Head and Neck cancer (HNC) is the sixth most common cancer in the world. The 5-year survival rate depends on early diagnosis and appropriate therapy. Typically, late diagnosis requires not only surgical intervention, but also radiotherapy treatment combined or not with chemotherapy. Ionizing radiation is known to increase the expression of a number of cytokines involved in inflammation, wound healing and toxicity areas. Salivary cytokines have promising features to be used as biomarkers for disease screening and outcome prediction in this malignancy. The aim of this article is to analyze the role of salivary inflammatory response elements in HNC patients treated with radiotherapy, their modulation and association with the treatment outcome.A bibliographical search was performed on Pubmed, Cochrane and Embase using the following keywords: cytokines, saliva, head and neck cancer, radiotherapy. The cut-off point for the research were scientific papers published over the last 10 years. After a two-step selection process, 15 articles were identified and subjected to review.Radiotherapy treatment was shown to influence a number of salivary cytokines. A trend towards a growth of IL-1β, IL-6, IL-8, MCP-1, and TNF-α levels was observed and it correlated with the irradiation dose.The analysis of salivary cytokines could be a useful biomarker for predicting radiotherapy outcome in HNC. However, large-scale investigations are required to validate the use of these cytokines in predicting and diagnosing HNC, as well as evaluating the response to the treatment. Key words:Cytokines, saliva, head and neck cancer, radiotherapy. Head and Neck cancer (HNC) is a complex and heterogeneous malignancy, encompassing a variety of tumors that originate in the hypopharynx, oropharynx, nasopharynx, larynx, lips, or oral cavity. The disease group is associated with a distinct epidemiology, etiology, and the required therapies are also different. Worldwide, it represents the sixth most common neoplasia and accounts for 6% of all cases, being responsible for approximately 1-2% of tumor deaths  increases, Russo  in 2016  investig in 2016 . Dealing in 2016 .Screening salivary cytokine levels could provide a useful approach to the identification of biomarkers for predicting radiotherapy outcomes. When applied to a high-risk population such as HNC survivors, a saliva-based test utilizing a panel of biomarkers for HNC could provide an accurate, non-invasive and relatively inexpensive monitoring method .The aim of this article is to make an overview of salivary cytokines modulation and their association with radiotherapy outcomes in HNC patients.A literature review was performed on scientific articles on HNC, salivary cytokines and radiotherapy treatment. The research included studies published on Pubmed during the past 10 years. This was then supplemented by a new search using the same key words in the following database: Cochrane and Embase.The inclusion criteria for selecting articles were as follows:- studies that focused on biomarkers for HNC diagnosis and/or treatment outcomes related with radiation or chemoradiation therapy.- studies that included patients with HNC and OSCC .- studies that used saliva for the analysis of these biomarkers.Studies that used different biological media such as blood, serum or body fluids instead of saliva as potential media diagnostics and/or to monitor HNC patients, and also articles that reported associations between saliva and cancer in experimental studies  were excluded.The references cited in the selected papers were also checked for any incremental references that may have inadvertently been omitted during the electronic database searches.The study selection was accomplished in two phases. During the first phase, a selection of the articles that appeared to meet the inclusion criteria based on their titles and abstracts was performed. In the second phase, full articles were evaluated and the final selection of 15 papers was based on the full text of the publication.For all the included articles, the following information was recorded: year of publication, author(s), country, sample size, patient age, study methods, list of cytokines analyzed, and main conclusions.The studies were conducted in six different countries: mostly in the United States, and the rest in Brazil, Canada, Croatia, Iran and Italy. The salivary cytokines were assessed by different methods, the most common being the enzyme-linked immunosorbent assay (ELISA), followed by the multiplexed immunobead-based assay technology. An overview of the summarized data regarding the selected articles is provided in et al. in 2016  and VEGF can be found in significantly elevated levels in the local environment of OSCC .et al. , and the findings suggest that IL-8 may hold promise as a biomarker for oral cancer.In 2015 Guerra et al.  in their . The concentration of salivary TNF-α, interleukin 1α and 8 in the disease group was higher than in the control group but it was not statistically significant (p > 0.05). These results show that more studies are needed to accept the utility of these cytokines in the prediction or diagnosis of oral squamous cell carcinoma and the evaluation of treatment.In 2008, SahebJamee et al.  confirmeet al. in 2017 (Finally, Sahibzada et al. (The result of this literature review indicates that radiation or chemoradiation therapy can influence a number of salivary cytokines and, consequently, the analysis of salivary cytokines could be a useful biomarker for predicting radiotherapy outcome in HNC. Several studies reported increases in salivary IL-8, TNF-α, IL-1, IL-6 in HNC compared to controls but did not quantify changes post-treatment. A surprising finding observed by Russo Another factor to be considered is the post-radiation mucositis which correlates with increases in cytokines . HoweverThe concurrent increase in IL-6 and IL-8 in post-treatment saliva suggests a common regulatory mechanism, such as NF-κB, which plays an important role in the development and progression of HNC; NF-κB-regulated cytokines are upregulated in saliva in HNC . The actNot only radiotherapy treatment but also CTRT seemed to cause a significant increase in IL-1β, IL-6 and TNF-α, all positively associated with the severity of mucosal toxicity. This finding suggests that the elevation of these cytokines three weeks after therapy initiation could be predictive of a more severe oral mucositis. Furthermore, it may represent a potential approach for early identification of risk patients .et al. (In several of the cytokines that Citrin