Volume 2, Issue 2

i

Aims and Scope

El Mednifico Journal is an open access, quarterly, peer-reviewed journal from Pakistan that aims to publish scientifically sound research across all fields of medicine. It is the first journal from Pakistan that publishes researches as soon as they are ready, without waiting to be assigned to an issue. The journal has certain unique characteristics:

 EMJ is one of the first journals from Pakistan that publishes articles in provisional versions as soon as they are ready, without waiting for an issue to come out. These articles are then proofread, copyedited and arranged into four issues per volume and one volume per year  EMJ is one of the few journals where students and undergraduates form an integral part of the

editorial team

 EMJ is one of the few journals that provides incentives to students and undergraduates

EMJ is published once every 3 months by Mednifico Publishers.

Editorial correspondence should be addressed to:

The Editor-in-Chief, El Mednifico Journal,

C2 Block R, North Nazimabad, Karachi, Sindh - 74700 - Pakistan.

Tel: (92-334-2090696); Email: [email protected]; Website: http://mednifico.com

Articles should be sent to:

Submissions EMJ, C2 Block R, North Nazimabad, Karachi, Sindh - 74700 - Pakistan. Email: [email protected]

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ii

Editorial Board

Senior Editor-in-Chief

Prof. Nazeer Khan

Executive Editors

Syed Salman Ahmed, Sajid Ali

Editor-in-Chief

Asfandyar Sheikh

Managing Editor

Syed Arsalan Ali

Assistant Editor-in-Chief

Haris Sheikh

_{Assistant Managing Editor}

Shanawer Khan

Prof. Asaad Javaid, Dr. Ye Yang, Dr. Abdul Hafeez Baloch,

Dr. Mansoor Husain, Dr. Muzaffar H Qazilbash, Dr. Tasneem Z Naqvi, Dr. Asim A Shah, Dr. Samina Abidi,

Senior Editors

Prof. Javed Akram, Prof. Abdul Bari Khan,

Prof. Ashraf Ganatra, Dr. Raza Ur Rehman, Dr. Waris Qidwai, Dr. Muhammad Ishaq Ghori,

Dr. Akber Agha, Dr. Adnan Mustafa Zubairi,

Dr. Saqib Ansari, Dr. Mohsina Ibrahim, Dr. Qamaruddin Nizami,

Dr. Samra Bashir, Dr. Nabeel Manzar, Muhammad Ashar Malik

Section Editors

Ali Sajjad,

Hafiz Muhammad Aslam, Syed Askari Hasan, Muhammad Uzair Rauf, Syed Mumtaz Ali Naqvi,

Statistics Editors

Mehwish Hussain, Syed Ali Adnan

Editors

Dr. Hussain Muhammad Abdullah, Asfandyar Khan Niazi, Muhammad Danish Saleem,

Iqra Ansari

Production Editors

Assistant Editors

Uzair Ahmed Siddiqui, Maheen Anwer,

Anum Saleem, Hira Hussain Khan,

Imran Jawaid, Hina Azhar Usmani,

Hira Burhan, Quratulain Ghori, Bushra Iqbal, Maria Rahim

Layout Editor

v

Table of Contents

FrontPage

i

Editorial Board

ii

Call for Papers

iii

Health Poster

iv

Table of Contents

v

Editorial

Novel anticancer agents in clinical and preclinical trials

38

Original Articles

Adverse neonatal and maternal outcomes in Pakistani tertiary care

hospitals: A prospective, observational study

Sarah Saleem, Elizabeth M McClure, Janet Moore, Samina Iqbal, Syed Hasan Ala, Fariha Khawaja, Omrana Pasha, Robert L Goldenberg

40

Incidental gallbladder carcinoma in laparoscopic cholecystectomy: Five

years local experience

Wagih Mommtaz Ghnnam, Turki Maed Al Salem Elbeshry, Jaweed Rafiq Malek, Emad Shebl Emarra, Mohammed Eid Alzahrany, Ahmad Ali Alqarni, Ammar Ahmad Khattab

47

Impact of SCARB2 on pro-inflammatory cytokines in tissues of

EV71-infected mice

Jian Li, Zhenliang Han, Qingxin Geng, Peipei Liu, Tiegang Lv, Dandan Xin, Yuanyuan Wang, Fei Lei, Long Song, Zongbo Chen

52

Comparative effect of antiplatelet drugs in streptozotocin-induced diabetic

nephropathy in experimental rats

Taruna Katyal, Jitender Negi, Monika Sachdeva, R D Budhiraja

59

Dorsal hippocampus histaminergic and septum GABAergic neurons work in

anxiety related behavior: Comparison between GABAA and GABAB

receptors

Leila Chodari, Shahrbanoo Oryan, Ramesh Ahmadi, Ghorbangol Ashabi

64

Examination of bone marrow mesenchymal stem cells seeded onto

poly(3-hydroxybutyrate-co-3-hydroxybutyrate) biological materials for myocardial

patch

Junsheng Mu, Hongxing Niu, Fan Zhou, Jianqun Zhang, Ping Hu, Ping Bo, Yan Wang

vi

Comparison of linear, logarithmic and mel-frequency filter-bank energy

cepstra in automatic seizure detection using radial basis function neural

network

Chandrakar Kamath

82

Evaluation of foramen magnum in sex determination from human crania by

using discriminant function analysis

Deepali Jain, O P Jasuja, Surinder Nath

89

Mineral content analysis and investigation of antimicrobial activities of

Evolvulus alsinoides (L.) L. against clinical pathogens

Duraisamy Gomathi, Manokaran Kalaiselvi, Ganesan Ravikumar, Kanakasabapathi Devaki, Chandrasekar Uma

93

Flexural and tensile strengths of three restorative materials used in

pediatric dentistry

Marcia Pereira Alves Dos Santos, Lucianne Cople Maia

97

Comparison of squash smears and frozen sections versus paraffin sections

in the intra-operative diagnosis of central nervous system lesions

Hephzibah Rani, Padmaja Kulkarni, Udupi Shastry Dinesh, Ravikala Vittal Rao, Sateesh Melkundi

101

Research knowledge and behavior of health workers at Federal Medical

Centre, Bida: A task before learned mentors

Ibrahim Taiwo Adeleke, Adedeji Olugbenga Adekanye, Abdullahi Daniyan Jibril, Fausat Fadeke Danmallam, Henry Eromosele Inyinbor, Sunday Akingbola Omokanye

105

Medical students' perception about teaching-learning and academic

performance at Nobel Medical College, Biratnagar, Nepal

Mukhtar Ansari, Attique ur Rahman Mufti, Salman Khan

110

Short Reports

Microalbuminuria: An early marker of diabetic kidney disease

114

A dermatological approach to the feet of soccer players

117

Pattern of deliveries during three calendar years in rural India

vii

Magnetic resonance imaging cholangiographic evaluation of normal

common bile duct size

Mustafa Fatih Erkoç, Sevil Alkan, Sinan Soylu, Aylin Okur

122

Review

Do socioeconomic inequalities lead to deceptive measurement of obstetric

morbidity in India?

