Volume 5 Issue 3, March 2018

Editorial
Madhva Prasad Sarvothaman

Rare Case Of Vilateral Labial Hemangioma And Massive Edema In Coexistence With Aortoarteritis
Sameriya A, Parulekar SV.

Takayasu Arteritis – Towards A Better Diagnosis
Parulekar SV

Elevated Placental Alkaline Phosphatase – A Soft Marker For Placental Injury
Singhania N, Sakpal V, Gupta AS.

A Rare Case Of Campomelia
Rane VV, Samant PY, Honnavar PU.

Case Of Virilization – Non-Classical Congenital Adrenal Hyperplasia
Ganapati T, Chaudhari HK.

Management Of Celiac Disease In Pregnancy
Ruhil MS, Desai G, Hatkar PA, Mayadeo NM.

Pregnancy In A Patient With Congenital Adrenal Hyperplasia
Jain D, Warke HS.

Benign Intracranial Hypertension And Pregnancy
Desai A, Desai G, Hatkar PA, Warke HS.

Chronic Discharging Sinus Of Labium Majus – An Unusual Case Report
Tiwari N, Chaudhari HK.


Editorial

Madhva Prasad Sarvothaman

Ambiguous genitalia at birth is a rare but challenging scenario faced by an obstetrician/ gynaecologist. An equally difficult scenario is the occurrence of virilization which causes a change of female habitus to a masculine one. Way back in the 1st century, Pliny the Elder in his magnum opus “Natural history” had described females transforming into males, as observed by himself in Africa. The basis of this is now ascertained. It is the biochemical interchangeability of the female and male hormones. 
Congenital Adrenal Hyperplasia is a syndrome complex which results from the disturbances in adrenal steroidogenesis. Historically, Tilesius (1803) is believed to be the first to report a relationship between adrenal tumours and precocious puberty, and Marchand (1891) is believed to have reported the first case of pseudo-hermaphroditism in the presence of an adrenocortical hyperplasia. 
The primary pathology is mutation of genes encoding enzymes involved in adrenal steroid synthesis. The most commonly affected is the 21-hydroxylase enzyme. The reduced activity of this enzyme results in deficiency of glucocorticoids and mineralocorticoids and diversion of the substrates, resulting in excessive androgen production. The classic CAH which is a result of loss-of-function mutation results in neonatal presentation. The screening test is 17-hydroxy progesterone, which is raised in CAH. The simple virilising type of CAH results in the early childhood presentation with virilisation. The late-onset non-classical CAH is the mildest form, and is an overlap with the polycystic ovarian syndrome. 
Glucocorticoid supplementation is the cornerstone of the management of CAH. Management involves balancing between overtreatment which can result in hypercortisolism and undertreatment which fails to correct the hyperandrogenism. 17-hydroxyprogesterone can be a marker for adequacy of treatment of CAH, though it does not correlate with androgen levels. Recent studies have shown raised risk of infertility, cardiovascular disease and psychological issues among those with CAH. A multi-disciplinary approach to a patient with CAH is advisable. Modified release glucocorticoids, parenteral glucocorticoids given as subcutaneous infusions, chemotherapeutic agents like mitotane, androgen synthesis inhibitors like abiraterone are novel agents being investigated for this condition. 
Pregnancy in a patient with risk of offspring with CAH is a complex issue. Involvement of endocrinologist is imperative. Prenatal diagnosis may be considered in those with couples having affected children. Though only those carrying female offspring need treatment, the issue of fetal sex determination raises complex questions. Prednisolone is preferred and dexamethasone is avoided; and treatment should be initiated by 8 weeks of gestation.
In this issue, we bring to you two interesting cases of CAH. One is a simple virilising form who required genitoplasty. Another is one who had undergone genitoplasty in her childhood and had 3 successful pregnancy outcomes. We are sure that the readers will enjoy reading these, and a variety of other interesting cases presented in this March issue of our journal. 
The month of March brings the memory of Dr Patrick Steptoe, a British obstetrician and gynaecologist who pioneered fertility research. His 30th death anniversary is celebrated on 21st March.  
Also, March 8th is celebrated as world women’s day. On this occasion, a special note of appreciation is made to all our readers, who are unceasingly committed to the improvement of health of the women of the world.

Rare Case Of Bilateral Labial Hemangioma And Massive Edema In Coexistence With Aortoarteritis

Author Information

Sameriya A*, Parulekar SV.
(** Second Year Resident, ** Professor and head, Department of Obstetrics and Gynecology, Seth G S Medical College & K E M Hospital, Mumbai, India.)

Abstract

Massive labial edema is generally related to underlying systemic pathology, mainly preclampsia and diabetes. It can also be associated with infection, autoimmune disorder, hypoprotienemia, trauma,  connective tissue disorder, neoplastic, and inflammatory conditions. Here we are describing rare case of hormone dependent bilateral hemangioma of labia minora which presented as peduncalated bilateral massive odema of labia minora in a normotensive, non-diabetic 25 weeks pregnant woman who also diagnosed to have aortoarterits. Such a tumor has not been described in the vulva in the world literature before.

Introduction

Massive vulval edema is usually sequelae of an underlying systemic disease in pregnancy.[1] Isolated vulval edema in pregnancy is rare. We are presenting  a case of bilateral peduncalated hemangiomas of the labia minora  in a 25 weeks pregnant woman, which was initially considered to be edema due to lymphatic obstruction. The prepregnancy symptoms of the woman were also curious. Treatment of Vulval edema depends on pathophysiology and treatment options are steroids, furosemide, drainage, and dressing. A hemangioma of the vulva and aortoarteritis are best treated only when the woman is not pregnant.

Case Report

A 25 year old woman, married since 2 years, gravida two with one spontaneous abortion at 2 months of amenorrhea in the past was referred to our tertiary center from a private hospital for further management of labial swellings. She had 25 weeks of amenorrhhea. Patient had been symptomatic since last 15-20 days with increasing pain and size of swellings. The swellings used to increase in size at midcyle from the time of menarche, and would reduce in size during menses. She had been treated with NAIDs with no relief prior to referral to our center. She did not have any history of fever or trauma locally. There was no history of claudication, tingling, numbness, blurring of vision, syncopal attacks, chest pain, breathlessness, palpitation, oral ulcers, or photosensitivity. Her general examination showed no abnormality. Her radial and brachial pulsations were not felt on both sides. The carotid, femoral and dorsalis pedis pulstions were felt well. Her blood pressure in the upper limbs was 90/60 mm Hg, and in the lower limbs 124/70 mm Hg.
Her systemic examination showed no abnormality. Local examination showed right labium minus swollen to a size of 5x4x4 cm, which was very tender. The left labium minus was bilobed,  very tender, and swollen to a size of 8x7x8 cm. The lower part of the swelling contained clear fluid like lymph. Its surface showed hemorrhagic vesicles and erythema. The uterus was enlarged to a size of 24-26 weeks of gestation. Fetal parts were felt and fetal heart sounds were normal. Her investigations showed normal plasma sugar levels, renal and liver function tests, and levels of ANCA, APLA, ACLA, C3, C4, ANA, dsDNA, Beta 2 Glycoprotein and RA factor.
Ultrasonographic examination of the masses showed presence of large hemangiomas in both the labia minora. Magnetic resonance imaging (MRI) of the pelvis showed multiple lobulated outpouching from labia minora measuring 3.7 cmx4.7 cmx 3.3 cm, which were T2/ STIR hyperintense & T1 hypointense with a leash of flow voids within. On post contrast study it shows intense homogenous enhancement. The diagnosis of a benign vascular lesion in each labium minus was made.
Doppler studies showed monophasic wave form with decreased velocity in bilateral ulnar arteries and right carotid artery suggestive of narrowing at brachiocephalic trunk and left subclavian origin.  MRI with contrast enhancing showed complete occlusion of left subclavian artery, high grade narrowing of segment 2 of right subclavian artery, wall irregularities involving the brachiocephalic trunk, proximal left common carotid artery. A diagnosis of aortoarteritis was made.
A general surgical reference was made. The surgeons drained the fluid component of the swelling of the left labium minus. Residual collection ruptured spontaneously later and the remaining fluid drained out. The patient was then treated with amoxycillin-clavulanic acid orally and glycerine magnesium sulphate dressing twice a day. The size of the swellings decreased considerably. She was discharged from the hospital, with instructions to continue local dressing at home. One month later the swellings were found to be reduced further. The patient was advised to have an institutional delivery, and then undergo interventional radiological treatment for her hemangiomas, and follow up with cardiologists and cardiovascular surgeons for her aortoateritis.

Sizes Of The Masses At Different Times After Admission

Day
1
13
30
Right (cm)
5x4x4
4x3x3
4x3x3
Left (cm)
8x7x8
5x4x4
3x2x2


Figure 1. Clinical appearance of the swellings: frontal view.


Figure 2. Clinical appearance of the swellings: inferior view.


Figure 3. Contrast enhanced MRI: complete occlusion of left subclavian artery, high grade narrowing of segment 2 of right subclavian artery, wall irregularities involving the brachiocephalic trunk and proximal left common carotid artery.


Figure 4. MRI of pelvis showing labial swellings.


Figure 5. The labial swellings 1 month after initial presentation.