et al.  analyzedet al. (The differential changes observed between different cytokines pre- and post-treatment support the idea that the variation is not entirely a function of reduced fluid content of post-treatment saliva, which would increase all cytokines. Moreover, since ionizing radiation increases expression of pro-inflammatory and proangiogenic factors, differences in cytokines between patients treated with radiation or surgery were also investigated by Russo et al. , suggestThere are limitations to this review that we should highlight. Firstly, not all the studies were comparable as only some of them were case-control studies. Besides, the cytokines were not measured using the same technique. Secondly, the sample size regarding the levels of salivary inflammatory proteins pre- and post-treatment was relatively small. A larger sample cohort would allow for a greater statistical comparison between the two groups.Radiation alone or in a combination with chemotherapy is frequently used in the management of malignancies in the head and neck, being the primary treatment option for advanced head and neck cancers. Despite the increasing number of studies and reviews concerning salivary biomarkers for HNC, there is no consensus regarding which biomarker has the best diagnostic value . This re


This transformation shows some functional‐group tolerance and notably proceeds with C6 substituted indoles. The directing group can be readily removed in situ and the products isolated as the pinacol boronate esters. Acyl‐directed electrophilic borylation can be extended to carbazoles and anilines with excellent ortho selectivity. 4‐amino‐indoles are amenable to this process, with acyl group installation and directed electrophilic C−H borylation enabling selective formation of C5‐BPin‐indoles.Indoles are privileged heterocycles found in many biologically active pharmaceuticals and natural products. However, the selective functionalization of the benzenoid moiety in indoles in preference to the more reactive pyrrolic unit is a significant challenge. Herein we report that N‐acyl directing groups enable the C7‐selective C−H borylation of indoles using just BBr B‐directed: Acyl‐directed electrophilic C−H borylation provides access to novel C5 and C7 borylated indoles using just BBr3 as the borylating agent via the formation of six‐membered boracycles. C−H borylation is a powerful methodology to form synthetically versatile C−B bonds.3 (X=Cl or Br) is an attractive method to form organoboranes,3 has proved to be a powerful route to form B−C bonds for organic materials applications.2N‐ or N‐heterocycle groups with borylation generally forming six membered boracycles preferentially over other ring sizes.3 to the C5/C7 positions of indoles would be highly attractive. However, this requires conditions that disfavour electrophilic C3−H borylation (which is relatively facile) and a directing group that: (i) is compatible with BX3; (ii) enables selective borylation at the desired position; (iii) is readily deprotected post C−H borylation. Transition metal‐catalysed C7−H indole functionalisation often uses bulky phosphinyl directing groups installed at N1 which are challenging to remove (requiring refluxing with LiAlH4),N‐acyl directing groups also have been usedN‐acyl directing groups are compatible with BBr3 and lead to C7−H borylation of indoles generating useful C7‐BPin products on work up  based on borylation proceeding via acyl→BBr3 formation, [acyl→BBr2]+ formation and then SEAr (see SI).To guide our selection of appropriate acyl directing groups initially we probed the thermodynamic outcome from indole borylation at C2 and C7 computationally. Notably, the C7 borylated isomer is calculated to be thermodynamically favoured over the C2 2 a at C3 selectively (see SI) with no C2 or C7 borylation observed . Subsequent addition of pinacol/Et3N led to formation of the pinacol boronate esters 3 a–5 a . Borylation of 2 a with BBr3 led to more selective C7 borylation, with compound 25 a‐BBr the major borylated product observed in situ . 25 a‐BBr and 26 a‐BBr are more soluble (than benzoyl congeners) enabling in situ reaction monitoring. Notably, while minor amounts of 26 a‐BBr were observed in situ no 6 a was observed after pinacol protection. To confirm regioselectivity ZnPh2 was added to the reaction mixture from 2 a/BBr3 to form predominantly 7 . 7 was isolated in 42 % yield and subsequently crystallised with X‐ray diffraction studies confirming the formulation as the C7‐borylated regioisomer. The solid state structure of 7 revealed a B−O distance of 1.610(2) Å and a O‐B‐C angle of 104.3(1)° that deviates from that calculated for 25 a‐BBr presumably due to the different steric demand of BPh2 vs. BBr2. The complete absence of C3‐borylation is consistent with the requirement for boranes more electrophilic than BBr3  to effect intermolecular indole C3 borylation.While BCla Scheme . The dis3 in moderate to good yields   in varying amounts depending on the amount of BBr3 used. Conditions for one‐pot C−H borylation, pinacol protection and pivaloyl deprotection simply required the addition of methanol after BPin formation and heating to 60 °C. The removal of the pivaloyl group occurs without any observable C−B cleavage. This enables three steps to be achieved in one‐pot with no solvent switches with 8 a formed in 71 % isolated yield. These conditions were applicable to indoles substituted at C2, C3, C4, C5 and C6 (8 g–8 l), and containing electron withdrawing and donating groups. The reaction was performed on a 3 mmol scale to provide 0.82 g of 8 g in 86 % yield. However, 5‐SMe, 5‐NO2 and 4‐CN substituted indoles did not furnish isolable C‐BPin products, while attempts with a bulkier group at C6, 6‐(p‐tolyl)‐N‐pivaloyl‐ indole, led to C2 borylation dominating (35:65 C7:C2). Compounds 8 x are useful in Suzuki–Miyaura cross couplings, allylations and halogenations,8 a readily undergoes oxidation with H2O2/NaOH to form 7‐hydroxy‐indole.The substrate scope was explored next and notably C6 substituted N‐pivaloyl‐indoles were amenable to C−H borylation using BBrd) Table . The 6‐m2 borylation (forming 26 x‐BBr) often was observed. Attempts to form the C7−BBr2 products (25 x‐BBr) selectively by heating  failed to change the C2:C7 ratio suggesting that C−H borylation of these indoles is irreversible under these conditions. However, it was observed that the ratio of C2:C7 BBr2 products was different to that of the C2:C7 BPin products (with C7‐BPin increasing). Furthermore, in a number of cases the amount of 5 x/8 x isolated