Kshipra Jain, Mayank Prakash

124

Case Reports

Bilateral mucoepidermoid carcinoma of parotid

131

Bilateral granulomatous mastitis after local nandrolone injection

134

Unusual presentation of a case of fallopian tube carcinoma

137

Ileoileal intussusception in a young adult secondary to a mucinous

adenocarcinoma

Archana Shetty, Mudasser Rehan, Chowdappa Vijaya

141

Phocomelia – A case study

Soniya B Parchake, Nilesh Keshav Tumram, A P Kasote, M M Meshram, Pradeep G Dixit

144

Rectopopliteal fecal fistula developed through an intra-abdominal adhesion

146

Atypical mesothelial hyperplasia mimicking mesothelioma in patient with

metastatic papillary carcinoma of thyroid

Mutahir A Tunio, Mushabbab AlAsiri, Syed Azfer Husain, Nagoud Mohamed Omar Ali, Shomaila S Akbar

148

Primary eosinophilic granuloma presenting as bilateral otitis media and

mastoiditis

Purnima Aggarwal, Uma Debi, Geetanjli Jindal

151

Peripheral ossifying fibroma

S V S G Nirmala, Ramasub Bareddy, Sivakumar Nuvvula, Swetha Alahari, Sandeep Chilamakuri

153

Lipoma of retromandibular space

Anand Gupta, Varun Chopra, Gurvanit Lehl, Shivani Jindal

viii

Opinions and Debates

Antidepressants in the management of bipolar depression - An appraisal

159

Pre-treatment evaluation: Setting a foundation in the management of

drug-resistant tuberculosis

Saurabh RamBihariLal Shrivastava, Prateek Saurabh Shrivastava, Jegadeesh Ramasamy

164

Essays

Stem cells from gynecological tissue: Trash to treasure

166

Evolutionary context of hypertensive disorders in human pregnancy

168

Therapeutic spectrum of diuretics in different diseases

Muhammad Majid Aziz, Muhammad Ikram Ur Rehman, Muhammad Wajid, Muhammad Ali Raza, Javed Ahmed

170

Letters to Editor

Anesthetic considerations and implications for non-cardiac surgery in a

patient presenting with aorto-occlusive disease

Teena Bansal, Manish Bansal, Sarla Hooda

173

Extra-abdominal breast fibromatosis: A rare breast pathology in medical

practice

Mehmet Yildirim, Nükhet Eliyatkın, Hakan Postaci, Nazif Erkan

176

Sarcomatoid lung cancer: a rare, aggressive form of non-small cell lung

cancer with an initially indolent presentation in one of the youngest

documented patients

Arpan Patel, Joshi Sumendra, Dinesh Ananthan, Hayas Haseer Koya

178

A new comprehensive method for treatment of severe intra-uterine

adhesions

Sefa Kelekci, Serpil Aydogmus, Emine Demirel, Mustafa Sengul

180

Organophosphate poisoning presenting as bradycardia

Hari Krishan Aggarwal, Deepak Jain, Shivraj Goyal, Shaveta Dahiya, Ashima Mittal

ix

Appendices

Instructions to Authors

ix

38 Novel anticancer agents in clinical and preclinical trials

Open Access

Editorial

Novel anticancer agents in clinical and preclinical trials

Adnan Salim1

Editorial

Billions of people worldwide are affected with various forms of can-cer of virtually any part of the human body. Despite vast amounts of funds being poured into cancer research, the production of a single drug, or a group of drugs, which may ‘cure’ cancer remains an elusive dream. The future is not so bleak, though. Many drugs have been approved recently which combat the cancerous growth and alleviate quality of life of the patient. Countless others are under trials. What follows is an attempt to summarize a few.

Akt, or protein kinase B (PKB), is a serine/threonine protein kinase which acts as a mediator in many cellular processes. Three members in the Akt family have been identified until now, of which Akt1 is the molecule playing a key role in cell survival and metabolism. It acts mainly via the activation of receptor tyrosine kinases (RTK), and pro-duces such effects as inhibition of apoptosis, promotion of cell cycle progression and stimulation of angiogenesis. Miltefosine is the only Akt inhibitor which has been approved (that too for leishmaniasis), while several others show promise in their pre-clinical trials. These have been divided into different classes according to their mode of actions, and some, like Perifosine have failed too. [1].

Poly(ADP-ribose) Polymerases (PARPs) are a group of 17 proteins which play a role in apoptosis, genetic maintenance, inflammatory responses and regulation of gene transcription. PARP inhibitors were developed as agents that seem to target cancer cells when they are undergoing DNA repair [2]. Olaparib (AZD2281) showed anti-tumor effects in patients with BRCA1/2 mutated cancers. Patients showed 40% response rate in platinum sensitive ovarian cancer with germline BRCA1/2 mutations [3]. Rucaparib, another PARP inhibitor showed promising results with chemopotention when used with te-mozolomide for metastatic melanoma [4].

c-Met is a proto-oncogene that encodes hepatocyte growth factor receptor (HGFR) [5]. It plays an important role in embryonic devel-opment, organ morphogenesis and healing reactions [6]. Met is a membrane receptor stimulating cell motility, invasion, protection from apoptosis and angiogenesis. Dysregulated activity of c-Met can cause a wide variety of cancers, including colorectal, gastric carci-noma, liver, thyroid, breast, pancreas, renal cell, ovary, prostate and melanoma [7]. c-Met inhibitors are quite recent drugs. Foretinib XL880 completed phase 2 clinical trial with indications for head and neck, gastric and renal cell carcinoma and is still experimental [8]. Cabozantinib (XL184) was approved by the U.S. Food and Drug Au-thority in November 2012 for the treatment of medullary thyroid cancer. There are several drugs of this category undergoing trials and there is promise shown that these used in conjunction with other

1_{Dow Medical College, Dow University Of Health Sciences, Baba-e-Urdu Road,}

Karachi, Pakistan

Correspondence: Adnan Salim Email: [email protected]

chemotherapeutic agents will significantly alter the course of the dis-ease [7].

Imatinib, a tyrosine Kinase Inhibitor, is being used widely for the treatment of chronic myeloid leukemia (CML) [9]. Nilotinib, Da-satinib, Bosutinib and Ponatinib are newer drugs of this class ap-proved for the treatment of imatinib resistant or intolerant CML [10, 11].

Histone de-acetylase inhibitors (HDIs) are yet another class of futur-istic anti-cancer drugs bring used. [12]. Vorinostat (SAHA) and ro-midepsin (ISTODAX) are FDA approved for the treatment of cutane-ous T cell lymphoma. Use of HDIs as other types of cancer shows moderate effects [13, 14].

Vismodegib, a hedgehog pathway inhibitor has been recently ap-proved for treatment of advanced basal cell carcinoma [15]. Cyclo-pamine is the prototype inhibitor of the Sonic Hedgehog (Shh) path-way and is currently undergoing preclinical and clinical studies as an agent in treatment of basal cell carcinoma, medulloblastoma and rhabdomyosarcoma [16, 17]. Saridegib, a synthetic analog of cyclo-pamine, has shown encouraging results in phase I trial of advanced solid tumors [18, 19].

