/m². Labs obtained prior to her visit show normal renal and liver function. Her high-density lipid (HDL) level is 55 mg/dL, her low-density lipid (LDL) level is 80 mg/dL, and her triglyceride level is 100 mg/dL; HbA_1c is 5.5 mmol/mol.
 

She is interested in learning more about menopausal hormone therapy (HT) and whether or not she would be a candidate.

What information do you need to know to counsel and manage this patient?

Menopausal HT prescribing practices have changed over the last few decades as a better understanding of the risks and benefits of treatment have emerged. Prior to 2002, HT was commonly used for treatment of symptoms associated with menopause and was thought to have beneficial effects for chronic disease prevention.^1-4 After data from the Women’s Health Initiative (WHI) was released, concerns arose around the effect of HT on cardiovascular health and risk of breast cancer. As a result, HT prescriptions fell precipitously after around 2002.⁵ Since then, postintervention analysis and cumulative 18-year follow-up of WHI data, along with results from subsequent randomized controlled trials, including the Kronos Early Estrogen Prevention Study (KEEPS) and the Early Versus Late Intervention Trial with Estradiol (ELITE), have demonstrated a favorable safety profile for healthy women starting HT early in menopause (less than age 60, or within 10 years from their final menstrual period).^5-11

There are many types, formulations, and routes of HT, and the effects and risks differ for each (TABLE). For example, oral estrogen therapy, such as conjugated equine estrogens, portend a higher risk of adverse effects compared with transdermal formulations. Topical and transdermal estrogens bypass first-pass hepatic metabolism and thus are associated with a lower risk of venous thromboembolism (VTE) compared with oral formulations.^12-14 A progestogen such as micronized progesterone is used in postmenopausal women with a uterus to protect the endometrium from unopposed estrogen therapy (ET). While it comes in oral and transdermal forms, the oral formulation is most widely used and studied in the United States; transdermal forms do not provide adequate endometrial protection and should not be used in combination therapy.^15,16

Risks and benefits

Cardiovascular risk

Over time, the benefits and risks of HT use in menopausal patients have been further elucidated and defined, although they remain complex and dependent on patient clinical characteristics. HT remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause.^17,18 In 2002, concerns for increased cardiovascular disease (CVD) and breast cancer risk resulted in early cessation of the WHI trial. Since that time the risk of CVD in postmenopausal women taking HT has been found to be more nuanced. In fact, updates in the literature have shown that HT results in a reduction of coronary heart disease if started in healthy women younger than age 60 years within 10 years of menopause.^7,9-11 With this updated information, the North American Menopause society (NAMS), American College of Obstetricians and Gynecologists and the Endocrine Society have published guidelines supporting the initiation of HT for symptomatic healthy women: under the age of 60, within 10 years of menopause, and without contraindications. After age 60 years and further from menopause, the benefits and risks become less known.^18-20

Risk stratification allows for more comprehensive counseling in use of HT for treatment of bothersome VMS. From a cardiovascular health standpoint, calculating an atherosclerotic CVD (ASCVD) risk score helps to evaluate appropriateness of HT prescribing:

• For those with low 10-year CVD risk (<5%), either oral or transdermal HT is appropriate.
• For those with moderate 10-year CVD risk (5%-10%), transdermal HT is recommended over oral HT.
• For those with high 10-year CVD risk (>10%), HT is not recommended.^19,21

Breast cancer risk

Follow up since the initial WHI publication have shown that breast cancer risk is largely dependent on the formulation and route of HT used. Oral estrogen combined with a progestogen has been shown to increase the risk of invasive breast cancer, though very rarely.²² To put it into context, the absolute risk of breast cancer based on follow-up studies from WHI showed less than 1 additional case per 1,000 person years of use; less risk than associated with drinking 2 glasses of wine per day and similar to that of obesity and/or sedentary lifestyle.^23,24 Studies have shown estrogen treatment alone for postmenopausal women does not appear to increase the risk of breast cancer. In fact, follow-up data from WHI showed a nonsignificant reduction in breast cancer risk for those taking ET alone.²⁵

Breast cancer risk stratification is helpful when determining appropriateness of HT in postmenopausal women. Generally, if using risk stratification models for breast cancer (ie, Gail Risk model or international breast cancer intervention study [IBIS] tool), a patient who is average to moderate risk, HT can be offered with appropriate counseling. By contrast, a patient who is high risk should have a more detailed discussion about their risk (surveillance and risk-reducing treatments), and they may consider nonhormonal options for treatment of VMS. Women with a history of breast cancer should not be prescribed systemic HT.

Continue to: Additional HT benefits...

Additional HT benefits

The benefits of HT in postmenopausal women include improved bone health and reduction of fractures; reduction of risk for type 2 diabetes mellitus (T2DM); improvement of insulin sensitivity; improvement of lipid profiles with increased HDL and decreased LDL levels; and reduction of colon cancer risk.²⁵ For women aged younger than 60 years who start HT within 10 years of their last menstrual period, HT has been shown to cause a reduction in all-cause mortality. Important risks to counsel patients on when starting HT include the low risk of stroke and venous thromboembolism (VTE) when using oral formulations.²⁶

CASE Resolved

Her ASCVD risk score, based on her history, estimates her 10-year CVD risk to be low (<5%). Thus, from a cardiovascular standpoint, either oral or transdermal HT would be an appropriate option. Her IBIS 10-year score is 1.5%, placing her in a low-risk category for breast cancer based on her personal and family history. Given that she is less than 60 years of age and within 10 years of menopause, along with her low-risk stratification for CVD and breast cancer, she would be an appropriate patient to begin combined HT with an estrogen plus an oral progesterone, such as an estradiol patch 0.0375 mg twice weekly, along with oral micronized progesterone 100 mg nightly. The dose could be increased over time based on symptoms and tolerability of the treatment.

ALTERNATE CASE 1 The patient has additional risk factors

Consider the patient case with the following additions to her history: the patient has a BMI of 34 kg/m², a history of well-controlled hypertension while taking amlodipine 5 mg, and an ASCVD risk score of 7.5%. She reports severe VMS that are greatly impacting her quality of life. How would your recommendations or counseling change?

Focus on healthy lifestyle

Obesity and hypertension, both common chronic conditions, pose additional risks to be accounted for when counseling on and approaching HT prescribing. Her alternate ASCVD risk score places her at moderate risk for CVD within 10 years, based on guidelines as discussed above. It would still be appropriate to offer her combined HT after a shared decision-making discussion that includes a focus on healthy lifestyle habits.

Consider transdermal HT in obese women

Longitudinal studies have found that weight gain is more a consequence of aging, regardless of menopausal status. Fat distribution and body composition changes are a menopause-related phenomenon driven by estrogen deficiency. HT has been shown to preserve lean body mass and reduce visceral adiposity, resulting in favorable effects of body composition. Still, obesity results in increased risk of CVD, VTE, and certain hormone-sensitive cancers.²⁷ When considering HT in obese patients, a transdermal estrogen route is preferred to reduce risks.

