Volume 3 Issue 8, August 2016

Editorial

Gupta AS

Women with complaints of pruritus vulvae, vulval pain, change in skin texture or color and any vulval lesions many a times consult a gynecologist rather than a dermatologist. Gynecologist has to be aware of the various epithelial and non epithelial lesions of the vulva and should be able to differentiate the normal variations from the abnormal lesions and benign from the malignant conditions. Some of these may represent systemic disease processes involving various mucocutaneous areas or they may be localized to the vulva. Reaching a clinical diagnosis needs good history taking, physical examination that includes the study of the morphology of the lesions and when required laboratory investigations.
The detailed history should elicit the onset, duration and progress of the lesions, symptoms associated with the lesion like itching, bleeding, discharge, and pain. Symptoms related to systemic involvement also need to be elicited like fever, joint pains, weight loss, etc. History should elicit sexually transmitted diseases, diabetes, or thyroid disorders, iron deficiency anemia, any history of urinary or fecal incontinence, use of various toiletries and personal care products. History of autoimmune disorders should be elicited in cases of suspected lichen planus with erosion's and lichen sclerosis. Specific attention should be directed towards examination of other mucosal surfaces like the naso-oral cavity, anal mucosa and vagina.  
The examination under good illumination and position should focus on morphology of the lesions. This includes using a noun to define the lesion like macule, papule, pustule, vesicle, plaque, patch, bulla, cyst, edema, erosion, excoriation, fissure, rash and ulcer. An adjective is used to describe each of these nouns like color (red, white, blue, brown, black, skin colored), margins (well demarcated, sharp, blurred, or poorly demarcated with a gradual change from the normal to the abnormal area), surface (rough or smooth is described after palpation), and shape or configuration of the lesion. Roughness of the surface is due to the formation of a crust or scale that occurs due to break in the epithelium and subsequent increase in the proliferative activity of the epithelium. Secondary changes like excoriation, lichenification, fissure, edema of the lesion should be documented. The number, site and formation of groups should also be studied. Further more these lesions may be polymorphic wherein the presentation may occur in more than one way as in Molluscum contagiousm. Examination of regional lymph nodes should not be forgotten. Colposcopy can be done to aid clinical examination and identify the area for taking the biopsy in suspected cases of genital warts, hyperkeratosis, HSIL or malignancy, or failure of treatment but is not required in all cases which can be clinically diagnosed especially vulval dermatoses.
Vulval disorders that are benign include vulvar atrophy, non neoplastic epithelial disorders, tumors, cysts. Benign tumors are not frequently seen on the vulva. These would include fibroma, lipoma, angiomyxoma, fibromyoma, hemangiomas, bartholins cysts. These would be managed surgically.
I hope the readers find the cases in the August issue of our journal interesting and gain some insight on reading the various aspects of these cases. This issue has one unusual case report of a keloid on the vulva which I hope the readers would like.

Extensive Intraperitoneal Calcification

Author Information

Parulekar SV
(Professor and Head, Department of Obstetrics and Gynecology, Seth GS Medical College & KEM Hospital, Mumbai, India.)

Abstract

Intraperitoneal calcification is an uncommon condition. It may be due to any one of a large number of conditions. All of these conditions are important. Unless a correct diagnosis is made in time and treatment is given, there can be serious consequences for the patient. A case of abdominal tuberculosis with an unusual presentation is presented.

Introduction

Extensive intraperitoneal calcification is the result of chronic irritation of peritoneum, as seen with tuberculosis,[1,2,3] chronic peritoneal dialysis,[4,5,6] rupture of an ovarian benign cystic teratoma,[7,8] hyperparathyroidism,[9] use of iodinated contrast material,[10] primary peritoneal serous psammocarcinoma,[11] and metastases to peritoneum from ovarian serous cystadenocarcinoma.[12] Some of these patients have symptoms and signs of the disease causing the calcification, while the others are asymptomatic. Such calcifications are rarely benign. Extensive evaluation may be required before a diagnosis can be made. A case of tuberculosis causing extensive peritoneal calcification is presented.

Case Report

A 25 year old woman presented with primary infertility. She had been diagnosed to have had a silent rupture of an ovarian benign cystic teratoma causing extensive intraperitoneal calcification on hysterosalpingography by another doctor (figure 1).


Figure 1. Hysterosalpingogram showing extensive intraperitoneal calcification. A large calcific shadow is seen above the uterus, on the left side of the midline (yellow arrows). The uterus is of normal size and shape. Both the fallopian tubes are blocked in the ampullary portions (pink arrows). There is venous intravasation of the dye (green arrows).

She had been married for four years and had not used any contraception at any time. Her menstrual cycles were regular, every 28 days, mildly painful, and with a moderate flow. There was no history of tuberculosis or contact with tuberculosis. There was no history of an acute abdomen in the past, which would have been expected in case of a rupture of an ovarian benign cystic teratoma. There were no bowel and bladder complaints. There was no history of chronic renal disease or peritoneal dialysis. There was no history suggestive of hyperparathyroidism. She had not undergone any operative procedure.. Her general and systemic examination revealed no abnormality. The breasts were normal. Abdominal examination revealed a firm, nontender mass measuring 3-4 cm in diameter, below and to the left of the umbilicus. The uterus was of normal size and mobile on bimanual pelvic examination. There was no adnexal mass. Speculum examination of the vagina revealed no abnormality. Her hemogram, urinalysis, fasting and postprandial blood sugar levels, liver and renal function tests including electrolyte levels showed no abnormality. Chest radiograph was normal. A contrast enhanced computerized tomography (CECT) was performed on her. It showed a calcific mass measuring 4 cm in diameter below the anterior abdominal wall below the level of the umbilicus, and scattered calcific lesions within the peritoneal cavity. The liver, spleen and gastrointestinal tract were normal. The left kidney was normal while the right kidney was absent. A sliding test was done, which showed no adhesions of bowel or omentum to the anterior abdominal wall.[13]


Figure 2. CECT of abdomen and pelvis, anteroposterior view. A large calcific lesion is seen (arrows).


Figure 3. CECT of abdomen and pelvis, transverse view. Left kidney (arrow) is seen, while the right kidney is absent.

A provisional diagnosis of abdominal tuberculosis was made, with a differential diagnosis of silent rupture of a benign cystic teratoma of an ovary. An open laparoscopy with Hassan’s technique was performed. It showed pelvic and intraperitoneal adhesions and scattered calcific nodules measuring 4 to 6 mm in diameter. A minilaparotomy was performed. A 4-5 cm diameter irregular cheesy mass was removed from omentum. Two calcific nodules were also removed. Bilateral tuboovarian masses were detected. Chromopertubation showed intravasation of methylene blue into the myometrium and no spill through the fallopian tubes. Bowel appeared normal. The abdomen was closed. The patient made an uneventful recovery. Histopathological examination of the cheesy mass confirmed the diagnosis of tuberculosis. The patient was put on antituberculous therapy and counseled to undergo in vitro fertilization and embryo transfer after completion of the antituberculous therapy, or adopt a child.