Heat Shock Protein (HSP) inhibitors, drugs which inhibit molecular chaperones, though still in phase II clinical trials, show promise in the treatment of a variety of malignancies [20].

Many rounds of preclinical and clinical trials are still needed to de-termine accurately the potential of anticancer medicines. While many may show promise, there is still the question of their therapeu-tic indices and toxicity profiles. Some of these agents may stop or revert the growth of a tumor but may adversely affect the patient’s health otherwise. Chemotherapy is an exciting and ever-growing field of research and intense work is being done which promises hope for health professionals and for the affected.

Competing interests: The authors declare that no competing interests exist. Received: 28 March 2014 Accepted: 30 March 2014 Published Online: 30 March 2014

References

1. Bhutani J, Sheikh A, Niazi A: Akt inhibitors: mechanism of action and implications for anticancer therapeutics. Infectious Agents and Cancer 2013, 8(1):49.

2. Carey LA, Sharpless NE: PARP and cancer--if it's broke, don't fix it. The New England journal of medicine 2011, 364(3):277-279.

3. Kummar S, Chen A, Parchment RE, Kinders RJ, Ji J, Tomaszewski JE, Doroshow JH: Advances in using PARP inhibitors to treat cancer. BMC medicine 2012, 10:25.

Salim A 39

4. Usmani H, Hussain S, Sheikh A: PARP inhibitors: current status and implications for anticancer therapeutics. Infectious Agents and Cancer 2013, 8(1):46. 5. Maulik G, Shrikhande A, Kijima T, Ma PC, Morrison PT, Salgia R: Role of the

hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition. Cytokine & growth factor reviews 2002, 13(1):41-59. 6. Christensen JG, Schreck R, Burrows J, Kuruganti P, Chan E, Le P, Chen J, Wang

X, Ruslim L, Blake R et al: A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer research 2003, 63(21):7345-7355. 7. Mughal A, Aslam HM, Sheikh A, Khan AMH, Saleem S: c-Met inhibitors.

Infectious Agents and Cancer 2013, 8(1):13.

8. Underiner TL, Herbertz T, Miknyoczki SJ: Discovery of small molecule c-Met inhibitors: Evolution and profiles of clinical candidates. Anti-cancer agents in medicinal chemistry 2010, 10(1):7-27.

9. Asaki T, Sugiyama Y, Hamamoto T, Higashioka M, Umehara M, Naito H, Niwa T: Design and synthesis of 3-substituted benzamide derivatives as Bcr-Abl kinase inhibitors. Bioorganic & medicinal chemistry letters 2006, 16(5):1421-1425.

10. Valent P: Standard treatment of Ph+ CML in 2010: how, when and where not to use what BCR/ABL1 kinase inhibitor? European journal of clinical investigation 2010, 40(10):918-931.

11. Mughal A, Aslam H, Khan AM, Saleem S, Umah R, Saleem M: Bcr-Abl tyrosine kinase inhibitors- current status. Infectious Agents and Cancer 2013, 8(1):23. 12. Johnstone RW: Histone-deacetylase inhibitors: novel drugs for the treatment

of cancer. Nature reviews Drug discovery 2002, 1(4):287-299.

13. Miller CP, Singh MM, Rivera-Del Valle N, Manton CA, Chandra J: Therapeutic strategies to enhance the anticancer efficacy of histone deacetylase inhibitors. Journal of biomedicine & biotechnology 2011, 2011:514261.

14. Khan RS, Hameed H, Bhutta RA, Kazi AN, Riaz H: Histone de-acetylase inhibitors: a promising future for cancer treatment? Infectious Agents and Cancer 2013, 8(1):10.

15. Dlugosz A, Agrawal S, Kirkpatrick P: Vismodegib. Nature reviews Drug discovery 2012, 11(6):437-438.

16. Kolterud Å, Toftgård R: Strategies for Hedgehog inhibition and its potential role in cancer treatment. Drug Discovery Today: Therapeutic Strategies 2007, 4(4):229-235.

17. Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, Scott MP, Beachy PA: Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 2000, 406(6799):1005-1009.

18. Jimeno A, Weiss GJ, Miller WH, Jr., Gettinger S, Eigl BJ, Chang AL, Dunbar J, Devens S, Faia K, Skliris G et al: Phase I study of the Hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 2013, 19(10):2766-2774.

19. Sheikh A, Alvi A, Aslam H, Haseeb A: Hedgehog pathway inhibitors - current status and future prospects. Infectious Agents and Cancer 2012, 7(1):29. 20. Shehzad A, Dawani O, Munir S, Hussain S: Molecular chaperone therapy- the

40 Adverse neonatal and maternal outcomes in Pakistani hospitals…

Open Access

Original Article

Adverse neonatal and maternal outcomes in Pakistani tertiary care hospitals: A prospective,

observational study

Sarah Saleem1_{, Elizabeth M McClure}2_{, Janet Moore}2_{, Samina Iqbal}3_{, Syed Hasan Ala}4_{, Fariha Khawaja}1_{, Omrana Pasha}1_{, Robert L Goldenberg}5

Introduction

Approximately 2.9 million neonatal deaths and 280,000 maternal deaths occur globally every year [1]. The majority of these deaths occur in low and middle-income countries (LMIC). Infections, as-phyxia, and the consequences of prematurity are leading causes of neonatal mortality [1-3]. Hemorrhage, infection and preeclamp-sia/eclampsia are leading causes of maternal mortality. Both neona-tal and maternal morneona-tality are largely preventable with appropriate care.

In LMIC with high neonatal mortality rates, approximately one-half of the neonatal deaths are due to infections acquired at home or in the hospital [2, 4-6]. While the majority of births occur at home, high risk of infection-related mortality has also been associated with in-adequate care among facility births. Relatively simple, inexpensive interventions such as clean delivery and cord care, exclusive breast-feeding, and hand-washing with clean water and soap should pre-vent most infection-related neonatal deaths [3, 7-9]. However, inad-equate antibiotic use also contributes to neonatal sepsis risk and to higher mortality rates [10].

Medical complications such as preeclampsia and placental abruption during pregnancy and the intrapartum and postpartum periods in-crease the likelihood of adverse outcomes for mothers and new-borns [11-14]. Infants born to mothers with intrapartum hemor-rhage, fever, prolonged labor and convulsions have higher risks of mortality compared to those born to women without complications [15, 16]. Clinical expertise and advanced technologies have signifi-cantly reduced neonatal and maternal mortality in higher income countries (HIC). In LMIC, even when simple, inexpensive interven-tions are available, low quality services, lack of training and health provider absenteeism are factors contributing to poor services and high maternal and neonatal mortality at health facilities [17-24]. On

1_{Department of Community Health Sciences, Aga Khan University, Karachi Pakistan} 2_{Department of Statistics and Epidemiology, Research Triangle Institute, Durham,}

NC, US

3_{Department of Obstetrics, Sobhraj Maternity Hospital, Karachi, Pakistan} 4_{Department of Obstetrics, Qatar Tertiary Care Hospital, Karachi Pakistan}

the other hand, over medicalization of maternal and newborn care are also becoming problematic in LMIC.