was greater than that possible based on the observed 25 x‐BBr:26 x‐BBr ratio (precluding C2‐selective protodeborylation during pinacol addition as the only origin of ratio changes). For example, substrate 2 k borylates to form a 25 k‐BBr:26 k‐BBr ratio of ca. 55:45 (by 1H NMR spectroscopy), however, post work up 8 k was isolated in 75 % yield. This indicates that addition of pinacol enables C2−B protodeborylation and C7−H borylation. As the BBr2 products are stable to isomerisation in the presence of HBr this suggests that it is a C−B(OR)Br or C−B(OR)2 species that is undergoing protodeborylation and leading to more selective C7−H borylation.2B‐Aryl has been previously observed.During substrate screening minor C2−BBrN‐pivaloyl‐carbazole did not undergo C−H borylation using BBr3 (even on heating). This is attributed to steric crowding between the two proximal C−H units , therefore N‐benzoyl carbazole, 9, was combined with BBr3. This did not lead to C−H borylation at room temperature, instead the Lewis adduct, 10, was formed which was poorly soluble in DCM facilitating isolation and characterisation  or protected at boron in situ to furnish the pinacol boronate ester 12 in excellent yield (96 %). For 10 and 11, the C=O (1.284(3) and 1.296(7) Å) and O−B distances (1.485(3) and 1.504(8) Å) reveal minimal difference, while the O‐B‐C angle in 11 (109.9(5)°) is comparable to that calculated for 25 a‐BBr and is close to ideal for four coordinate boron centres. Notably the B−O distance in 11 is significantly shorter than in 7 indicative of the greater Lewis acidity of the BBr2 moiety relative to BPh2.Heating combinations of ortho borylation of anilines . Directed borylation with BBr3 also can be applied to tertiary amides with the N‐Me derivative, 13 f, formed in good yield (83 %). Smith, Chattopadhyay and co‐workers have recently developed directed iridium‐catalysed ortho‐borylation of anilines using B2eg2 (eg=ethylene glycolate).N‐Me substituted anilines (<25 %),13 f using just commercially available DCM solutions of BBr3.This methodology was applicable to N‐Bn‐indol‐4‐yl‐2,2‐dimethylpropanamide, 14, next was investigated with it hypothesised that borylation would occur at C5 instead of C3 (the preferred site for SEAr in indoles) due to the preference for the formation of six membered boracycles over seven.15A to be more stable than the C3 isomers 15B . Attempts to monitor the borylation of 14 at the BBr2 stage were prevented by this intermediate being poorly soluble. Finally, the ability to perform a C5/C7 double C−H borylation using BBr3 was demonstrated using 17 (made in one step from 4‐amino‐indole). This formed 18 selectively post pinacol protection. Notably, in situ NMR spectra prior to pinacol addition show that the C3, C7 diborylated compound, 19, was formed as the major product and this does not isomerise on standing. However, addition of pinacol induces isomerisation of the C3−B moiety to form the thermodynamically favoured C5‐BPin unit and yield the desired C5/C7 product in good conversion (72 %).N‐pivaloyl is an effective and readily removed directing group enabling C7 borylation of indoles and ortho borylation of anilines simply using commercial solutions of BBr3. The process is complementary to borylation with [(amine)BBr2]+ and to iridium‐catalyzed directed borylation as C6‐substituted indoles are tolerated using BBr3, while it has complementary functional group tolerance to directed lithiation methods. Notably, in a number of cases pinacol induced isomerisation of the initial borylated regioisomer is essential to access the desired products containing C5−B and C7−B units. Due to the simplicity of this process and the many heterocycles containing N−H groups we believe acyl‐directed borylation with BBr3 will be applicable to many other systems.In summary, The authors declare no conflict of interest.As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.SupplementaryClick here for additional data file.


Most pregnancies are unplanned in Ethiopia. This is due to ignorance of the types and efficacy of each method of contraception they are associated with vast and unpredictable complications. Most of the time, these complications result in adverse birth outcomes. Information about prevalence of adverse birth outcome and it’s factors are relevant for designing, and initiating and intervening programs to decrease these undesirable out comes.To assess prevalence of adverse birth outcome and associated factors among women who delivered in Hawassa town governmental health institutions, south Ethiopia, in 2017.P-value< 0.05 considered as significance.We conducted institutional based cross sectional study among 580 pregnant women from december1–30/2017, by multistage systematic random sampling method in governmental health institution in Hawassa town. Data were collected through structured pre-tested, close ended and interview administered questionnaire in their post-partum period. Collected data was entered in Epi-info version 7 and analyzed using SPSS. Odds ratio with 95% confidence interval on multivariable logistic regression was computed and From a total of 580 respondents 106(18.3%) respondent’s had child related adverse birth outcome. Previous History of child related adverse pregnancy outcome 4.2 , Attend at list one antenatal care visit 2.3 (95%CI = 1.1–4.3), Own cat in the house 2.2 , Had any chronic disease/s 2.1, Age of the mother (from 35 to 45 Years) 2.3, Poor participants’ Knowledge on preconception care 3 (95%CI = 1.4–1.6) were significant predictor of adverse birth outcome in this study .Prevalence of adverse birth outcome was found to be significant in the current study. Presence of Previous History of adverse pregnancy outcome, on ante-natal attendance, presence of cat in the house, presence of chronic disease/s, younger mother and Poor Knowledge of preconception care were significant predictor of adverse pregnancy outcome. Therefore it is better to give more attention on expanding preconception and antenatal care. Creating awareness about family planning methods type and efficacy for women of reproductive health is mandatory. Services, increasing health education on personal hygiene vaccination of cats. Moreover, early detecting and treatment of chronic disease. Most pregnancy and childbirth is a joyful experience. But it sometimes end up in adverse birth outcome which disrupt the family condition leading to high individual and social costs. Adverse birth outcome in current study includes pregnancy loss/miscarriage, congenital anomaly or birth defect, preterm baby, low