Discussion

While edema is common in gravid women, it is generally present in the lower limbs, face, hands and rarely in the vulva. Isolated vulvar edema generally found to be associated with severe preclampsia, diabetes mellitus, septicaemia, anemia, renal problems, infection,trauma, hypoalbuminea, obstructed labour. Depending upon the pathophysiology it is treated with steroids , furosemide, albumin. The patient presented here was initially diagnosed as a case of massive edema of the vulva and treated accordingly. After investigations the diagnosis of hemangiomas was made. However there was some local infection and edema resulting from it. So the treatment was continued, which reduced the swelling to some extent. Lymphatic collection in the left labium minus was thought to be a lymphocele, due to lymphatic obstruction. The surgeons believed it to be due to ‘Labial Compartment syndrome’, which is characterized by prolonged standing of swelling resulting into microvascular necrosis of tissue. Hence they drained the fluid. However it might have been unnecessary, as the residual collection ruptured spontaneously later and the fluid drained out. It might have been somewhat helpful in increasing flow to the edematous tissues. 
In our case, vulvar edema was probably secondary to local superficial infection. The main bulk of the swellings was the hemangiomas. Aortoarteritis was a coincidental finding, and had nothing to do with the swellings. A curious feature of the hemangiomas was that they were hormone dependent. From the time of menarche, they increased in size midcycle, when estrogen production peaked, and reduced in size during menstrual flow. Thus it was a (estrogen) hormone dependent tumor. Such a tumor has not been described in the vulva in the world literature.
Hemangioma is a vascular malformation, a developmental anomaly which does not regress and is composed of dysmorphic vessels with normal endothelial turnover. It is of arterial, venous, capillary, lymphatic or mixed type. Vascular malformations can also be differentiated at the hemodynamic level between low-flow malformations, that include capillary and venous malformations, and high-flow malformations that include arterial malformations, arterio-venous fistula. The diagnosis of vascular malformations can be strongly suspected by careful history and physical examination. Bluish, easily compressible non-pulsatile masses that increase in size with manoeuvres to increase venous pressure (Valsalva maneuver) are usually venous malformations.3 6 Pulsations are present in high flow vascular malformations. Clinical symptoms include superficial dyspareunia, swelling, discomfort, pain, discharge, secondary infections and cosmetic problems.[2,3,8] Vascular malformations may be complicated by cutaneous ulceration and haemorrhage, limb hypertrophy or even high-output cardiac failure.[7] In our case it was an arterial type malformation.
Differential diagnosis of vulvar vascular malformations are: varicosities, vulvar malignancies, nevi, melanomas, endometriosis, nevi and bartholins cyst. Venous malformations should be distinguished from vulvar varicosities. Pelvic venous hypertension may lead to vulvar varicosities in pregnancy, one of its typical complication and they appear as a grape-like cluster of veins on the vulva.[3-6] While vulvar varicosities result from venous insufficiency or stasis, vascular malformations of the vulva are developmental anomalies composed of abnormal vessels and they do not regress. Vascular malformations may undergo a rapid increase in size as a result of infection, thrombosis, trauma, surgical intervention and hormonal changes (as during puberty or in pregnancy).[2,5,7] 
Vulvar vascular malformation need no treatment if there is no significant symptom. All complicated vascular malformations require treatment. Surgical excision is the curative procedure but can be complicated by significant loss of motor function, nerve damage and massive bleeding. Alternative treatment methods are available. Sclerotherapy is indicated in case of small and not diffuse venous malformations. Large arterio-venous malformations can be treated by embolization, where it can be an alternative to, or a preparation for operation. Selective embolization sometimes has to be carried out through two or more steps to avoid or reduce risks of complications, primarily  causing occlusion of important anomalous arteries.
In our case , patient was managed conservatively with daily dressing with glycerine magnesium sulphate, size of odema decreased. Patient symptoms were improved and was also started on steroids, aspirin for aortoarteritis as per medical opinion. Vascular surgeons advised bilateral internal iliac angiogram post delivery to decide final mode of treatment. Obstetric plan of management was to achieve a vaginal delivery, aided by holding the vulvar masses laterally.

References
  1. Jakobi P, Friedman M, Goldstein I, Zaidise I, Itskovitz-Eldor J.. Massive vulvar edema in pregnancy. A case report. J Reprod Med 1995;40:479–81.
  2. Guven ES, Guven S, Durukan T, Onderoglu L. Massive vulval oedema complicating pregnancy. Journal of Obstetrics and Gynaecology 2005;25: 216–218.
  3. Wang S, Lang JH, Zhou HM. Venous malformations of the female lower genital tract. Eur J Obstet Gynecol Reprod Biol 2009;145:205–8.
  4. Marrocco-Trischitta MM, Nicodemi EM, Nater C, et al. Management of congenital venous malformations of the vulva. Obstet Gynecol 2001;98(5 Pt 1):789–93 
  5. Eifert S, Villavicencio JL, Kao TC, Taute BM, Rich NM.. Prevalence of deep venous anomalies in congenital vascular malformations of venous predominance. J Vasc Surg 2000;31:462–71
  6. Kempinaire A, De Raeve L, Roseeuw D, Boon L, De Raeve H. Capillary-venous malformation in the labia majora in a 12-year-old girl. Dermatology (Basel) 1997;194:405–7.
  7. Herman AR, Morello F, Strickland JL. Vulvar venous malformations in an 11-year-old girl: a case report. J Pediatr Adolesc Gynecol 2004;17:179–81.
  8. Messina ML, Carnevale FC, Baracat EC. Percutaneous embolization of large vulvar vascular malformation. Int J Gynaecol Obstet 2008;100:85–6.
Citation

Sameriya A, Parulekar SV. Rare Case Of Bilateral Labial Hemangioma And Massive Edema In Coexistence With Aortoarteritis. JPGO 2018. Volume 5 No.3. Available from: http://www.jpgo.org/2018/03/rare-case-of-bilateral-labial.html

Takayasu Arteritis – Towards A Better Diagnosis

Author Information

Parulekar SV
(Professor and head, Department of Obstetrics and Gynecology, Seth G S Medical College & K E M Hospital, Mumbai, India.)

Abstract

Takayasu arteritis (TA) is an idiopathic, chronic  granulomatous vasculitis. It is probably due to autoimmune cell-mediated immunological reaction. It causes segmental stenosis, occlusion, thrombosis and/or aneurysm formation in aorta and its branches. A high degree of suspicion is necessary in making its diagnosis. A case is presented in which the diagnosis was curiously missed at multiple levels.

Introduction

A large-vessel vasculitis in an adult is a chronic inflammation of aorta and its major branches. It includes giant cell arteritis and TA.[1] TA is an idiopathic, chronic  granulomatous vasculitis which is associated with an inflammation that begins from the adventitia and progresses to the intima, leading to vascular segmental stenosis, occlusion, and/or formation of aneurysm. Its diagnosis can be difficult, unless a high degree of suspicion is exercised. A case of TA in a young parous woman is presented in which the diagnosis was curiously missed at multiple levels.

Case Report

A 26 year old woman, gravida 3 para 2 abortion 1, was transferred to our center from another center in emergency. She was transferred for critical care in view of being pulseless and with no recordable blood pressure after an abortion. She had two cesarean sections in the past, the second one being 7 months before this abortion. The abortion was actually a medical termination of pregnancy by self prescribed and self administered mifepristone-misoprostol combination after 2 months of amenorrhea. She had mild bleeding for 4 days, soaking 2 pads per day, followed by passage of products of conception vaginally. When she presented to a hospital near her home, she was found to have no palpable radial pulse and no recordable blood pressure in the right upper limb. A diagnosis of hemorrhagic shock was made. She was transfused two bottles of Ringer's lactate 500 ml each, and two bottles of plasma expander (Hetastarch or hydroxyl starch, 500 ml each) rapidly. When the pulse and blood pressure did not come up, she was started on a noradrenaline drip at a rate of 0.4 mg/hour. When that did not achieve any improvement in her pulse and blood pressure, she was put in a cardiac ambulance and rushed to our center for critical care, an intensivist accompanying her. When she was seen in our emergency medical services, her general condition was fair. She was conscious, well oriented, and speaking coherently. Her heart rate was 76/min and respiratory rate was 16/min. Her radial pulse was not palpable and BP was not recordable in the right upper limb. There was no cyanosis or pallor. The noradrenaline drip was continued and an urgent obstetric call was made. The obstetric resident and junior consultant confirmed the findings of the emergency room resident. Obstetric examination showed that the abdomen was soft and supple, there was minimal vaginal bleeding, the uterus was of 6 weeks' size and the products of conception were felt through open cervix. An obstetric diagnosis of an incomplete abortion was made. The state of no palpable pulse and no recordable blood pressure in the presence of normal heart and respiratory rate and an otherwise good condition of the patient could not be explained. The urinary bladder was catheterized and 600 ml of clear urine was drained. Then the head of the obstetric services was contacted on phone for advice. After hearing about the findings and the response to medical treatment, he made a provisional diagnosis of an incomplete abortion in case of chronic vasculitis, probably TA. An evacuation of the retained products of conception and evaluation of the occlusive vasculitis in due course was advised.
The emergency medical unit continued administration of the noradrenaline drip. A CT angiography was obtained, which showed occlusion of the distal right subclavian artery, right carotid artery and left subclavian artery. The arch or aorta, renal arteries and uterine arteries were normal. A diagnosis of type I TA was made. The noradrenaline drip was then discontinued by the emergency medical service unit. The patient was transferred to the obstetric unit. Investigations for fitness for anesthesia showed normal results. A blunt curettage was done under local anesthesia to remove the retained products of conception. The patient made an uneventful recovery after the procedure. Careful questioning of the patient the next morning by the head of the obstetric unit revealed that she had been diagnosed to have some vascular condition at the time of her previous cesarean section 7 months ago at another hospital, but she did not undergo any investigations as advised, and she also hid this history when she presented for management of her abortion. She did not give any explanation for her actions. Counseling was done about her illness, illegality of self-induced medical abortion, the risks of medical abortion in view of two previous cesarean sections and lack of exclusion of an extrauterine pregnancy prior to administration of the drugs, the need for disclosing all past medical history to her treating doctor and akways following medical advice. She was subsequently transferred to the medical unit for further management of TA.


