Case Report
Herpes Simplex Virus Cervicitis Mimicking Preterm Premature Rupture of Membranes Christina N. Cordeiro, MD, Janyne Althaus, MD, Anne Burke, MD, and Cynthia Argani, MD BACKGROUND: The diagnosis of preterm premature rupture of membranes (PROM) is based on pooling, ferning, and Nitrazine tests; definitive diagnosis is made with a blue dye test. CASE: A 21-year-old woman, gravida 1 para 0, at 25 5/7 weeks of gestation was admitted for preterm PROM with positive findings of pooling, Nitrazine, and ferning. Her cervix was bluish with white plaques. Amniotic fluid volume was normal. On hospital day 8, her discharge ceased; examination was negative for pooling, Nitrazine, and ferning. A blue dye tampon test was negative. A Pap test result from her hospitalization returned consistent with herpes infection. CONCLUSION: The diagnosis of preterm PROM should be constantly reevaluated in the setting of a normal amniotic fluid volume. (Obstet Gynecol 2015;126:378–80) DOI: 10.1097/AOG.0000000000000700
I
n this case report, we describe a patient who was initially diagnosed with preterm premature rupture of membranes (PROM). A blue dye test was performed, which was negative, and the patient was ultimately diagnosed with herpetic cervicitis that had mimicked preterm PROM.
CASE The patient is a 21-year-old woman, gravida 1 para 0, at 25 5/7 weeks of gestation transferred to our tertiary care center with a diagnosis of preterm PROM. At the transferring From the Johns Hopkins Hospital Bayview Medical Center, Johns Hopkins University, Baltimore, Maryland. Corresponding author: Christina N. Cordeiro, MD, Johns Hopkins Hospital Bayview Medical Center, Johns Hopkins University, 777 South Eden Street #1108, Baltimore, MD 21231; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/15
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Teaching Points 1. The diagnosis of preterm premature rupture of membranes is made based on pooling, Nitrazine, and ferning tests; however, in equivocal cases, it should be confirmed with a blue dye test. 2. The diagnosis of preterm premature rupture of membranes should be reevaluated periodically in the setting of a normal amniotic fluid index. 3. Herpes simplex virus infection can be detected on a Pap test.
hospital, she had received magnesium sulfate, betamethasone, and penicillin owing to a concern for preterm labor. On arrival, the patient denied vaginal bleeding and contractions but reported leakage of fluid. Gross vaginal pooling was seen on speculum examination, and the fluid was both Nitrazine- and ferning-positive. Her cervix had multiple white plaques against a bluish stromal background, concerning for possible malignancy or premalignancy. The patient’s medical history and antepartum course were notable for hypertension and morbid obesity. At 20 weeks of gestation, she was started on 250 mg methyldopa twice daily, which was discontinued after 2 weeks secondary to premature ventricular complexes. Blood pressures at her prenatal visits ranged from 130s to 140s/60s to 80s mm Hg. She was also morbidly obese, with a body mass index (calculated as weight (kg)/[height (m)]2) of 40. Her prenatal laboratory values were unremarkable. The patient denied a history of abnormal Pap test results or sexually transmitted infections. She had no prior surgeries and denied alcohol, tobacco, or intravenous drug use. The patient was admitted and started on ampicillin and erythromycin. Magnesium was discontinued after she received her second dose of betamethasone on hospital day 2. An ultrasound scan performed on admission demonstrated a normal amniotic fluid index of 11.7 cm; however, she continued to report leakage of clear fluid. Results of gonorrhea and chlamydia cultures obtained on admission were negative. On hospital day 3, she stated her leakage of fluid had decreased significantly, and by hospital day 8 it had ceased entirely. An amniotic fluid index was repeated on hospital day 7 and was again normal (12.7 cm). A repeat speculum examination demonstrated a brown discharge with a normal pH, no pooling, and no ferning. Fetal fibronectin obtained at that time returned positive. The white lesions seen on her initial examination were absent. A Pap test was performed at that time. On hospital day 10, in the setting of normal amniotic fluid indices, a blue dye tampon test was performed, which was negative for ruptured membranes. The patient was discharged to home under the care of her primary obstetrician later that day, undelivered.
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
After discharge, the Pap test result returned showing cellular changes consistent with herpes simplex virus (HSV) infection. The patient was informed regarding this diagnosis and started on valacyclovir. She continued care with her primary obstetrician and eventually had a cesarean delivery at 38 6/7 weeks of gestation for failure to progress after onset of spontaneous labor. She delivered a 7-pound 14-ounce male neonate with Apgar scores of 8 and 9 without complications. The neonate displayed no signs of herpetic infection.