birth weight, perinatal death, macrosomia and intrauterine growth restriction. Most risk factors contributing to adverse birth outcome are amenable to modification. These poor reproductive life planning, substance use, abnormal pre-gestational BMI, irrational medication use, exposure to environmental toxin and contaminants, underlying chronic pre-gestational diseases, anemia and folic acid deficiency, poor regular exercise and physical activity, and presence of stress are included.The current study use a multistage systematic random sampling technique to select the study participants. Data was collected using a validated structured pre-tested interviewer-administered questionnaire. From a total of 580 respondents 106 (18.3%) respondents had child related adverse birth outcome. Previous history of child-related adverse birth outcome, nonattendance to antenatal care owning cat in the house, having any chronic diseases, being in the age group from, and having poor knowledge about preconception care were found to be significant predictor of child-related adverse birth outcome. In conclusion: Overall prevalence of child-related abnormal birth outcome was found to be significant. Almost all predictors found as significant predictors of abnormal birth outcome are all preconception risk factors. Focusing on prevention and management of preconception risk factors through the provision of preconception care along with early engagement in maternity care continuums is highly advised.Adverse birth outcome is a critical health issue in developing countries like Ethiopia. It resulted in many bad consequences neonatal and infant morbidity and mortality. Globally, 15 million babies are born too prematurely each year. More than a million of them die immediately after birth; many other suffer from lifelong physical, neurological, or educational disabilities [According to Ethiopian Demographic and Health Survey in 2016, there was high rate of perinatal mortality. Thirty-three death per 1000 live birth was reported. It was associated with increased maternal age, primi-parity, pregnancy interval of less than 15 months and urban residence [Neonatal mortality has shown less improvement than under five mortality in Ethiopia. A modeled data, indicate that Ethiopia reduced its under five mortality rate to 64/1000 live birth in 2013. It is a 69% reduction since 1990 [Increased number of intrauterine growth restriction is caused by low pregnancy body mass index, low short maternal stature and gestational weight. This finally leads to many low birth weight neonates in developing countries . A studyAdverse pregnancy outcome generally increase with age. A study conducted in Nigeria, 2012 indicated that perinatal mortality, intrauterine fetal death, and neonatal death increased with age . As evidThe achievement of sustainable development goal is highly associated with declining of neonatal death. Though, there are studies on the various forms of adverse birth outcomes particularly in developing countries and few part of Ethiopia, there is limited data on the overall adverse birth outcome at country level specifically at Hawassa town governmental health institution. Therefore, the aim of this study is to determine the prevalence and associated factor of adverse birth outcomes among women who give birth in Governmental health institution in Hawassa town.Hawassa city administration is a capital city of southern nation nationality people region and located 275 km South from Addis Ababa. Hawassa city in which 359,358 people are living according to city’s Health Department Estimation in 2017, has been structured by 7 urban sub-cities collectively have 21 kebeles and 1 Rural sub-city includes 11 kebeles. The city has 83 public and private health institutions. In detail, these are one public referral and teaching hospital, one public general hospital, four private primary hospitals, 9 Public Health Centers, 17 Public Health Posts and 51 Private Clinics.There are about a total of 852 health professionals working in the randomly selected PHIs of the city. Together with about 600 health professionals working in Hawassa University Comprehensive Specialized Hospital, the number reached1452.Hawassa University Comprehensive Specialized Hospital is the largest hospital in southern Ethiopia with more than 300 beds which renders service to both the people in the region and other people coming from the neighboring region. The hospital was established in 2004/05, provides specialized services and comprehensive health services . The outpatient department consists of 17 rooms and inpatient service consists of five main departments. The average number of patients flow at the outpatient department is more than 200 people per day. The Hawassa University Comprehensive Specialized Hospital and Adare General Hospital are the only public health hospitals providing comprehensive essential obstetric care in the City. The remaining nine PHC are giving Basic essential obstetric care. In the past 6 months of the year 2009, there were a total of 4780 deliveries reported from Hawassa University Comprehensive Specialized Hospital (2073), Adare General public health officer (2022), Adare primary health care (313), Millennium primary health care (311), and Tilte primary health care (61).The dependent variable was the ‘overall adverse birth outcomes ’. Whereas, the independent variables tested in this study included factors grouped into five categories. The first category includes socio-demographic factors such as age, parity, educational status, religion, occupation, partner’s occupation, residence, and family size. The next category is the mother’s current obstetric condition. This obstetric condition includes parity, gravidity, antenatal care attendance, gestation, pregnancy complication, birth order, and mother’s age at current pregnancy.The third category is the presence of pre-existing medical conditions. This included conditions such as diabetes mellitus, hypertension, cardiac disease, HIV/AIDS, anemia, malaria, and oral health status. The preconception risk factors occurring before pregnancy such as the woman’s pregnancy intention, psychoactive substance use, coffee consumption, pre-gestational BMI, periodontal disease, medication use, previous history of, the use of traditional medicine, environmental exposure, pre-gestational disease, preconception folic acid supplementation use status, presence of external stressors, familial/genetic history, medical insurance status, physical abuse, women’s preconception health/care knowledge, inter-pregnancy interval, regular exercise, and uptake of preconception counseling. The last or fifth category is health facility-related factors. This included factors such as availability of health facility, distance, and cost of service.