For women with hypertension, prescribe transdermal HT

Overall, studies have found that HT has a neutral effect on blood pressure.²⁵ When considering formulation of HT, micronized progesterone, dydrogesterone, and drospirenone seem to be most neutral and possibly even beneficial on blood pressure compared with synthetic progestins.²⁶ Oral estrogen is associated with increased vasoconstriction and/or increased sodium retention with resultant worsened regulation of blood pressure in women with hypertension, so transdermal estrogen is preferred for women with hypertension.²⁶ Hypertension is a component of the ASCVD risk score; factoring this into a patient’s clinical picture is important when discussing appropriateness of HT prescribing. To minimize risks, the transdermal route of estrogen is preferred for those with hypertension.

Continue to: ALTERNATE CASE 1 Resolved...

ALTERNATE CASE 1 Resolved

She has a moderate ASCVD risk score, is obese, and has a history of hypertension. Through shared decision making, you ultimately start her on transdermal estrogen and micronized progesterone to treat her quality-of-life-impacting VMS, a formulation that is most likely to mitigate the possible risks in her clinical case. You see her back in the clinic every 3-6 months to monitor her blood pressure.

ALTERNATE CASE 2 The patient has a high risk for breast cancer

The patient reveals further her significant family history of breast cancer in her maternal grandmother and mother, both diagnosed in their 50s. You calculate her risk of breast cancer with a model that incorporates family history. Her Tyrer Cuzick-IBIS 10-year risk score is >5% and lifetime risk is >20%, putting her at high risk for breast cancer. Since she has a uterus and would need concomitant progesterone therapy, her risk for breast cancer is higher than if she was taking ET alone. Ultimately, together you and the patient decide to trial nonhormonal options for her VMS.

What are nonhormonal options for treatment of VMS?

While HT remains the most effective treatment for VMS, there are multiple nonhormonal treatments for women who are either at too high a risk for HT or who favor other options, which are outlined in the NAMS 2015 nonhormonal management position statement.²⁷ Cognitive behavioral therapy (CBT) has been shown to decrease bother related to VMS but not frequency. Clinical hypnosis has been shown to reduce hot flash frequency and improve sleep. Paroxetine salt (7.5 mg/day) remains the only FDA nonhormonal-approved medication for treatment of moderate to severe vasomotor symptoms. Off label use of other selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors have been shown in studies to reduce VMS including paroxetine at slightly higher doses (10 mg/day–20 mg/day), citalopram (10 mg/day–20 mg/day), escitalopram (10 mg/day–20 mg/day), venlafaxine (37.5 mg/day–150 mg/day), and desvenlafaxine (50 mg/day–100 mg/day). Other treatments that could be considered include off-label use of gabapentin (900 mg/day–2,400 mg/day), oxybutynin (2.5–5 mg twice daily) or clonidine (0.1 mg/day–1 mg/day divided in doses) since they all have data demonstrating they are beneficial at reducing VMS.

Nonhormonal options that may be helpful but are recommended with caution due to lack of data include weight loss, mindfulness-based stress reduction, s-equol derivatives of soy isoflavones and a stellate ganglion block. Further evidence and studies are needed for the aforementioned options.²⁷

ALTERNATE CASE 2 Resolved

She may consider any of the nonhormonal options discussed. If she meets with a medical breast specialist to discuss her elevated risk of breast cancer and considers starting risk-reducing medications, particularly tamoxifen, you will want to avoid medications that have significant CPY 2D6 inhibition, such as paroxetine and fluoxetine. Safer choices would include venlafaxine, escitalopram, or citalopram.

The bottom line

In summary, the benefits and risks of HT in the treatment of VMS remain nuanced. For healthy women younger than 60 years of age and within 10 years from their last menstrual period, the benefits of HT largely outweigh the risks. Shared decision making, along with individualized and appropriate risk stratification specific for women, can guide appropriateness of HT prescribing. For those women who cannot take HT or choose not to, there are many nonhormonal options that will help manage their bothersome VMS. ●

CASE Healthy woman with hot flashes inquires about HT

A 54-year-old healthy woman with a history of hypothyroidism taking thyroid replacement medication comes in for her annual visit. Her last menstrual period was over 2 years ago and she reports severe hot flashes. They have greatly affected her quality of life and she must take frequent breaks at work. She wakes up frequently at night due to night sweats, which is impacting her sleep and, subsequently, her energy level. She has noted increased vaginal dryness so has been abstaining from sexual intercourse due to the discomfort. She has an intact uterus. Her family history is significant for heart disease, diagnosed in her mother at age 75.

On physical examination, she is normotensive and well-appearing. Her body mass index (BMI) is 21 kg/m². Labs obtained prior to her visit show normal renal and liver function. Her high-density lipid (HDL) level is 55 mg/dL, her low-density lipid (LDL) level is 80 mg/dL, and her triglyceride level is 100 mg/dL; HbA_1c is 5.5 mmol/mol.
 

She is interested in learning more about menopausal hormone therapy (HT) and whether or not she would be a candidate.

What information do you need to know to counsel and manage this patient?

Menopausal HT prescribing practices have changed over the last few decades as a better understanding of the risks and benefits of treatment have emerged. Prior to 2002, HT was commonly used for treatment of symptoms associated with menopause and was thought to have beneficial effects for chronic disease prevention.^1-4 After data from the Women’s Health Initiative (WHI) was released, concerns arose around the effect of HT on cardiovascular health and risk of breast cancer. As a result, HT prescriptions fell precipitously after around 2002.⁵ Since then, postintervention analysis and cumulative 18-year follow-up of WHI data, along with results from subsequent randomized controlled trials, including the Kronos Early Estrogen Prevention Study (KEEPS) and the Early Versus Late Intervention Trial with Estradiol (ELITE), have demonstrated a favorable safety profile for healthy women starting HT early in menopause (less than age 60, or within 10 years from their final menstrual period).^5-11

There are many types, formulations, and routes of HT, and the effects and risks differ for each (TABLE). For example, oral estrogen therapy, such as conjugated equine estrogens, portend a higher risk of adverse effects compared with transdermal formulations. Topical and transdermal estrogens bypass first-pass hepatic metabolism and thus are associated with a lower risk of venous thromboembolism (VTE) compared with oral formulations.^12-14 A progestogen such as micronized progesterone is used in postmenopausal women with a uterus to protect the endometrium from unopposed estrogen therapy (ET). While it comes in oral and transdermal forms, the oral formulation is most widely used and studied in the United States; transdermal forms do not provide adequate endometrial protection and should not be used in combination therapy.^15,16

Risks and benefits

Cardiovascular risk

Over time, the benefits and risks of HT use in menopausal patients have been further elucidated and defined, although they remain complex and dependent on patient clinical characteristics. HT remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause.^17,18 In 2002, concerns for increased cardiovascular disease (CVD) and breast cancer risk resulted in early cessation of the WHI trial. Since that time the risk of CVD in postmenopausal women taking HT has been found to be more nuanced. In fact, updates in the literature have shown that HT results in a reduction of coronary heart disease if started in healthy women younger than age 60 years within 10 years of menopause.^7,9-11 With this updated information, the North American Menopause society (NAMS), American College of Obstetricians and Gynecologists and the Endocrine Society have published guidelines supporting the initiation of HT for symptomatic healthy women: under the age of 60, within 10 years of menopause, and without contraindications. After age 60 years and further from menopause, the benefits and risks become less known.^18-20