Figure 1. CT angiography showing occlusion of the distal right subclavian artery (yellow arrow), right carotid artery (green arrow) and left subclavian artery (red arrow).

Discussion

TA has an incidence of 1.2-2.6/million per year in the western world and even greater incidence in Southeast Asia, Africa, and central and South America.[2] It is generally seen in young adults with a predilection for women. It is an autoimmune condition, influenced by both genetic and environmental factors. It is believed to have an association with Mycobacterium tuberculosis.[3] A patient with TA may be asymptomatic with incidental finding of unequal pulses or may present with features of vascular occlusion such as cerebrovascular accidents or renal failure. The diagnosis is not very difficult if the lower limb pulses are checked when the upper limb pulses are not palpable, and blood pressure is measured in the lower limbs when it is not recordable in the upper limbs. The carotid pulses may or may not be palpable in TA.

Conventional angiography is the time tested traditional method for the diagnosis of TA.[4] In modern times multidetector CT angiography (CTA) is preferred for this purpose as it is less invasive, early and accurate in depicting luminal as well as mural lesions of the aorta and its branches.[5] It shows concentric mural thickening, calcification in the thickened wall, a double ring enhancement pattern on the post-enhanced CTA images (the inside ring being poorly enhanced and the outside ring being obviously enhanced).[6-11] Luminal stenosis is seen in about 90% of patients.[12]

The differential diagnoses includes atherosclerosis, polyarteritis nodosa and giant cell arteritis.[6,13] It does not include a hemorrhagic shock. It was unfortunate that this diagnosis was made in the case presented. The error stemmed from a failure to observe the basic examination algorithm when peripheral pulses are not palpable. It ignored the fact that a woman in hemorrhagic shock cannot have normal pulse and respiratory rates, and will not converse normally and do other things that healthy people do. There was a failure to realize that mild vaginal bleeding does not produce shock. The cause of such deviation is probably a sharp focus on one's own specialty and a refusal to apply knowledge of other subjects like obstetrics gained during medical graduation. Transferring the patient in a cardiac ambulance with an intensivist showed that the treating doctor was working in a well equipped hospital. But the noradrenaline infusion was unwarranted. It was fortunate that this patient did not develop any adverse effects to it. The patient's failure to get herself treated before planning another pregnancy and also to disclose her past medical history to her doctor was contributory to inadequacies in her treatment.

Conclusion

TA is a condition that is uncommon and sometimes difficult to diagnose. But strict adherence to clinical examination protocols and application of at least basic knowledge of other specialties, combined with use of imaging by CTA helps clinch the diagnosis. It cannot be concluded that noradrenaline does not help in the management of TA by the study of this case, but it has never been used for this indication in the past. Anyway the pathophysiology of TA and pharmacological actions of noradrenaline do not suggest that noradrenaline would be a useful drug in managing TA. It cannot be concluded with the study of a single case that the use of noradrenaline does not harm a patient of TA, but I hope that further cases of this nature are not reported to help draw that conclusion.

References
  1. Luqmani R. Large vessel vasculitides: Update for the cardiologist. Curr Opin Cardiol. 2012;27:578–84.
  2. Epidemiology of large-vessel vasculidities. Richards BL, March L, Gabriel SE. Best Pract Res Clin Rheumatol. 2010 Dec; 24(6):871-83.
  3. Kothari SS. Aetiopathogenesis of Takayasu's arteritis and BCG vaccination: The missing link. Med Hypotheses. 1995;45:227–30.
  4. Brunner J, Feldman BM, Tyrrell PN, Kuemmerle-Deschner JB, Zimmerhackl LB, Gassner I, et al. Takayasu arteritis in children and adolescents. Rheumatology 2010;49:1806–14.
  5. Zhu FP, Luo S, Wang ZJ, Jin ZY, Zhang LJ, Lu GM. Takayasu arteritis: imaging spectrum at multidetector CT angiography. The British Journal of Radiology. 2012;85(1020):e1282-e1292. doi:10.1259/bjr/25536451.
  6. Khandelwal N, Kalra N, Garg MK, Kang M, Lal A, Jain S, et al. Multidetector CT angiography in Takayasu arteritis. Eur J Radiol 2011;77:369–74.
  7. Gotway MB, Araoz PA, Macedo TA, Stanson AW, Higgins CB, Ring EJ, et al. Imaging findings in Takayasu's arteritis. AJR Am J Roentgenol 2005;184:1945–50.
  8. Matsunaga N, Hayashi K, Sakamoto I, Ogawa Y, Matsumoto T. Takayasu arteritis: protean radiologic manifestations and diagnosis. Radiographics 1997;17:579–94.
  9. Park JH, Chung JW, Im JG, Kim SK, Park YB, Han MC. Takayasu arteritis: evaluation of mural changes in the aorta and pulmonary artery with CT angiography. Radiology 1995;196:89–93.
  10. Kim SY, Park JH, Chung JW, Kim HC, Lee W, So YH, et al. Follow-up CT evaluation of the mural changes in active Takayasu arteritis. Korean J Radiol 2007;8:286–94 [PMC free article]
  11. Kissin EY, Merkel PA. Diagnostic imaging in Takayasu arteritis. Curr Opin Rheumatol 2004;16:31–7. 
  12. Mason JC. Takayasu arteritis—advances in diagnosis and management. Nat Rev Rheumatol 2010;6:406–15.
  13. Weyand CM, Goronzy JJ. Medium- and large-vessel vasculitis. N Engl J Med 2003;349:160–9.

Citation

Parulekar SV. Takayasu Arteritis – Towards A Better Diagnosis. JPGO 2018. Volume 5 No.3. Available from: http://www.jpgo.org/2018/03/takayasu-arteritis-towards-better.html

Elevated Placental Alkaline Phosphatase – A Soft Marker For Placental Injury

Author Information

Singhania N*, Sakpal V**, Gupta AS***.
(* First year Resident, ** Senior Resident, *** Professor. Department of Obstetrics and Gynecology, Seth GS Medical College and KEM Hospital, Mumbai, India.)

Abstract

Elevated levels of serum alkaline phosphatase (ALP) is not uncommon in obstetrics. High levels of ALP may indicate HELLP syndrome, intrahepatic cholestasis, liver disease, bone disease. It is essential to remember and not to forget that it can be solely of placental origin. We present a case where alkaline phosphatase levels were highly raised and the cause was most probably placental.

Introduction

Alkaline phosphatase is secreted by liver, bone, intestine and placental tissues.[1] Alkaline phosphatase is secreted by the syncitiotrophoblast layer of placenta.[2] It appears in maternal circulation between 15 to 26 weeks of gestation and increases during the third trimester.[3,4] Extremely high values of ALP has been associated with premature birth, low birth weight and intrauterine growth restriction (IUGR).[5,6]  We report a similar case, where dramatic elevation in ALP was associated with IUGR and  fetal distress in early 3rd trimester leading to preterm emergency cesarean section.