Figure 4. Omental lesion 

Discussion

When a patient has a disease that can cause extensive intraperitoneal adhesions, finding the same comes as no surprise and it usually does not alter the course of the treatment. Chronic peritoneal dialysis is an example of such a situation. But when it is accidentally discovered when the patient is being investigated for some other reason, it needs to be evaluated critically. Such a patient can suffering from a serious disorder like tuberculosis, rupture of an ovarian benign cystic teratoma, hyperparathyroidism, psammocarcinoma, carcinomatosis, and metastases to peritoneum from ovarian serous cystadenocarcinoma. Ultrasonography, CECT and magnetic resonance imaging can help differentiate the conditions to a large extent. Hyperparathyroidism requires assay of serum calcium and parathormone for diagnosis. The final diagnosis may require histopathological examination of the lesion, the tissue being obtained by laparoscopy or laparotomy. A viscera sliding test is recommended to diagnose adhesions of bowel and/or omentum to the anterior abdominal wall.[13] An open laparoscopy is recommended to avoid injury bowel and/or omentum to the anterior abdominal wall prior to a laparoscopy or laparotomy.[14]

In the case presented, a negative history ruled out chronic renal disease treated with peritoneal dialyses and radiographic study with iodinated contrast material. It made the diagnosis of a silent rupture of a benign cystic teratoma of an ovary unlikely. An absence of any abdominal abnormality made primary peritoneal malignancy unlikely. Absence of an ovarian tumor on ultrasonography and CECT made metastases from an ovarian papillary serous cystadenocarcinoma unlikely. This tuberculosis was the most likely diagnosis. It was confirmed by histopathological examination of a lesion in the omentum. What made the case unusual was that there was no involvement of the bowel with peritoneal tuberculosis, no significant intraperitoneal adhesions, and presence of only scattered calcific lesions which did not affect the function of the abdominal organs in any adverse way. Her infertility was the result of genital tuberculosis. It is possible that she has a tuberculous pyosalpinx, which leaked into the peritoneal cavity and produced scattered lesions all over the peritoneal cavity.

Acknowledgment

I thank Dr Neha Agrawal for taking pictures of the imaging films and intraoperative findings.

References
  1. Roy KK, Banerjee N, Sinha A. Diffuse peritoneal calcification: a rare manifestation of abdominal tuberculosis. Int J Gynaecol Obstet 2001; 73:269 –270.
  2. Bhansali SK. Abdominal tuberculosis: experiences with 300 cases. Am J Gastroenterol 1977; 67:324–337.
  3. Lundstedt C, Nyman R, Brismar J, Hugosson C, Kagevi I. Imaging of tuberculosis. II. Abdominal manifestations in 112 patients. Acta Radiol 1996; 37:489 –495.
  4. Krediet R.T., Zweers M.M., van Westrhenen R. What can we do to preserve the peritoneum? Perit Dial Int. 2003;23:14–19.
  5. Maruyama Y., Nakayama M. Encapsulating peritoneal sclerosis in Japan. Perit Dial Int. 2008;28:201–204.
  6. Gayomali C., Hussein U., Cameron S.F., Protopapas Z., Finkelstein F.O. Incidence of encapsulating peritoneal sclerosis: a single-center experience with long-term peritoneal dialysis in the United States. Perit Dial Int. 2011;31:279–286.
  7. Fibus TF. Intraperitoneal rupture of a benign cystic ovarian teratoma: findings at CT and MR imaging. AJR Am J Roentgenol. 2000;174 (1): 261-2.
  8. Park SB, Kim JK, Kim KR et-al. Imaging findings of complications and unusual manifestations of ovarian teratomas. Radiographics. 28 (4): 969-83.
  9. Kuo C.W., Lee P.T., Fang H.C., Chou K.J., Chung H.M., Chen C.L. Extensive peritoneal calcifications as a complication of long-term peritoneal dialysis and secondary hyperparathyroidism: a case report and review of the literature. Perit Dial Int. 2006;26:609–613.
  10. Eisenberg A.D., Winfield A.C., Page D.L., Holburn G.E., Schifter T., Segars J.H. Peritoneal reaction resulting from iodinated contrast material: comparative study. Radiology. 1989;172:149–151.
  11. Togănel RD, Ioan Şimon I, Zolog A, Simescu R, Cozma A, Muntean V. Primary Peritoneal Serous Psammocarcinoma: a Case Report. JGLD 2014 Available from: http://www.jgld.ro/2015/2/23.html.
  12. Joshi D, Kaushik S, Larsen-Disney P, Bush J. Severely calcified peritoneal metastases masquerading as retained barium on CT scan. BMJ Case Reports 2015; doi:10.1136/bcr-2015-211487.
  13. Larciprete G, Valli E, Meloni P, Malandrenis I, Romanini ME, Jarvis S, et al. Ultrasound detection of the "sliding viscera" sign promotes safer laparoscopy. J Minim Invasive Gynecol. 2009 Jul-Aug;16(4):445-9.
  14. Hasson HM, Rotman C, Rana N, Kumari NA. Open laparoscopy: 29-year experience. Obstet Gynecol 2000;96:63–6.
Citation

Parulekar SV. Extensive Intraperitoneal Calcification. JPGO 2016. Volume 3 No. 8. Available from: http://www.jpgo.org/2016/08/extensive-intraperitoneal-calcification.html

Vulvar Keloid Following Friction Burns

Author Information

Parulekar SV
(Professor and Head, Department of Obstetrics and Gynecology, Seth G S Medical College & KEM Hospital, Mumbai, India.)

Abstract

A keloid is the result of an abnormal and excessive formation of scar tissue, usually following burns. It differs from a hypertrophic scar in that it extends beyond the limits of the original injury, tends to spread, and recur after excision. A case of keloid formation following friction burns on the vulva is presented. It is the first such case in the world literature.

Introduction

The word keloid originates from the Greek word ‘chele’, which means ‘crab claw’. It is the result of an aberrant healing process seen in some persons, characterized by formation of excessive scar tissue which extends beyond the limits of the original wound.[1] Both environmental and genetic factors are involved in formation of keloids.[2] A person predisposed to keloid formation may have keloids in multiple sites. It is more common in burns scars. Common sites of keloid formation include ear lobes, chest, upper back and shoulders. It has rarely been reported on the vulva.[3] A case of keloid formation following friction burns on the vulva is presented. It is the first such case in the world literature.

Case Report

A 21 year old single girl presented with a complaint of a mass of the right side of the vulva for 2.5 years. It had developed after she underwent an orthopedic operation on the neck of the right femur. She had intense burning pain on the right side of the vulva after the operation, and was told that she had developed burns there. It was at the site where the vertical rod of the operation table came in contact with the groin. Friction between the rod and her vulva resulted in those burns. The burns wound healed with conservative treatment using antiseptic dressings. However she developed a mass at that site over a period of 1.5 months. She was not sexually active. The mass caused discomfort while walking and sitting down to work. There was a history of pruritus over the mass off and on. She was also disturbed about the cosmetic disturbance of the appearance of the vulva. There was no family history of keloids. Local examination showed an irregular mass arising from the skin lateral to the right labium majus (figure 1). It measured 10x3x2 cm. It was pedunculated, had a base measuring 1.5 cm in diameter, and it was hanging down from its attachment. No trophic changes were found in the mass. A diagnosis of vulvar keloid following friction burns was made. General and systemic examination revealed no abnormality. There were no keloid at any other site on her body.
The patient desired surgical excision of the mass. After confirming fitness for anesthesia, the mass was excised by plastic surgery. The patient made an uneventful recovery. Histopathological examination showed epidermis of normal thickness showing regular and palliating basal cell organization, and vacuolar change in basal cells, keloid collagen, horizontal fibrous bands in collagen, moderate perivascular chronic inflammatory infiltrate, and prominent telangiectasia. The diagnosis of vulvar keloid was thus confirmed. There was no recurrence of the mass over a period of nine months after the excision.