Risk stratification allows for more comprehensive counseling in use of HT for treatment of bothersome VMS. From a cardiovascular health standpoint, calculating an atherosclerotic CVD (ASCVD) risk score helps to evaluate appropriateness of HT prescribing:

• For those with low 10-year CVD risk (<5%), either oral or transdermal HT is appropriate.
• For those with moderate 10-year CVD risk (5%-10%), transdermal HT is recommended over oral HT.
• For those with high 10-year CVD risk (>10%), HT is not recommended.^19,21

Breast cancer risk

Follow up since the initial WHI publication have shown that breast cancer risk is largely dependent on the formulation and route of HT used. Oral estrogen combined with a progestogen has been shown to increase the risk of invasive breast cancer, though very rarely.²² To put it into context, the absolute risk of breast cancer based on follow-up studies from WHI showed less than 1 additional case per 1,000 person years of use; less risk than associated with drinking 2 glasses of wine per day and similar to that of obesity and/or sedentary lifestyle.^23,24 Studies have shown estrogen treatment alone for postmenopausal women does not appear to increase the risk of breast cancer. In fact, follow-up data from WHI showed a nonsignificant reduction in breast cancer risk for those taking ET alone.²⁵

Breast cancer risk stratification is helpful when determining appropriateness of HT in postmenopausal women. Generally, if using risk stratification models for breast cancer (ie, Gail Risk model or international breast cancer intervention study [IBIS] tool), a patient who is average to moderate risk, HT can be offered with appropriate counseling. By contrast, a patient who is high risk should have a more detailed discussion about their risk (surveillance and risk-reducing treatments), and they may consider nonhormonal options for treatment of VMS. Women with a history of breast cancer should not be prescribed systemic HT.

Continue to: Additional HT benefits...

Additional HT benefits

The benefits of HT in postmenopausal women include improved bone health and reduction of fractures; reduction of risk for type 2 diabetes mellitus (T2DM); improvement of insulin sensitivity; improvement of lipid profiles with increased HDL and decreased LDL levels; and reduction of colon cancer risk.²⁵ For women aged younger than 60 years who start HT within 10 years of their last menstrual period, HT has been shown to cause a reduction in all-cause mortality. Important risks to counsel patients on when starting HT include the low risk of stroke and venous thromboembolism (VTE) when using oral formulations.²⁶

CASE Resolved

Her ASCVD risk score, based on her history, estimates her 10-year CVD risk to be low (<5%). Thus, from a cardiovascular standpoint, either oral or transdermal HT would be an appropriate option. Her IBIS 10-year score is 1.5%, placing her in a low-risk category for breast cancer based on her personal and family history. Given that she is less than 60 years of age and within 10 years of menopause, along with her low-risk stratification for CVD and breast cancer, she would be an appropriate patient to begin combined HT with an estrogen plus an oral progesterone, such as an estradiol patch 0.0375 mg twice weekly, along with oral micronized progesterone 100 mg nightly. The dose could be increased over time based on symptoms and tolerability of the treatment.

ALTERNATE CASE 1 The patient has additional risk factors

Consider the patient case with the following additions to her history: the patient has a BMI of 34 kg/m², a history of well-controlled hypertension while taking amlodipine 5 mg, and an ASCVD risk score of 7.5%. She reports severe VMS that are greatly impacting her quality of life. How would your recommendations or counseling change?

Focus on healthy lifestyle

Obesity and hypertension, both common chronic conditions, pose additional risks to be accounted for when counseling on and approaching HT prescribing. Her alternate ASCVD risk score places her at moderate risk for CVD within 10 years, based on guidelines as discussed above. It would still be appropriate to offer her combined HT after a shared decision-making discussion that includes a focus on healthy lifestyle habits.

Consider transdermal HT in obese women

Longitudinal studies have found that weight gain is more a consequence of aging, regardless of menopausal status. Fat distribution and body composition changes are a menopause-related phenomenon driven by estrogen deficiency. HT has been shown to preserve lean body mass and reduce visceral adiposity, resulting in favorable effects of body composition. Still, obesity results in increased risk of CVD, VTE, and certain hormone-sensitive cancers.²⁷ When considering HT in obese patients, a transdermal estrogen route is preferred to reduce risks.

For women with hypertension, prescribe transdermal HT

Overall, studies have found that HT has a neutral effect on blood pressure.²⁵ When considering formulation of HT, micronized progesterone, dydrogesterone, and drospirenone seem to be most neutral and possibly even beneficial on blood pressure compared with synthetic progestins.²⁶ Oral estrogen is associated with increased vasoconstriction and/or increased sodium retention with resultant worsened regulation of blood pressure in women with hypertension, so transdermal estrogen is preferred for women with hypertension.²⁶ Hypertension is a component of the ASCVD risk score; factoring this into a patient’s clinical picture is important when discussing appropriateness of HT prescribing. To minimize risks, the transdermal route of estrogen is preferred for those with hypertension.

Continue to: ALTERNATE CASE 1 Resolved...

ALTERNATE CASE 1 Resolved

She has a moderate ASCVD risk score, is obese, and has a history of hypertension. Through shared decision making, you ultimately start her on transdermal estrogen and micronized progesterone to treat her quality-of-life-impacting VMS, a formulation that is most likely to mitigate the possible risks in her clinical case. You see her back in the clinic every 3-6 months to monitor her blood pressure.

ALTERNATE CASE 2 The patient has a high risk for breast cancer

The patient reveals further her significant family history of breast cancer in her maternal grandmother and mother, both diagnosed in their 50s. You calculate her risk of breast cancer with a model that incorporates family history. Her Tyrer Cuzick-IBIS 10-year risk score is >5% and lifetime risk is >20%, putting her at high risk for breast cancer. Since she has a uterus and would need concomitant progesterone therapy, her risk for breast cancer is higher than if she was taking ET alone. Ultimately, together you and the patient decide to trial nonhormonal options for her VMS.

What are nonhormonal options for treatment of VMS?

While HT remains the most effective treatment for VMS, there are multiple nonhormonal treatments for women who are either at too high a risk for HT or who favor other options, which are outlined in the NAMS 2015 nonhormonal management position statement.²⁷ Cognitive behavioral therapy (CBT) has been shown to decrease bother related to VMS but not frequency. Clinical hypnosis has been shown to reduce hot flash frequency and improve sleep. Paroxetine salt (7.5 mg/day) remains the only FDA nonhormonal-approved medication for treatment of moderate to severe vasomotor symptoms. Off label use of other selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors have been shown in studies to reduce VMS including paroxetine at slightly higher doses (10 mg/day–20 mg/day), citalopram (10 mg/day–20 mg/day), escitalopram (10 mg/day–20 mg/day), venlafaxine (37.5 mg/day–150 mg/day), and desvenlafaxine (50 mg/day–100 mg/day). Other treatments that could be considered include off-label use of gabapentin (900 mg/day–2,400 mg/day), oxybutynin (2.5–5 mg twice daily) or clonidine (0.1 mg/day–1 mg/day divided in doses) since they all have data demonstrating they are beneficial at reducing VMS.