Case Report

A 26 years old gravida 2 para1 living 1 married since 7 years had registered in our hospital at 9 weeks of gestation. A routine antenatal (ANC) workup showed hemoglobin (Hb) of 13.0 gm%, serum TSH was 0.18 mIU/ml, HIV, HbsAg, and VDRL were non reactive. Her blood sugars were within normal limit. She had regular ANC follow up every 4 weekly. At 31 weeks of gestation her blood pressure (BP) was recorded as 160/100 mmHg. On per abdomen examination uterine size was 26 weeks, uterus was relaxed and fetal heart sounds (FHS) were regular. She was admitted for BP monitoring and evaluation of intrauterine growth restriction (IUGR). After admission her BP was monitored 6 hourly and was in the range of 160/100 mm Hg and hence was started on oral Nifedepine 5mg qid and oral enteric coated acetylsalicylic acid 75 mg OD. Her investigations were repeated. Urine was negative for albumin. Her Hb was 10.1 gm%, platelets were 2.0 lakh/cmm, INR was 0.86, blood urea nitrogen (BUN) was  17 mg%, creatinine was 1.4 mg%, total proteins were 6.5 gm%, albumin was 3.0 gm%, serum glutamic oxaloacetic transaminase (SGOT) was 62.0 u/l, serum glutamic pyruvic transaminase (SGPT) was 48 u/l, ALP was 1088 IU/L (normal range: 44 to 147 international units per liter (IU/L)), and uric acid was 8.2 mg%. Ultrasound  (USG) showed mean gestation age of 26 weeks and 2 days with estimated fetal weight of 836 gms and severe oligohydraminos (amniotic fluid index was 3-4 cm). Uteroplacental Doppler study revealed mean umblical artery S/D ratio of 4, pulsality index of middle cerebral artery as 1 with absent diastolic notch in both the uterine arteries. Daily fetal kick count, bi weekly non stress test (NST) and weekly Doppler were done. Two doses of injection Betnesol 12 mg, 24 hours apart were given for fetal lung maturity. Liver function test were repeated 2 days later where ALP, SGOT and SGPT values remained the same. Gamma glutamyl transferase (GGT)  was 43.3u/l. Her anti phospholipid antibody  screen was negative.  Whole abdomen ultrasound was done which showed normal findings. Gastroenterologist was consulted for highly elevated ALP. In the light of normal findings of USG and normal levels SGOT, SGPT, GGT, the gastroenterologist were of the opinion that the source of the raised ALP is extra hepatic, most probably placental. Her pregnancy was continued for another 2 weeks with close monitoring. At 32 weeks of gestation her NST showed repeated variable decelerations, hence emergency lower segment cesarean section was done. She delivered a female baby of 774 gms with Apgar score of 9/10. Placental weight was 500 gm. Neonate was admitted in NICU in view of low birth weight. Immediate postpartum serological tests showed ALP, SGOT, SGPT   levels at 1234 u/l, 44 u/l, 42 u/l respectively. Four weeks later ALP level was 256 u/l. Baby was discharged from NICU at birth weight of 1.5 kg.

Discussion

Our patient had gestational hypertension and IUGR. Her platelet counts, SGOT, and  SGPT levels were normal thus excluding the diagnosis of HELLP syndrome. Her USG hepatobiliary evaluation was unremarkable. She had no renal and skeletal complaints. Thus making placenta the major source of elevated ALP, a diagnosis by exclusion. Our patient had IUGR, oligohydramnios, Doppler changes and non reactive NST; all suggestive of fetal compromise due to uteropacental insufficiency.
In one case report acutely rising ALP was attributed to placental infarction and damage that resulted in intra uterine death.[7] In another study elevated ALP was associated with spontaneous preterm birth.[8] In review of literature there is one case report of isolated elevated ALP in uncomplicated pregnancy[1] and two case reports of isolated rise in gestational diabetes mellitus (GDM).[9,10]  In one of these cases genetic abnormality was present. There is another case report of raised ALP in patient with antiphospholipid antibody syndrome.[11]  The autoimmune profile of our patient was normal and she also did not have GDM. Antenatal USG and post delivery neonatal evaluation by neonatologist did not suggest any genetic abnormality. This evidence allows us to draw an inference that the raised ALP in our patient was due to placental injury.
Thus we can postulate from the above study that extremely high placental ALP could be a biochemical marker for placental injury that can lead to adverse fetal outcomes.

Conclusion

In cases where adverse fetal outcome is anticipated a close watch should be kept on serial ALP levels. In patients with rising trend of ALP obstetrics Doppler study must be done to look for fetoplacental insufficiency. 

References
  1. Vongthavaravat V, Nurnberger MM, Balodimos N, Blanchette H, Koff RS. Isolated elevation of serum alkaline phosphatase level in an uncomplicated pregnancy: a case report. Am J Obstet Gynecol. 2000;183(2):505-6.
  2. Boronkai A, Than NG, Magenheim R, Bellyei S, Szigeti A, Deres P, et al. Extremely high maternal alkaline phosphatase serum concentration with syncytiotrophoblastic origin. J Clin Pathol. 2005;58(1):72-6.
  3. Fishman L, Miyayama H, Driscoll SG, Fishman WH. Developmental phase-specific alkaline phosphatase isoenzymes of human placenta and their occurrence in human cancer. Cancer Res. 1976;36(7 PT 1):2268-73.
  4. Okensina AB, Donaldson D, Lascelles PT, Morris P. Effect of gestational age on levels of serum alkaline phosphatase isoenzymes in healthy pregnant women. Int J Gynecol Obstet. 1995;48(1):25-9.
  5. Meyer RE, Thompson SJ, Addy CL, Garrison CZ, Best RG. Maternal serum placental alkaline phosphatase level and risk for preterm delivery. Am J Obstet Gynecol. 1995;173(1):181-6.
  6. Brock DJH, Barron L. Measurement of placental alkaline phosphatase in maternal plasma as an indicator of subsequent low birth weight outcome. Br J Obstet Gynecol. 1988;95(1):79-83. 
  7. Ranganath L, Taylor W, John L, Alfirevic Z. Biochemical diagnosis of placental infarction /damage: acutely rising alkaline phosphatase. Ann Clin Biochem. 2008;45(Pt 3):335-338.
  8. Moawad AH, Goldenberg RL, Meercer B, Meis PJ, Iams JD, Das A et al. The preterm Prediction Study : the value of serum alkaline phosphatase, alpha fetoprotein, plasma corticotrophin – releasing hormone and other serum markers for the prediction of spontaneous preterm birth. Am J Obstet Gynecol. 2002;186(5):990-6.
  9. Wojcicka-Bentyn J, Czajkowski K, Sienko J, Grymowicz M, Bros M. Extremely elevated activity of serum alkaline phosphatase in gestational diabetes: a case report. Am J Obstet Gynecol. 2004;190(2):566-7.
  10. Heazell AE, Judge JK, Bhatti NR. A case of isolated peripartum elevation of alkaline phosphatase in pregnancy complicated by gestational diabetes. J Matern Fetal Neonatal Med. 2006;19(5):311-3 
  11. C. Delluc,  N. Costedoat-Chalumeau,  D. Saadoun,  D. Vauthier-Brouzes,  B. Wechsler, J.-C. Piette. Elevation of alkaline phosphatase in a pregnant patient with antiphospholipid syndrome: HELLP syndrome or not? Rheumatology.2008;47(4):554–555.

Citation

Singhania N, Sakpal V, Gupta AS. Elevated Placental Alkaline Phosphatase – A Soft Marker For Placental Injury. JPGO 2018. Volume 5 No.3. Available from: http://www.jpgo.org/2018/03/elevated-placental-alkaline-phosphatase.html

A Rare Case Of Campomelia

Author Information

Rane VV*, Samant PY**, Honnavar PU***
(* Junior resident, ** Additional professor, *** Assistant professor, Department of Gynecology and Obstetrics, Seth GS Medical College and KEM Hospital, Mumbai, India.)

Abstract

Campomelia is a rare lethal osteodysplastic syndrome characterized by abnormal curving of the long bones. Here, we present a case of a 29 year old primigravida with 19 weeks gestation with campomelic dysplasia who underwent termination of pregnancy.

Introduction

Campomelia is derived from Greek words campto, meaning bent and melia, meaning limb. It is rare skeletal disorder with incidence of 1 in 10,000.[1]   It has autosomal dominant inheritance caused by alterations in SRY-related HMG-Box Gene 9 (SOX9) located on chromosome 17.[2] This gene is essential for both chondrocyte differentiation and sex determination. This condition involves various systems, characteristic being shortening and bowing of long bones.

Case Report

A 29 year old primigravida who had conceived after multiple cycles of ovulation induction (details of which were not known) presented at 19 weeks and 4 days for termination of pregnancy. Maternal screening for dual markers was normal. Ultrasonography was suggestive of bilateral femur length of 20 mm, corresponding to 16 weeks which was less than third percentile for that gestational age with bow legs. (Figure 1) There were only eleven pairs of ribs. These findings were consistent with campomelic dysplasia. Other systems appeared to be normal in malformation scan.


Figure 1. Bowed femur on ultrasound (arrows).

Genetic counselling was done by geneticists. She and her relatives were counselled about anomalies and poor prognosis. They opted for termination of pregnancy. Hemogram, liver and renal function tests, blood sugar levels and thyroid function tests were all normal. Abortion was induced with 400 microgram misoprostol and she aborted after five doses of misoprostol on the second day. A 300 gram female fetus with short thighs and no other obvious external dysmorphic features. The X-ray of abortus revealed curved and short femora. (Figure 2) Genetic studies on the abortus were not done as the parents could not afford the test. Karyotyping of both parents and chorionic villous sampling in the next pregnancy was advised at discharge.


Figure 2. Infantogram showing bilateral bowed femora (arrows).