‘Adverse birth outcome” in this study implies the presence of at least one or more of the following conditions in the current pregnancies. These include fetal loss/miscarriage, low birth weight, congenital anomaly, and preterm labour. Thus, if the mothers admitted to the labour ward gave birth to a baby with a congenital anomaly, low birth weight, preterm labour, small for gestational age, perinatal death, macrosomia then the these were labeled as “mothers with a child-related adverse birth outcome. Those who gave normal live birth, without the above mentioned abnormal birth outcome , were labeled as “mothers with normal child related pregnancy outcome”.Perinatal mortality: Is defined as deaths inside uterus (Macerated and fresh stillbirths) and early neonatal deaths (first week of life).Perinatal mortality rate is the sum of both of them per 1000 total deliveries [liveries .Miscarriage: Is the natural death of an embryo or fetus before it is able to survive independently [endently .Low birth weight: The weight of the newborn < 2.5 kg [< 2.5 kg .Preterm labour: Preterm labor is defined as regular contractions of the uterus resulting in changes in the cervix that start before 37 weeks of pregnancy [regnancy .Macrosomia: Macrosomia is defined as birth-weight over 4000 g irrespective of gestational age [onal age .Congenital anomaly: A congenital anomaly defined as any abnormality of physical structure found at birth or during the first few weeks of life; or any irreversible condition exiting in a child before birth in which there is sufficient deviation in the usual number, size, shape, location of any part, organ, cell to warrant its designation as abnormal [abnormal , 17.At first stage, out of the 11 public health institutions, five public health institutions were selected using simple random sampling technique. At the second stage, we applied a systematic random sampling method to identify and include all the study participants. The calculated sampling interval (K) was 1.2. Based on the finding we consecutively recruited the study subject’s i.e. using SRS up until the minimum sample size obtained. This is in accord with the assumption that deliveries in nature happened randomly. The samples were taken proportionate to the number of expected deliveries from each selected PHIs. All participants included in the study were all consented verbally to participate in the study. Excluded out of the study were mothers with a twin pregnancy.A cross-sectional study was conducted among women giving birth in public health institution of Hawassa City Administration. The source populations were all pregnant women living in the Hawassa City Administration. Whereas, the study population were those laboring mothers who attended the randomly selected public health institutions for delivery service during the study period.This study applied a multistage sampling technique to identify a total of 580 study participants.The sample size required for this study was determined using the formula for estimating single population proportion. Since there is no research (as per the investigators best systematic literature search) no published article reported the overall prevalence of abnormal birth outcome, and also the proportion of client’s attitude towards preconception care. Thus a prevalence value of 0.5 was assumed to calculate the minimum sample size. On the basis of this assumption the minimum possible sample size (n) sufficient enough to meet objectives of the study. The sample size determination considered the following assumptions. This included a 95% confidence interval (CI), a margin of error (α = 0.05), population correction factor, a design effect of 2 and 10% non-response rate.The principal investigator developed the instrument used in this study by referring to various literatures. The instrument is developed based on the objectives of the study. It was primarily designed to measure all the variables listed in the preceding two paragraphs. The instrument was a validated interviewer-administered questionnaire. The instrument was first developed in English and translated into Amharic and then back to English to check the accuracy. Before the actual data collection, the questionnaire was tested on 10% of health care providers working in Public health Institutions of a nearby town called Shashemene.Every woman who came to deliver in the selected primary health institutions during the data collection period was all interviewed. In addition to the interview, the data collectors abstracted clinical data by reviewing the mother and the babies’ medical records. They also measured and confirmed the baby’s birth weight, and conducted selected examinations for which they get additional training. The Data was collected by 5 BSC female midwives and 5 BSC female nurses after one-day Training about informed consent, techniques of interviewing, data collection procedures, and different sections of the questionnaire. Two health officers were assigned as Supervisors for the data collectors.P-value ≤0.20 in the bi-variable logistic regression model were fitted into the multivariable logistic regression model to control the effect of confounding variables. Multivariable analysis using standard logistic regression technique was done to evaluate the independent effect of each covariate on ‘child-related adverse birth outcome ’ by controlling the effect of others. Variable having P-value of less than 0.05 in the multivariable logistic regression analysis was considered as significantly associated factors of ‘child-related adverse birth outcome ’. The adjusted odds ratios with the 95% Confidence Intervals (CI) were reported. Before the actual logistic regression analysis was done, the necessary assumption of logistic regression model was checked by using Hosmer-Lemeshow test of goodness of fit which has a chi-square distribution. For further analysis, descriptive statistics like frequencies and cross tabulation were performed. Tables and bar chart were used to present the findings of the study.Overall supervision also made by the Principal Investigators. All collected questionnaires were rechecked for completeness and coded. Then these data were entered and cleaned using SPSS version 20 for analysis. Bivariable and multivariable logistic regression was employed to identify an association between the independent