Volume 2, Issue 2

Volume 2, Issue 2

April - June, 2014

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: 

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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] Want to partner with EMJ? Send your proposal to: [email protected] We’re hiring! Send your CVs to: [email protected] i

Editorial Board Senior Editor-in-Chief Prof. Nazeer Khan

Executive Editors

Editor-in-Chief

Managing Editor

Syed Salman Ahmed, Sajid Ali

Asfandyar Sheikh

Syed Arsalan Ali

Assistant Editor-in-Chief

Assistant Managing Editor

Haris Sheikh

Shanawer Khan

Senior Editors

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

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,

Dr. Rashid Mazhar, Dr. Mosaddiq Iqbal, Prof. Javed Akram, Prof. Abdul Bari Khan, Prof. Ashraf Ganatra, Dr. Raza Ur Rehman, Dr. Waris Qidwai, Dr. Muhammad Ishaq Ghori,

Section Editors

Editors

Assistant Editors

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

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

Gulrayz Ahmed, Raza Mahmood Hussain, Uzair Ahmed Siddiqui, Maheen Anwer, Anum Saleem, Hira Hussain Khan, Imran Jawaid, Hina Azhar Usmani, Hira Burhan, Quratulain Ghori, Bushra Iqbal, Maria Rahim

Statistics Editors Mehwish Hussain, Syed Ali Adnan

Production Editors Muhammad Hamid Chaudhary, Adnan Salim, Bushra Mufti, Parisa Aijaz, Mariam Farooqi

Layout Editor Shahzad Anwar

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Table of Contents FrontPage Editorial Board Call for Papers Health Poster Table of Contents

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Editorial Novel anticancer agents in clinical and preclinical trials

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Adnan Salim

Original Articles Adverse neonatal and maternal outcomes in Pakistani tertiary care hospitals: A prospective, observational study

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

Incidental gallbladder carcinoma in laparoscopic cholecystectomy: Five years local experience

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

Impact of SCARB2 on pro-inflammatory cytokines in tissues of EV71infected mice

52

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

Comparative effect of antiplatelet drugs in streptozotocin-induced diabetic nephropathy in experimental rats

59

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

Dorsal hippocampus histaminergic and septum GABAergic neurons work in anxiety related behavior: Comparison between GABAA and GABAB receptors

64

Leila Chodari, Shahrbanoo Oryan, Ramesh Ahmadi, Ghorbangol Ashabi

Examination of bone marrow mesenchymal stem cells seeded onto poly(3hydroxybutyrate-co-3-hydroxybutyrate) biological materials for myocardial patch Junsheng Mu, Hongxing Niu, Fan Zhou, Jianqun Zhang, Ping Hu, Ping Bo, Yan Wang

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Comparison of linear, logarithmic and mel-frequency filter-bank energy cepstra in automatic seizure detection using radial basis function neural network

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Chandrakar Kamath

Evaluation of foramen magnum in sex determination from human crania by using discriminant function analysis

89

Deepali Jain, O P Jasuja, Surinder Nath

Mineral content analysis and investigation of antimicrobial activities of Evolvulus alsinoides (L.) L. against clinical pathogens

93

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

Flexural and tensile strengths of three restorative materials used in pediatric dentistry

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Marcia Pereira Alves Dos Santos, Lucianne Cople Maia

Comparison of squash smears and frozen sections versus paraffin sections in the intra-operative diagnosis of central nervous system lesions

101

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

Research knowledge and behavior of health workers at Federal Medical Centre, Bida: A task before learned mentors

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

Medical students' perception about teaching-learning and academic performance at Nobel Medical College, Biratnagar, Nepal

110

Mukhtar Ansari, Attique ur Rahman Mufti, Salman Khan

Short Reports Microalbuminuria: An early marker of diabetic kidney disease

114

Zahra Ali, Muhammad Adnan, Saira Bashir, Iffat Shabbir, Tayyaba Rahat

A dermatological approach to the feet of soccer players

117

Asli Feride Kaptanoğlu, Hasan Ulaş Yavuz, Kaya Süer

Pattern of deliveries during three calendar years in rural India Rajiv Mahendru, Sunita Siwach, Richa Kansal, Vijayata Sangwan, Ritika Kaur, Pooja Gupta

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Magnetic resonance imaging cholangiographic evaluation of normal common bile duct size

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

Review Do socioeconomic inequalities lead to deceptive measurement of obstetric morbidity in India?