Discussion

Campomelic dysplasia is a rare form of congenital short limbed dwarfism. It is an autosomal dominant condition caused by heterozygous mutation in SRY related HMG-Box gene (SOX9) on chromosome 17q24. This gene codes for a protein transcription factor which is responsible for both bone formation and sex organ development. Alteration in this gene prevents the SOX9 protein from properly controlling the genes essential for normal development of skeleton, reproductive organs, and other parts of the body. Defects in skeletal features include small scapula, small bell-shaped chest, twisted spine, club foot, dislocated hips, short fingers and toes and eleven pair of ribs.  The characteristic features are short limb bones and bowing of femur and tibia. Various systems may be involved, but respiratory distress is a common cause of death in such infants.[3] Postmortem may have revealed presence of any other fetal abnormalities in this fetus, but the parents were not willing for the same. 
Campomelia can be a part of a rare syndromes like called FATCO syndrome (fibular aplasia, tibial campomelia, oligosyndactyly), Al-Awadi syndrome and Shinzel phocomelia.[4] Spinal appearance, thoracic shape, associated hydrops and polyhydramnios along with short limbs are helpful in determining fetal skeletal dyplasia. Skeletal dysplasias with bent long bones can occur in osteogenesis imperfecta type II, kyphomelic dysplasia, and Stuve-Wiedemann syndrome. 
Babies with these dysplasias have high mortality rate, and in those who survive, high morbidity. A 17 years old teenager with intelligence quotient of 45 is the oldest reported case of campomelic dysplasia.[5] Mortality in neonatal period is 77% according to a study conducted in 1995.[6] In this case, the patient was already counselled by the private practitioner about genetic risks and wanted termination of pregnancy. Amniocentesis and confirmation of diagnosis would not have been possible within 3-4 days for termination, hence termination was conducted. After termination of pregnancy, the placenta can be sampled to acquire DNA for SOX9 gene mutation. The terminated abortal products could have been considered for genetic examination and the exact genetic problem could have been ascertained. However, the parents were not affording for the same. 
Preimplantation genetic diagnosis during in vitro fertilization(IVF-PGD) is a technique which helps in diagnosis of such single gene disorders within an embryo which may be passed when one or both parents are carriers.[7] Only the unaffected embryos are transferred in this procedure. This avoids time consuming prenatal diagnosis done after conception and avoids a difficult decision of termination of an ongoing pregnancy once fetus is found to be affected. Whether this malformation was related to ovulation induction drugs could not be ascertained and may also need further detailed analysis. 
There are non-profit organisations like ‘Little people of America’ and ‘European skeletal dysplasias network’ which provide support to people with short stature and their families.

Conclusion

Campomelic dysplasia is a rare lethal disorder with morbid outcome and is caused by mutation in SOX9 gene. It can be diagnosed prenatally by doing a thorough fetal sonogram or using invasive prenatal diagnosis; either chorion villous sampling or amniocentesis. Parental counselling and support is essential in such cases. Early identification and termination of pregnancy is the mainstay of the management.

References
  1. Quercia N. Campomelic dysplasia. In Blachford SL, editor. The Gale Encyclopedia of Genetic Disorders. 1st ed. Farmington: Gale Group 2001; pp.183-5.
  2. Bien-Willner GA, Stankiewicz P, Lupski JR. SOX9cre1, a cis-acting regulatory element located 1.1 Mb upstream of SOX9, mediates its enhancement through the SHH pathway. Hum Mol Genet. 2007; 16:1143-56.
  3. Mansour S, Offiah AC, McDowall S, Sim P, Tolmie J, Hall C. The phenotype of survivors of campomelic dysplasia. J Med Genet. 2002; 39:597-602. 
  4. Woods CG, Stricker S, Seemann P, Stern R, Cox J, Sherridan E. Mutations in WNT7A cause a range of limb malformations, including Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome. American journal of Human Genetics. 2006; 79:402–08.
  5. Argaman Z, Hammerman CA, Kaplan M. Campomelic dysplasia. Am J Dis Chil 1993; 147:205–206. 
  6. Mansour S, Hall CM, Pembrey ME, Young ID. A clinical and genetic study of campomelic dysplasia. J Med Genet 1995; 32:415–420.
  7. Geraedts JP, De Wert GM. Preimplantation genetic diagnosis. Clinical Genetics 2009; 76:315-25.

Citation

Rane VV, Samant PY, Honnavar PU. A Rare Case Of Campomelia. JPGO 2018. Volume 5 No.3. Available from: http://www.jpgo.org/2018/03/a-rare-case-of-campomelia.html

Case Of Virilization – Non-Classical Congenital Adrenal Hyperplasia

Author Information

Ganapati T*, Chaudhari HK**
(* Ex-resident, ** Associate professor, Department of Obstetrics and Gynecology, Seth GS Medical College and KEM Hospital, Mumbai, India.)

Abstract

In India, many a time genital ambiguity at birth gets overlooked and these children present later in life with growth disorders or menstrual abnormalities. When a young patient presents with virilization and menstrual abnormality without electrolyte disturbances or hypotension a clinician should suspect simple virilizing type of Congenital Adrenal Hyperplasia (CAH) as one of the differential diagnosis. Patient with CAH presenting with secondary amenorrhea can present a diagnostic challenge to even an experienced gynecologist. We present a case of non-classical CAH presenting with secondary amenorrhea and infertility.

Introduction

CAH is an autosomal recessive condition. It is a group of disorders resulting from disruption in the balance of adrenal cortical hormone biosynthesis.  It is a genetic and an endocrinological disorder that may demand diagnosis and treatment right from the birth. The clinical presentation of CAH is classified as classic, the severe form and non-classic (mild or late-onset) form. Classic CAH can be subdivided into salt-losing or non-salt-losing (simple virilizing), depending on the degree of aldosterone deficiency. In more than 90% of cases of CAH, the inability to synthesize cortisol is due to 21-hydroxylase deficiency. Females with classic 21-hydroxylase deficiency are exposed to excess androgens in the intrauterine period and are born with ambiguous external genitalia. Most patients cannot produce sufficient aldosterone to keep sodium balance and may develop potentially develop disastrous "salt wasting" crises if it remains untreated.[1] Classical CAH occurs in around 1:15,000 live births whereas non-classical or late onset congenital adrenal hyperplasia (LCAD) is more common than classical CAH.[2] The case presented here is a non-classic late-onset CAH.

Case Report

A 20 year old lady married since 1 year came with history of menses every 3-4 months, lasting for 1 day, for one year. She also complained of severe dyspareunia.  She gave history of amenorrhea during the preceding year. She had attained menarche at 15 years of age with past cycles being regular with moderate menstrual flow. She was born of a second-degree consanguineous marriage. She belonged to a lower class of society, had completed schooling and a house wife by occupation. Her mother felt that she had normal female external genitalia at birth, and had not given much importance to it during the adolescent period. There was no history of recurrent vomiting, hyperpigmentation or recurrent hospital admissions in childhood or adolescence or prior abdominal surgery. There were no other signs of virilization like hoarseness of voice, masculinization.  She had a younger brother who was otherwise normal. On examination, BMI was 29.3 kg/ m2 and her blood pressure was normal. Axillary hair and pubic hair distribution was Tanner stage 5, while breasts were Tanner stage 3. Local examination showed clitoromegaly with clitoral index of 600 mm2. Vagina was healthy but shallow. Cervix was flush with vagina with external os pin-point. Urethral opening was normal and 3 cm below the clitoris.(Figure 1) Serum FSH, LH, thyroid hormones and electrolytes were within normal limits. Karyotyping showed normal 46XX pattern with no detectable Y element on Fluorescent in situ hybridization.


Figure 1. Virilized external genitalia.

Serum basal 17-hydroxy progesterone was elevated (6.84 ng/ ml) (Normal: 0.11–1.2) and serum testosterone was elevated 2.19 ng/ ml (Normal: 0.1-1.2 ng/ml) and ACTH was 43.5 pg/ ml (Normal: 5-27 pg/ ml) were also elevated.  CYP21A1 testing was not done because she could not afford it. MRI was suggestive of adrenal hyperplasia. Diagnostic laparoscopy showed normal size uterus pulled towards right. Both fallopian tubes were normal. Both ovaries were bulky with thickened white glistening capsule suggestive of anovulation. Chromopertubation was attempted with pediatric Foley’s catheter no.8 but no spill was observed. Diagnosis of late-onset Congenital Adrenal Hyperplasia resulting in clitoromegaly and masculinization of external genitalia, with otherwise normal internal reproductive organs was ascertained.
Psychological counseling of family members was done. She attained withdrawal bleeding with tablet medroxyprogesterone acetate 5 mg twice a day for 5 days.  She was given tablet dexamethasone 0.5 mg for 5 days followed by oral prednisolone, the dose of which was titrated with 17 hydroxy progesterone, and finalized at 2.5 mg/ day. She was referred to plastic surgeon and she underwent clitoroplasty (figure 2). Perioperatively, she was given injectable steroids, and then switched back to prednisolone 2.5 mg/ day. She achieved spontaneous regular menstruation thereafter.


Figure 2. Picture after clitoroplasty.

