Elisabeth Quint, MD

Part 1 of this series on pediatric adolescent gynecologic emergencies focuses on cases about premenarchal bleeding, urethral prolapse, and the cause of a mysterious vaginal discharge. 

Monica Woll Rosen, MD, is a clinical assistant professor of obstetrics and gynecology at the University of Michigan Medical School in Ann Arbor. She specializes in pediatric and adolescent gynecology.

Elisabeth H. Quint, MD, is a clinical professor in obstetrics and gynecology at the University of Michigan Medical School in Ann Arbor. She is also fellowship director of the Pediatric and Adolescent Gynecology Fellowship and assistant dean for clinical faculty.

Young patients with gynecologic concerns may present to a general obstetrician-gynecologist as their first local contact. But prior to surgical intervention in a child, consultation with or referral to a pediatric and adolescent gynecologist in an academic medical center may be indicated. This review presents several cases of adolescents with genital and pelvic pain, with guidance for work-up and treatment.

You are called to evaluate a 12-year-old girl who fell on the balance beam during a gymnastics class. Her legs landed on either side of the beam. She is unable to void and is in tremendous pain. She was given several doses of pain medication but she continues to experience severe pain (

Figure 1. A 12-year-old girl with vulvar hematoma 

Credit: Collection of Monica Woll Rosen, MD, University of Michigan

This patient has extensive vulvar hematoma. Nonobstetric vulvar hematomas are rare, accounting for only 3.7% of all vulvar hematomas.

 They can occur from blunt trauma due to a fall, foreign body insertion, sexual assault, saddle injury, or intercourse. The rich vascular supply from the pudendal vessel branches makes this site vulnerable to hematoma formation.

A hematoma can be managed conservatively unless the hematoma is expanding, the skin is necrotic, or the patient is in too much pain.

 Ultrasound, CT, or MRI can be used to investigate the size, site, and expansion of the hematoma. Cases requiring surgical management involve an incision, evacuation of blood, and ligation of bleeding vessels.

Because this patient’s hematoma prohibited her from voiding, she needed a Foley catheter placed. Her urine was evaluated for hematuria. Because of her extensive hematoma and continued pain despite medication, she required an exam under anesthesia to assess the extent of her injury, insertion of the Foley catheter, and incision and drainage of the hematoma.

A 13-year-old girl presents to the emergency department with several days of worsening vulvar pain that is now severe. A few days ago, she developed a runny nose, fever, and sore throat. She otherwise has a negative review of systems. She is having trouble urinating because of the vulvar pain and has dysuria when she does urinate. Today she noticed a thick, yellow discharge in her underwear. On exam you notice several large painful ulcerations (

Aphthous or Lipshütz ulcers. Credit: Collection of Monica Woll Rosen, MD, University of Michigan

Aphthous or Lipschütz ulcers are acute vulvar ulcers that occur mainly in non–sexually active girls and are thought to be viral in nature.

 They commonly appear during or following a prodromal viral illness.

 have been associated with the ulcers, the causative virus often cannot be identified. There have been recent case reports of vulvar ulcers following a COVID-19 infection6 or after receiving the COVID-19 vaccine.

A patient may have black, necrotic, shallow, or deep ulcers in the labia minora or majora.

 There can be overlying purulent discharge. When assessing any ulcers it is important to evaluate for underlying sexually transmitted infections, such as herpes simplex. Other considerations include Crohn disease with multiple tracks and ulceration or Behçet disease, which presents with recurrent vulvar ulcers in conjunction with recurring oral ulcers.

Treatment for aphthous ulcers is supportive, as it is a self-limiting condition. Topical lidocaine gel can be used for pain control, and a topical clobetasol ointment can be used twice daily.

If a patient is severely affected, an oral steroid taper may be considered, as well as an admission for intravenous pain control. If the patient cannot void because of dysuria, a Foley catheter should be placed.