DISCUSSION This case represents a unique presentation of HSV infection in pregnancy, which was initially misdiagnosed as preterm PROM. The diagnosis of preterm PROM is typically made through a speculum examination evaluating for fluid pooling, ferning, and Nitrazine to test vaginal pH. One study evaluating the efficacy of this method, giving the diagnosis if two of the aforementioned three conditions were present, reported a sensitivity of 85%, specificity of 98%, and positive and negative predictive values of 99% and 77%, respectively. The positive and negative predictive values reported for ferning were 80% and 99% and for Nitrazine, 90% and 88%.1 Based on the patient’s lack of symptoms and lack of knowledge regarding any history of infection with HSV, this case likely represents a primary HSV outbreak. It has been estimated that in the United States, approximately 22% of pregnant women are infected with HSV-2, the virus most commonly associated with sexually transmitted anogenital lesions. Two percent of women acquire a primary infection during pregnancy.2 Typically, primary symptomatic genital herpes presents with blistering and ulceration of the external genitalia and cervix.2,3 In a prospective analysis of primary HSV infections, lesions were described as ulcers (HSV-1, 75%; HSV-2, 52%), vesicles (HSV-1, 64%; HSV-2, 48%), and papules (HSV-1, 61%; HSV-2, 57%).4 Additionally, 90% of patients with primary symptomatic HSV infections describe pain, burning, or itching in affected areas4 or constitutional symptoms such as fevers, headaches, myalgias, or, occasionally, urinary retention secondary to autonomic neuropathy.2,3 In this case, the patient’s only symptom was watery discharge, and the only lesions present were an asymptomatic bluish ectocervix with multiple white cervical plaques, which regressed 8 days later. Her lesions were, in fact, more concerning for a premalignant or malignant lesion of the cervix, prompting a Pap test on repeat speculum examination. Cervical disease is uncommon in HSV infections; in
VOL. 126, NO. 2, AUGUST 2015
one study of HSV infections, only five of 10 patients had HSV DNA detectable on cervicovaginal lavage samples when they had clinically recognizable lesions of the external genitalia.5 The patient’s only subjective complaint, as mentioned, was leakage of fluid; this symptom is consistent with herpetic infection. In the aforementioned study of primary herpes infections, 50% of patients reported vaginal discharge.4 Another study reported that women with herpes infections recalled a history of thin watery discharge6 specifically. This case, in which traditional criteria for diagnosis of preterm PROM were met, yet the amniotic fluid index remained normal, serves as a poignant reminder of the importance of maintaining differential diagnoses in situations in which clinical pictures are not entirely consistent with a given diagnosis. The reason for the falsepositive tests is unclear. Perhaps the cervix was producing copious, more watery mucus as a result of the HSV infection. Her fetal fibronectin test may have been positive in the setting of recent speculum examinations. The inflammatory exudate may have been sufficiently salinic to fern under microscopy or the ferns may have in fact been cervical mucous ferns. Contamination on the slide is possible, although the ferning tests were positive at two different hospitals, making this explanation less likely. Diagnosis of HSV infection in this case was made through findings on a Pap test result. Herpetic infections are classically described as containing multinucleated giant cells with nuclei having a ground glass appearance and prominent eosinophilic inclusions (also known as Cowdry A nuclei).6 Typically, genital herpes is diagnosed through detection of viral DNA through polymerase chain reaction (100% specific, 99% sensitive), by culture of the genital tract, or by antibody detection.2,3,7 Confirmatory diagnoses are made through serologic testing of antibodies to HSV or viral culture. Several authors have reported polymerase chain reaction as a reliable alternative method of diagnosis. In one study, Bukhari et al6 detected HSV infection on Pap test results in 1.8% of cases (seven patients) based on cell changes as described previously. Additionally, Fiel-Gan et al8 previously reported the use of HSV DNA detection using specimens in ThinPrep fixative to decrease false-positive diagnoses of HSV, which may result in unnecessary cesarean deliveries. Further study is needed with respect to the costeffectiveness of this type of screening as well as the sensitivity and specificity of such methods in detecting primary or secondary HSV infections. This case report highlights the importance of constantly reevaluating a diagnosis of preterm PROM