In addition to gaps in health care, socio-demographic and other household factors clearly contribute to newborn mortality and mor-bidity. Newborn care practices, such as applying dung to the umbil-ical cord, have been associated with increased risk for morbidity and mortality in many LMIC [16-18]. Clean birth care, umbilical cord care and appropriate hand-washing, in particular, have often been cited as relatively simple practices that may significantly reduce newborn mortality [22, 25]. Additionally, the mother’s ability to make timely and appropriate health-seeking choices directly or indirectly affects her survival and that of her neonate [16-18].

Given the facility and home practices associated with mortality, our goal was to define the extent of maternal and neonatal mortality and morbidity occurring in hospital births in urban Pakistan and to de-termine some of the risk factors related to these outcomes. To do this, we conducted secondary analyses of data collected as part of a randomized trial of chlorhexidine vaginal wipes during labor and in-fant wipes immediately after delivery to prevent perinatal morbidity and mortality [26].

Methods

From 2005 to 2008, three large tertiary level hospitals serving the poor, urban population of Karachi, Pakistan participated in a ran-domized controlled trial of chlorhexidine vaginal and infant wipes [26]. Each woman in the treatment group received a vaginal wipe with 0.6% chlorhexidine in labor and the newborn was wiped with chlorhexidine after birth. Exclusions were known contraindication to cervical examination, active genital herpes, vulvo-vaginal ulceration, face presentation, fetal death or planned cesarean delivery. Since

5_{Department of Obstetrics and Gynecology, Columbia University, New York, NY, US} Correspondence: Sarah Saleem

Email: [email protected]

Abstract

Background: Neonatal and maternal death rates remain high in low-income countries, with little improvement with increasing facility births.

We sought to examine risks for neonatal mortality/morbidity among low-risk hospital deliveries in a low-resource setting.

Methods: Deliveries at tertiary hospitals in Karachi, Pakistan from 2005-2008 were prospectively enrolled with follow-up to 42 days

postpartum.

Results: Of 5,008 women enrolled, 98% were followed 28 days post-delivery. 4.3% of infants had severe illness or neonatal death. 28-day

neonatal mortality rate was 19.1/1,000 births. Newborn death/severe illness was associated with being unbooked, low birth weight, newborn intensive care, and lack of cord/neonatal skin cleansing and hand-washing before handling the baby.

Conclusion: Although most were low-risk and all were hospital deliveries, maternal and perinatal morbidity and mortality rates were high.

Lack of cord care and maternal hand washing was significantly associated with adverse outcomes. Results suggest that in addition to improving hospital care, simple interventions such as hand-washing may reduce maternal and newborn morbidities. (El Med J 2:2; 2014)

Saleem S, McClure EM, Moore J et al 41 there were no significant differences in neonatal infection-related

se-vere morbidity or mortality between the treatment groups, the en-tire population was combined for this secondary analysis. To reduce potential confounding from twins, only data from the first born was considered in this analysis.

The primary outcome for this secondary analysis was severe neonatal morbidity and neonatal death through 28 days after birth. To deter-mine the outcome, newborns were followed in-hospital until dis-charge or death, while an independent field team examined the mothers and the newborns in home visits on days 7 and 28. The In-tegrated Management of Childhood Illness (IMCI) screening tool was used to identify severe illness in neonates [27]. Mothers were inter-viewed regarding fever, lower abdominal pain, and vaginal discharge and were examined by trained study doctors. A supplementary ques-tionnaire on household assets, maternal hygienic practices, and new-born care practices was completed during the 7 or 28 day home visit on the final 4,132 study subjects enrolled. This questionnaire ad-dressed infant cord and skin cleansing, and maternal hand-washing. Because of the small number of positive responses for several ques-tions and the overlap in responses, for the final regression analysis, a single variable was created consisting of appropriate responses to maternal cord and skin cleansing, and hand-washing prior to han-dling the baby.

Data was analyzed using SAS version 9.3. For descriptive analyses, means and standard deviations were calculated for continuous vari-ables and proportions and percentages were calculated for categor-ical variables. To determine predictors for neonatal severe illness and death, logistic regression was used. Crude odds ratios (95% confi-dence intervals) were generated for each of the risk factors including maternal and demographic characteristics, intrapartum events, cord care and hand-washing practices. Risk factors with significant unad-justed odds ratios were included in a stepwise multivariate logistic regression analysis to select a final model best describing the effect of various factors on the risk of neonatal severe illness and mortality. The institutional review boards at Drexel University (Philadelphia, PA, USA), RTI International (Durham, North Carolina, USA), and at Aga Khan University (Karachi, Pakistan) approved the study as did each of the three study hospitals. The trial was monitored by an independ-ent data and safety committee established for the Global Network by the NICHD. The women provided written informed consent prior to study enrollment.

Results

A total of 5,008 women/infants were enrolled in the study and 5,004 had delivery information available. The 28-day follow-up was ob-tained for 4,895 infants (97.8%). Ninety three (1.9%) infants were lost to follow-up (figure 1).

The mean maternal age at enrollment was 25.4 years (SD 4.6) while the mean and standard deviation (SD) for gravidity was 2.8 (SD 2.0). Data from the supplemental socio-demographic interview which col-lected information from the study population on education, employ-ment, income, and household characteristics are summarized in ta-ble 1.

Figure 1: Enrolment summary of the research participants Table 1: Maternal characteristics (n=5,008)

Variable Results

Maternal age, mean (SD) _{25.4 (4.6)}

Gravidity, mean (SD) _{2.8 (2.0)}

Number of living children, mean (SD) _{1.5 (1.8)}

Number of miscarriages, mean (SD) _{0.2 (0.6)}

Mother received formal schooling*, n (%) _{2760 (66.8)}

Mother unemployed*, n (%) _{4003 (96.9)}

Husband unemployed*, n (%) _{90 (2.2)}

Monthly income*, Rupees, median (range) _{5000 (1000-60000)}

Rooms in household*, mean (SD) _{2.6 (1.5)}

Residents of household*, mean (SD) _{9.1 (5.0)}

*n=4,132

Table 2 presents data related to the delivery hospitalization. 10% of the study subjects were unregistered to deliver in the study hospitals and 3.8% were referred from non-tertiary facilities. Upon admission, 7% of women had a known co-morbidity, including hypertension, hepatitis B and C, tuberculosis, asthma, and diabetes. Of the vaginal deliveries, 33.7% received an episiotomy and nearly 7% were by for-ceps or vacuum extractor. 8.3% of the deliveries were cesarean. Nearly 51% of all women had artificial rupture of membranes (AROM) to augment labor. More than 11% and 0.4 % of women had meconium-stained and foul-smelling amniotic fluid, respectively. While in the hospital, most (94.1%) women received antibiotics. Table 3 presents the maternal, fetal and neonatal outcomes of 5,004 mothers with delivery data, all singleton infants, and the first born of 61 twins at delivery and at the 7 and 28 day visits. At delivery, 16 infants were stillborn (0.3%). The remaining 4,988 infants (99.7%) were live births. Approximately 9% of these infants weighed less than 2500 grams. More than 9% (n=467) of the newborns were re-ferred to a Newborn Intensive Care Unit (NICU) or another hospital for an Apgar score <8 at 5 minutes (4.0%) or for other signs of illness.