Figure 1. Clinical appearance of the vulvar keloid.

Discussion

A keloid is the result of an abnormal and excessive formation of scar tissue after loss of tissue. It occurs more often in genetically predisposed individuals. It is 15 times more common in ethnic groups with deeply pigmented skin as compared to those with white skin. It needs to be differentiated from a hypertrophi scar. Both lesions are elevated. Keloids were differentiated from hypertrophic scars by Mancini and Peacock.[4] A comparison of the two conditions is shown in the following table.

Comparison of a Keloid and a Hypertrophic Scar

Feature
Keloid
Hypertrophic scar
Heredofamilial
Yes
No
Race
Black more than white
No effect
Sex
Female > Male
No effect
Growth beyond limits of wound
Yes
No
Regression
No
Possible
Irregular, spreading margin
Yes
No
Pruritus
Yes
No
Pain
Yes
No
Multiple sites on body
Yes
No
Recurrence
Yes
No
Histopathology
Epidermis of normal thickness showing regular and palliating basal cell organization, and vacuolar change in basal cells.
Papillary dermis shows scarring.
Epidermis flattened, showing disarray of basal cells,  and vacuolar change in a few cases.

Keloid collagen: large, broad, glassy, eosinophilic focally fragmented and haphazardly arranged collagen complexes with variable amounts of myxoid extracellular matrix. Location in full thickness of the reticular dermis. Positivity for α-SMA expressing myofibroblasts in 33% cases.
No keloid collagen.
Nodules containing fibrillar collagen of regular thickness arranged parallel to the epidermis, extracellular matrix with high density of cells, without myxoid change. Location in the upper one third of the reticular dermis. No positivity for α-SMA expressing myofibroblasts.

Horizontal fibrous bands in all cases, with an advancing edge under the epidermis in 66% cases.
Absent

Prominent telangiectasia: small blood vessels just below the epidermis appearing to grow from it.
Blood vessels arranged vertically around the nodules.

Moderate perivascular chronic inflammatory infiltrate;
mast cells seen in the reticular dermis in 70% cases.
mast cells seen in the reticular dermis in 20-30% cases.

Treatment of a keloid depends on its site, size and depth, the patient’s age and response to treatment in the past, if any. Conventional treatment options include intralesional injections of corticosteroids, surgical excision, cryosurgical ablation, laser ablation, radiation, and use of interferon, adriamycin, 5-fluorouracil, bleomycin, retinoic acid, verapamil, tamoxifen, imiquimod, tacrolimus, and botulinum toxin. Use of vascular endothelial growth factor inhibitors like bevacizumab, transforming growth factor–beta3, phototherapy, recombinant human epidermal growth factor, tumor necrosis factor-alpha inhibitors like etanercept and recombinant human interleukin shows promise.

Special care needs to be exercised during excision of a keloid to prevent its recurrence. Such measures include intrakeloidal excision, avoiding tension on the suture line, avoiding excessive inflammation in the operative site postoperatively. Steroids may be used locally, such as triamcenalone. The results may not always be very satisfactory. 

The case presented here was different from the usual cases of keloids in many ways. The patient did not have a genetic predisposition as evidenced by an absence of keloids at other sites of injuries, such as piercing of ears and injection sites. Its location in the vulva was unusual. It occurred after friction burns, which has not been reported in the literature so far. The fact that the friction burns were iatrogenic shows the importance of avoiding such an occurrence during orthopedic surgery on the hip joint area.

References
  1. Robles DT, Berg D. Abnormal wound healing: Keloids. Clin Dermatol. 2007;25:26–32.
  2. Moshref SS, Mufti ST. Keloid and hypertrophic scars: Comparative histopathological and immunohistochemical study. Med Sci. 2010;17:3–22.
  3. Gürünlüoglu R, Dogan T, Numanoglu A. A case of giant keloid in the female genitalia. Plast Reconstr Surg 1999;104:594.
  4. Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG. Hypertrophic scarring and keloids: Pathomechanisms and current and emerging treatment strategies. Mol Med. 2011;17:113–25.
Citation

Parulekar SV. Vulvar Keloid Following Friction Burns. JPGO 2016. Volume 3 No. 8. Available from: http://www.jpgo.org/2016/08/vulvar-keloid-following-friction-burns.html

Uterocutaneous Fistula Following Cesarean Section

Author Information

Swaminathan G*, Warke H**, Mayadeo NM***
(* Third Year Resident, ** Associate Professor, *** Professor, Department of Obstetrics and Gynecology,  KEM Hospital, Mumbai, India.)

Abstract
Uterocutaneous sinus tract is indeed a rare phenomenon. These generally occur following uterine surgery. As these patients present with discharge from the scar site, they can be misdiagnosed as wound infection or abscess at the scar site. Clinical suspicion should be aided by radiological investigations mainly ultrasonography. Computed tomography or MRI may be done if required for confirmation. We present a case report of a sinus tract which developed after cesarean section extending from the skin upto the uterine fundus and later resulted into an uterocutaneous fistula. Failed conservative management in this case facilitated the need for exploratory laparotomy with excision of the entire fistulous tract.

Introduction

Sinus tract is an opening below the skin that can extend and create a dead space with potential for abscess formation. A fistula is an abnormal tract formed between two epithelial surfaces. Fistulas are generally  lined by granulation  tissue  but  can  get  epithelized.[1] Uterocutaneous fistulas are mostly seen postoperatively. Prompt diagnosis can be made with contrast enhanced computed tomography or MRI.[2] Uterine perforation due to a migrated laminaria tent or an intrauterine contraceptive device may also lead to the formation of an uterocutaneous fistula.[3] We present a case report of a discharging uterocutaneous sinus tract leading to a fistula following cesarean section.