Cordeiro et al
Herpes Cervicitis Mimics Preterm PROM
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
379
in the setting of a normal amniotic fluid volume, because other disease processes can produce findings that give a false-positive diagnosis of preterm PROM using standard diagnostic criteria. REFERENCES 1. Thomasino T, Levi C, Draper M, Neubert AG. Diagnosing rupture of membranes using combination monoclonal/polyclonal immunologic protein detection. J Reprod Med 2013;58:187–94. 2. Straface G, Selmin A, Zanardo V, De Santis M, Ercoli A, Scambia G. Herpes simplex virus infection in pregnancy. Infect Dis Obstet Gynecol 2012;2012:385697. 3. Sauerbrei A, Wutzler P. Herpes simplex and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therapy. part 1: herpes simplex virus infections. Med Microbiol Immunol 2007;196:89–94. 4. Bernstein DI, Bellamy AR, Hook EW III, Levin MJ, Wald A, Ewell MG, et al. Epidemiology, clinical presentation, and
380
Cordeiro et al
antibody response in primary infection with herpes simplex virus type 1 and type 2 in young women. Clin Infect Dis 2013;56: 344–51. 5. Keller MJ, Madan RP, Shust G, Carpenter CA, Torres NM, Cho S, et al. Changes in the soluble mucosal immune environment during genital herpes outbreaks. J Acquir Immune Defic Syndr 2012;61:194–202. 6. Bukhari MH, Majeed M, Qamar S, Niazi S, Syed SZ, Yusuf AW, et al. Clinicopathological study of Papanicolaou (Pap) smears for diagnosing of cervical infections. Diagn Cytopathol 2012; 40:35–41. 7. Peña KC, Adelson ME, Mordechai E, Blaho JA. Genital herpes simplex virus type 1 in women: detection in cervicovaginal specimens from gynecologic practices in the United States. J Clin Microbiol 2010;48:150–3. 8. Fiel-Gan MD, Villamil CF, Mandavilli SR, Ludwig ME, Tsongalis GJ. Rapid detection of HSV from cytologic specimens collected into ThinPrep fixative. Acta Cytol 1999;43: 1034–8.
Herpes Cervicitis Mimics Preterm PROM
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Herpes Simplex Virus Cervicitis Mimicking Preterm Premature Rupture of Membranes Christina N. Cordeiro, MD, Janyne Althaus, MD, Anne Burke, MD, and Cynthia Argani, MD BACKGROUND: The diagnosis of preterm premature rupture of membranes (PROM) is based on pooling, ferning, and Nitrazine tests; definitive diagnosis is made with a blue dye test. CASE: A 21-year-old woman, gravida 1 para 0, at 25 5/7 weeks of gestation was admitted for preterm PROM with positive findings of pooling, Nitrazine, and ferning. Her cervix was bluish with white plaques. Amniotic fluid volume was normal. On hospital day 8, her discharge ceased; examination was negative for pooling, Nitrazine, and ferning. A blue dye tampon test was negative. A Pap test result from her hospitalization returned consistent with herpes infection. CONCLUSION: The diagnosis of preterm PROM should be constantly reevaluated in the setting of a normal amniotic fluid volume. (Obstet Gynecol 2015;126:378–80) DOI: 10.1097/AOG.0000000000000700
I
n this case report, we describe a patient who was initially diagnosed with preterm premature rupture of membranes (PROM). A blue dye test was performed, which was negative, and the patient was ultimately diagnosed with herpetic cervicitis that had mimicked preterm PROM.
CASE The patient is a 21-year-old woman, gravida 1 para 0, at 25 5/7 weeks of gestation transferred to our tertiary care center with a diagnosis of preterm PROM. At the transferring From the Johns Hopkins Hospital Bayview Medical Center, Johns Hopkins University, Baltimore, Maryland. Corresponding author: Christina N. Cordeiro, MD, Johns Hopkins Hospital Bayview Medical Center, Johns Hopkins University, 777 South Eden Street #1108, Baltimore, MD 21231; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/15
378
VOL. 126, NO. 2, AUGUST 2015
Teaching Points 1. The diagnosis of preterm premature rupture of membranes is made based on pooling, Nitrazine, and ferning tests; however, in equivocal cases, it should be confirmed with a blue dye test. 2. The diagnosis of preterm premature rupture of membranes should be reevaluated periodically in the setting of a normal amniotic fluid index. 3. Herpes simplex virus infection can be detected on a Pap test.