predictors and the outcome variable i.e. “child-related adverse birth outcome”. Those factors found with their From a total of 580 women delivered at governmental health institutions in Hawassa town, all participated fully in this study making a response rate of 100%. The mean age of respondents is 25.63 + 4.9 years. Majorities 492(84.6%) were in the age range of 20–34 years. Most of the study participants 560(96.6%) were married. More than half, 325(56%), of participants attended in elementary education. Whereas, only few (8.3%) attended college or university level education.Most of the study participants (68.8%) were housewives and the greater proportion (78.6%) had a family size less than five person per a household. From the total of 580 study participants, most 375(64.7%) of the study participants were living in urban Table . Almost Pregnancy induced hpertension which account(4.3%) is the observed predominant maernal related adverse outcome Fig. .The current study reveal that 47281.3%) births are normal live births, while the remaining 108(18.6%) births were births with child related adverse birth outcomes. The current study identified 7 types of abnormal birth outcome. Out of which 67 (11.6%) was low birth weight and the perinatal death was 16(2.7%). The magnitude of congenital anomaly was 6(1%). The study also identified two types of abnormal birth outcome among 33 (5%) of the newborns . Compared to mothers within the age range 20–34 years, those mothers within the age range 35–45 had two-fold higher odds of giving birth to a baby with APO than those mothers who aged 20–34 years . Non attendance to antenatal care, in contrast to attending at least one ANC, showed an increased odd of APO . The likely hood of giving a baby with an adverse pregnancy outcome was by two times higher among those mothers owned a cat in their house  and those who had any chronic diseases. The analysis also revealed that the odds of giving birth to a baby with APO are by three-fold higher among mother with poor preconception care/health knowledge than those with good preconception care/health knowledge  . Whereas, the types and proportions of the specific abnormal birth outcome identified in this study were; low birth weight 67(11.6%), macrosomia 26(4.5%), preterm birth 21(3.6%), congenital anomaly 6(1.0%), intrauterine growth restriction 3(0.5%), and perinatal death 16 (2.7%).The magnitude of abnormal birth outcome in the current study is significant. Compared to other similar study findings reported from Ethiopia , 19, theMoreover, since most of the current study participants were urban residence their level of knowledge and utilization of health service might be the other reason to the observed lower abnormal birth outcome. Except for the mother’s non-attendance to ante natal care, all of the five predictors identified in the current studies are preconception risk factors contributing to the development of child-related abnormal birth outcome. Similar to two studies in Gondar and DessiThe chance of developing an abnormal birth outcome among mothers with a previous history of child-related abnormal birth outcome was by four times higher than those mothers who had not had the history . Having had a child with abnormal birth outcome, in the previous pregnancy/ies, is one of the most important predictors of all the five predictors identified in this study. A similar study conducted in Shire town of North Ethiopia showed the fact those mothers with the previous history of child related abnormal birth outcome are at greater risk of giving birth to a baby with . There iSimilarly, the odd of giving birth to a baby with abnormal birth outcome was by 2 times higher among women with chronic diseases than those who didn’t have. This finding is consistent with a study conducted at Dessie . ChronicThe last predictor identified by the current study showed that those women who have cat in their house had two times higher odds of abnormal birth outcome than those who didn’t have . The possible explanation for this result may be toxoplasmosis infection that uses cats as a reservoir can lead leads adverse birth outcome like premature birth and low birth weight. Studies conducted at different areas of Ethiopia showed high prevalence of Sero-prevalence of Toxoplasma gondii (T.gondii) antibodies for IgM among pregnant women –32. ThisIn general this study identified five preconception risk factors or that increased the mothers odds of giving birth to a baby with abnormal birth outcome. Nevertheless, his study is not without limitation. Some of participants of the study may not remember some of the questions. This may lead to underreporting of the findings reported in this study. For some of the variables, such as previous history of abnormal birth outcomes, this study relied on the study participants verbal response. This study never included abnormal birth outcomes s happening at an and post pregnancy period. This include abnormal birth outcome such as miscourage, pregnancy loss, neonatal and infant death. As a cross sectional study this study do didn’t determined causal relationship and also temporal relationship. Despite this study, might tried to focus on preconception risk factors contributing to abnormal birth outcomes. To the best of authors best systematic search, there are not published articles reported preconception risk factors contributing to abnormal birth outcomes in Ethiopia.The prevalence of the overall adverse birth outcome is significant. Previous History of child related abnormal birth outcomes, women’s poor knowledge of preconception health/care, having any chronic diseases, advanced maternal age (35–45 years), and having a cat in the house were all preconception risk factors that increased the likelihood of developing child related abnormal birth outcomes. Non attendance to antenatal care was the other factor that increased the odds of the occurrence of abnormal birth outcomes. Provision of preconception and inter-conception care is the best approach to the identification and early management of risk factors to abnormal birth outcomes. The continuums of the maternal and child health care services are incomplete without the inclusion of PCC. Adverse pregnancy outcome reduction strategies should consider early identification and management of the preconception risk factors. The preconception care should include educating all eligible or reproductive-aged couples about preconception care/health. Creating awareness about family planning methods type and efficacy for women of reproductive health is mandatory.