42 Adverse neonatal and maternal outcomes in Pakistani hospitals… On day 7 of follow-up, a total of 4,943 mothers/infants (99%)

re-ceived a home visit. Thirty four infants had died in the hospital and an additional 45 infants had died between discharge and the day 7 visit for a total of 79. Two mothers were reported dead by day 7, one in the hospital, and one after discharge. A total of 4,895 mothers/in-fants (98%) were seen at day 28. Between day 7 and day 28, 16 ad-ditional infants died, for a total of 95 neonatal deaths (a neonatal mortality rate of 19.1 per 1,000 live births). By day 28, 212 neonates had died or were diagnosed with or remained hospitalized for severe illness. One additional woman died between day 7 and day 28, for a total of 3 maternal deaths by day 28. Fifty three women (1.1%) were noted to have a wound or episiotomy infection or dehiscence prior to 28 days post-delivery.

Table 2: Maternal hospital admission and delivery (n=5,004)

Variable n (%)

Reason for hospital admission

Registered case for delivery 4,313 (86.2) Not registered for delivery 500 (10.0) Referred from other hospitals 188 (3.8)

Known maternal morbidity at admission 348 (7.0)

Type of delivery

Vaginal delivery without episiotomy 2,556 (51.2) Vaginal delivery with episiotomy 1,684 (33.7) Vaginal delivery with forceps 86 (1.7) Vacuum assisted delivery 239 (4.8)

Cesarean section 415 (8.3)

Assisted breech delivery 12 (0.2)

Rupture of membranes

Artificial 2,542 (50.9)

Spontaneous 2,456 (49.1)

Meconium stained liquor 565 (11.4)

Foul smelling vaginal discharge 18 (0.4)

Received antibiotics 4,708 (94.1)

Table 3: Maternal and newborn outcomes (n=5,004)

Outcomes n (%) Birth outcomes Live birth 4,988 (99.7) Stillbirth 16 (0.3) Male infant 2,652 (53.2) Birth weight < 2500 g 460 (9.2) Apgar score < 8 at 5 minutes 200 (4.0) Newborn referred to NICU

or other hospital 467 (9.4) Day 0-7 outcomes Neonatal death 79 (1.6) Maternal death 2 (0.04) Day 7-28 outcomes Neonatal death 16 (0.3) Maternal death 1 (0.02) Cumulative 28 day outcomes

Primary neonatal outcome:

death or severe illness 212 (4.3)

Neonatal death 95 (1.9)

Neonatal severe illness 117 (2.4)

Maternal death 3 (0.1)

Maternal wound or episiotomy

dehiscence/infection 53 (1.1)

Table 4 shows the frequency of various neonatal cord and skin care practices and maternal hand-washing in the last 4,085 study enrol-lees. Most mothers reported washing hands before eating or using the toilet, but nearly 23% of the women reported not usually wash-ing their hands before handlwash-ing the baby. 92% of the mothers cleaned their newborn’s umbilical cord stump: most often with oil (78%), water (57%), or antibiotic powder or antiseptic lotions (23%) (data not shown). Approximately 96% of the mothers reported using one or more substances to clean or massage the skin. Water (95%) was most commonly used followed by oil (90%). Other substances used less frequently were talcum powder, indigenous medicines, topical corticosteroids and baby lotion.

Table 4: Cord care and hand-washing (n=4,085)

Care n (%)

Usually washes hands before eating

Yes 4,036 (98.8)

No 49 (1.2)

Usually washes hands after using toilet

Yes 4,064 (99.5)

No 21 (0.5)

Usually washes hands before handling baby

Yes 3,159 (77.3)

No 926 (22.7)

Cleansing of cord (water, oil or other)

Yes 3,725 (92.0)

No 322 (8.0)

Cleansing of skin (water, oil or other)

Yes 3,882 (95.9)

No 165 (4.1)

Table 5 provides the unadjusted odds ratios (OR) for potential risk factors for neonatal severe illness and mortality. Neonates of primi-gravida women (unadjusted OR 1.6, 1.1-2.2) were at increased risk of severe illness and death as compared to neonates of multiparous women (p=0.01). Known co-morbidities, extent of maternal school-ing, and employment status were not associated with severe illness and neonatal mortality. Neonates whose births were assisted by in-struments (unadjusted OR 2.8, 95 % CI, 1.9-4.2), or through cesarean section (unadjusted OR 2.5, 95 % CI 1.7-3.7) were at increased risk compared to normal vaginal deliveries. Neonates of mothers who were referred from another hospital (unadjusted OR 3.3, 95 % CI 2.0-5.3) or whose mothers were not registered (unadjusted OR 1.7, 1.1-2.5) were at greater risk of developing severe illness or death com-pared to neonates whose mothers were registered to deliver in the study hospitals. Those who were born with meconium-stained liquor (unadjusted OR 3.0, 95% CI 2.2-4.1), had birth weight < 2500 g (un-adjusted OR 3.4, 95 % CI 2.4-4.7), males (un(un-adjusted OR 1.4, 95 % CI 1.1-1.9), those with low Apgar scores at 5 minutes (unadjusted OR 26.2, 95% CI 18.8-36.6), and those who were referred to the NICU (unadjusted OR 23.0, 95 % CI 17.0-31.1) were at increased risk of se-vere illness or death compared to their counterparts.

Neonates of mothers who did not wash hands before eating (unad-justed OR 4.2, 95 % CI 1.9-9.6), did not wash their hands after using the toilet (unadjusted OR 4.2, 95 % CI 1.2-14.4), or before handling the baby (unadjusted OR 2.8, 95 % CI 2.0-3.8) were at increased risk of developing severe illness and mortality as compared to neonates whose mothers usually washed hands at those times. Infants who did not receive cord cleansing were at increased risk of the primary outcome (unadjusted OR 6.4, 95% CI 4.4-9.4) as were infants with lack of skin cleansing (unadjusted OR 16.2, 95% CI 10.9, 24.2).