hospital, she had received magnesium sulfate, betamethasone, and penicillin owing to a concern for preterm labor. On arrival, the patient denied vaginal bleeding and contractions but reported leakage of fluid. Gross vaginal pooling was seen on speculum examination, and the fluid was both Nitrazine- and ferning-positive. Her cervix had multiple white plaques against a bluish stromal background, concerning for possible malignancy or premalignancy. The patient’s medical history and antepartum course were notable for hypertension and morbid obesity. At 20 weeks of gestation, she was started on 250 mg methyldopa twice daily, which was discontinued after 2 weeks secondary to premature ventricular complexes. Blood pressures at her prenatal visits ranged from 130s to 140s/60s to 80s mm Hg. She was also morbidly obese, with a body mass index (calculated as weight (kg)/[height (m)]2) of 40. Her prenatal laboratory values were unremarkable. The patient denied a history of abnormal Pap test results or sexually transmitted infections. She had no prior surgeries and denied alcohol, tobacco, or intravenous drug use. The patient was admitted and started on ampicillin and erythromycin. Magnesium was discontinued after she received her second dose of betamethasone on hospital day 2. An ultrasound scan performed on admission demonstrated a normal amniotic fluid index of 11.7 cm; however, she continued to report leakage of clear fluid. Results of gonorrhea and chlamydia cultures obtained on admission were negative. On hospital day 3, she stated her leakage of fluid had decreased significantly, and by hospital day 8 it had ceased entirely. An amniotic fluid index was repeated on hospital day 7 and was again normal (12.7 cm). A repeat speculum examination demonstrated a brown discharge with a normal pH, no pooling, and no ferning. Fetal fibronectin obtained at that time returned positive. The white lesions seen on her initial examination were absent. A Pap test was performed at that time. On hospital day 10, in the setting of normal amniotic fluid indices, a blue dye tampon test was performed, which was negative for ruptured membranes. The patient was discharged to home under the care of her primary obstetrician later that day, undelivered.
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
After discharge, the Pap test result returned showing cellular changes consistent with herpes simplex virus (HSV) infection. The patient was informed regarding this diagnosis and started on valacyclovir. She continued care with her primary obstetrician and eventually had a cesarean delivery at 38 6/7 weeks of gestation for failure to progress after onset of spontaneous labor. She delivered a 7-pound 14-ounce male neonate with Apgar scores of 8 and 9 without complications. The neonate displayed no signs of herpetic infection.
DISCUSSION This case represents a unique presentation of HSV infection in pregnancy, which was initially misdiagnosed as preterm PROM. The diagnosis of preterm PROM is typically made through a speculum examination evaluating for fluid pooling, ferning, and Nitrazine to test vaginal pH. One study evaluating the efficacy of this method, giving the diagnosis if two of the aforementioned three conditions were present, reported a sensitivity of 85%, specificity of 98%, and positive and negative predictive values of 99% and 77%, respectively. The positive and negative predictive values reported for ferning were 80% and 99% and for Nitrazine, 90% and 88%.1 Based on the patient’s lack of symptoms and lack of knowledge regarding any history of infection with HSV, this case likely represents a primary HSV outbreak. It has been estimated that in the United States, approximately 22% of pregnant women are infected with HSV-2, the virus most commonly associated with sexually transmitted anogenital lesions. Two percent of women acquire a primary infection during pregnancy.2 Typically, primary symptomatic genital herpes presents with blistering and ulceration of the external genitalia and cervix.2,3 In a prospective analysis of primary HSV infections, lesions were described as ulcers (HSV-1, 75%; HSV-2, 52%), vesicles (HSV-1, 64%; HSV-2, 48%), and papules (HSV-1, 61%; HSV-2, 57%).4 Additionally, 90% of patients with primary symptomatic HSV infections describe pain, burning, or itching in affected areas4 or constitutional symptoms such as fevers, headaches, myalgias, or, occasionally, urinary retention secondary to autonomic neuropathy.2,3 In this case, the patient’s only symptom was watery discharge, and the only lesions present were an asymptomatic bluish ectocervix with multiple white cervical plaques, which regressed 8 days later. Her lesions were, in fact, more concerning for a premalignant or malignant lesion of the cervix, prompting a Pap test on repeat speculum examination. Cervical disease is uncommon in HSV infections; in