An 11-year-old girl presents after track practice with severe, unilateral right lower quadrant pain. Her last menstrual period was 3 weeks ago. The pain is sharp and radiates to her back. She has associated nausea and vomiting. On exam, she has rebound tenderness and guarding of her lower abdomen. On a pelvic ultrasound, she has a 6-cm simple cyst and a normal appendix. What do you do next?

Arrow shows torsed infundibulopelvic ligament.

Credit: Collection of Monica Woll Rosen, MD, University
of Michigan

This patient most likely is experiencing ovarian and/or tubal torsion 

. Ovarian torsion accounts for 2.7% of gynecologic emergencies.

 It occurs when the ovary twists on its attachments, which causes decreased blood flow and eventually leads to necrosis. Ovarian and paraovarian cysts, increased length of ovarian ligaments, and enlarged ovaries are risk factors for this condition. A patient is typically evaluated with an ultrasound to assess for a mass and blood flow to the ovary.

Ovarian torsion can be difficult to diagnose preoperatively—the differential includes appendicitis, hemorrhagic cyst, ovarian rupture, and other bowel etiologies. Absent Doppler flow to the ovary suggests torsion, but torsion may be present even with normal flow. 

A recent study of 87 girls with suspected ovarian torsion found that a preoperative diagnosis was confirmed in 48% of postmenarchal patients.

Treatment involves detorsion of the ovary when possible and cystectomy to prevent recurrence.

 There is limited indication for oophorectomy. Detorsion with cystectomy can almost always be done, regardless of ovarian size. There is insufficient evidence to dictate oophoropexy, although this may be considered, particularly in the case of recurrent torsion.

A 14-year-old girl presents to the emergency department with significant abdominal pain. She is premenarchal but has had pelvic cramping for the past 6 to 9 months. She has Tanner stage V breasts and genitalia. On pelvic exam, there is a bulging hymen with a blue hue (

On rectal exam, there is a large anterior bulge immediately inside her rectal opening. On ultrasound, you see a large mass and have difficulty distinguishing the uterus or ovaries. What is your diagnosis?

This presentation and exam are consistent with an imperforate hymen, which occurs in 0.05% to 0.1% of girls.

Abdominal pain at the time of expected menarche is the most common presenting symptom of this condition (54.2%), followed by urinary retention (20.3%) and dysuria (9.7%).

Of note, this condition can and should potentially be diagnosed in the neonatal nursery, as maternal estrogen allows easy visualization of the vaginal introitus. If the neonate is asymptomatic and voiding without difficulty, surgical management can be deferred until puberty. 

More typical is a missed diagnosis until after menarche. Surgical incision of the hymen is then indicated to relieve the backup of menstrual blood. 

Traditionally, this procedure was performed using a cruciate incision, but many providers now use a circular incision to open the hymen. It is important to suture with interrupted stitches so as not to constrict the hymen. This heals very well and should not recur or cause stenosis. No postoperative dilation is needed. Hormonal suppression of menses may be considered until surgery can be performed. This condition, although urgent, is not emergent, particularly if the diagnosis is in question.

Vaginal agenesis also can present with primary amenorrhea and occasional pain due to obstructed uterine remnants. However, there will usually be some hymenal remnants visible on exam and no bulge will be felt on rectal examination. Further imaging with ultrasound followed by MRI is the next step in distinguishing this condition. Other rare obstructing anomalies include a transverse vaginal septum or cervical agenesis.

A 13-year-old girl presents with significant cyclical abdominal pain and amenorrhea. She has Tanner stage V breasts and genitalia. Her external genital exam is completely normal with an appropriate hymenal opening. There is no bulge on the perineum. A small cotton swab placed through the hymen stops at 4 cm. On rectal exam you feel a bulge anteriorly, approximately 4 cm into the rectal canal. Ultrasound reveals a large blood-filled cavity, so you obtain an MRI (

. MRI of a 13-year-old girl with transverse vaginal septum. 

This scenario is most consistent with a transverse vaginal septum. The septum can be located at different levels of the vagina, but external genitalia appear normal. Septa can vary in thickness, with whole segments of the vagina undeveloped.