Saleem S, McClure EM, Moore J et al 43

Table 5: Odds ratios (unadjusted) for demographic and maternal characteristic and severe newborn illness or death by day 28

Variables Severe illness or death by day 28 Unadjusted

OR (95% CI)

P-value No+ _{[N (%)] Yes}@ _{[N (%)]}

Maternal medical/socio-demographic

Known co-morbidities Yes 319 (6.8) 20 (9.4) 1.42 (0.88, 2.28) 0.1483

No 4,345 (93.2) 192 (90.6) Reference

Gravidity One 1,660 (35.5) 97 (45.8) 1.56 (1.11, 2.20) 0.0099

Two to three 1,630 (34.8) 63 (29.7) 1.03 (0.71, 1.50)

More than three 1,390 (29.7) 52 (24.5) Reference

Mother received formal schooling Yes 2,618 (66.9) 116 (67.1) Reference 0.9643 No 1,296 (33.1) 57 (32.9) 0.99 (0.72, 1.37) Mother's employment status Employed 118 (3.0) 7 (4.0) Reference 0.4415 Not employed 3,795 (97.0) 166 (96.0) 0.74 (0.34, 1.60) Husband's employ-ment status Employed 3,827 (98.0) 165 (95.4) Reference 0.0206 Not employed 77 (2.0) 8 (4.6) 2.41 (1.14, 5.07)

Type of delivery Normal vaginal delivery 4,000 (85.6) 146 (69.2) Reference <0.0001

Assisted delivery 302 (6.5) 31 (14.7) 2.81 (1.88, 4.22)

Cesarean section 370 (7.9) 34 (16.1) 2.52 (1.71, 3.71)

Select health care factors

Reason for admission Registered case for delivery 4,063 (86.9) 160 (75.8) Reference <0.0001

Not registered for delivery 451 (9.6) 30 (14.2) 1.69 (1.13, 2.52) Referred from other hospital 163 (3.5) 21 (10.0) 3.27 (2.02, 5.29)

Rupture of membranes Artificial 2,392 (51.1) 98 (46.4) 0.91 (0.66, 1.24) 0.1562

Spontaneous rupture at hospital 1,573 (33.6) 71 (33.6) Reference Spontaneous rupture at home 712 (15.2) 42 (19.9) 1.31 (0.88, 1.93)

Meconium stained liquor Yes 499 (10.8) 55 (26.6) 2.99 (2.16, 4.12) <0.0001 No 4,120 (89.2) 152 (73.4) Reference Birth weight* < 2500 g 402 (8.6) 51 (24.2) 3.39 (2.43, 4.72) <0.0001 ≥ 2500 g 4,274 (91.4) 160 (75.8) Reference

Newborn gender Male 2,475 (52.9) 130 (61.6) 1.43 (1.08, 1.90) 0.0133

Female 2,206 (47.1) 81 (38.4) Reference

Apgar score at 5 minutes

< 8 115 (2.5) 84 (39.8) 26.22 (18.81, 36.55) <0.0001

≥ 8 4,559 (97.5) 127 (60.2) Reference

Baby referred to NICU Yes 322 (6.9) 133 (63.0) 23.04 (17.04, 31.15) <0.0001

No 4,351 (93.1) 78 (37.0) Reference

Maternal hand washing Usually washes hands before eating

Yes 3,838 (99.0) 159 (95.8) Reference 0.0006

No 40 (1.0) 7 (4.2) 4.22 (1.86, 9.58)

Usually washes hands after using toilet

Yes 3,861 (99.6) 163 (98.2) Reference 0.0235

No 17 (0.4) 3 (1.8) 4.18 (1.21, 14.41)

Usually washes hands before handling baby

Yes 3,039 (78.4) 94 (56.6) Reference <0.0001

No 839 (21.6) 72 (43.4) 2.78 (2.02, 3.81)

Cleansing of cord (water, oil or other)

Yes 3,601 (92.9) 92 (67.2) Reference <0.0001

No 274 (7.1) 45 (32.8) 6.43 (4.41, 9.37)

Cleansing of skin (water, oil or other)

Yes 3,758 (97.0) 91 (66.4) Reference <0.0001

No 117 (3.0) 46 (33.6) 16.24 (10.89, 24.21)

*28 missing birth weight; +_N=4,683; @_N=212

Table 6a presents the multivariate analysis of risk factors for the in-fant dying, or having severe illness by day 28 on all subjects in the study. Referrals for delivery from other hospitals (adjusted OR 2.4 95% CI 1.2-4.5), mothers who were unregistered (unadjusted OR 1.9 95% CI 3.0), birth weight < 2500 g (adjusted OR 1.9, 95% CI 1.2-2.8), had low Apgar scores at 5 minutes (adjusted OR 7.3, 95% CI 4.9-10.9) and referral to an NICU or other hospital (adjusted OR 11.7, 95

% CI 8.2-16.5) remained independent risk factors for neonatal severe illness and mortality after adjustment for confounding factors. Table 6b presents the multivariate analysis of risk factors for the infant dy-ing, or having severe illness by day 28 on all 4,032 subjects whose mothers answered the questionnaire, including data on hand-wash-ing, cord and skin care. A single variable was created that included responses to the questions on cord and skin cleansing and maternal

44 Adverse neonatal and maternal outcomes in Pakistani hospitals…

Table 6(a): Adjusted odds ratios for factors associated with neonatal severe illness or death before 28 days (total population).

Variables Severe illness or death by day 28 Adjusted*

OR (95% CI)

P-value No+ _{[N (%)] Yes}@ _{[N (%)]}

Reason for admission Registered case for delivery 4,056 (87.0) 160 (76.2) Reference 0.0015

Not registered for delivery 446 (9.6) 30 (14.3) 1.88 (1.17, 3.03) Referred from other hospital 162 (3.5) 20 (9.5) 2.41 (1.29, 4.52)

Birth weight < 2500 g 400 (8.6) 51 (24.3) 1.86 (1.24, 2.79) 0.0026 ≥ 2500 g 4,264 (91.4) 159 (75.7) Reference Apgar score at 5 minutes < 8 114 (2.4) 83 (39.5) 7.29 (4.88, 10.88) <0.0001 ≥ 8 4,550 (97.6) 127 (60.5) Reference

Baby referred to NICU Yes 322 (6.9) 132 (62.9) 11.66 (8.23, 16.50) <0.0001

No 4,342 (93.1) 78 (37.1) Reference

*Adjusted for listed factor; +_N=4,664; @_N=210

Table 6(b): Adjusted odds ratios for factors associated with neonatal severe illness or death before 28 days (population with questionnaire data only).

Variables Severe illness or death by day 28 Adjusted*

OR (95% CI)

P-value No+ _{[N (%)] Yes}@ _{[N (%)]}

Reason for admission Registered case for delivery 3,460 (89.5) 131 (79.4) Reference 0.0210

Not registered for delivery 342 (8.8) 23 (13.9) 1.80 (1.03, 3.15) Referred from other hospital 65 (1.7) 11 (6.7) 2.57 (1.03, 6.43)

Birth weight < 2500 g 335 (8.7) 43 (26.1) 1.88 (1.19, 2.99) 0.0074 ≥ 2500 g 3,532 (91.3) 122 (73.9) Reference Apgar score at 5 minutes < 8 93 (2.4) 65 (39.4) 7.39 (4.64, 11.78) <0.0001 ≥ 8 3,774 (97.6) 100 (60.6) Reference

Baby referred to NICU Yes 261 (6.7) 106 (64.2) 11.87 (7.98, 17.66) <0.0001

No 3,606 (93.3) 59 (35.8) Reference

Cleansing of cord, cleansing of skin and usually washes hands before handling baby

Yes 2,813 (72.7) 62 (37.6) Reference <0.0001

No 1,054 (27.3) 103 (62.4) 3.33 (2.30, 4.83)

*Adjusted for listed factor; +_N=3,867; @_N=165

hand-washing before handling the baby. In this model, referrals for delivery from other hospitals (adjusted OR 2.6 95% CI 1.0-6.4), moth-ers who were unregistered (unadjusted OR 1.8 95% CI 1.0-3.2), had a low birth weight (adjusted OR 1.9, 1.2, 3.0), had low Apgar scores at 5 minutes (adjusted OR 7.4, 95% CI 4.6-11.8) and referral to an NICU or other hospital (adjusted OR 11.9, 95 % CI 8.0-17.7) remained independent risk factors for neonatal severe illness and mortality, af-ter adjustment for confounding factors. Failure to provide cord and skin cleansing, and hand-washing prior to handling the baby com-pared to those mothers who usually performed each of these tasks was associated with an adjusted OR for the primary outcome of death or severe illness of 3.33 (2.30, 4.83).