VOL. 126, NO. 2, AUGUST 2015
one study of HSV infections, only five of 10 patients had HSV DNA detectable on cervicovaginal lavage samples when they had clinically recognizable lesions of the external genitalia.5 The patient’s only subjective complaint, as mentioned, was leakage of fluid; this symptom is consistent with herpetic infection. In the aforementioned study of primary herpes infections, 50% of patients reported vaginal discharge.4 Another study reported that women with herpes infections recalled a history of thin watery discharge6 specifically. This case, in which traditional criteria for diagnosis of preterm PROM were met, yet the amniotic fluid index remained normal, serves as a poignant reminder of the importance of maintaining differential diagnoses in situations in which clinical pictures are not entirely consistent with a given diagnosis. The reason for the falsepositive tests is unclear. Perhaps the cervix was producing copious, more watery mucus as a result of the HSV infection. Her fetal fibronectin test may have been positive in the setting of recent speculum examinations. The inflammatory exudate may have been sufficiently salinic to fern under microscopy or the ferns may have in fact been cervical mucous ferns. Contamination on the slide is possible, although the ferning tests were positive at two different hospitals, making this explanation less likely. Diagnosis of HSV infection in this case was made through findings on a Pap test result. Herpetic infections are classically described as containing multinucleated giant cells with nuclei having a ground glass appearance and prominent eosinophilic inclusions (also known as Cowdry A nuclei).6 Typically, genital herpes is diagnosed through detection of viral DNA through polymerase chain reaction (100% specific, 99% sensitive), by culture of the genital tract, or by antibody detection.2,3,7 Confirmatory diagnoses are made through serologic testing of antibodies to HSV or viral culture. Several authors have reported polymerase chain reaction as a reliable alternative method of diagnosis. In one study, Bukhari et al6 detected HSV infection on Pap test results in 1.8% of cases (seven patients) based on cell changes as described previously. Additionally, Fiel-Gan et al8 previously reported the use of HSV DNA detection using specimens in ThinPrep fixative to decrease false-positive diagnoses of HSV, which may result in unnecessary cesarean deliveries. Further study is needed with respect to the costeffectiveness of this type of screening as well as the sensitivity and specificity of such methods in detecting primary or secondary HSV infections. This case report highlights the importance of constantly reevaluating a diagnosis of preterm PROM
Cordeiro et al
Herpes Cervicitis Mimics Preterm PROM
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
379
in the setting of a normal amniotic fluid volume, because other disease processes can produce findings that give a false-positive diagnosis of preterm PROM using standard diagnostic criteria. REFERENCES 1. Thomasino T, Levi C, Draper M, Neubert AG. Diagnosing rupture of membranes using combination monoclonal/polyclonal immunologic protein detection. J Reprod Med 2013;58:187–94. 2. Straface G, Selmin A, Zanardo V, De Santis M, Ercoli A, Scambia G. Herpes simplex virus infection in pregnancy. Infect Dis Obstet Gynecol 2012;2012:385697. 3. Sauerbrei A, Wutzler P. Herpes simplex and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therapy. part 1: herpes simplex virus infections. Med Microbiol Immunol 2007;196:89–94. 4. Bernstein DI, Bellamy AR, Hook EW III, Levin MJ, Wald A, Ewell MG, et al. Epidemiology, clinical presentation, and
380
Cordeiro et al
antibody response in primary infection with herpes simplex virus type 1 and type 2 in young women. Clin Infect Dis 2013;56: 344–51. 5. Keller MJ, Madan RP, Shust G, Carpenter CA, Torres NM, Cho S, et al. Changes in the soluble mucosal immune environment during genital herpes outbreaks. J Acquir Immune Defic Syndr 2012;61:194–202. 6. Bukhari MH, Majeed M, Qamar S, Niazi S, Syed SZ, Yusuf AW, et al. Clinicopathological study of Papanicolaou (Pap) smears for diagnosing of cervical infections. Diagn Cytopathol 2012; 40:35–41. 7. Peña KC, Adelson ME, Mordechai E, Blaho JA. Genital herpes simplex virus type 1 in women: detection in cervicovaginal specimens from gynecologic practices in the United States. J Clin Microbiol 2010;48:150–3. 8. Fiel-Gan MD, Villamil CF, Mandavilli SR, Ludwig ME, Tsongalis GJ. Rapid detection of HSV from cytologic specimens collected into ThinPrep fixative. Acta Cytol 1999;43: 1034–8.
Herpes Cervicitis Mimics Preterm PROM
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