Because cases of transverse septa are rare and difficult to repair, they should be managed at tertiary centers by experienced pediatric and adolescent gynecologists or other gynecological surgeons. 

Surgery is usually performed vaginally, with assistance abdominally or laparoscopically. Surgery involves resection of the septum, which relieves the obstruction, followed by either a simple pull-through vaginoplasty or by using a skin or buccal graft to cover the defect.

It is imperative that patients perform patient-led vaginal dilation after surgery. A recent study showed that of 21 patients who underwent transverse septum resections and had a postoperative complication of vaginal stenosis or scarring, 14 (56%) either did not dilate afterward or did not dilate correctly.

Therefore, when a transverse septum is diagnosed, menstrual suppression is usually initiated until a patient is old enough to dilate on her own.

The cases above outline gynecological situations and emergencies that are unique to children and adolescents. Pediatric patients may need an exam under anesthesia to thoroughly evaluate anatomy or vaginal complaints. When uncertainties exist, and especially prior to surgical intervention in a child, consider consulting with a gynecologist experienced in pediatric and
adolescent gynecology.

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2.Kim MS, Lee HJ, Joo E, Kang S, Lee MH, Kim HC. Management of non-obstetric traumatic vulvar haematoma: a retrospective review of 33 cases.

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3.Vismara SA, Lava SAG, Kottanattu L, et al. Lipschütz’s acute vulvar ulcer: a systematic review. 

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4.Lorenzo CV, Robertson WS. Genital ulcerations as presenting symptom of infectious mononucleosis. 

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5.Martin JM, Godoy R, Calduch L, Villalon G, Jordá E. Lipschütz acute vulval ulcers associated with primary cytomegalovirus infection. 

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6.Krapf JM, Casey RK, Goldstein AT. Reactive non-sexually related acute genital ulcers associated with COVID-19. 

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7.Wojcicki AV, O’Flynn, O’Brien KL. Vulvar aphthous ulcer in an adolescent after Pfizer-BioNTech (BNT162b2) COVID-19 vaccination. 

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8. Rosman IS, Berk DR, Bayliss SJ, White AJ, Merritt DF. Acute genital ulcers in nonsexually active young girls: case series, review of the literature, and evaluation and management recommendations. 

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9. Bandow GD. Diagnosis and management of vulvar ulcers. 

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10. Childress KJ, Dietrich JE. Pediatric ovarian torsion. 

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11.Melcer Y, Maymon R, Pekar-Zlotin M, Pansky M, Smorgick N. Clinical and sonographic predictors of adnexal torsion in pediatric and adolescent patients.

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12.Dasgupta R, Renaud E, Goldin AB, et al. Ovarian torsion in pediatric and adolescent patients: a systematic review.

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13.Lee KH, Hong JS, Jung HJ, et al. Imperforate hymen: a comprehensive systematic review. 

14.Brander EPA, Vincent S, McQuillan SK. Transverse vaginal septum resection: technique, timing, and the utility of dilation. A scoping review of the literature. 

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15.Wancura M, McCracken JM, Steen E, Cosgriff-Hernandez E, Keswani S, Hakim JCE. Emerging technologies in pediatric gynecology: new paradigms in women’s health care. 

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Articles

Part 2 in a series on emergencies in pediatric and adolescent gynecology

Managing genital and pelvic pain in young patients

Gynecologic conditions that are common in girls and adolescents are often not seen in adult patients or can present differently, creating a dilemma for the provider.

 Because these are relatively rare occurrences, this review is designed to guide a general obstetrician-gynecologist through several case-based scenarios of premenarchal vaginal bleeding. These scenarios are intended to give the general gynecologist guidance, but consultation with or referral to a pediatric and adolescent gynecologist in an academic medical center may be indicated.

: A 4-year-old presents with 1 day of spots of blood in her underwear that the mother noticed when helping her daughter change. The child denies any falls; does not complain of pain, dysuria, or itching; and has been supervised by her mother all day. 