Discussion

In this observational study of more than 5,000 relatively low risk women presenting for delivery in three urban Pakistani hospitals, the maternal and perinatal outcomes were substantially worse than those seen in HIC. Although these women presented to the hospitals with a live fetus and did not appear to require emergency measures, 16 of their fetuses were stillborn, 95 were neonatal deaths and an-other 117 had severe illness. Additionally, three women lost their lives. The maternal and neonatal mortality rates were 5-fold or greater than those seen in HIC.

Experts propose that effective care at the time of birth is a litmus test of health system performance [22]. It seems likely that better prena-tal and labor and delivery care for the mother and improved neona-tal care for the newborn in Pakistani tertiary level hospineona-tals could improve these outcomes, thereby reducing the high burden of ma-ternal and neonatal mortality and morbidity. This should include the use of appropriate technology, presence of skilled staff and imple-mentation of standard evidence based treatment protocols. Linking different levels of the health system with communities has been pro-posed to avoid delays in care [22]. In our study, women who were not registered to deliver in a hospital or were referred from another facility were at higher risk of having adverse outcomes for them-selves and for their newborns.

The over medicalization of maternal care, which has been a concern among HIC for decades, is becoming a concern for LMIC as well. Prac-tices fitting this description include routine episiotomy incisions, in-judicious use of oxytocics, overuse of cesarean sections and artificial rupture of membranes (AROM) [29]. Unnecessary use of episiotomy incisions and cesarean sections and their associated risks to mothers and babies have frequently been noted in the literature [30, 31]. In our study, one in every three women had an episiotomy incision, which included women with previous births. Approximately 94% of

Saleem S, McClure EM, Moore J et al 45 the women received prophylactic antibiotics either in the

intrapar-tum or in the post natal period.

More than half the women had AROM. AROM is generally recom-mended when there is fetal distress or some maternal indication so that the delivery process can be expedited [30, 32]. We did not col-lect information on the indications for AROM for this study, but we believe that the high rate of this practice suggests unnecessary in-tervention. In a recently published study of 26 hospitals from eight developing countries, records were reviewed retrospectively to iden-tify adverse events associated with healthcare management rather than the underlying disease process [30]. Reported adverse events ranged from 2.5% to 18.4% per country with nearly 30% resulting in death of the patient. About 34% of the adverse events followed ther-apeutic errors in relatively non-complex clinical situations. Inade-quate training and supervision of clinical staff or the failure to follow policies or protocols contributed to most adverse events.

In our study, nearly one percent of women remained hospitalized for more than a week, usually due to complications resulting from sur-gical and instrumental intervention. In addition, a number of other infections and dehiscence of episiotomy and cesarean section wounds occurred after returning to their homes. Therefore, there is a need to ensure that evidence-based practices are used and used correctly in hospitals in LMIC.

Some elements of home-based maternal/neonatal care practices were also explored. Care practices involving the umbilical stump and skin were generally appropriate, but those infants that did not re-ceive cord care or cleansing had worse outcomes. Recent papers suggest that 4% chlorhexidine cord treatment may play an im-portant role in reducing omphalitis and subsequent systemic infec-tions [26, 33-35]. Most women reported washing their hands prior to eating or after using the toilet, but those that did not had worse outcomes. Nearly a fourth of women did not routinely wash their hands prior to handling the baby. Failure to do so was also associ-ated with poor newborn health outcomes.

Potential limitations of the study include that these data were de-rived from a randomized trial of chlorhexidine targeted at predomi-nantly low risk mothers and their newborns. The mortality and mor-bidity rates, while high, would likely have been higher if the popula-tion of all births was studied. In addipopula-tion, although the percentage of mothers and infants lost to follow-up was small, it may be that some of those lost had died. The actual mortality rates might there-fore be higher. It would have been interesting to know the cause of death for mothers, fetuses and newborns, but actual or verbal au-topsies were not feasible in this setting. We also did not seek infor-mation on maternal wound care practices for episiotomy and cesar-ean section incisions. Nevertheless, we believe the data presented here illustrates some of the practices related to the high maternal and perinatal mortality rates in LMIC hospitals and emphasizes that simply moving women from their homes into hospitals for delivery will not automatically reduce those mortality rates.

In summary, women at apparently low-risk for obstetric complica-tions who delivered in tertiary level hospitals, all too often faced mor-bidity, mortality and loss of their newborns. Women mostly faced

morbidities as a sequel of treatment they received while at the hos-pital. Factors associated with neonatal severe illness and death were maternal transfers, unregistered status of mother, depressed babies, and mothers who did not wash hands before handling their babies.

Conclusion

Multiple approaches are required to reduce neonatal and maternal mortality in facility based care. Improving the quality of care at de-livery and in the NICU, high quality training of practitioners, appro-priate use of technology and use of evidence based practices are needed. At the household level, efforts to make women aware of the need for clean care practices and especially hand-washing are re-quired. More research is needed in urban areas to determine the household factors associated with severe illness and mortality in ne-onates.

Authors’ Contribution: SS led the study design and provided overall study

oversight, wrote the initial draft of the manuscript; EMM and RLG participated in the study design, study oversight and monitoring, and helped write the manuscript; JM provide statistical monitoring of the study and statistical analyses for the manuscript; SI, HA and FK provided study design input and oversaw study implementation; OP and LLW assisted in protocol development, study monitoring and editing the manuscript. All authors read and approved the final manuscript.

Acknowledgement: This study was funded by grants from the Eunice Kennedy

Shriver National Institute of Child Health and Human Development (NICHD) (grants U01 HD040607, U01 HD040636), the Bill and Melinda Gates Foundation and Aga Khan University. CLINICALTRIALREGISTRATION: clinicaltrials.gov, NCT00121394.