Discussion

CAH is an autosomal recessive condition affecting both genders equally. It is due to mutations of genes required for enzymes mediating the production of cortisol from the adrenal glands.[3] The most common mutation is CYP21A2 gene resulting in 21-hydroxylase deficiency.[4] Depending on the severity of enzyme deficiency, the clinical spectrum varies from mild form of non-classical CAH to severe form. Depending on the time of onset, quantity of androgens and duration of exposure, CAH tends to have varied manifestation. It can range from serious salt wasting type with ambiguous genitalia at birth, due to intrauterine exposure to androgens; to simple virilization in adult. Salt-losing classical CAH approximates nearly 67% of the cases reported, and the non-classical forms the remaining 33%.[2] The patient described here is a case of non-classical CAH presenting with clitoromegaly.
The primary management of the disease is replacing the corticosteroids.[5] Replacement of steroids normalizes the ACTH levels in the body and in turn the levels of other enzymes like 11β-Hydroxylase and 3β- hydroxysteroid dehydrogenase normalize.[6] This administration of steroids resulted in successful, but gradual reversal of virilization in our patient also. However, reconstructive genital surgery was necessary.
Our patient presented at 20 years of age. Lack of knowledge and ignorance about normal genitalia delayed the need for seeking medical care for abnormal genitalia.
Due to intrauterine exposure and abnormality, genital reconstructive surgery may be required in the first few years of life. Studies have shown that despite relatively poor outcome of the initial single-stage surgery in infancy and the inevitable re-operation in puberty, the adult outcome of psychosexual outcome has been positive. The surgical treatment and the subsequent hormonal therapy has bearings on psychological health and sexual life, which should be factored in while managing patients.[7,8].
Our patient presented with infertility. Fertility in a case of CAH is generally reduced usually due to chronic anovulation and in some due to poor surgical results of genital reconstruction. The rate of miscarriages can be reduced with glucocorticoid treatment [9].
Our patient was phenotypically female at birth and there was no ambiguity in genitalia. The clitoromegaly and subsequent virilization of the genital parts resembling male parts, must have taken place during the teen years of the patient.
However, those which present earlier should be offered genetic testing at the earliest. Genetic testing should be offered to newborns with ambiguous genitalia, positive CAH screening test (elevated 17hydroxy progesterone), those with adrenal insufficiency and those with unexplained electrolyte abnormalities. In women with polycystic ovary syndrome and hirsutism, non-classical CAH could be considered as a rare differential diagnosis. Since the effects on the offspring start within the intrauterine life, pregnant women at risk of having a fetus affected with CYP21A2 mutations should be offered prenatal diagnosis. Adults with detected CAH but preserved fertility should consider genotyping of themselves before planning for children. Some studies have recommend universal screening of all newborns for CAH.[4]

Conclusion

CAH is a multicentric disorder requiring involvement of various specialties such as gynecologist, endocrinologist, urologist, plastic surgeons and psychologist should work together in order to achieve the best results. Treatment challenge is to individualize therapy and effectively control the excess androgen symptoms by using the lowest possible therapeutic dose, in order to avoid glucocorticoid side effects and optimize the reproductive, sexual, and bone health.

Acknowledgement

Dr Vinita Puri (Head of Plastic surgery department, KEM Hospital) is acknowledged for intraoperative images.

References
  1. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000; 21: 245-91.
  2. Beeresh CS, Doopadapalli D, Ray A, Lingegowda K. Non-classical congenital adrenal hyperplasia presenting as primary amenorrhoea with virilization. Int J Reprod Contrac Obstet Gynaecol 2015; 4:1627-9.
  3. Puri N, Talwar A. A Case Report of Classic Adrenal Hyperplasia – A Rarity. J Int Med Sci Acad 2014; 27: 51-2
  4. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2010; 95:4133–60.
  5. Hindmarsh PC. Management of the child with congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab 2009; 23:193–208.
  6. Belinda G, Vinay D, Moolechery J, Mathew V, Anantharaman R, Ayyar, et al. Congenital adrenal hyperplasia - experience from a tertiary centre in South India. Indian J Endocrinol Metab 2012; 16(Suppl 2): S385-6
  7. Krone N, Dhir V, Ivison HE, Arlt W. Congenital adrenal hyperplasia and P450 oxidoreductase deficiency. Clin Endocrinol (Oxf) 2007; 66:162–172 
  8. Stikkelbroeck NM, Beerendonk CC, Willemsen WN, Schreuders-Bais CA, Feitz WF, Rieu PN, et al. The long term outcome of feminizing genital surgery for congenital adrenal hyperplasia: anatomical, functional and cosmetic outcomes, psychosexual development, and satisfaction in adult female patients. J Pediatr Adolesc Gynecol 2003; 16: 289-96 
  9. Bidet M, Bellanné-Chantelot C, Galand-Portier MB, Golmard JL, Tardy V, Morel Y, et al. Fertility in women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 2010; 95: 1182-90.

Citation

Ganapati T, Chaudhari HK. Case of virilization – Non-Classical Congenital Adrenal Hyperplasia. JPGO 2018. Volume 5 No.3. Available from: http://www.jpgo.org/2018/03/case-of-virilization-non-classical.html

Management Of Celiac Disease In Pregnancy

Author Information

Ruhil MS*, Desai G**, Hatkar PA***, Mayadeo NM****
(* Second Year Resident, ** Assistant Professor, *** Associate Professor, **** Ex-Professor, Department of Obstetrics and Gynecology, Seth G.S. Medical College and K.E.M. Hospital, Mumbai, India.)

Abstract

Celiac disease is a rare autoimmune disorder with multisystem involvement.  It has a significant impact on the pregnancy and menstrual health. We present a case of successful pregnancy in a patient of celiac disease.

Introduction

Celiac disease is an autoimmune inflammatory condition with intestinal involvement predominantly. It gets triggered by diet containing gluten.[1] It affects around 0.5-1 % of the general population. Patients may complain of diarrhea, abdominal pain, abdominal bloating and weight loss. Late menarche, secondary amenorrhea, infertility, early menopause, recurrent pregnancy wastage and intrauterine growth restriction are other features of this disorder.[2,3] We present a case of celiac disease in pregnancy and its outcome.

Case Report

A 25 year old woman, married since 2 years, G2SA1 known case of celiac disease, came to the antenatal outpatient department at 7 weeks of gestation for antenatal registration. She had regular menstrual cycles.
At the age of 11 years, she had presented with pain in abdomen, vomiting and confusion, with normal blood pressure. Raised blood sugars (240 mg/ l) and positive urinary ketones suggested ketoacidosis, and diagnosis of type 1 diabetes mellitus was made. She was started on insulin and initiated regular follow up with endocrinologists. Menarche was at 13 years, with no problems. Around 2 years prior to current presentation, evaluation for hypothyroidism revealed positive anti-TPO and anti-TTG antibodies, suggestive of autoimmune thyroiditis. Gastroenterologists were consulted for anti-TTG positivity. She was kept on gluten free diet and duodenal biopsy was performed which showed villi with normal architecture and minimal increase in intraepithelial lymphocytes and mild lymphocytic inflammation in lamina propria. Repeat biopsy was done four months later after keeping her on gluten diet. The villi were found to be of normal architecture, there was patchy increase in intraepithelial lymphocytes and moderate lymphoplasmocytic infiltrates with eosinophils. Hence, she was diagnosed with silent celiac disease and was advised gluten free diet. She continued following up with gastroenterologists also regularly. 
Around a year later, she conceived spontaneously. She was admitted in the antenatal ward for management of deranged sugar levels ranging up to 250 mg/ dl.  Endocrinologists advised insulin (regular) 8-8-8-8 units and insulin (long acting) 0-0-8 units subcutaneously, with blood sugar monitoring 6 times a day. She was continued on same dose of tablet levothyroxine (25 microgram) and recent TSH value was normal (1.84 U/ L). Renal function tests and detailed neurological examination showed that there were no neurological or renal sequelae. Diabetic retinopathy was ruled out. She also developed acneiform eruptions over face and upper back, which was managed with topical medications. Upon normalization of sugars, she was discharged with antenatal care advise. Hemoglobin level was normal (10.5 mg %). There were no fetal malformations and fetal 2 D echo was normal. She was continued on gluten free diet, and dietician was consulted for specific advice.
She was readmitted at 32 weeks of gestation for evaluation of polyhydramnios (AFI of 25 cms). She was otherwise asymptomatic. Sugars (FBS 72 mg/ dl and PLBS 147 mg/ dl) and HbA1c (5.8) were within normal range.  Two doses of steroids injections were given. Dinoprostone gel induction of labor was done at 38 weeks of gestation and sugars levels during labor were well maintained. Healthy female child of 3.5 kg with Apgar score of 9/ 10 was delivered by outlet forceps application in view of fetal distress in second stage of labor. After brief observation period in NICU, baby was shifted back to mother.  She was discharged on day 4 of delivery with no complications.

Discussion

Celiac disease is a prototype of malabsorption syndromes and is caused by hypersensitivity to gluten, and gluten free diet is the main treatment. Malnutrition caused by the malabsorption is responsible for the intrauterine growth restriction and still birth. It is crucial for these patients and their fetuses to receive the daily amount of nutrition due to the increased metabolism during pregnancy. Our patient had been on gluten free diet and was continued on the same during pregnancy. 
The deficiency of certain essential minor elements and vitamins due to malabsorption may lead to multiple complications. Supplementation of multivitamins throughout the course of pregnancy is necessary. Though newer approaches such as enzymes that can break bonds between proline and glutamine in gluten are being tried, experience in pregnancy is limited. 
Celiac disease can present with wide spectrum of clinical manifestations including higher rates of infertility, recurrent abortions, intrauterine growth retardation and still births.[4,5] To screen the patients for celiac disease, the preferred test is the measurement of IgA tissue transglutaminase levels. The diagnosis is confirmed by endoscopic biopsy of small intestine. 
There is higher risk of preterm births in celiac disease. Autoimmune responses resulting in increased circulatory antibodies (anti-glial and anti-endomysial) may lead to the premature delivery. Since the disease was under good control, our patient did not have a preterm birth.  
Our patient had one prior spontaneous abortion, and no other major obstetric comorbidity in this pregnancy. Reproductive problems such as infertility, congenital anomalies, spontaneous abortions, abruptio placenta, still births and the development of preeclampsia are prevalent.[6] Our patient was not anemic. Iron deficiency may result in increased rates of feto-maternal morbidity and mortality and folate deficiency has been found to cause congenital malformations, abruptio placenta and preeclampsia.[7,8,9] However, this case is presented here to show that early diagnosis and appropriate management can help reduce these complications and entail good pregnancy outcome.