Nonhormonal options that may be helpful but are recommended with caution due to lack of data include weight loss, mindfulness-based stress reduction, s-equol derivatives of soy isoflavones and a stellate ganglion block. Further evidence and studies are needed for the aforementioned options.²⁷

ALTERNATE CASE 2 Resolved

She may consider any of the nonhormonal options discussed. If she meets with a medical breast specialist to discuss her elevated risk of breast cancer and considers starting risk-reducing medications, particularly tamoxifen, you will want to avoid medications that have significant CPY 2D6 inhibition, such as paroxetine and fluoxetine. Safer choices would include venlafaxine, escitalopram, or citalopram.

The bottom line

In summary, the benefits and risks of HT in the treatment of VMS remain nuanced. For healthy women younger than 60 years of age and within 10 years from their last menstrual period, the benefits of HT largely outweigh the risks. Shared decision making, along with individualized and appropriate risk stratification specific for women, can guide appropriateness of HT prescribing. For those women who cannot take HT or choose not to, there are many nonhormonal options that will help manage their bothersome VMS. ●

Von Willebrand disease (VWD) represents the most common inherited bleeding disorder, with a prevalence of approximately 1 in 1,000 people. Type 1 disease, associated with a quantitative reduction in von Willebrand factor (VWF), is the most common type of VWD and accounts for approximately 70% of VWD patients enrolled in hemophilia treatment centers; transmission is autosomal dominant. Type 2 disease, associated with a qualitative defect in VWF, accounts for most of the remaining 30% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal dominant. Type 3 disease, associated with a near absence of VWF, accounts for less than 1% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal recessive.

Bruising and mucocutaneous bleeding (epistaxis, gingival bleeding, and bleeding after dental extraction) are the most common presenting symptoms of VWD. Because VWD substantially increases the risk of heavy menstrual bleeding (HMB) and, to some extent, intrapartum bleeding complications, and postpartum hemorrhage, women experience a disproportionate burden from VWD. Thus, ObGyns are likely to be called on to make treatment recommendations in VWD patients with these concerns.¹

In 2017, the American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia determined that among clinical issues related to VWD, updating guidelines for women with VWD represented the highest priority.² Accordingly, an international group of hematologists/coagulation specialists performed systematic literature reviews to address 3 questions faced by women with VWD and their clinicians:

• What are the most effective treatments for HMB?
• What is the safest approach for women desiring neuraxial analgesia for intrapartum pain?
• What is the impact of postpartum administration of tranexamic acid (TxA) on postpartum hemorrhage (PPH)?³

Evidence on management strategies for HMB in women with VWD

The prevalence of HMB in women with VWD ranges from 50% to 92%. Reports suggest that between 5% and 24% of women presenting with this symptom have VWD.³ However, the prevalence of VWD among women seeking care for HMB relates to referral patterns, with the prevalence of VWD substantially higher in patient populations who are referred to clinicians or centers that focus on care of patients with bleeding disorders.

The systematic review authors³ identified 2 comparative studies that assessed the treatment of HMB in women with VWD. One was a crossover trial that enrolled 116 VWD patients with HMB with a mean age of 36 years.⁴ All participants in this trial chose not to use combination oral contraceptives (COCs) as they had not experienced good results with prior COC use. Trial participants were randomly assigned to receive either intranasal desmopressin (DDAVP; a synthetic analog of the antidiuretic agent vasopressin, which stimulates the release of VWF from endothelial cells) or oral TxA therapy for 2 menstrual cycles. Participants then crossed over to the other drug for 2 additional cycles. Although both agents significantly reduced estimated menstrual blood loss, TxA was more effective in decreasing bleeding than intranasal DDAVP.⁴

In a retrospective cohort study, investigators compared COC use with intranasal DDAVP in 36 adolescents who had VWD and HMB.⁵ Participant follow-up ranged from 6 months to 4 years. The estimated efficacy of COCs and intranasal DDAVP was 86% and 77%, respectively, a difference that did not achieve statistical significance. Some of the adolescents who used intranasal DDAVP reported severe headaches and flushing.⁵

In addition, the systematic review authors³ identified 5 case series that described the use of the levonorgestrel (52 mg)-releasing intrauterine device (LNG 52 IUD) in women with VWD and HMB; 4 of these addressed the efficacy of progestin-releasing IUDs in reducing HMB in this patient population.^6-9 Using different approaches to define HMB, the authors of these reports followed between 7 and 26 patients with bleeding disorders (most with confirmed VWD) and HMB for variable amounts of time after placement of an LNG 52 IUD. Many of the women described in these case series had tried other HMB treatments, including COCs, without success. Although these 4 reports assessed different outcomes, all reported that placement of the LNG 52 IUD substantially reduced menstrual blood loss, often resulting in amenorrhea. Several of these reports also noted important improvements in quality of life following LNG 52 IUD placement. One case series reported LNG 52 IUD placement in 13 adolescents with VWD and HMB. The mean time to achieve amenorrhea or occasional spotting was 94 days.⁶

The fifth report, which followed 20 women (median age, 31 years) with HMB associated with VWD or other bleeding disorders who underwent LNG 52 IUD placement, aimed to describe IUD expulsions and malpositioned IUDs in this population. In this small group of patients, 3 IUD expulsions and 2 malpositioned IUDs were observed. Furthermore, an additional 5 women had their device removed prematurely due to patient dissatisfaction. Accordingly, the IUD continuation rate in this case series was only 50%.¹⁰

Evidence on management of pregnancy, delivery, and the postpartum period

Heavy menstrual bleeding is not the only challenge for women with VWD. While pregnancy is accompanied by higher levels of VWF, potentially offsetting the risk of bleeding at the time of delivery, the levels do not achieve the same magnitude as they would in unaffected women.¹¹ Women are at an increased risk of primary PPH^12,13 and, importantly, since VWF levels fall exponentially after delivery when women are still experiencing lochia,¹¹ they are at increased risk of secondary or delayed PPH.

Two questions arise frequently in the care of women with VWD at the time of delivery and during the postpartum period:

• What is the safest approach for women who desire neuraxial analgesia for intrapartum pain?
• What is the impact of postpartum administration of TxA on PPH?

The second systematic review the authors performed³ focused on VWF levels in women receiving neuraxial anesthesia during labor. After screening 27 studies, the authors included 5 case series, which did not describe outcomes based on VWF levels but rather described the outcomes of women with VWF levels of greater than 0.50 IU/mL (> 50% of normal compared with a normal standard).