The perinatal mortality rate (PMR) in Nigeria rose by approximately 5% from 39 to 41 deaths per 1000 total births between 2008 and 2013, indicating a reversal in earlier gains. This study sought to identify factors associated with increased PMR.Nationally representative data including 31,121 pregnancies of 7 months or longer obtained from the 2013 Nigeria Demographic and Health Survey were used to investigate the community-, socio-economic-, proximate- and environmental-level factors related to perinatal mortality (PM). Generalized linear latent and mixed models with the logit link and binomial family that adjusted for clustering and sampling weights was employed for the analyses.Babies born to obese women  and babies whose mothers perceived their body size after birth to be smaller than the average size  showed greater odds of PM. Babies delivered through caesarean section were more likely to die  than those born through vaginal delivery. Other factors that significantly increased PM included age of the women (≥40 years), living in rural areas, gender  and a fourth or higher birth order with a birth interval ≤ 2 years.Newborn and maternal care interventions are needed, especially for rural communities, that aim at counselling women that are obese. Promoting well-timed caesarean delivery, Kangaroo mother care of small-for-gestational-age babies, child spacing, timely referral for ailing babies and adequate medical check-up for older pregnant women may substantially reduce PM in Nigeria. Perinatal mortality (PM) includes foetal death from 22 weeks of gestation (stillbirth) and death within the first week after live birth  . PM reflStillbirths and early neonatal deaths remain unacceptably high in Nigeria. Nigeria currently ranks second globally with nearly half a million stillbirths  and thirFew studies of PM have been conducted , 11 in NAccordingly, this study used national household data, which captured every locality and ethnic group in Nigeria, to investigate the community-, socio-economic-, proximate-  and environmental-level factors associated with PM. We also estimated the adjusted PAR proportions to provide the magnitude of the PM attributable to each significant risk factor in Nigeria. Estimates from this study will greatly assist health and economic policymakers in formulating cost-effective evidence-based national intervention programs to ensure that existing limited healthcare resources are used appropriately to scale down PM across the six geopolitical zones, including rural, metropolitan and urban areas in Nigeria.The 2013 NDHS cross-sectional household dataset publicly available online was used in this study. Information relating to pregnancies (stillbirths and live births) was detailed by eligible women aged between 15 and 49 years. Approximately 38,948 women were successfully interviewed during the 2013 NDHS survey. The statistical methodology used to report the number of pregnancies was described previously . There wIn the study analysis, stillbirths (≥28 weeks gestation) and singleton early neonatal deaths (0–6 days) were combined and defined as PM. Information regarding perinatal deaths was restricted to the 5-year period to reduce recall errors of birth or death dates by mothers.The dependent variable was PM defined as death of foetuses at or after 28 weeks of gestation to newborn first week of age. The dependent variable takes a binary form such that “PM” was observed as a “case” (1 = if death occurred between 28 weeks of gestation and first week of age) and “non-case” (0 = if death did not occur between 28 weeks of gestation and first week of age).Independent variables used for the study analyses were based on previous studies on stillbirths and early neonatal mortality , 14, 15,The community-level factors comprised place of residence  and geopolitical zone .The socio-economic-level factors included maternal marital status, education, work status and paternal education. Another socio-economic factor was the household wealth index, which estimated the economic strength of each of the households interviewed during the survey period. Households were classified as rich, middle and poor.The proximate-level factors were maternal factors (body mass index (BMI), desire for pregnancy and age at birth); delivery factors ; and child factors . Delivery assistance herein refers to birth deliveries assisted by trained birth attendants  or untrained birth attendants . Birth weight at birth was not used because almost 50% of the newborns were not weighed at the time of birth , but perThe PMRs for all the potential coexistings were obtained. A multivariable Generalized linear latent and mixed models (GLLAMM) with the logit link and binomial family that adjusted for clustering and sampling weights was used to identify the associations between perinatal deaths and independent factors. In addition, crude estimates were also obtained for each of the independent factors.p-values < 0.05 were retained in the model (model 1). In the second stage of modelling, socio-economic-level factors were added to model 1 and significant variables with p-values < 0.05 were retained in the model (model 2). A similar process was followed in the third stage of modelling, i.e., proximate-level factors were assessed with the variables that were significantly related to the mortality outcome in model 2, and again those variables with p-values < 0.05 were retained in the model (model 3). In the final stage of modelling, environmental-level factors were entered into model 3, and only those variables with p-values < 0.05 were retained in the final model. All analyses were carried out with STATA software .A stage modelling approach similar to that of Dibley et al.  was adopThe total risk of perinatal deaths in the population between 2008 and 2013 attributable to each of the significant independent variables in the final multivariable model was measured by calculating PAR using the formula below:where pr is the weighted proportion of deaths during perinatal period (between 28 weeks of gestation and first 1 week of age) and aOR is the adjusted odds ratio for PM.There was a weighted total of 1196 perinatal deaths comprising 396 third semester stillbirths (≥28 weeks of gestation) and 800 singleton early neonatal deaths (0–6 days) during the 5-year study period (2008–2013). A greater PMR was observed among newborn babies whose mothers were obese compared with those who had normal weight (PMR: 58 vs 37). Newborn babies delivered through caesarean section (CS) had a higher PMR than those who had a vaginal birth (PMR: 73 vs 25). Similarly, newborn babies perceived by their mothers as small or very small had a higher PMR than those of average or larger size (PMR: 46 vs 21)  had significant odds of perinatal deaths (adjusted odds ratio (aOR) = 1.35, 95% confidence interval [CI]: 1.06–1.73) compared with those born to mothers aged < 20 or 30–39 years. Babies whose birth size was perceived as small or smaller by their mothers were 1.92 times more likely to die during the perinatal period than those perceived as average or larger in size. Male babies  were also more likely to die during the perinatal period than their female counterparts, as were babies delivered through CS  , babies of a fourth or higher birth order with a birth interval ≤ 2 years , babies of first birth order  and babies of a second or third birth order with a birth interval ≤ 2 years . In addition, babies born to obese mothers were more likely to die  compared with those having low BMI . Similarly, around 12% of perinatal deaths were attributed to male babies  . During the same period, approximately 4% of perinatal deaths were attributed to babies whose mother’s BMI (MBMI) was ≥30 kg/m2), having small or smaller birth size, birth through CS and having a fourth or higher birth order with a short birth interval ≤ 2 years after adjusting for necessary coexisting risk factors, including environmental-level factors.The risk of perinatal death in Nigeria between 2008 and 2013 was significantly elevated by a range of risk factors, including babies born to older women (≥40 years of age), residing in rural areas, male gender, mother being obese (MBMI ≥30 kg/mThe limitations of the current study are: (1) It is possible that over- or under-estimation may have affected PM risk estimates identified in this study because characteristics such neonatal jaundice, gestational age, sepsis or congenital anomalies, which were earlier found to be significantly related to early neonatal deaths in various hospital-based studies , 11 wereNotwithstanding these aforementioned weaknesses, this study used a nationally representative sample compared with earlier hospital-based studies in Nigeria , 11. MorBabies born to obese mothers had a 1.46 times greater risk of dying in the perinatal period than those having normal MBMI (18.5 ≤ MBMI ≤24.9). Similar findings were reported in earlier studies conducted in both developing and developed countries Nigeria , sub-SahThe odds of perinatal deaths were greater in older mothers aged 40 years or higher compared with younger mothers. This finding is in contrast with earlier studies in Russia and Bangladesh , 30, whiBabies perceived as small size after birth by their mothers remain a significant public health problem in Nigeria. A recent Nigerian population-based study suggested that nearly 30,000 newborn deaths in their first week of life were attributable to small-sized babies . The curFurthermore, studies in low- and middle-income countries , 36 haveBabies delivered by CS exhibited an almost threefold risk of perinatal death compared with vaginally born babies, which contradicts a previous study conducted in Swaziland . HoweverTo accelerate progress towards reducing prenatal mortality in Nigeria by 2030, public health interventions are needed at the community and individual level. At the community level intervention, screening programmes during pregnancy should be encouraged among older mothers especially those who live in rural areas, At the individual level intervention, educating mothers on kangaroo mother care approach on small-sized or low birth weight newborns including those delievered by caesarean section. However, to achieve these goals, the political, economic and social obligation of the three tiers of government  are very important to substantially reduce perinatal deaths.This finding suggests that newborn care interventions are urgently needed, at the community and individual level that aim to educate mothers on the benefits of weight loss or control, kangaroo mother care of small-sized babies, child spacing, timely referral for unwell babies, planned or elective CS, and promote regular medical monitoring of older pregnant mothers. These interventions will remarkably improve the rate of PM in Nigeria.