Discussion: In this patient, the exam shows whitening of her vulva (classically, in a “figure of 8” distribution that can surround the anus) in addition to several areas of subepithelial hemorrhage (“blood blisters”) and scarring around the clitoral hood, consistent with lichen sclerosus (LS)—a chronic inflammatory skin disease that primarily presents in the anogenital region. It most commonly affects females and may occur premenarche or after menopause, likely due to lower estrogen levels.

 The disease is estimated to occur in 1 in 900 prepubertal girls.

 The pathogenesis of LS is multifactorial and can be associated with other autoimmune conditions including thyroiditis, alopecia, pernicious anemia, and vitiligo.

 Occasionally, LS may look like significant bruising and has been mistaken for abuse.

 The whiteness of the surrounding skin and the presence of scarring should alert the provider to the correct diagnosis.

 Although the association of vulvar cancer has been made in adults, this has not been described in children. Treatment is indicated to alleviate symptoms—usually itching or pain—and to prevent further scarring. Ultrapotent topical corticosteroids are often used initially with tapering to lower-potency ointment for maintenance; tacrolimus may be used as second-line therapy.

It is important to note that, besides trauma-related bleeding (both accidental and nonaccidental/abuse), most of the possible reasons for premenarchal vaginal bleeding are not true emergencies; however, they often present as such due to anxiety in the patient
and caregiver.

The differential diagnosis list for premenarchal vaginal and vulvar bleeding is long 

, with trauma and precocious puberty as the diagnoses that initially need to be ruled out. Vulvar concerns and urologic factors are the most encountered etiologies.

The physical exam of the premenarchal girl who presents with bleeding should always include a breast exam, as any breast development prior to age 7 is cause for concern for precocious puberty.

After an abdominal exam, a vulvar exam should be attempted. This can be more complicated than it would be in an adolescent or adult patient. First, the provider must explain the plan to the patient and parent, including that only an external exam will likely be performed. A speculum examination of a prepubertal girl in the office is never indicated. For a very anxious girl, it is helpful to consider having a child life specialist at the exam if feasible.

The child should sit in a lithotomy position, either on the parent’s lap or in frog-leg position on the exam table, with the desired parent or caregiver by her side. Stirrups are usually not used, as this can make the child uncomfortable. Gentle, lateral traction on the labia majora should be used for vulvar visualization. Gently gripping the labia majora and pulling anteriorly allows the edges of the hymen to be seen.

 Deep breathing should be encouraged, as this helps to open the vagina and further enables the hymenal edges to be more easily appreciated.

 The child should always be informed of the examiner’s actions prior to every maneuver.

If there is a need to look deeper into the vagina or if the child is more comfortable on her abdomen, the child can lie in a prone knee-chest position. In this position, the child lies on her knees with her buttocks elevated and her head resting on the table. Her arms can be positioned above her head or by her side. An otoscope can be used to see inside the lower vagina. Topical lidocaine jelly may be helpful with this exam.

With a similar story but different exam, this patient could also have had a urethral prolapse 

, which has an incidence of 1 in 3000 premenarchal girls.10 The most common presentation is vaginal bleeding, as the prolapsed tissue can be friable; pain may also occur.

 This happens when there is a lack of urethral support, enabling the urethral mucosa to prolapse and form a friable mass, and is more common in Black girls. The distinction between urethral prolapse and a vaginal mass or tumor can be facilitated by observing the child voiding on a bedpan; urine exits through the center of the prolapsed urethra, and anterior to a vaginal mass. Sitzbaths and topical estrogen are the mainstays of treatment; surgical intervention is rarely necessary if necrosis is present.

: A 5-year-old girl presents with foul-smelling bloody vaginal discharge that she has had for 1 week. Based on a normal vulvar exam, except for purulent discharge, you diagnose vulvovaginitis and treat her with oral antibiotics for 7 days. The discharge disappears but returns when the antibiotic course is complete. What is the most likely diagnosis and treatment?