Case Report

A 24 year old Para 2 Living 2 previous 2 LSCS came to our emergency department with complaints of tender swelling at the cesarean scar site. Patient had undergone an emergency lower segment cesarean section (LSCS) with bilateral tubal ligation seven months ago in view of previous LSCS not willing for vaginal birth. Intraoperatively there were dense adhesions between the omentum and the anterior uterine wall which were released and tied with linen. Postoperative course was uneventful and patient was discharged on day 7. Suture removal was done on day 10 and there was no wound discharge or gape. 
Six months later patient started noticing a 2 - 3 cm painful nodule at the suture line on left side. There was no fever or discharge from the nodule. She had no complaints of pain in abdomen or bowel or bladder complaints. Her menstrual history was normal. On examination, she perceived tenderness over the nodule. Ultrasound examination revealed a small collection of 1-2 ml extending from the fundus upto the skin surface. MRI pelvis showed features suggestive of an abscess underneath the skin scar site with extension into the intermuscular plane, reaching up to the anterior wall of the uterine fundus. Ultrasound guided tapping of this abscess was done and the pus was sent for culture and antibiotic sensitivity. It revealed growth of staphylococcus aureus species sensitive to linezolid, clindamycin and gentamicin. No acid fast bacilli were seen on ZN staining and TB PCR was negative. Patient was managed conservatively with linezolid based on her culture report and was discharged. 
A month later, she presented to us with complaints of watery discharge from the scar site on left side. On examination, she was clinically stable with all parameters normal. Pfannensteil scar was present with a sinus tract opening on the left side with induration and sero-purulent discharge. On vaginal examination, the uterus was bulky, anteverted, mobility appeared restricted; both fornices were free and non-tender. Blood investigations were normal. She underwent examination under anesthesia with probing of the sinus tract from the abdomen which revealed a sinus tract extending up to the uterus. Ultrasound examination revealed a sinus tract of about 2 -2.5 cm width extending from the fundus of the uterus upto the skin with surrounding inflammation. MRI pelvis, with instillation of saline through the sinus opening for better visualization of the tract, showed features suggestive of a sinus tract extending from the abdominal wall up to serosa of fundus of the uterus without evidence of any extension into the uterine myometrium or endometrium, or bowel or bladder. In view of above findings and failure of conservative management a decision for exploratory laparotomy with excision of the sinus tract was taken. Patient then gave history of bleeding through the sinus opening during the last menses.


Figure 1. Probe through the sinus tract opening on the skin.

Preoperative workup was done and the patient underwent exploratory laparotomy with sinus tract excision along with surgeons. Methylene blue dye was instilled into the sinus tract through the opening on the skin. Probe was inserted into sinus tract and tissue dissection done around the probe. Approximately 1 cm of skin and subcutaneous tissue around the sinus tract was excised. Rectus sheath around the sinus tract was dissected from underlying muscle and 1.5 cm of rectus sheath was excised. Rectus muscle was separated. Uterus was found to be adherent to parietal peritoneum and extension of sinus tract was noted up to the uterine fundus on left side as the entire tract was delineated with methylene blue.


Figure 2. Dissection of the sinus tract.

Abdomen was opened in layers till the peritoneum. Peritoneum was adherent to anterior abdominal wall. Sinus tact extended up to the uterine fundus on left side. Anterior wall of uterus was adherent to anterior abdominal wall.


Figure 3. Sinus tract seen extending up to the uterine fundus.

Multiple linen threads were seen which were cut and removed. Tubal ligation sites were seen on bilateral fallopian tubes at isthmic region. 2 x 3 cm cyst was noted on right ovary. Left ovary was normal. Bladder was advanced up to lower third of the anterior uterine wall. Sinus tract extending to left side of uterine fundus was excised by sharp dissection. Approximately 0.5 cm of myometrium was excised around the sinus tract and in the process, endometrial cavity was opened. Sinus tract delineated by methylene blue was excised completely.


Figure 4. Uterus after excision of the sinus tract showing opened endometrial cavity.


Figure 5. Uterine fundus after suturing.

Endometrium was approximated with no. 2- 0 in continuous interlocking manner. Myometrium was approximated with polyglactin no.1-0 in 2 layers. Intraperitoneal drain was inserted and abdomen closed in layers. Postoperative course was uneventful and she went home on day 7.
Discussion

A fistula is an abnormal tract formed between two epithelial surfaces. Fistulas are generally lined by granulation tissue but they can get epithelized. Most fistulas arise as a result of trauma or after some kind of infectious process resulting in disruption of the continuity of the tissues involved.[4] Septic abortion caused by insertion of laminaria tent into the cervix leading to uterocutaneous fistula was reported by Gupta et al.[5] LSCS as a cause of uterocutaneous fistula was reported by Jain et al.[6] Other causes of uterocutaneous fistulas include: previous history of abdominal surgeries, improper closure of uterine incision following cesarean section, intra-abdominal sepsis in previous scar and secondary abdominal pregnancy. Once a fistula is diagnosed, the basic principle in the treatment is to obliterate the entire fistulous tract. There is no role of conservative management for fistula. Our patient had a sinus tract which extended from the skin upto the uterine fundus which later became an uterocutaneous fistula which had most probably developed as a result of foreign body reaction to the linen that was used for adhesiolysis during her cesarean section. Initially conservative management was tried but later surgical excision of entire fistulous tract had to be done after which the patient's symptoms settled.

References
  1. Yadav R, Reddy R, Jayalakshmi D. Uterocutaneous fistula. J Obstet Gynecol India. 2006; 56: 81-82.
  2. Eldem G, Turkbey B, Balas S, Akpinar E. MDCT diagnosis of uterocutaneous fistula, European Journal of Radiology Extra 67 (2008) e129–e130.
  3. Vellanki VS, Gogineni S, Kanakamedala JS. Case Report of Uterocutaneous Fistula. J Women’s Health Care. 2015; 4: 231.
  4. Shukla D, Pandey S, Pandey LK, Shukla VK. Repair of uterocutaneous fistula. Obstet Gynecol. 2006: 108: 732-3.
  5. Gupta SK, Shukla VK, Varma DN, Roy SK. Uterocutaneous fistula. Postgrad Med J. 1993; 69(816): 822-3.
  6. Jain V, Jain S. Post cesarean utero cutaneous fistula- A rare clinical entity. J Obstet Gynecol Ind. 2003; 53: 978.
Citation

Swaminathan G, Warke H, Mayadeo NM. Uterocutaneous Fistula Following Cesarean Section. Volume 3 No. 8. Available from: http://www.jpgo.org/2016/08/uterocutaneous-fistula-following.html

Autoimmune Hepatitis in Pregnancy

Author Information

Mehta V*, Prasad M**, Gupta AS***
(* Third Year Resident, ** Assistant Professor, *** Professor, Department of Obstetrics and Gynecology, Seth G.S. Medical College and K.E.M. Hospital, Mumbai, India.)

Abstract

The common causes of derangement in liver enzymes during pregnancy include HELLP syndrome, acute fatty liver of pregnancy, cholestasis of pregnancy and viral hepatitis. Rarely, other causes may be present. A case of autoimmune hepatitis in pregnancy is presented here.

Introduction

Autoimmune hepatitis (AIH) is a condition characterised by destruction of liver parenchyma which eventually leads to cirrhosis. Abnormal presentation of HLA class 2 on surface of liver either due to genetic cause or due to infection leads to cell mediated immune response and subsequent autoimmune hepatitis. The disease is more common in women in the age group of 15-40 years of age. This disease is also called as lupoid hepatitis, when associated with ANA positivity. Common early symptoms are fatigue, muscle ache and sign of acute inflammation of liver leading to fever, abdominal pain and jaundice. Many a times incidental abnormality in liver function test is the only manifestation.