Conclusion

Celiac disease is a malabsorption syndrome resulting from inflammation at the mucosa of the small intestine due to nutrients including gluten, and can have implications on reproductive outcomes in women. Celiac disease can coexist with type 1 diabetes mellitus as seen in this case. Successful obstetric outcome is possible with a multidisciplinary approach involving obstetricians and other specialties. In this case, involvement of the gastroenterologists, endocrinologists and dieticians helped in the overall successful outcome. 

References
  1. Green PH, Cellier C. Celiac disease. N Engl J Med. 2007; 357:1731–43. 
  2. AGA Institute. AGA Institute Medical Position Statement on the Diagnosis and Management of Celiac Disease. Gastroenterology. 2006; 131:1977-80. 
  3. Fasano A, Catassi C. Clinical practice. Celiac disease. N Engl J Med. 2012; 20:2419–26. 
  4. Salvatore S, Finazzi S, Radaelli G, Lotzniker M, Zuccotti GV. Prevalence of undiagnosed celiac disease in the parents of preterm and/or small for gestational age infants. Am J Gastroenterol. 2007; 102:168–73. 
  5. Martinelli D, Fortunato F, Tafuri S, Cinzio AG, Prato R. Reproductive life disorders in Italian celiac women. A case-control study. BMC Gastroenterol. 2010; 10:89–97. 
  6. Choi JM, Lebwohl B, Wang J, Lee SK, Murray JA, Sauer MV et al. Increased prevalence of celiac disease in patients with unexplained infertility in the United States. J Reprod Med. 2011; 56:199–203.  
  7. Jackson JE, Rosen M, McLean T, Moro J, Croughan M, Cedars MI. Prevalence of celiac disease in a cohort of women with unexplained infertility. Fertil Steril. 2008; 89:1002–4. 
  8. Machado AP, Silva LR, Zausner B, de A OJ, Diniz DR, de Oliveira J. Undiagnosed celiac disease in women with infertility. J Reprod Med. 2013; 58:61–6. 
  9. Kumar A, Meena M, Begum N, Kumar N, Gupta RK, Aggarwal S. Latent celiac disease in reproductive performance of women. Fertil Steril. 2011; 95:922–7. 

Citation

Ruhil MS, Desai G, Hatkar PA, Mayadeo NM. Management Of Celiac Disease In Pregnancy. JPGO 2018. Volume 5 No.3. Available from: http://www.jpgo.org/2018/03/management-of-celiac-disease-in.html

Pregnancy In A Patient With Congenital Adrenal Hyperplasia

Author Information

Jain D*, Warke HS**.
(* First Year Resident, ** Associate Professor.  Department of Obstetrics and Gynaecology, Seth G.S Medical College and KEM Hospital, Mumbai, India.)

Abstract

Congenital adrenal hyperplasia (CAH) is a rare autosomal recessive disorder, the most common cause of which is 21 hydroxylase enzyme deficiency. Fertility in women with congenital adrenal hyperplasia is decreased due to various reasons. We present a case of a woman with a diagnosed case of CAH who had undergone genitoplasty surgery in childhood, but conceived spontaneously without any assisted reproductive technique and gave birth to three consecutive healthy female children.

Introduction

CAH is a group of inherited disorders characterised by inability to synthesise cortisol. More than 90% of the cases are due to 21 hydroxylase deficiency.[1] Other deficiencies could affect genes coding for 11-beta-hydroxylase, 17-alpha-hydroxylase, 3-beta-hydroxysteroid dehydrogenase, aldosterone synthase and steroid acute regulatory protein (STAR); and these deficiencies have varied presentations. The gene encoding 21 hydroxylase enzymes is CYP21, and in classical CAH the production of cortisol and aldosterone is decreased or absent, which results in excessive production of pituitary ACTH. This in turn leads to excessive production of adrenal androgens and progesterone, including 17-hydroxy-progesterone.

Case Report

A 30 year old woman, G3P2L2 with previous two lower segment caesarean sections, a diagnosed case of 21- hydroxylase deficiency (simple virilising variant of CAH) presented to the antenatal outpatient department at 15 weeks of gestation. She had been diagnosed as CAH at 5 years of age with ambiguous genitalia, raised 17- hydoxyprogesterone level, enlarged clitoris and normal karyotype (46, XX).
At the age of 7 years, she underwent reduction clitoroplasty and vaginoscopy. On vaginoscopy normal vagina and cervix was visualised. Urethral and anal orifices were normal. Ultrasonography showed a hypoplastic uterus with normal bilateral ovaries. She was started on tablet prednisolone 5 mg daily. She had regular follow up with endocrinologists at our institute.
Menarche was attained at the age of 13 years, but cycles were irregular. She developed salt craving. Her blood pressure was normal (110/70 mm of Hg). Endocrinologist changed her medications from tablet prednisolone to tablet dexamethasone 0.5 mg at bed time.
She got married at the age of 18 years. She had spontaneous conception after 1 year of marriage and a second conception after two years. During both the pregnancies she was registered at our hospital and tablet dexamethasone 0.5 mg once a day was continued throughout the pregnancies. Both previous pregnancies resulted in healthy female children delivered by lower segment cesarean sections (first for breech 6 years back and second for failure of induction of labor 4 years back). Postoperatively she was continued on tablet prednisolone 5mg once a day. Both the children had normal karyotype and a normal growth pattern. 
She again conceived spontaneously and came for registration at 15 weeks of gestation at our hospital. The development of fetus was appropriate for the gestational age. Tablet dexamethasone 0.5 mg once a day was continued in consultation with endocrinologist. Antenatal course was otherwise uneventful. Elective cesarean section was performed at 39 weeks gestation in view of previous two lower segment cesarean sections. She delivered a healthy female child with normal appearing genitalia weighing 2.99 kgs with normal Apgar score. Perioperatively injection hydrocortisone 100 mg was administered intravenously. Postoperatively she was started on tablet prednisolone 5 mg OD which was continued in the postpartum period. 
Discussion
CAH was first described by De Crecchio in 1865 and academically confirmed by Wilkins et al.[2] Congenital adrenal hyperplasia is a rare congenital disorder acquired by autosomal recessive inheritance. It is known that 21- hydroxylase deficiency is the main cause of CAH in 90% to 95% cases. Our patient had classical type of CAH.
The classical form is diagnosed with early clitoromegaly necessitating surgical correction, as was done in our patient. Internal reproductive organs, ovaries, uterus, fallopian tubes, upper vagina and mullerian structures are normal, as was seen in our patient.
Due to genetic deficiency of 21 hydroxylase, synthesis of cortisol is decreased and secretion of ACTH is increased as the hypothalamus-pituitary reacts to low levels of cortisol. It induces hyperplasia of adrenal cortex, resulting in increased precursors of cortisol and testosterone and distinctive clinical symptoms, with a wide spectrum of severity. The cornerstone of the management of CAH is suppression of ACTH with orally administered steroids.[3] 
The dose of steroids should be carefully adjusted in order to protect external genitalia of the fetus and at the same time to avoid cushingoid features in the mother. Dexamethasone (20 μg/kg/day) should be instituted before the ninth week of gestation and continued throughout pregnancy. The fetal hypothalamic-pituitary-adrenal axis gets inhibited and the excess androgen secretion from the adrenal is reduced which prevents virilization in affected females. Dexamethasone is preferred due to its propensity to cross the placenta and reach  the fetal circulation.[4]
An increased incidence of cesarean section has been reported in females with CAH. This is due to cephalopelvic disproportion in these females because of android nature of the pelvis due to excess of androgens. It can also be due to reconstructive surgeries done on the genitalia.
All three pregnancies in our patient resulted in female babies. There is an increased propensity of female infants in those with classic congenital adrenal hyperplasia. Among children born to women with congenital adrenal hyperplasia, it was found that only 25% were boys as compared to 55% in control population. This uneven sex ratio can be due to feminine environment in these mothers during the time of implantation due to steroid administration.[5]
To summarize, the goals of therapy in a pregnancy with CAH include prevention of adrenal insufficiency, reduction of fetal exposure to androgens by use of glucocorticoids and avoidance of damage to reconstructed genitalia. Prenatal glucocorticoid therapy is key to management. 

Conclusion

Women with congenital adrenal hyperplasia have lower rates of conception. They should regularly receive glucocorticoid therapy in order to prevent the occurrence of ambiguous genitalia in the fetus. With a multidisciplinary approach involving endocrinologists, successful pregnancy outcomes are possible.

References
  1. Lin-Su K, Nimkarn S, New MI. Congenital adrenal hyperplasia in adolescents: diagnosis and management. Ann NY Acad of Sci. 2008; 1135: 95-8.
  2. Wilkins L, Lewis RA, Klein R, Gardner LI, Crigler JF Jr, Rosemberg, et al. Treatment of congenital adrenal hyperplasia with cortisone. J Clin Endocrinol Metab. 1951; 11:1-25.
  3. Temeck JW, Pang SY, Nelson C, New MI. Genetic defects of steroidogenesis in premature pubarche. J Clin Endocrinol Metab 1987; 64:609-17
  4. Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet 2005; 365:2125-36.
  5. Hagenfeldt K, Janson PO, Holmdahl G, Falhammar H, Filipsson H, Frisén L, et al. Fertility and pregnancy outcome in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Reprod 2008; 23:1607–13.