: When discharge persists despite antibiotics, there is suspicion for a foreign body. Foreign bodies occur in up to 18% of girls with bleeding and discharge.

 Until the foreign body is removed, the discharge or bleeding will likely continue. The most common foreign body is toilet paper, although all manner of objects may be intentionally placed in the vagina by the child. It may be hard to see the foreign body in clinic on the exam, even in a knee-chest position. If the foreign body can be easily seen at the introitus, it can be carefully removed with a small instrument. A rectal exam may aid in palpating a firm object, and the object can sometimes be removed by “milking” it toward the introitus. Again, lidocaine jelly may be helpful.

Options for removal of a deeper or nonvisible foreign body include a lavage or irrigation in an office setting, office vaginoscopy or irrigation with an office hysteroscope (Endosee; CooperSurgical). This choice is based on patient anxiety, tolerance of the initial examination, and family preference. If the decision is a clinic lavage, child life assistance can be invaluable. Before performing a lavage, the gynecologist can apply topical lidocaine jelly to the hymen for comfort. With the patient in a frog-leg position, a small pediatric feeding tube or foley is attached to a 20-mL syringe of warm saline. The catheter tube is passed through the hymenal opening and irrigation of the vagina is initiated. Some water pressure may be required to help loosen the foreign body. During irrigation of the vagina, touching the hymen should be avoided. A small foreign object may exit the vagina with this technique.

If an office exam is not desired, pelvic imaging can be obtained, although this does not always show the foreign body.

 A vaginoscopy under general anesthesia using a pediatric cystoscope can be performed to better visualize the vagina and the foreign body. With vaginoscopy, the labia majora can be held closed to allow for vaginal distension and better visualization. Common culprits are toilet paper or cotton balls 

With premenarchal vaginal bleeding, it is important to remember a rare reproductive system malignancy: embryonal rhabdomyosarcoma—also known as sarcoma botryoides.

 This malignancy involves the vagina, uterus, bladder, and urethra and typically presents with the passage of grape-like lesions and/or vaginal bleeding or discharge. Ninety percent of these tumors occur before a child turns 5 years of age, with most occurring before age 2. Growth is rapid and treatment involves a combination of surgery, chemotherapy, and radiation, decided upon using a multidisciplinary team approach.

 Fortunately there are high cure rates, so early detection is imperative.

You are paged urgently to the emergency department to see an 8-year-old girl who reports falling on the side of the bathtub an hour ago. She reports pain in her genital area after straddling the tub, along with some vaginal spotting. What do you do next?

Discussion: This girl has suffered a straddle injury. Straddle injuries are the most common gynecologic injury in this age group and are usually the result of blunt trauma,

 which occurs when soft tissue is compressed against bone, causing bruising and superficial lacerations. Hymenal involvement
is rare.

In this case, the provider should first assess the patient’s stability, then take a history. There may be concern for nonaccidental trauma, so this should include the exact circumstances of how the trauma occurred and if it was witnessed. If possible, the provider should interview the child alone if she is of an appropriate age. On examination of the vulva, it is important to specifically evaluate whether the injury fits the history that was given. The hymen should be assessed to see if it is involved. In a typical straddle injury on a nonsharp surface, a hymenal laceration is uncommon; therefore further evaluation of the circumstances of this trauma must occur, possibly with the help of a child protection team or social worker.

In findings from recent studies, 1 in 5 girls are estimated to experience sexual abuse during childhood.

 It is important to remember, however, that most children who are evaluated for suspected sexual abuse will not have any signs of injury; minor injuries can heal quickly, and bruising, abrasions, and lacerations are rare in children examined more than 72 hours after experiencing abusive trauma.

If there is significant bleeding, irrigating with warm water may help delineate the extent of the trauma. Applying topical lidocaine prior to the exam can also be helpful, although it may sting on an open wound. An exam under anesthesia with possible vaginoscopy should be considered for any of the following: the patient is unable to tolerate an exam, vital signs are unstable, the extent of the injury or laceration cannot be appreciated at the bedside, there is active bleeding, or the pain is not responding to appropriate measures.