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Kshipra Jain, Mayank Prakash

Case Reports Bilateral mucoepidermoid carcinoma of parotid

131

Mayank Baid, Vikram Chaturvedi, Jayesh Jha

Bilateral granulomatous mastitis after local nandrolone injection

134

Sadaf Alipour, Akram Seifollahi

Unusual presentation of a case of fallopian tube carcinoma

137

Latika Sahu, Gouri Gandhi, Krishna Agarwal, Sunita Dubey, Preeti Yadav, Richa Gupta

Ileoileal intussusception in a young adult secondary to a mucinous adenocarcinoma

141

Archana Shetty, Mudasser Rehan, Chowdappa Vijaya

Phocomelia – A case study

144

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

Rectopopliteal fecal fistula developed through an intra-abdominal adhesion

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Mustafa Emiroglu, Abdullah Inal, Ismail Sert, Cem Karaali, Cengiz Aydın

Atypical mesothelial hyperplasia mimicking mesothelioma in patient with metastatic papillary carcinoma of thyroid

148

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

Primary eosinophilic granuloma presenting as bilateral otitis media and mastoiditis

151

Purnima Aggarwal, Uma Debi, Geetanjli Jindal

Peripheral ossifying fibroma

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

Lipoma of retromandibular space

156

Anand Gupta, Varun Chopra, Gurvanit Lehl, Shivani Jindal

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Opinions and Debates Antidepressants in the management of bipolar depression - An appraisal

159

Siddharth Sarkar

Pre-treatment evaluation: Setting a foundation in the management of drug- 164 resistant tuberculosis Saurabh RamBihariLal Shrivastava, Prateek Saurabh Shrivastava, Jegadeesh Ramasamy

Essays Stem cells from gynecological tissue: Trash to treasure

166

S Indumathi, B Padmanav, D Sudarsanam, B Ramesh, M Dhanasekaran

Evolutionary context of hypertensive disorders in human pregnancy

168

Abhay Kumar Pandey, Anjali Rani, Shripad B Deshpande, B L Pandey

Therapeutic spectrum of diuretics in different diseases

170

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

Letters to Editor Anesthetic considerations and implications for non-cardiac surgery in a patient presenting with aorto-occlusive disease

173

Teena Bansal, Manish Bansal, Sarla Hooda

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

176

Mehmet Yildirim, Nükhet Eliyatkın, Hakan Postaci, Nazif Erkan

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

178

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

A new comprehensive method for treatment of severe intra-uterine adhesions

180

Sefa Kelekci, Serpil Aydogmus, Emine Demirel, Mustafa Sengul

Organophosphate poisoning presenting as bradycardia Hari Krishan Aggarwal, Deepak Jain, Shivraj Goyal, Shaveta Dahiya, Ashima Mittal

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Appendices Instructions to Authors Sponsorship Information

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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 cancer 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 produces 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 temozolomide 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 development, 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 carcinoma, 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 Authority 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

Dow Medical College, Dow University Of Health Sciences, Baba-e-Urdu Road, Karachi, Pakistan Correspondence: Adnan Salim Email: [email protected]