Citation

Jain D, Warke HS. Pregnancy In A Patient With Congenital Adrenal Hyperplasia. JPGO 2018. Volume 5 No.3. Available from: http://www.jpgo.org/2018/03/pregnancy-in-patient-with-congenital.html

Benign Intracranial Hypertension And Pregnancy

Author Information

Desai A*, Desai G**, Hatkar PA***, Warke HS***
(* Second year Resident, ** Assistant Professor, *** Associate Professor, Department of Obstetrics and Gynecology, Seth GS Medical College and KEM Hospital, Mumbai, India.)

Abstract

Benign intracranial hypertension (BIH) (or idiopathic intracranial hypertension) is commonly seen in women of reproductive age group with obesity. A successfully managed case of pregnancy with BIH, who had features of papilledema but no visual deterioration, and delivered by cesarean section is presented here. A multidisciplinary approach involving ophthalmologists and neurologists helped in the management of the patient.

Introduction

IIH is characterized by the presence of papilledema, headache, and raised intracranial pressure without any specific neurologic abnormality in otherwise healthy individuals. The diagnostic criteria include papilledema, visual loss and lumbar CSF opening pressure > 250 mm of water when the patient is in the lateral decubitus position with legs extended. Annual incidence of IIH is about 0.9/ 100,000 persons.  It is higher (3.5/ 100,000) in females of reproductive age group.[1]
It can occur in any trimester during pregnancy. Pregnancy does not cause worsening or recurrence of symptoms and thus therapeutic abortions are not indicated and also the number of spontaneous abortions is also not affected by BIH. The pregnancy rates and outcome is not different from that of general population and the incidence of papilledema is not affected by pregnant state. Risk of recurrence is not very clear, although recurrent IIH in successive pregnancies has been reported.[2] The symptoms worsen during pregnancy and usually resolve after abortion or delivery.
Case Report
A 30 year old G5P1L1MTP1SA2 antenatally registered with us at 8 weeks of gestation with seven uneventful antenatal follow-up visits is presented here. 
Four years back she had history of severe headache and vomiting episodes not responding to medications for which she consulted a neurologist. MRI brain showed mild short segmental narrowing at the junction of transverse and sigmoid sinuses bilaterally. As the MRI findings were mild and not specific, a diagnosis of BIH was made and she was started on acetazolamide and oral potassium supplements. There was no other significant past medical or surgical history. There was no history of tuberculosis. She had one full term vaginal delivery and underwent one medical termination of pregnancy prior to detection of this neurological problem. After this, she had two spontaneous abortions, for which curettage was done and neurology review suggested continuation of same management. In current pregnancy, she was on regular neurological and ophthalmologic consultation.  Continuation of acetazolamide was advised. Fundus examination was not suggestive of papilledema. Ultrasonography showed no fetal malformations. She was admitted at 39 weeks of gestation in early labor.  
Her BMI was normal. Her blood pressure was 130/ 80 mm Hg and she had no complaints of headache or visual blurring then. Ophthalmologists reviewed her and features of early papilledema with blurring of disc margins superiorly and nasally were found. Neurologists opined that in view of grade 1 papilledema, it would be preferable to deliver by cesarean section, to avoid the risks of increased intracranial tension during Valsalva maneuver that occurs in labor. She was taken up for lower segment cesarean section under general anesthesia after adequate preoxygenation. The surgery was uneventful, she delivered a healthy male child of 3.4 kg with Apgar of 9/ 10, and post-operative course was uneventful. Neurologists and ophthalmologists reviewed and advised to continue the same treatment (tablet acetazolamide) in view of persistence of early signs of papilledema.

Discussion

IIH is a disease of unknown etiology. Two mechanisms that have been postulated are vasogenic extracellular brain edema and a reduced conductance of cerebrospinal fluid outflow at arachnoid villi. PCOS, exogeneous estrogen and pregnancy can all worsen IIH. Hypofibrinolysis, exacerbated by thrombophilic exogenous estrogens, seen in PCOS is considered a treatable causal factor for BIH.[3] Vitamin A toxicity may play a role in the pathogenesis of BIH and doxycycline use has been shown to aggravate BIH.[4]
Acute management depends on the immediate risk to vision. The treatment goal is to preserve vision and improve symptoms as blindness may develop in 10 % of pregnant women with BIH. Visual loss in BIH may be permanent despite medical treatment. In 50 % of pregnant females, the symptoms of visual loss may worsen however it improves in postpartum period.[5] Our patient did not have any specific visual complaint throughout pregnancy. Most therapies used during the non-pregnant state can also be used during pregnancy. Treatment includes analgesics, diuretics, steroids, and serial lumbar punctures. Surgical procedures may be options in severe cases resistant to medical therapy. However, our patient was well controlled with only medical management with diuretics. Steroids was not required in our patient. 
A weight gain of 5–9 kg during the pregnancy is recommended (0.22 kg/ week in the second and third trimester) in those with a BMI of ≥30 kg/m2.[6] Disease-modifying therapy is weight loss, but significant caloric restriction is not a recommended approach during pregnancy to avoid ketosis. Our patient had a normal BMI and hence approaches of weight loss and caloric modification was not required. 
Obesity can cause IIH. Central obesity raises intra-abdominal pressure, causing increased pleural pressure and cardiac filling pressures, which impedes venous return and causes raised intracranial venous pressure and in turn increased intracranial pressure.
Glucocorticoids, diuretics, carbonic-anhydrase inhibitors (acetazolamide), and lumbar punctures are treatment options. Though rare occurrence of sacrococcygeal teratoma has been reported with acetazolamide use, this is the preferred agent. In our patient, acetazolamide was continued for maternal benefit, and is justifiable.[2] 
Though IIH is not a very rare condition, the dilemma regarding mode of delivery remains. Uterine contractions and bearing down efforts with associated increased BP, cardiac output, central venous pressure, and consequently, increased CSF pressure can cause onset of or worsening of preexisting papilledema. Labor analgesia is recommended in vaginal delivery. Even though the increase in CSF pressure is independent of pain, it can be exaggerated by it.  So, epidural analgesia can minimize these hemodynamic changes caused by pain.[7] Second stage of labor may be shortened by instrumental delivery.[8] However, our patient had newly developing papilledema detected during admission at term, which was not present during the prior antenatal visits, and hence vaginal trial was avoided. 
Our patient underwent cesarean section under general anesthesia. However, regional anesthesia can be used if papilledema is absent and per se, BIH is not a contraindication.[9]  Majority of patients with BIH remain stable and a normal vaginal delivery is possible. 

Conclusion

BIH is a relatively rare condition seen in women of reproductive age. Pregnancy in these patients can be successfully managed with a multidisciplinary approach in tertiary center involving obstetricians, neurologists, ophthalmologists and anesthesiologists. Vaginal delivery is permitted unless signs of raised intracranial pressure exist (absence of papilledema in cases of BIH under treatment). In presence of papilledema elective caesarean section is indicated.

References
  1. Chen J, Wall M. Epidemiology and risk factors for idiopathic intracranial hypertension. Int Ophthalmol Clin. 2014; 54(1):1–11. 
  2. Kesler A, Kupferminc M. Idiopathic Intracranial Hypertension and Pregnancy. Clin Obstet Gynecol. 2013; 56(2):389–96. 
  3. Glueck CJ, Aregawi D, Goldenberg N, Golnik KC, Sieve L, Wang P. Idiopathic intracranial hypertension, polycystic-ovary syndrome, and thrombophilia. J Lab Clin Med. 2005; 145(2): 72–82
  4. Goadsby PJ, Raskin NH. Headache: Introduction. In Longo DL, Kasper DL, Jameson JL, Fauci AS, Hauser SL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine.18th ed. New York: McGraw Hill 2012; pp.94.
  5. Karmaniolou I, Petropoulos G, Theodoraki K. Management of idiopathic intracranial hypertension in parturients: Anesthetic considerations. Can J Anaesth 2011; 58:650-7.
  6. Rasmussen KM, Yaktine AL. Weight Gain During Pregnancy: Reexamining the Guidelines. Washington, DC: National Academies Press (US) National Academy of Sciences; 2009.
  7. Aly EE, Lawther BK. Anaesthetic management of uncontrolled idiopathic intracranial hypertension during labour and delivery using an intrathecal catheter. Anaesthesia 2007; 62:178-81.
  8. Gumma AD. Recurrent benign intracranial hypertension in pregnancy. Eur J Obstet Gynecol Reprod Biol. 2004; 115:244.
  9. Bagga R, Jain V, Das CP, Gupta KR, Gopalan S, Malhotra S. Choice of therapy and mode of delivery in idiopathic intracranial hypertension during pregnancy. Med Gen Med 2005;7(4):42.

Citation

Desai A, Desai G, Hatkar PA, Warke HS. Benign Intracranial Hypertension And Pregnancy. JPGO 2018. Volume 5 No.3. Available from: http://www.jpgo.org/2018/03/benign-intracranial-hypertension-and.html