This patient’s hymen was annular and no hymenal tear or injury was noted. She had a small laceration below the labium minus that became hemostatic without repair. In this instance, her injury fit her history, her parents had observed her accident, and abuse was not suspected. Treatment was supportive, as she did not require a laceration repair. An ice pack applied intermittently may be helpful; a package of frozen food, such as peas, can be wrapped in cloth and will conform to the vulvar area.

Although patients and caregivers often perceive the cases described above as true crises, many such patients may present to a general obstetrician-gynecologist in an office setting. When performing an exam on children, having them adopt the frog-leg or knee-chest position can reduce their anxiety and make them feel more at ease. When in doubt, consider consulting with a gynecologist experienced in pediatric gynecology. 

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5. Simms-Cendan J, Hoover K, Marathe K, Tyler K. NASPAG clinical opinion: diagnosis and management of lichen sclerosis in pediatric and adolescent patients. 

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6. Alaniz VI, Rosen M, Mohr B, Markman L, Quint EH. 4-year-old girl · genital discomfort and dysuria · clitoral hood swelling · blood blister on the labia minora · Dx? 

7. Craighill MC. Pediatric and adolescent gynecology for the primary care pediatrician. 

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8. Fishman A, Paldi E. Vaginal bleeding in premenarchal girls: a review

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9. French A, Emans SJ. Office evaluation of the child and adolescent. In: Emans SJ, Laufer MR, DiVasta A, eds

Goldstein’s Pediatric and Adolescent Gynecology

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10. Ballouhey Q, Galinier P, Gryn A, Grimaudo A, Pienkowski C, Fourcade L. Benefits of primary surgical resection for symptomatic urethral prolapse in children. 

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11. Fernandes ET, Dekermacher S, Sabadin MA, Vaz F. Urethral prolapse in children. 

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12. Striegel AM, Myers JB, Sorensen MD, Furness PD, Koyle MA. Vaginal discharge and bleeding in girls younger than 6 years. 

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13. Smith YR, Berman DR, Quint EH. Premenarchal vaginal discharge: findings of procedures to rule out foreign bodies. 

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14. Nayak S, Witchel SF, Sanfilippo JS. Vaginal foreign body: a delayed diagnosis. 

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15. Pommert L, Bradley W. Pediatric gynecologic cancers

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16. Strickland AL, Fadare O. Pediatric vulvar malignancies: rare but important to know. 

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17. Spitzer RF, Kives S, Caccia N, Ornstein M, Goia C, Allen LM. Retrospective review of unintentional female genital trauma at a pediatric referral center. 

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Part 1 in a series on emergencies in pediatric and adolescent gynecology.

Have no fear! Premenarchal vaginal bleeding

Abnormal uterine bleeding (AUB) is common among premenopausal women.

 For many women, hormonal medications including estrogen and/or progestins is the mainstay of AUB management. Every provider, no matter how experienced with hormonal management of AUB, faces difficult clinical situations concerning the best hormonal regimen to choose in women at increased risk for venous thromboembolism (VTE). 

Incidence of VTE in women of childbearing age is 1 to 10 in 10,000 yearly.

 weight, smoking, certain clotting disorders, and use of combined hormonal contraceptives.

 Initially it was thought that estrogen alone increased VTE risk, however, it is now known that different progestins have varied VTE risk.

 This article reviews the current literature and guidelines to assist ob/gyns in evidence-based management of AUB with progestins, focusing on risk of VTE. Four patient cases are presented, each centered on a commonly used progestin for management of AUB in premenopausal women: the levonorgestrel intrauterine system (LNG-IUS), depot medroxyprogesterone, norethindrone acetate (DMPA), and megestrol acetate. Also included are guidance on patient counseling and a review of the available literature (Table 1). 