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chemotherapeutic agents will significantly alter the course of the disease [7]. Imatinib, a tyrosine Kinase Inhibitor, is being used widely for the treatment of chronic myeloid leukemia (CML) [9]. Nilotinib, Dasatinib, Bosutinib and Ponatinib are newer drugs of this class approved for the treatment of imatinib resistant or intolerant CML [10, 11]. Histone de-acetylase inhibitors (HDIs) are yet another class of futuristic anti-cancer drugs bring used. [12]. Vorinostat (SAHA) and romidepsin (ISTODAX) are FDA approved for the treatment of cutaneous T cell lymphoma. Use of HDIs as other types of cancer shows moderate effects [13, 14]. Vismodegib, a hedgehog pathway inhibitor has been recently approved for treatment of advanced basal cell carcinoma [15]. Cyclopamine is the prototype inhibitor of the Sonic Hedgehog (Shh) pathway 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 cyclopamine, 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 determine accurately the potential of anticancer medicines. While many may show promise, there is still the question of their therapeutic 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.

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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):14211425. 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.

39 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 future in cancer. Infectious Agents and Cancer 2012, 7(1):20.

http://www.mednifico.com/index.php/elmedj/article/view/153

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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 McClure2, Janet Moore2, Samina Iqbal3, Syed Hasan Ala4, Fariha Khawaja1, Omrana Pasha1, Robert L Goldenberg5

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) Keywords: Neonatal Mortality, Neonatal Morbidity, Maternal Mortality, Low-resource Countries, Maternal Risk Factors

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, asphyxia, and the consequences of prematurity are leading causes of neonatal mortality [1-3]. Hemorrhage, infection and preeclampsia/eclampsia are leading causes of maternal mortality. Both neonatal and maternal mortality 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 inadequate care among facility births. Relatively simple, inexpensive interventions such as clean delivery and cord care, exclusive breastfeeding, and hand-washing with clean water and soap should prevent most infection-related neonatal deaths [3, 7-9]. However, inadequate 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 increase the likelihood of adverse outcomes for mothers and newborns [11-14]. Infants born to mothers with intrapartum hemorrhage, 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 significantly reduced neonatal and maternal mortality in higher income countries (HIC). In LMIC, even when simple, inexpensive interventions 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 Department of Community Health Sciences, Aga Khan University, Karachi Pakistan Department of Statistics and Epidemiology, Research Triangle Institute, Durham, NC, US 3Department of Obstetrics, Sobhraj Maternity Hospital, Karachi, Pakistan 4Department of Obstetrics, Qatar Tertiary Care Hospital, Karachi Pakistan 1 2

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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 morbidity. Newborn care practices, such as applying dung to the umbilical 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 determine 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 infant 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 randomized 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

Department of Obstetrics and Gynecology, Columbia University, New York, NY, US Correspondence: Sarah Saleem Email: [email protected]

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there were no significant differences in neonatal infection-related severe morbidity or mortality between the treatment groups, the entire 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 determine the outcome, newborns were followed in-hospital until discharge or death, while an independent field team examined the mothers and the newborns in home visits on days 7 and 28. The Integrated Management of Childhood Illness (IMCI) screening tool was used to identify severe illness in neonates [27]. Mothers were interviewed regarding fever, lower abdominal pain, and vaginal discharge and were examined by trained study doctors. A supplementary questionnaire on household assets, maternal hygienic practices, and newborn care practices was completed during the 7 or 28 day home visit on the final 4,132 study subjects enrolled. This questionnaire addressed infant cord and skin cleansing, and maternal hand-washing. Because of the small number of positive responses for several questions 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 handling the baby. Data was analyzed using SAS version 9.3. For descriptive analyses, means and standard deviations were calculated for continuous variables and proportions and percentages were calculated for categorical variables. To determine predictors for neonatal severe illness and death, logistic regression was used. Crude odds ratios (95% confidence 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 unadjusted 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 independent 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 obtained 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 collected information from the study population on education, employment, income, and household characteristics are summarized in table 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 forceps 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 referred to a Newborn Intensive Care Unit (NICU) or another hospital for an Apgar score