Case Report

A 26 year old primigravida with 35 weeks of gestation was referred to our tertiary care centre in view of breech presentation with IUGR and oligohydramnios. On admission, patient was well oriented, with normal pulse and blood pressure. Cardiovascular and respiratory systems were unremarkable. Abdominal examination showed live fetus of 32 weeks size in breech presentation. Cervical os was closed. There was no show or leak. BP monitoring was done and remained within normal limits. There was no proteinuria. Ultrasonography showed gestational age of 33 weeks with abdominal circumference (AC) lag of 2 weeks and amniotic fluid index of 6 cm. Investigations were sent. Bedside bleeding time, clotting time tests were within normal limits. Hemoglobin was 11.2 gm/ dl and white blood count was 9000 /cu mm. Platelet count was 1.8 lakh /cu mm. Bilirubin was not elevated. Prothrombin time was in normal range and INR was 1.1. Only abnormal reports were SGOT (234 IU/ml) and SGPT (290 IU/ml). Specialist gastroenterology opinion was taken. Viral markers for hepatitis, γ glutaryltransferase, complete coagulation profile, hepato-renal Doppler ultrasonography were advised along with blood glucose monitoring to prevent hypoglycemia. Viral markers for hepatitis A, B, C and E were negative. γ glutaryltransferase was within normal limits and all coagulation parameters were in the normal range. Ultrasonography showed normal liver echotexture and no focal lesions or ascites. Patient did not develop episodes of hypoglycemia. SGOT /SGPT serial values are shown in the table 1.
Provisional diagnosis of autoimmune hepatitis was considered. However, patient went in to spontaneous labour and emergency LSCS was done for breech with IUGR under spinal anesthesia. A male child of 1.36 kg was delivered with an Apgar score of 9/10. LSCS was uneventful.  Baby was transferred to NICU and was discharged on day 10 of life.  Patient had unremarkable post-operative course. Hepatotoxic drugs were avoided in the postoperative period.  Liver function tests continued to be monitored and showed stable SGOT/ SGPT levels (as shown in the table). Autoimmune profile was sent, and serum IgG, IgA and IgM levels were sent; IgG was found to be raised: (normal range 736-1195 mg/dl) patient’s value being 1400 mg/dl. However, ANA and anti-smooth muscle antibody (ASMA) were negative. In view of the raised IgG levels, the diagnosis of autoimmune hepatitis was confirmed, and the gastroenterologist decided to start her on oral prednisolone in the dose of 10 mg per day and she was advised follow up.

Discussion

When elevated liver enzymes are encountered in pregnancy, the main issue would be to rule   out the common causes. Our patient remained normotensive throughout, hence hypertensive disorders of pregnancy and related syndrome such as HELLP syndrome was ruled out. Viral markers were sent but all were negative. There were no other features of cholestasis or of acute fatty liver of pregnancy. In such a setting, a more detailed approach was followed in investigating the cause of the isolated elevation of liver enzymes in our patient, which ultimately lead to the recognition of AIH. 
Autoimmune hepatitis is a disorder with continuing hepatocellular necrosis, inflammation and fibrosis with propensity to progress to cirrhosis and liver failure. Though there is a 40% chance of mortality in severe untreated cases, the reported 10-year survival is 90% in treated cases.  
Clinical features are similar to chronic viral hepatitis. Patient may present with features of arthalgia, jaundice, upper quadrant pain, fever, thrombocytopenia and myalgia. Traditionally, a term called “lupoid hepatitis” was used for patients with positive ANA titres. These patients are predominantly middle-aged women having marked hyperglobulinemia and circulating ANAs in high-titre. There may be overlap with other autoimmune disorders.[1]
Diagnostic criteria based on elevation of IgG, autoantibody demonstration, histological characterisation of hepatic inflammation in the absence of viral disease are helpful. The cornerstone of management in AIH is glucocorticoid therapy. The treatment objectives include restoration of the normality of liver function tests, which need to be weighed closely against the possible adverse effects of immunosuppressive therapy. Prednisolone is the preferred drug. Our patient responded to prednisolone and there was a prompt reduction in the SGOT and SGPT values (Table 1).

Table 1: Serial values of SGOT and SGPT
SGOT (IU/ml)
SGPT ( IU/ml)
At admission (35 wk1day)
234
290
35wk 2 days
250
300
35wk 4 days
663
934
Pre- LSCS 35 wk 6 day
343
718
Post LSCS
428
209
On day 2 of steroids
88
265
On day 3 of steroids
58
204

Approximately 60-70% respond to therapy. In these, immunosuppressive requirement may reduce. However, a large number suffer from relapses. Aminotransferase levels can be taken as indicators of relative disease activity but should be interpreted cautiously. Though histologic improvement may be delayed by many months, serial liver biopsies are not recommended to guide continuation of therapy. In medically refractory cases, intensive treatment with high-dose glucocorticoid monotherapy is needed; failure of which may necessitate combination of glucocorticoids with high-dose azathioprine (150 mg daily) therapy.[1,2] Newer modalities of treatment such as calcineurin inhibitors, mycophenolatemofetil may be required if failure occurs with conventional therapy. Sometimes, lifelong glucocorticoid therapy is needed. In decompensated patients, liver transplantation may be necessary.  It is well recognised that elderly patients and pregnant patients need treatment modifications.[3] Saini et al have described a patient whose condition was recognized in the postpartum period, which is quite similar to our patient.[4] While the fetal affection has not been extensively documented, fetal intestinal perforation and meconium peritonitis have been described.[5] Thrombocytopenia worsens the outcomes in patients with autoimmune hepatitis.[6] Very few studies have followed the course of patients of AIH with pregnancy.  In a cohort of 81 patients with AIH studied by Westbrook et al, the live birth rate was 73%. A flare in the disease activity occurred in 1/3rd of the patients. 11% of the patients had a serious maternal adverse event in the year following delivery.  Poor control during the year prior to conception was a significant determinant of poor maternal and neonatal outcome.[7] Our patient had a preterm birth and delivered a SGA neonate.  A 5 year cohort study of all pregnancies with 171 births in women with diagnosed autoimmune hepatitis concluded that women with AIH had an increased risk of gestational diabetes, preterm birth and of low-birth-weight child. There was no significant association between autoimmune hepatitis and pre-eclampsia, cesarean section, low 5 minute Apgar score, congenital malformation and neonatal mortality.[8]
One particular concern is the effect of glucocorticoids and other immunosuppressants during pregnancy on the offspring.  While cyclophosphamide and methotrexate are contraindicated during pregnancy, drugs such as glucocorticoids, cyclosporine and hydroxychloroquine are not associated with any major risk of congenital malformations.  The risk of preterm delivery, low birth weight and IUGR is probably related to a combination of both the maternal disorder and immunosuppressive therapy. However long term follow-up of such babies show normal neuro-cognitive maturity. [9, 10]
As concluded by Czaja et al, with the advent of modern drugs, patients should be counselled regarding the nature of the disease and good control should be attempted peri-conceptionally.  Pregnancy is usually well-tolerated by mother and fetus. However, protection against postpartum exacerbation needs to kept in mind. Our patient has been advised to monitor LFTs and follow up regularly with the gastroenterologist.[11]