	A 25-year-old G0P0 with systemic lupus erythematosus (SLE) and positive anti-phospholipid antibodies presents to discuss management of heavy periods, a hemoglobin of 10.5 g/dL and a need for contraception. She denies a personal or family history of VTE. The woman doesn’t remember to take her other medications regularly and desires an option that lightens her cycle, while also providing longer-term effective contraception. 

You counsel your patient that the Centers for Disease Control and Prevention Medical Eligibility Criteria (CDC-MEC)

 guidelines characterize the LNGIUS as category 3 (risks generally outweigh benefits) in patients with SLE and positive antiphospholipid antibodies. However, you also educate her that citations behind the MEC recommendation are mostly based on a theoretical risk of VTE rather than studies of LNG-IUS use in her specific situation. Based on this patient’s positive antiphospholipid antibodies, the MEC guidelines recommend only one option for her: the copper IUD;

 however, with her heavy bleeding and mild anemia, it is not an ideal option. You counsel her that the literature does not demonstrate any increased risk of VTE with LNG-IUS use, in both low- and high-risk populations, and engage in shared decision-making. 


	The LNG-IUS is available in several versions, with its active progestin component levonorgesterol ranging from 13.5 to 52 mg. With use of the device, the stable plasma level of levonorgestrel is at most approximately 3% of the level seen with a levonorgestrel-containing combination oral contraceptive (COC) pill.

 The 52-mg LNG-IUS is approved by the US Food and Drug Administration (FDA) for contraception for up to 5 years and for heavy menstrual bleeding. There is no FDA warning for VTE risk on the package insert.

Multiple studies have evaluated use of the 52-mg LNG-IUS and VTE risk in a low-risk population.

 The largest was a 2009 national registry cohort study in Denmark involving non-pregnant women aged 15 to 49, with no history of cardiovascular disease or malignancy.

 The study evaluated 10.4 million woman-years and reported 4,214 VTE episodes. The authors concluded that compared to non-use of hormones, use of the 52-mg LNG-IUS was not associated with increased risk of VTE (RR 0.90; 95% CI 0.64-1.26).

 Two systematic reviews were conducted, one prior to and one including this article,

 both of which concluded that the 52-mg LNG-IUS does not increase VTE risk in low-risk populations.  

The relationship between the 52-mg LNG-IUS and VTE risk also has been evaluated in populations at higher VTE risk. A 2016 systematic review included nine studies of the the device in high-risk women with SLE, hypertension, smoking, thrombophilia, and history of VTE. The study concluded that there was no statistically significant increased risk of VTE in women using the 52-mg LNG-IUS in these high-risk populations.


	A 21-year-old G0P0 presents with amenorrhea for 6 months using intramuscular (IM) DMPA, which was started for menorrhagia. She is not sexually active and tells you she “doesn’t want a foreign object in my body.” Her friend was recently diagnosed with deep vein thrombosis after a car accident and leg fracture. Although your patient doesn’t have any other personal risk factors for VTE, she is concerned about her own VTE risk on an upcoming trip while using DMPA.   

You counsel your patient that a meta-analysis that found no increased VTE risk with other progestin-only agents did find a doubling in VTE risk with DMPA use.

 Despite this increased relative risk, the baseline risk of VTE is 1 to 10 per 10,000 yearly in a young, healthy population,

 so her absolute risk of VTE remains low on the order of 2 to 20 per 10,000. MEC guidelines are category 2 (benefits generally outweigh risks) for DMPA use in women with current VTE, history of VTE, or risk factors for it.

 You discuss with your patient that estrogen-containing options including COC pills would also be an option for her, however, they increase VTE risk 3-5 fold,

 which is a greater risk compared to progestin-only agents.


	Injectable DMPA is FDA-approved for prevention of pregnancy at a dose of 150 mg IM every 3 months.

 Contraindications listed on the package insert include active VTE and history of VTE.