Competing interests: The authors declare that no competing interests exist. Received: 20 January 2014 Accepted: 27 February 2014 Published Online: 27 February 2014

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Ghnnam WM, Elbeshry TMAS, Malek JR et al 47

Open Access

Original Article

Incidental gallbladder carcinoma in laparoscopic cholecystectomy: Five years local experience

Wagih Mommtaz Ghnnam1_{, Turki Maed Al Salem Elbeshry}2_{, Jaweed Rafiq Malek}2_{, Emad Shebl Emarra}2_{, Mohammed Eid Alzahrany}2_,

Ahmad Ali Alqarni2_{, Ammar Ahmad Khattab}2

Introduction

Carcinoma of the gallbladder (GBC) is the fifth most common cancer of digestive tract and the most common malignancy of the biliary tract. It is an aggressive disease because symptoms and signs usually appear late and most patients are seen at an advanced stage (which is due to both the anatomic position of the gallbladder, and the vagueness and non-specificity of symptoms) with a poor prognosis [1, 2]. More than 80% of gallbladder cancers are adenocarcinomas [3]. The clinical manifestations of GBC are generally indistinguishable from those associated with cholecystitis or cholelithiasis. Around 90% of GBC have accompanying cholelithiasis [4]. Stones and chronic inflammation are the risk factors for GBC. However, only 0.5– 3% of patients with cholelithiasis will actually develop GBC [5]. Cholecystectomy is the most common major abdominal procedure performed worldwide. This procedure is being performed at an in-creasing rate according to hospital records [6]. Reports from many regions of Saudi Arabia show a striking increase in occurrence of gall-stones during the last two decades [7]. In the era of laparoscopic cholecystectomy (LC), despite advancements in various diagnostic procedures, preoperative diagnosis of GBC is an exception rather than the rule, occurring in fewer than 20% of patients [8]. The inci-dence of incidental GBC is 0.3-5% of all cholecystectomies. Incidental GBC has dramatically increased and is now the major way patients present with GBC. GBC not only presents a diagnostic dilemma but also poses a difficult treatment option in the era of laparoscopic chol-ecystectomy [9, 10].

In this single-center study, we report our experience with gallbladder cancer incidentally diagnosed during or after laparoscopic cholecys-tectomy performed for gallstone disease.

Patients and Methods

We evaluated the medical records of patients with gallstone disease who underwent LC in the Department of General Surgery of our

1_{Mansoura University, Egypt}

2_{Khamis Mushayt General Hospital, Saudi Arabia} Correspondence: Wagih Mommtaz Ghnnam Email: [email protected]

eral Hospital over the past five years. Routine preoperative assess-ment was performed in all patients, including liver function tests and abdominal ultrasonography. Exclusion criterion was existence of gallbladder polyps detected during preoperative ultrasonography. All operations were carried out by the authors using the standard four-port, two-hand technique [11}. Post-operatively all gall bladder specimens were sent for histopathological examination. Tumor stag-ing was based on the 7th _{edition of the American Joint Committee}

on Cancer (AJCC) manual (Table 1) [12].

Recorded data included patients’ demographics, details of operative procedures, perioperative outcomes, tumor histopathology, follow-up, and long-term survival. All the cases were further consulted with the oncologists for further adjunctive therapy and postoperative fol-low-up was done. Folfol-low-up data were obtained for all patients through them. Statistical analysis was done using SPSS 19 software. The study was ethically approved by the ethical committee of our hospital.

Results

During the period from December 2007 to December 2012, we per-formed 1982 LC procedures. Nearly all patients had cholecystitis or cholelithiasis. Out of those cases, 10 cases were found to have GBC. Among them, eight were females and two were males, giving a male to female ratio of 1:4. These patients were between the ages of 56 and 91 years old. The mean age was 73.6 years (Table 2). Nausea, vomiting and pain in the right upper quadrant (RUQ) of the abdo-men was the common clinical presentation in all the ten cases. Two patients presented with the features of acute cholecystitis, with a positive Murphy’s sign. In the remaining patients, the symptoms were more chronic in nature and of a longer duration, which ranged from 6 months to 5 years. None of the ten cases were clinically sus-pected to have GBC preoperatively although all had preoperative routine ultrasound imaging (Figure 1).

Abstract

Background: Carcinoma of the gallbladder is the most common malignancy of the biliary tract. Most of the cases are diagnosed as an

incidental case among patients undergoing cholecystectomy. The objectives of this study were to report the rate of incidental carcinoma of gallbladder in patients undergoing cholecystectomy and to study the demographic profile and prognosis of these patients in our locality.

Methods: A retrospective study was carried out in our general hospital during 2007-2012. The hospital records and histopathology reports

of 1982 patients who had undergone elective laparoscopic cholecystectomy were studied.

Results: Out of 1982 cases of cholecystectomy, gallbladder cancer was detected in 10 (0.5%) cases and was more common in females (M:F

ratio = 2:8) .The mean age of occurrence was 73.6 years. Most of the cases diagnosed, were at their early stages and only two of them were in pT3 pathological stage. Five of those patients survived to date with a mean follow up duration of 26 months.

Conclusion: The rate of incidental carcinoma of gallbladder is 0.5% in our locality and nearly half of patients were early stage with acceptable

five year survival rates. Routine postoperative histopathology of gall bladder is mandatory. (El Med J 2:2; 2014)

48 Incidental gallbladder carcinoma in laparoscopic cholecystectomy…

Table 1: TNM staging of gallbladder cancer [12] Primary

Tumor (T)

TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in-situ

T1 Tumor invades lamina propria or mus-cle layer

T1a Tumor invades lamina propria T1b Tumor invades the muscle layer T2 Tumor invades the perimuscular

con-nective tissue; no extension beyond the serosa or into the liver

T3 Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent or-gan or structure, such as the stomach, duodenum, colon, or pancreas, omen-tum or extra hepatic bile ducts T4 Tumor invades main portal vein or

he-patic artery or invades multiple extra hepatic organs or structures

Regional Lymph Nodes (N)

NX Regional lymph nodes cannot be as-sessed

N0 No regional lymph node metastasis N1 Regional lymph node metastasis

Distance Metastasis

MX Distant metastasis cannot be assessed M0 No distant metastasis

M1 Distant metastasis

All cases had gallbladder stones. None of those patients were diag-nosed for GBC preoperatively. Three cases needed conversion to open cholecystectomy and two of them were suspected during con-version, so extended cholecystectomy was done for both of them with excision of a wedge shaped area of the liver from the gallblad-der bed (cleared later by histopathology [Figure 2]) with resection of visible and palpable lymph nodes.

Out of the 10 cases of incidental GBC, two patients died during hos-pitalization due to unrelated causes (acute myocardial infarction and massive cerebral hemorrhage). Two more cases died after 8 and 13 months of diagnosis due to causes unrelated to GBC. One patient died due to metastatic disease 3 months after surgery. Five patients (50%) have survived to date with a mean follow up duration of 26 months. The details of the 10 cases of incidental GBC has been de-scribed in (Table 2).

Since, our hospital is a secondary care center, the cases were referred to an oncology center after histological diagnosis of malignancies for further treatment but we did establish contact with patients and rel-atives for estimation of the survival and mortality. The majority of the patients were in early pathological stages (pT1-3) and none was in pT4 stage (Figures 3-6).

Figure 1: Pre-operative ultrasonographic picture of one case of GBC with thick walled gallbladder and multiple gall stones.

Figure 2: Attached hepato-parenchymal tissue. There is no tumor invasion.

Figure 3: Intact mucosa is seen on the right. Abrupt area of tumor in which neoplastic structures invade the adventitia/serosa layer through the fragmented

muscular layer.

Figure 4: Mucinous adenocarcinoma with mucin secretion (mucin pools).

Figure 5: Gross picture of one case of GBC with diffuse wall thickening more in the neck and multiple gallstones.