References 
  1. Dienstag JL. Chronic Hepatitis. in: Longo DL, Kasper DL, Jameson JL, Fauci AS, Hauser SL, Loscalzo J, Eds. Harrison’s Principles of Internal Medicine.18th Ed. McGraw Hill; 2012, New York, pp. 2568.
  2. Lohse AW, Mieli-Vergani G. Autoimmune hepatitis. J Hepatol. 2011;55(1):171–82. 
  3. Czaja AJ. Difficult treatment decisions in autoimmune hepatitis. World J Gastroenterol 2010;16(8): 934–47. 
  4. Saini V, Gupta M, Mishra SK. Auto-immune hepatitis following delivery. J Indian Med Assoc 2013; 111(5):341–2. 
  5. Charlagorla P, Sublett S, Sy F, Kessler E, Gad A. Fetal intestinal perforation and meconium peritonitis associated with maternal autoimmune hepatitis. J Neonatal Perinatal Med 2014;7(1):71–4. 
  6. Nomuras RMY, Kleine RT, Igai AMK, Francisco RPV, Zugaib M. Clinical and obstetrical management of pregnant women with autoimmune hepatitis complicated by moderate or severe thrombocytopenia. Rev Assoc Med Bras 2013; 59(1):28-34.
  7. Westbrook RH, Yeoman AD, Kriese S, Heneghan MA. Outcomes of pregnancy in women with autoimmune hepatitis. J Autoimmun. 2012; 38(2-3):J239–44. 
  8. Stokkeland K, Ludvigsson JF, Hultcrantz R, Ekbom A, Höijer J, Bottai M, et al. Increased risk of preterm birth in women with autoimmune hepatitis - a nationwide cohort study. Liver Int. 2016; 36(1):76–83. 
  9. Motta M, Rodriguez-Perez C, Tincani A, Lojacono A, Nacinovich R, Chirico G. Neonates born from mothers with autoimmune disorders. Early Hum Dev 2009; 85(10 Suppl):S67-70. 
  10. Motta M, Tincani A, Meroni PL, Cimaz R. Follow-up of children exposed antenatally to immunosuppressive drugs. Rheumatology (Oxford) 2008; 47(suppl 3): iii32–iii34. doi: 10.1093/rheumatology/ken149
  11. Czaja AJ. Autoimmune hepatitis in special patient populations. Best Pract Res Clin Gastroenterol. 2011;25(6): 689–700. 
Citation

Mehta V, Prasad M, Gupta AS. Autoimmune Hepatitis in Pregnancy. JPGO 2016. Volume 3 No. 8. Available from: http://www.jpgo.org/2016/08/autoimmune-hepatitis-in-pregnancy.html

Recurrent Pregnancy Loss And Hypothyroidism

Author information

Wani R *, Shah Y **, Jalvee R ***, Shah S ****
(* Additional Professor, ** Assistant Honorary, *** Assistant Professor, **** Senior Registrar, Department of Obstetrics & Gynecology, H.B.T. Medical College & Dr R.N. Cooper Municipal Hospital, Mumbai, India)

Abstract

Recurrent pregnancy loss (RPL) may be defined as three consecutive pregnancy losses prior to 20 weeks. The reported incidence of RPL is 1-2%.[1] The causes of RPL include genetic abnormalities (2 – 5 %), anatomic (10 – 15 %), autoimmune (20 %), endocrine (17 – 20 %), unexplained (17 – 20 %). Endocrine factors which are implicated are luteal phase defect, polycystic ovarian disease, diabetes mellitus and thyroid disease. 
Hypothyroidism complicates up to 3% of pregnancies, 0.3- 0.5 % is overt and 2 - 2.5 % is subclinical.[2] We present a case report of recurrent pregnancy loss due to uncontrolled hypothyroidism with successful obstetrical outcome.

Introduction

Hypothyroidism is diagnosed by noting a high TSH associated with subnormal T4 concentration. Subclinical hypothyroidism (SCH)  is present when the TSH is high but the T4 level is in the normal range. It is the most common form of hypothyroidism in pregnancy. It is usually due to progressive destruction of the thyroid gland. Overt and subclinical hypothyroidism is associated with poor maternal and fetal outcomes, if ignored in the preconception and antenatal period.[3] Obstetrical outcomes observed are infertility, spontaneous abortions, anemia in pregnancy, preeclampsia, abruption, and postpartum hemorrhage. Fetal  outcomes include preterm delivery, low birth weight, respiratory distress.[4] It is also implicated as a preventable cause of mental retardation in neonates.

Case Report

A 32 year old fourth gravida with previous intrauterine fetal death and 2 spontaneous abortions came for the first time at 9 months of gestation with physical appearances as below and with a pulse rate of 60/ minute and blood pressure of 120/ 70 mm Hg . She was irritable, had a hoarse voice with dry myxematous skin changes. Her face was puffy, with periorbital edema and non pitting pedal edema, but no neck swelling. ECG showed low QRS voltages with widespread T- wave inversions.


Figure 1. Facial features and skin changes.

On abdominal examination uterine size corresponded to 34 weeks with regular fetal heart sounds. She had been seen at a private clinic earlier where ultrasonography at 34 weeks had shown gestational age of 30 weeks with estimated baby weight of 1.5 kg, and color Doppler done was suggestive of early fetoplacental insufficiency. Laboratory investigations had shown a high TSH level of 21.24 µIU/ l.  Her free T3 was 4.41 pg/ml, free T4 26.61 pmol/ l (both low) but she had not been started on any medications.  
With endocrine reference we started her on tablet thyroxine 75 µg/ day and 150 µg on weekends before breakfast. She was advised to repeat TSH levels after 4 weeks, at which time her tests showed free T3 of 2.53 pg/ ml, T4 of 1.14 ng/ dl and TSH of 14.31 µIU/ l. 
An endocrine review was done and the dosage was increased to 100 µg / day and 150 µg on weekends and levels were again repeated after 4 weeks. She opted for outpatient treatment and after 4 weeks her free T3 was 4.01 pg/ ml, free T4 was 1.18 ng/ dl and TSH was 10.44 µIU/ ml. Patient came to our emergency ward in labor at 41 weeks of gestation. She underwent emergency LSCS in view of non-reassuring NST at 41 weeks of gestation. Intra-operatively there was scanty liquor (clear). She delivered a male weighing 1.9 kg with Apgar of 8/10 at 1 minute and 9/10 at 5 minutes. 
Baby was admitted in NICU in view of small for gestational age and low birth weight with large ears and protruding tongue. His TSH on day 3 was 2.6 µ IU/l. In the postpartum period, the patient was continued on 100 µg of  tablet thyroxine and after 6 weeks her TSH was 2.67 µ IU/l.


Figure 2: SGA with hypothyroid features.