A 2012 Dutch metaanalysis in women at low risk of VTE found no increased risk of VTE among overall users of a progestin-only contraceptive compared to non-users (relative risk 1.03; 95% CI 0.76 to 1.39). Importantly, the subgroup analysis of DMPA users demonstrated that, unlike other progestin-only options like the LNG-IUS and norethindrone, DMPA was associated with a doubling in VTE risk compared to that in non-users of hormones (relative risk 2.67; 95% CI 1.29 to 5.53).

Two studies assessed VTE risk with DMPA use in populations at higher VTE risk. The first found a trend toward an increased risk of VTE in smokers using DMPA (OR 7.0; 95% CI 0.4–138) compared to smokers not using hormones (OR 1.3; 95% CI 0.97–1.6), however, the confidence intervals were wide and the results were not statistically significant.

 The second is a case control study of women with Factor V Leiden mutations, which found no increased risk of VTE in women using other progestin-only agents, however, an increased risk of VTE was found in users of DMPA (OR 2.2; 95% CI 1.3-4.0).


	A 41-year-old G3P3 with a tubal ligation, migraine with aura, depression, and VTE during her third pregnancy presents to the Emergency Department with regular heavy menstrual bleeding. She has been bleeding for 5 days and is hemodynamically stable with moderate continued bleeding and a hemoglobin of 9.2 g/dL. 

You counsel your patient that due to her migraine with aura and history of VTE, estrogen-containing medications are not an option for her (MEC category 4, unacceptable health risk with method).

 However, for a rapid response and amenorrhea, contraceptive dosing of progestins may not be adequate. Available evidence shows that contraceptive doses of norethindrone acetate (0.35 mg) do not increase VTE risk. However, VTE data on higher doses of norethindrone acetate 2.5 mg to 15 mg commonly used for AUB

 are less clear. Your patient elects to start norethindrone acetate 2.5 mg and you both agree to start with the lowest dose that controls her bleeding. You schedule follow-up in your clinic to discuss longer-term options including the LNG-IUS and endometrial ablation. 


	Norethindrone acetate is FDA-approved for contraception at a dose of 0.35 mg, and for secondary amenorrhea, endometriosis, and AUB at a dose of 5 to 15 mg.

 The FDA does list “active deep vein thrombosis, pulmonary embolism or history of these conditions” as a contraindication for use of the higher doses of norethindrone but not for the contraceptive dose.

Several large studies on norethindrone acetate 0.35 mg used for contraception conclude that there is no increased risk of VTE with this dose.

 However, there are no studies on VTE risk with the higher doses of the drug used to manage AUB. Interestingly, a small study measured in vivo conversion of norethindrone acetate to ethinyl estradiol and concluded that 20 mg of norethindrone acetate may be equivalent to taking a pill containing 30 mcg of ethinyl estradiol.

 Prior small studies had varied results, with one suggesting no clinically significant conversion,

 another suggesting significant conversion at higher doses of norethindrone acetate,

 and a third suggesting rates of conversation of 6 µg ethinyl estradiol per 1 mg norethindrone acetate which could be significant based on dose.

 The in vivo impact of this conversion on VTE risk has not been evaluated, however, these findings could have implications for the VTE risk of the higher doses of norethindrone acetate used for AUB.

Oral medroxyprogesterone acetate is also used for AUB management at a dose of 5 to 10 mg, and is an option in this scenario. Little research has been done on VTE risk with oral medroxyprogesterone in premenopausal woman. A single relevant study was identified that included low-risk patients taking oral Provera; there was no association between VTE and progestin-only agents including oral medroxyprogesterone acetate, however, the size was small.

 Clearly, this is an area where more research is needed. 


	DD is a 52-year-old G2P2 obese, perimenopausal hypertensive and diabetic woman with irregular heavy bleeding. You perform an in-office endometrial biopsy, which demonstrates disordered proliferative endometrium. She is started on norethindrone acetate 5 mg daily, increased to 15 mg, however, she continues to bleed heavily.

These four patient cases can help improve your decision-making about the best hormonal regimen for this population.

Elisabeth Quint, MD

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