Meta-analysis showed that the proportion of anesthesia complications was 6%, which sounds high, but the range of complications was what would be expected in any population (hypotension, accidental dural puncture, inadequate anesthesia, and bloody tap with no further complications). No spinal, subdural, or epidural hematomas were noted.³ Such hematomas are an extremely rare complication of neuraxial anesthesia, occurring in only 1 in 200,000 or 1 in 250,000 obstetric patients^14,15; accordingly, an increase in the rate of hematomas among women with VWD could go undetected. The absence of hematomas among women with VWD as reported in the systematic review does not mean there is not an increase in the rate of hematomas in women with VWD. The relative risk is unknown and caution would be advised.

The third systematic review that the authors performed³ was on TxA treatment in the postpartum period. After screening 41 studies, the authors included 2 retrospective cohort studies.^16,17 The majority of the participants had VWD. With very-low-certainty evidence, the authors found that TxA reduces the risk of:

• severe primary PPH (risk ratio [RR], 0.36; 95% confidence interval [CI], 0.05–2.59)
• primary PPH (RR, 0.25; 95% CI, 0.04–1.75)
• secondary PPH (RR, 0.42; 95% CI, 0.02–0.91—does not cross 1.0).

Note that the 95% confidence intervals for severe as well as primary PPH crossed 1.0 and therefore these reductions in risk did not achieve statistical significance. Additionally, there was very-low-certainty evidence on the effect of TxA on blood transfusions, vaginal hematomas, blood loss, and thrombotic complications.³

Continue to: Our recommendations for HMB management...

When first evaluating any woman with HMB, it is important to check a blood count and ferritin level, if not already done. If there is any suggestion of iron deficiency (with or without anemia), we recommend oral iron supplementation. This is best accomplished with slow-release iron supplement formulations (or less expensive generic or house brands that contain less than 65 mg of elemental iron per tablet) taken every other day. Such preparations may cause fewer gastrointestinal adverse effects than other oral iron formulations.¹⁸ Although it may appear counterintuitive, oral iron is better absorbed (and also may cause fewer gastrointestinal adverse effects) when taken every other day.¹⁹

Initial management of HMB, whether or not a bleeding disorder is present, often consists or oral hormonal management. If no contraindications are present, we recommend initiation of a COC with a short hormone-free interval (for example, a 24/4 formulation). If contraindications to contraceptive doses of estrogen are present, continuous use of norethindrone acetate 5-mg tablets or off-label use of combination tablets with 5 µg of ethinyl estradiol and 1 mg of norethindrone acetate (a formulation approved for the treatment of menopausal symptoms) is appropriate.²⁰

Once a patient is established on oral hormonal management, placement of a levonorgestrel-releasing IUD should be considered. Given that expulsion rates may be higher in women with HMB, if feasible, consider using abdominal ultrasound guidance for IUD placement.

For women with VWD who fail first-line therapy (hormonal management) or are trying to become pregnant, TxA (two 650-mg tablets 3 times daily for up to 5 days during episodes of heavy flow) can reduce HMB.^20,21

Our recommendations for management of pregnancy and delivery

The second and third systematic reviews discussed above provide very limited guidance on comprehensive management. The care of the pregnant patient with VWD starts with assessment of VWF levels and making an accurate diagnosis. This usually requires the input of a hematologist or other expert in hemostasis. If no recent VWF levels are available, the ObGyn can obtain a von Willebrand panel that includes VWF antigen, VWF activity (most commonly ristocetin cofactor), and factor VIII.

Levels should be reassessed around 36 weeks’ gestation in anticipation of delivery. VWF levels increase during pregnancy; accordingly, in mild, type 1 VWD, half the time treatment is not necessary.¹¹ If VWF activity is less than 50 IU/dL (less than 50% of normal) at 36 weeks’ gestation, the patient should receive VWF concentrate (dosed in VWF units). This requires consultation with hematology and specialized pharmacy support.

For these reasons, the patient with a VWF level less than 50% should be delivered in a referral center with the necessary resources. Anesthesia should be aware of the patient. Unless they have sustained VWF and factor VIII levels greater than 50 IU/dL, neuraxial anesthesia should not be offered to pregnant women with VWD.

Due to the quantity of fluids administered during labor or at the time of delivery and the coexistent administration of oxytocin, desmopressin (synthetic vasopressin) should not be used without monitoring sodium levels, should not be dosed more than once, or should be avoided altogether due to the risk of water intoxication.

If the patient has sustained VWF and factor VIII levels greater than 50 IU/dL, she would be a candidate to deliver in her local hospital and receive neuraxial anesthesia.

Based on the best data we have for women with VWD, a patient with a VWF greater than 50 IU/dL is no more likely to experience PPH than other women.¹¹ Intravenous TxA can be used for prevention or treatment of immediate postpartum bleeding per protocol (1 g after cord clamp and 1 g 30 minutes or more later).²² Oral TxA can be used for prevention or treatment of delayed postpartum bleeding as per HMB. Regardless of the outcome of any testing during pregnancy, nonsteroidal anti-inflammatory drugs should be avoided postpartum and the patient should be monitored closely for bleeding.

Neonatal care

As for the fetus/neonate, the parents should be aware that the infant has a 50% chance of inheriting VWD. If the baby’s father has no history of bleeding, it is unlikely that the infant would be any more affected than the patient herself. Nonetheless, cord blood (in one or more light blue top tubes) should be obtained at the time of delivery and sent for a von Willebrand panel. If the infant is male, a circumcision should be postponed until VWD is ruled out. In addition, fetal invasive procedures should be avoided during labor. Fetal scalp electrode placement should be avoided. Operative vaginal delivery also should be avoided. Cesarean delivery would be preferred to operative vaginal delivery, but if operative vaginal delivery is unavoidable, use of forceps is preferred to vacuum extraction. ●

Von Willebrand disease (VWD) represents the most common inherited bleeding disorder, with a prevalence of approximately 1 in 1,000 people. Type 1 disease, associated with a quantitative reduction in von Willebrand factor (VWF), is the most common type of VWD and accounts for approximately 70% of VWD patients enrolled in hemophilia treatment centers; transmission is autosomal dominant. Type 2 disease, associated with a qualitative defect in VWF, accounts for most of the remaining 30% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal dominant. Type 3 disease, associated with a near absence of VWF, accounts for less than 1% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal recessive.

Bruising and mucocutaneous bleeding (epistaxis, gingival bleeding, and bleeding after dental extraction) are the most common presenting symptoms of VWD. Because VWD substantially increases the risk of heavy menstrual bleeding (HMB) and, to some extent, intrapartum bleeding complications, and postpartum hemorrhage, women experience a disproportionate burden from VWD. Thus, ObGyns are likely to be called on to make treatment recommendations in VWD patients with these concerns.¹

In 2017, the American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia determined that among clinical issues related to VWD, updating guidelines for women with VWD represented the highest priority.² Accordingly, an international group of hematologists/coagulation specialists performed systematic literature reviews to address 3 questions faced by women with VWD and their clinicians:

• What are the most effective treatments for HMB?
• What is the safest approach for women desiring neuraxial analgesia for intrapartum pain?
• What is the impact of postpartum administration of tranexamic acid (TxA) on postpartum hemorrhage (PPH)?³

Evidence on management strategies for HMB in women with VWD

The prevalence of HMB in women with VWD ranges from 50% to 92%. Reports suggest that between 5% and 24% of women presenting with this symptom have VWD.³ However, the prevalence of VWD among women seeking care for HMB relates to referral patterns, with the prevalence of VWD substantially higher in patient populations who are referred to clinicians or centers that focus on care of patients with bleeding disorders.