Discussion

Subclinical hypothyroidism is defined as TSH > 3mIU/ l but < 10 mIU/l with normal FT3 and  FT4. Overt hypothyroidism includes a TSH > 10 mIU/l with low FT4  levels. Treatment includes levothyroxine which is a stereoisomer of physiologic thyroxine which can be started as soon as diagnosis is made. 
Although universal screening is not recommended (ACOG), the indications for screening include presence of goiter or thyroid nodules, history  of thyroid surgery, infertility, previous history of neck radiation, thyroid dysfunction in the postpartum period, previous birth of infant with thyroid and other autoimmune chronic conditions like type 1 diabetes mellitus. [5]
This case had bad obstetric history and clinical features of overt hypothyroidism but unfortunately had not been screened till late third trimester when growth restriction had already set in. The current recommendations suggest to use laboratory-specific and trimester-specific reference ranges in pregnancy. When not available, aim to maintain the TSH between 0.3 -3 mIU/ l and check TSH in every trimester. [6]

Conclusion

Uncontrolled overt and subclinical hypothyroidism if neglected lead to poor perinatal outcomes, and timely diagnosis and treatment is essential. We believe that offering at least one TSH test at the booking visit especially in those with risk factors will improve obstetric outcomes.

References
  1. Stephenson MD. Frequency of factors associated with habitual abortion in 197 couples. Fertil Steril. 1996; 66(1): 24-29. 
  2. Neale DM, Cootauco AC, Burrow G. Thyroid disease in pregnancy. Clin Perinatol. 2007; 34(4): 543-557, v-vi.
  3. Glinoer D,  Soto MF,  Bourdoux P,  Lejeune B,  Delange F,  Lemone M, et al. Pregnancy in patients with mild  thyroid  abnormalities: maternal and neonatal repercussions. J Clin Endocrinol Metab. 1991; 73(2): 421-427. 
  4. Davis LE, Leveno KJ, Cunningham FG. Hypothyroidism complicating pregnancy. Obstet Gynecol. 1988; 72(1): 108-112. 
  5. ACOG Practice Bulletin Number 148: Thyroid disease in pregnancy. Obstet Gynecol. 2015; 125: 996–1005.
  6. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011; 21:1081-1125.
Citation

Wani R, Shah Y, Jalvee R, Shah S. Recurrent Pregnancy Loss And Hypothyroidism. JPGO 2016. Volume 3 No. 8. Available from: http://www.jpgo.org/2016/08/recurrent-pregnancy-loss-and.html

Paroxysmal Nocturnal Hemoglobinuria In Pregnancy

Author Information

Kale KG*, Deshmukh P**, Chauhan AR***
(* Assistant Professor, ** 3rd year resident, ***Professor, department of Obstetrics and Gynecology, Seth G. S. Medical College and KEM hospital, Mumbai, India.)

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by episodes of intravascular hemolysis, bone marrow failure and venous thrombosis. This is a rare acquired condition of the hematopoietic stem cells. PNH in pregnancy is associated with adverse maternal and perinatal outcome. However with careful monitoring and timely treatment in a tertiary care setting, a reasonably good maternal and fetal outcome may be expected. We present a successfully managed case of PNH in pregnancy.

Introduction

Paroxysmal nocturnal hemoglobinuria is an uncommon disorder of the hematopoietic stem cells resulting from an acquired gene mutation leading to episodes of intravascular hemolysis, bone marrow failure and thrombosis.[1] The estimated prevalence of this disease is around 15.9 cases per million populations and literature has only few case reports and small case series describing its occurrence in pregnancy. The maternal mortality rate in pregnancy associated with PNH is very high (8-21 %), almost all deaths occurring secondary to thrombotic complications. The perinatal mortality rate is as high as 4-9 %.[2- 4] Hence, PNH is considered as a relative contraindication to pregnancy.[5]

Case Report

A 24 year old primigravida, known case of PNH, presented to the outpatient department at 11 weeks of gestation for routine antenatal registration. The diagnosis of PNH was made at the age of 13 years when she had severe puberty menorrhagia, dyspnea on exertion, easy fatigability and weakness. At that time, investigations revealed pancytopenia (hemoglobin- 6.5 gm/dl, total leukocyte count- 2200/cmm, platelet count- 33,000/cmm, packed cell volume- 18.4%). Peripheral smear showed hypochromasia, microcytosis, anisopoikilocytosis, tear drop cells, pencil cells and schistocytes. Investigations also revealed ongoing hemolysis with elevated serum total and indirect bilirubin (4.2 mg/dl and 3 mg/dl respectively), raised LDH (2000 U/L) and reduced serum haptoglobin (< 6 mg/dl). The coagulation profile and serum iron studies were normal and Coomb’s test was negative; hence a diagnosis of hemolytic anemia (Coomb’s negative) was made. Bone marrow biopsy was performed which showed erythrocyte excess with decreased myeloid cell lineage. She was further evaluated with screening tests for PNH, namely acid Hams test and sucrose lysis test, both of which were negative. However, due to high index of suspicion, she was subjected to peripheral blood flow cytometry which revealed absent CD55 and CD59 molecules in 33 % and 23 % neutrophils respectively, confirming the diagnosis of PNH. She received multiple blood transfusions to correct anemia and thrombocytopenia and was started on oral folic acid and danazol. She tolerated the treatment well. Dose of danazol was tapered and stopped 3 years ago. Six monthly hemoglobin and complete blood count was monitored. 
She got married at 23 years of age and conceived spontaneously within one year. She was counseled jointly by the hematologist and obstetricians about the increased maternal and fetal risks associated with the disease, need of multidisciplinary management and meticulous follow up. However, she and her spouse chose to continue the pregnancy and agreed to comply with the treatment. As soon as the pregnancy was confirmed, she was started on injection LMWH (low molecular weight heparin) in a daily dose of 0.6 mg subcutaneously along with oral iron (100 mg/d) and folic acid supplementation (5 mg/d). At each antenatal visit she was evaluated for clinical signs of disease progression, possible complications, and fetal well being. Complete blood count was obtained monthly for early diagnosis of bone marrow failure. It remained normal. The antenatal course was uneventful and she did not develop severe anemia or thrombocytopenia. Hence, she did not require any transfusion. At 37 weeks of gestation she developed chickenpox for which oral acyclovir therapy along with symptomatic treatment was initiated. She recovered well from the febrile episode without any complications and went into spontaneous labor at 39 weeks of gestation. LMWH was omitted and labor was monitored carefully using partograph. Oxytocin augmentation was used. An outlet forceps delivery (in view of maternal exhaustion) of a healthy male child weighing 2.6 kg with an Apgar score of 9/10 was accomplished without any maternal or fetal complications. There was no postpartum hemorrhage or a thrombotic event. Injection  LMWH was restarted subcutaneously 12 hours after delivery and was continued for 6 weeks postpartum. She was discharged on 7th postpartum day and was followed up weekly to look for possible complications. She was advised to use barrier contraception. The puerperal period was uneventful and she is currently following up with the hematologist.