The systematic review authors³ identified 2 comparative studies that assessed the treatment of HMB in women with VWD. One was a crossover trial that enrolled 116 VWD patients with HMB with a mean age of 36 years.⁴ All participants in this trial chose not to use combination oral contraceptives (COCs) as they had not experienced good results with prior COC use. Trial participants were randomly assigned to receive either intranasal desmopressin (DDAVP; a synthetic analog of the antidiuretic agent vasopressin, which stimulates the release of VWF from endothelial cells) or oral TxA therapy for 2 menstrual cycles. Participants then crossed over to the other drug for 2 additional cycles. Although both agents significantly reduced estimated menstrual blood loss, TxA was more effective in decreasing bleeding than intranasal DDAVP.⁴

In a retrospective cohort study, investigators compared COC use with intranasal DDAVP in 36 adolescents who had VWD and HMB.⁵ Participant follow-up ranged from 6 months to 4 years. The estimated efficacy of COCs and intranasal DDAVP was 86% and 77%, respectively, a difference that did not achieve statistical significance. Some of the adolescents who used intranasal DDAVP reported severe headaches and flushing.⁵

In addition, the systematic review authors³ identified 5 case series that described the use of the levonorgestrel (52 mg)-releasing intrauterine device (LNG 52 IUD) in women with VWD and HMB; 4 of these addressed the efficacy of progestin-releasing IUDs in reducing HMB in this patient population.^6-9 Using different approaches to define HMB, the authors of these reports followed between 7 and 26 patients with bleeding disorders (most with confirmed VWD) and HMB for variable amounts of time after placement of an LNG 52 IUD. Many of the women described in these case series had tried other HMB treatments, including COCs, without success. Although these 4 reports assessed different outcomes, all reported that placement of the LNG 52 IUD substantially reduced menstrual blood loss, often resulting in amenorrhea. Several of these reports also noted important improvements in quality of life following LNG 52 IUD placement. One case series reported LNG 52 IUD placement in 13 adolescents with VWD and HMB. The mean time to achieve amenorrhea or occasional spotting was 94 days.⁶

The fifth report, which followed 20 women (median age, 31 years) with HMB associated with VWD or other bleeding disorders who underwent LNG 52 IUD placement, aimed to describe IUD expulsions and malpositioned IUDs in this population. In this small group of patients, 3 IUD expulsions and 2 malpositioned IUDs were observed. Furthermore, an additional 5 women had their device removed prematurely due to patient dissatisfaction. Accordingly, the IUD continuation rate in this case series was only 50%.¹⁰

Evidence on management of pregnancy, delivery, and the postpartum period

Heavy menstrual bleeding is not the only challenge for women with VWD. While pregnancy is accompanied by higher levels of VWF, potentially offsetting the risk of bleeding at the time of delivery, the levels do not achieve the same magnitude as they would in unaffected women.¹¹ Women are at an increased risk of primary PPH^12,13 and, importantly, since VWF levels fall exponentially after delivery when women are still experiencing lochia,¹¹ they are at increased risk of secondary or delayed PPH.

Two questions arise frequently in the care of women with VWD at the time of delivery and during the postpartum period:

• What is the safest approach for women who desire neuraxial analgesia for intrapartum pain?
• What is the impact of postpartum administration of TxA on PPH?

The second systematic review the authors performed³ focused on VWF levels in women receiving neuraxial anesthesia during labor. After screening 27 studies, the authors included 5 case series, which did not describe outcomes based on VWF levels but rather described the outcomes of women with VWF levels of greater than 0.50 IU/mL (> 50% of normal compared with a normal standard).

Meta-analysis showed that the proportion of anesthesia complications was 6%, which sounds high, but the range of complications was what would be expected in any population (hypotension, accidental dural puncture, inadequate anesthesia, and bloody tap with no further complications). No spinal, subdural, or epidural hematomas were noted.³ Such hematomas are an extremely rare complication of neuraxial anesthesia, occurring in only 1 in 200,000 or 1 in 250,000 obstetric patients^14,15; accordingly, an increase in the rate of hematomas among women with VWD could go undetected. The absence of hematomas among women with VWD as reported in the systematic review does not mean there is not an increase in the rate of hematomas in women with VWD. The relative risk is unknown and caution would be advised.

The third systematic review that the authors performed³ was on TxA treatment in the postpartum period. After screening 41 studies, the authors included 2 retrospective cohort studies.^16,17 The majority of the participants had VWD. With very-low-certainty evidence, the authors found that TxA reduces the risk of:

• severe primary PPH (risk ratio [RR], 0.36; 95% confidence interval [CI], 0.05–2.59)
• primary PPH (RR, 0.25; 95% CI, 0.04–1.75)
• secondary PPH (RR, 0.42; 95% CI, 0.02–0.91—does not cross 1.0).

Note that the 95% confidence intervals for severe as well as primary PPH crossed 1.0 and therefore these reductions in risk did not achieve statistical significance. Additionally, there was very-low-certainty evidence on the effect of TxA on blood transfusions, vaginal hematomas, blood loss, and thrombotic complications.³

Continue to: Our recommendations for HMB management...

When first evaluating any woman with HMB, it is important to check a blood count and ferritin level, if not already done. If there is any suggestion of iron deficiency (with or without anemia), we recommend oral iron supplementation. This is best accomplished with slow-release iron supplement formulations (or less expensive generic or house brands that contain less than 65 mg of elemental iron per tablet) taken every other day. Such preparations may cause fewer gastrointestinal adverse effects than other oral iron formulations.¹⁸ Although it may appear counterintuitive, oral iron is better absorbed (and also may cause fewer gastrointestinal adverse effects) when taken every other day.¹⁹

Initial management of HMB, whether or not a bleeding disorder is present, often consists or oral hormonal management. If no contraindications are present, we recommend initiation of a COC with a short hormone-free interval (for example, a 24/4 formulation). If contraindications to contraceptive doses of estrogen are present, continuous use of norethindrone acetate 5-mg tablets or off-label use of combination tablets with 5 µg of ethinyl estradiol and 1 mg of norethindrone acetate (a formulation approved for the treatment of menopausal symptoms) is appropriate.²⁰

Once a patient is established on oral hormonal management, placement of a levonorgestrel-releasing IUD should be considered. Given that expulsion rates may be higher in women with HMB, if feasible, consider using abdominal ultrasound guidance for IUD placement.