Discussion

PNH is a rare disorder resulting from expansion of a clone of hematopoietic stem cells that have acquired a mutation in the PIG-A gene. The PIG-A gene is responsible for the synthesis of glycosyl phosphatidylinositol (GPI) which anchors certain proteins, mainly CD55 and CD59, to the surface membrane of marrow cells. CD55 and CD59 serve as membrane bound regulators of complement that inhibit complement mediated lysis of erythrocytes. Absence of these regulating proteins on cell surface leads to intravascular hemolysis and hemoglobinuria.[1] Other essential features of this condition are episodes of bone marrow failure and venous thrombosis at unusual sites viz. hepatic, mesenteric, portal veins, cerebral veins etc.[6] The exact reason for venous thrombosis remains unclear; however, it is the most dreaded complication responsible for 40-75% of PNH related deaths.[7]
The median age at diagnosis of PNH is 34 years, thus affecting women in their reproductive age group, although fertility appears to be unaffected.[5] Presenting symptoms are often non specific, ranging from those secondary to anemia (weakness, dizziness, dyspnea on exertion), hemoglobinuria (cola colored urine), to venous thrombosis involving various sites like brain (headache, nausea, vomiting), retina (loss of vision), deep veins of legs (pain and swelling of legs), kidney (oliguria), pulmonary embolism (sudden onset breathlessness). Our patient presented at 13 years of age with symptoms of anemia and menorrhagia (probably secondary to thrombocytopenia). She also conceived spontaneously within 1 year of marriage. The clinical course of the disease is usually chronic with intermittent flare-ups. This requires monitoring, as was done in our case. The initial laboratory investigations in PNH are usually suggestive of hemolytic anemia of Coomb's negative type. The diagnosis is established only after flow cytometric analysis of peripheral blood showing increased population of erythrocytes and/ or leukocytes deficient in GPI anchoring proteins, CD55 and CD59. In our case, 33% and 23% of the neutrophils were deficient in CD55 and CD59 respectively, thus confirming the diagnosis. The traditional screening tests for PNH; the acid Hams and the sucrose lysis test, have low sensitivity, which probably lead to the false negative result as  was obtained in our patient.[1, 6]
PNH during pregnancy poses an increased risk for both the mother and the fetus.  The rate of spontaneous miscarriage is as high as 45%.[5] They have high risk of developing severe anemia during pregnancy, more severe than the non pregnant state, requiring frequent blood transfusions. [7] It may be due to intravascular hemolysis which is frequently increased (due to activation of complement cascade in pregnancy),[5] episodic bone marrow failure and concurrent iron deficiency due to loss of hemoglobin in urine. Thrombocytopenia is also more common in pregnancy as compared to the non pregnant state. Pregnancy being a prothrombotic state appears to increase the risk of PNH related venous thrombosis both antenatally and in the postpartum period and is the most important cause of maternal mortality. Infections occur with an increased frequency during pregnancy, as evident by development of chickenpox in our patient.[2,6,7] Thus, these cases require careful clinical and laboratory evaluation during pregnancy for early detection and treatment of complications, as was done for our case. Although most of them can be delivered vaginally, one retrospective study has reported increased rates of cesarean sections, possibly due to increased incidence of planned inductions of labor and PNH related smooth muscle dystonia hampering the progress of normal labor.[2] There is an increased incidence of preterm induction of labor, major reasons being- a) worsening of hematological parameters, and b) associated obstetric complications viz. preeclampsia and intra uterine growth restriction.[2,8] Perinatal mortality in PNH ranges from 4%-9%, mostly due to iatrogenic prematurity. However, the surviving infants usually have a normal growth and development.[6]
Blood and blood product transfusion forms the mainstay of management of anemia/ thrombocytopenia in a pregnant woman with PNH. Hemolysis and subsequent hemoglobinuria leads to urinary iron loss and iron deficiency requiring iron supplementation. In classic PNH, the
iron loss is usually so large that iron overload is a rarity (inspite of repeated transfusions) and parenteral iron supplementation may be necessary.[6] Nonetheless, anemia in PNH is complex, requires complete hematological workup and consultation with hematologist for appropriate treatment. Oral folate supplementation is a must owing to the increased metabolic demands due to heightened erythropoiesis (secondary to hemolysis). Prophylactic anticoagulation with heparin is recommended, starting as soon as the pregnancy is confirmed and is continued for up to 6 weeks postpartum. Those women who develop thrombosis should receive therapeutic anticoagulation. Warfarin is contraindicated in pregnant PNH patients as it carries increased risk of hemorrhage (may be given in the postpartum period).[5-7] All the above recommendations were strictly followed in our case leading to a good maternal and fetal outcome without any complications. Eculizumab, a human monoclonal antibody directed against complement protein C5, has been increasingly used recently in the treatment of PNH with good results. Few published case reports have documented the safety and efficacy of eculizumab in pregnancy, however, this needs to be confirmed with larger studies.[5- 7]

Pregnancy is usually discouraged in patients with PNH. Patients should be counseled in detail about the increased feto-maternal risks and option of termination of pregnancy should be given to the patient. However, when patient desires pregnancy, a multidisciplinary management in a tertiary care hospital, involving experts  in the field of obstetrics, hematology and intensive care is a must. [8, 9] 

Conclusion

Pregnancy in a woman with PNH is a high risk situation with definite increase in the maternal and perinatal morbidity and mortality. It requires multidisciplinary management with careful monitoring, early diagnosis and prompt treatment of complications to prevent adverse events.

References
  1. Sahin F, Ozkan MC, Mete NG, Yilmaz M, Oruc N, Gurgun A et al. Multidisciplinary clinical management of paroxysmal nocturnal hemoglobinuria. Am J Blood Res. 2015;5(1): 1-9.
  2. de Guibert S, de Latour RP, Varoqueaux N, Labussière H, Rio B, Jaulmes D et al. Paroxysmal nocturnal hemoglobinuria and pregnancy before the eculizumab era: the French experience. Haematologica. 2011;96(9):1276-83.
  3. Fieni S, Bonfanti L, Gramellini D, Benassi L,  Delsignore R. Clinical management of paroxysmal nocturnal hemoglobinuria in pregnancy: a case report and updated review. Obstet Gynecol Surv. 2006;61(9):593–601.
  4. Ray JG, Burows RF, Ginsberg JS, Burrows EA. Paroxysmal nocturnal hemoglobinuria and the risk of venous thrombosis: review and recommendations for management of the pregnant and nonpregnant she. Haemostasis.2000;30(3):103-17.
  5. Sharma R, Keyzner A, Liu J, Bradley T, Allen S. Successful pregnancy outcome in paroxysmal nocturnal hemoglobinuria (PNH) following escalated eculizumab dosing to control breakthrough hemolysis. Leukemia Research Reports.2015;4(1):36-8.
  6. Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood.2005;106(12):3699- 709.
  7. Kelly R, Arnold L, Richards S, Hill A, Bomken C, Hanley J et al. The management of pregnancy in paroxysmal nocturnal hemoglobinuria on long term eculizumab. Br J Hematol.2010;149(3):446-50.
  8. Melo A, Gorgal-Carvalho R, Amaral J, Marques MC, Andrade J, Guimaraes JT, et al. Clinical management of paroxysmal nocturnal haemoglobinuria in pregnancy: three case reports. Blood Transfus. 2011;9(1):99–103.
  9. Bjørge L, Ernst P, Haram KO. Paroxysmal nocturnal hemoglobinuria in pregnancy. Acta Obstet Gynecol Scand. 2003;82(12):1067-71.

Citation

Kale KG, Deshmukh P, Chauhan AR. Paroxysmal Nocturnal Hemoglobinuria In Pregnancy. JPGO 2016. Volume 3 No. 8. Available from: http://www.jpgo.org/2016/08/paroxysmal-nocturnal-hemoglobinuria-in.html