For women with VWD who fail first-line therapy (hormonal management) or are trying to become pregnant, TxA (two 650-mg tablets 3 times daily for up to 5 days during episodes of heavy flow) can reduce HMB.^20,21

Our recommendations for management of pregnancy and delivery

The second and third systematic reviews discussed above provide very limited guidance on comprehensive management. The care of the pregnant patient with VWD starts with assessment of VWF levels and making an accurate diagnosis. This usually requires the input of a hematologist or other expert in hemostasis. If no recent VWF levels are available, the ObGyn can obtain a von Willebrand panel that includes VWF antigen, VWF activity (most commonly ristocetin cofactor), and factor VIII.

Levels should be reassessed around 36 weeks’ gestation in anticipation of delivery. VWF levels increase during pregnancy; accordingly, in mild, type 1 VWD, half the time treatment is not necessary.¹¹ If VWF activity is less than 50 IU/dL (less than 50% of normal) at 36 weeks’ gestation, the patient should receive VWF concentrate (dosed in VWF units). This requires consultation with hematology and specialized pharmacy support.

For these reasons, the patient with a VWF level less than 50% should be delivered in a referral center with the necessary resources. Anesthesia should be aware of the patient. Unless they have sustained VWF and factor VIII levels greater than 50 IU/dL, neuraxial anesthesia should not be offered to pregnant women with VWD.

Due to the quantity of fluids administered during labor or at the time of delivery and the coexistent administration of oxytocin, desmopressin (synthetic vasopressin) should not be used without monitoring sodium levels, should not be dosed more than once, or should be avoided altogether due to the risk of water intoxication.

If the patient has sustained VWF and factor VIII levels greater than 50 IU/dL, she would be a candidate to deliver in her local hospital and receive neuraxial anesthesia.

Based on the best data we have for women with VWD, a patient with a VWF greater than 50 IU/dL is no more likely to experience PPH than other women.¹¹ Intravenous TxA can be used for prevention or treatment of immediate postpartum bleeding per protocol (1 g after cord clamp and 1 g 30 minutes or more later).²² Oral TxA can be used for prevention or treatment of delayed postpartum bleeding as per HMB. Regardless of the outcome of any testing during pregnancy, nonsteroidal anti-inflammatory drugs should be avoided postpartum and the patient should be monitored closely for bleeding.

Neonatal care

As for the fetus/neonate, the parents should be aware that the infant has a 50% chance of inheriting VWD. If the baby’s father has no history of bleeding, it is unlikely that the infant would be any more affected than the patient herself. Nonetheless, cord blood (in one or more light blue top tubes) should be obtained at the time of delivery and sent for a von Willebrand panel. If the infant is male, a circumcision should be postponed until VWD is ruled out. In addition, fetal invasive procedures should be avoided during labor. Fetal scalp electrode placement should be avoided. Operative vaginal delivery also should be avoided. Cesarean delivery would be preferred to operative vaginal delivery, but if operative vaginal delivery is unavoidable, use of forceps is preferred to vacuum extraction. ●

Von Willebrand disease (VWD) represents the most common inherited bleeding disorder, with a prevalence of approximately 1 in 1,000 people. Type 1 disease, associated with a quantitative reduction in von Willebrand factor (VWF), is the most common type of VWD and accounts for approximately 70% of VWD patients enrolled in hemophilia treatment centers; transmission is autosomal dominant. Type 2 disease, associated with a qualitative defect in VWF, accounts for most of the remaining 30% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal dominant. Type 3 disease, associated with a near absence of VWF, accounts for less than 1% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal recessive.

Bruising and mucocutaneous bleeding (epistaxis, gingival bleeding, and bleeding after dental extraction) are the most common presenting symptoms of VWD. Because VWD substantially increases the risk of heavy menstrual bleeding (HMB) and, to some extent, intrapartum bleeding complications, and postpartum hemorrhage, women experience a disproportionate burden from VWD. Thus, ObGyns are likely to be called on to make treatment recommendations in VWD patients with these concerns.¹

In 2017, the American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia determined that among clinical issues related to VWD, updating guidelines for women with VWD represented the highest priority.² Accordingly, an international group of hematologists/coagulation specialists performed systematic literature reviews to address 3 questions faced by women with VWD and their clinicians:

• What are the most effective treatments for HMB?
• What is the safest approach for women desiring neuraxial analgesia for intrapartum pain?
• What is the impact of postpartum administration of tranexamic acid (TxA) on postpartum hemorrhage (PPH)?³

Evidence on management strategies for HMB in women with VWD

The prevalence of HMB in women with VWD ranges from 50% to 92%. Reports suggest that between 5% and 24% of women presenting with this symptom have VWD.³ However, the prevalence of VWD among women seeking care for HMB relates to referral patterns, with the prevalence of VWD substantially higher in patient populations who are referred to clinicians or centers that focus on care of patients with bleeding disorders.

The systematic review authors³ identified 2 comparative studies that assessed the treatment of HMB in women with VWD. One was a crossover trial that enrolled 116 VWD patients with HMB with a mean age of 36 years.⁴ All participants in this trial chose not to use combination oral contraceptives (COCs) as they had not experienced good results with prior COC use. Trial participants were randomly assigned to receive either intranasal desmopressin (DDAVP; a synthetic analog of the antidiuretic agent vasopressin, which stimulates the release of VWF from endothelial cells) or oral TxA therapy for 2 menstrual cycles. Participants then crossed over to the other drug for 2 additional cycles. Although both agents significantly reduced estimated menstrual blood loss, TxA was more effective in decreasing bleeding than intranasal DDAVP.⁴

In a retrospective cohort study, investigators compared COC use with intranasal DDAVP in 36 adolescents who had VWD and HMB.⁵ Participant follow-up ranged from 6 months to 4 years. The estimated efficacy of COCs and intranasal DDAVP was 86% and 77%, respectively, a difference that did not achieve statistical significance. Some of the adolescents who used intranasal DDAVP reported severe headaches and flushing.⁵

In addition, the systematic review authors³ identified 5 case series that described the use of the levonorgestrel (52 mg)-releasing intrauterine device (LNG 52 IUD) in women with VWD and HMB; 4 of these addressed the efficacy of progestin-releasing IUDs in reducing HMB in this patient population.^6-9 Using different approaches to define HMB, the authors of these reports followed between 7 and 26 patients with bleeding disorders (most with confirmed VWD) and HMB for variable amounts of time after placement of an LNG 52 IUD. Many of the women described in these case series had tried other HMB treatments, including COCs, without success. Although these 4 reports assessed different outcomes, all reported that placement of the LNG 52 IUD substantially reduced menstrual blood loss, often resulting in amenorrhea. Several of these reports also noted important improvements in quality of life following LNG 52 IUD placement. One case series reported LNG 52 IUD placement in 13 adolescents with VWD and HMB. The mean time to achieve amenorrhea or occasional spotting was 94 days.⁶

The fifth report, which followed 20 women (median age, 31 years) with HMB associated with VWD or other bleeding disorders who underwent LNG 52 IUD placement, aimed to describe IUD expulsions and malpositioned IUDs in this population. In this small group of patients, 3 IUD expulsions and 2 malpositioned IUDs were observed. Furthermore, an additional 5 women had their device removed prematurely due to patient dissatisfaction. Accordingly, the IUD continuation rate in this case series was only 50%.¹⁰

Evidence on management of pregnancy, delivery, and the postpartum period

Heavy menstrual bleeding is not the only challenge for women with VWD. While pregnancy is accompanied by higher levels of VWF, potentially offsetting the risk of bleeding at the time of delivery, the levels do not achieve the same magnitude as they would in unaffected women.¹¹ Women are at an increased risk of primary PPH^12,13 and, importantly, since VWF levels fall exponentially after delivery when women are still experiencing lochia,¹¹ they are at increased risk of secondary or delayed PPH.

Two questions arise frequently in the care of women with VWD at the time of delivery and during the postpartum period:

• What is the safest approach for women who desire neuraxial analgesia for intrapartum pain?
• What is the impact of postpartum administration of TxA on PPH?

The second systematic review the authors performed³ focused on VWF levels in women receiving neuraxial anesthesia during labor. After screening 27 studies, the authors included 5 case series, which did not describe outcomes based on VWF levels but rather described the outcomes of women with VWF levels of greater than 0.50 IU/mL (> 50% of normal compared with a normal standard).

Meta-analysis showed that the proportion of anesthesia complications was 6%, which sounds high, but the range of complications was what would be expected in any population (hypotension, accidental dural puncture, inadequate anesthesia, and bloody tap with no further complications). No spinal, subdural, or epidural hematomas were noted.³ Such hematomas are an extremely rare complication of neuraxial anesthesia, occurring in only 1 in 200,000 or 1 in 250,000 obstetric patients^14,15; accordingly, an increase in the rate of hematomas among women with VWD could go undetected. The absence of hematomas among women with VWD as reported in the systematic review does not mean there is not an increase in the rate of hematomas in women with VWD. The relative risk is unknown and caution would be advised.

The third systematic review that the authors performed³ was on TxA treatment in the postpartum period. After screening 41 studies, the authors included 2 retrospective cohort studies.^16,17 The majority of the participants had VWD. With very-low-certainty evidence, the authors found that TxA reduces the risk of:

• severe primary PPH (risk ratio [RR], 0.36; 95% confidence interval [CI], 0.05–2.59)
• primary PPH (RR, 0.25; 95% CI, 0.04–1.75)
• secondary PPH (RR, 0.42; 95% CI, 0.02–0.91—does not cross 1.0).

Note that the 95% confidence intervals for severe as well as primary PPH crossed 1.0 and therefore these reductions in risk did not achieve statistical significance. Additionally, there was very-low-certainty evidence on the effect of TxA on blood transfusions, vaginal hematomas, blood loss, and thrombotic complications.³

Continue to: Our recommendations for HMB management...

When first evaluating any woman with HMB, it is important to check a blood count and ferritin level, if not already done. If there is any suggestion of iron deficiency (with or without anemia), we recommend oral iron supplementation. This is best accomplished with slow-release iron supplement formulations (or less expensive generic or house brands that contain less than 65 mg of elemental iron per tablet) taken every other day. Such preparations may cause fewer gastrointestinal adverse effects than other oral iron formulations.¹⁸ Although it may appear counterintuitive, oral iron is better absorbed (and also may cause fewer gastrointestinal adverse effects) when taken every other day.¹⁹

Initial management of HMB, whether or not a bleeding disorder is present, often consists or oral hormonal management. If no contraindications are present, we recommend initiation of a COC with a short hormone-free interval (for example, a 24/4 formulation). If contraindications to contraceptive doses of estrogen are present, continuous use of norethindrone acetate 5-mg tablets or off-label use of combination tablets with 5 µg of ethinyl estradiol and 1 mg of norethindrone acetate (a formulation approved for the treatment of menopausal symptoms) is appropriate.²⁰

Once a patient is established on oral hormonal management, placement of a levonorgestrel-releasing IUD should be considered. Given that expulsion rates may be higher in women with HMB, if feasible, consider using abdominal ultrasound guidance for IUD placement.

For women with VWD who fail first-line therapy (hormonal management) or are trying to become pregnant, TxA (two 650-mg tablets 3 times daily for up to 5 days during episodes of heavy flow) can reduce HMB.^20,21

Our recommendations for management of pregnancy and delivery

The second and third systematic reviews discussed above provide very limited guidance on comprehensive management. The care of the pregnant patient with VWD starts with assessment of VWF levels and making an accurate diagnosis. This usually requires the input of a hematologist or other expert in hemostasis. If no recent VWF levels are available, the ObGyn can obtain a von Willebrand panel that includes VWF antigen, VWF activity (most commonly ristocetin cofactor), and factor VIII.

Levels should be reassessed around 36 weeks’ gestation in anticipation of delivery. VWF levels increase during pregnancy; accordingly, in mild, type 1 VWD, half the time treatment is not necessary.¹¹ If VWF activity is less than 50 IU/dL (less than 50% of normal) at 36 weeks’ gestation, the patient should receive VWF concentrate (dosed in VWF units). This requires consultation with hematology and specialized pharmacy support.

For these reasons, the patient with a VWF level less than 50% should be delivered in a referral center with the necessary resources. Anesthesia should be aware of the patient. Unless they have sustained VWF and factor VIII levels greater than 50 IU/dL, neuraxial anesthesia should not be offered to pregnant women with VWD.

Due to the quantity of fluids administered during labor or at the time of delivery and the coexistent administration of oxytocin, desmopressin (synthetic vasopressin) should not be used without monitoring sodium levels, should not be dosed more than once, or should be avoided altogether due to the risk of water intoxication.

If the patient has sustained VWF and factor VIII levels greater than 50 IU/dL, she would be a candidate to deliver in her local hospital and receive neuraxial anesthesia.

Based on the best data we have for women with VWD, a patient with a VWF greater than 50 IU/dL is no more likely to experience PPH than other women.¹¹ Intravenous TxA can be used for prevention or treatment of immediate postpartum bleeding per protocol (1 g after cord clamp and 1 g 30 minutes or more later).²² Oral TxA can be used for prevention or treatment of delayed postpartum bleeding as per HMB. Regardless of the outcome of any testing during pregnancy, nonsteroidal anti-inflammatory drugs should be avoided postpartum and the patient should be monitored closely for bleeding.

Neonatal care

As for the fetus/neonate, the parents should be aware that the infant has a 50% chance of inheriting VWD. If the baby’s father has no history of bleeding, it is unlikely that the infant would be any more affected than the patient herself. Nonetheless, cord blood (in one or more light blue top tubes) should be obtained at the time of delivery and sent for a von Willebrand panel. If the infant is male, a circumcision should be postponed until VWD is ruled out. In addition, fetal invasive procedures should be avoided during labor. Fetal scalp electrode placement should be avoided. Operative vaginal delivery also should be avoided. Cesarean delivery would be preferred to operative vaginal delivery, but if operative vaginal delivery is unavoidable, use of forceps is preferred to vacuum extraction. ●