Birth ball is one of the non-pharmacologic pain relief methods to help mothers cope with the labouring process. A randomised controlled trial (RCT) is conducted to evaluate the effectiveness, safety and harm of birth ball use by pregnant women in labour compared to treatment as usual group.A prospective multi-centre randomised controlled trial (RCT) will be conducted in Obstetrics and Gynaecological units of five public hospitals in Hong Kong, China. Data will be collected from March 2016 onward for 2 years. The target population is Chinese women with an uncomplicated singleton pregnancy at gestational age of 37 to 42 weeks. Participants are randomised based on parity (nulliparous and multiparous) and type of labour onset (spontaneous and induced). Women in the intervention group are actively offered and taught how to use a birth ball; those in the control group receive the usual midwifery care. The target sample size is 512. The primary outcome measures are maternal pain intensity, satisfaction with pain relief, sense of control in labour, assisted delivery and satisfaction with childbirth experience. Labour pain relief is measured by visual analogue scale (VAS). Other outcomes will be measured through four different validated questionnaires. To control for potential cluster effects, a linear mixed model will be used. An intention-to-treat analysis is adopted and performed by researchers unknown to subjects’ group allocation.Results will provide rigorous scientific evidence for policy development and practice. We are using stratified randomisation according to potential confounders of parity and type of labour onset to give four possible combinations. If the results are favourable, it will facilitate systematic implementation to promote birth ball use for women in labour.ChiCTR-IIC-16008275, Date of registration 12 April 2016 (retrospectively registered), Date of enrolment of the first participant to the trial 1 March 2016.Chinese Clinical Trial Register (ChiCTR), Registration number:  Pain relief in labour was identified by an overwhelming majority (78%) of consumer groups and researchers to be one of the most important topics related to pregnancy and childbirth . Given tThe birth ball, also called fitball or swiss ball, is a large ball commonly with a diameter of 55 cm or 65 cm. It provides a soft surface for women to sit on or lean against while carrying out simple exercises. Birth ball exercises can directly relieve women’s physical pain by improving pelvic dimensions, mobility and foetal positioning . ConcurrThree local observational studies –10 reporAccording to the result of the systematic review, more rigorous RCTs are necessary to evaluate the effect of birth balls on pain relief . SearcheA randomised controlled trial (RCT) is designed and the objective is to evaluate the effectiveness, safety and harm of birth ball use by pregnant women in labour compared to treatment as usual group. The research hypothesis is that participants randomised to the birth ball intervention group have better pain relief, higher satisfaction with pain control, higher sense of control in labour and higher satisfaction with childbirth experience, when compared to subjects in control group. This study protocol follows the SPIRIT checklist.Recruitment for the study is conducted in all three regions of Hong Kong to enhance the generalizability of the results: Hong Kong Island ; Kowloon ; and the New Territories . The study was initiated in March 2016 and continues until the end of 2017. Figure This study adopts a two-arm  randomised intervention-control trial design with block randomisation, as this is the most robust method of minimising selection bias and strengthening statistical power. We further enhance statistical power by using stratified randomisation according to potential confounders of parity (nulliparous or non-nulliparous) and type of labour onset (spontaneous or induced) – two strata give four possible combinations. Allocation is concealed by using sequentially numbered opaque sealed envelopes (in four separate sets) that contain group assignments determined by computer-generated random sequences. A research officer gives the sealed envelope to the health care worker who is intended to carry out the intervention. No intervention if subject is assigned to control.Data to estimate sample size is only available from two randomised trials , 14. BotWithout existing rigorous research enabling more accurate estimation of effect size, we re-calculated sample size with a conservative Cohen’s d of 0.25 in pain relief measured by VAS, alpha 0.05 and a power of 0.8. This was calculated using software G*Power (version 3.1.9.2). In order to have an equal number of participants in intervention and control groups, participants of each stratified block are further amended as 64 in each stratum. This gives a sample size of 512.For safety reason, pregnant women who are admitted to the hospital for labour and vaginal birth will not be considered unless they meet all the inclusion criteria. 1) Chinese women able to provide informed consent; 2) singleton pregnancy in cephalic presentation planned for vaginal birth; 3) gestational age of 37 to 42 weeks admitted into a single room in labour unit, either in spontaneous active labour and the second stage not imminent, or for induction of labour; 4) uncomplicated past obstetrical and antenatal history enabling them to be under independent midwifery care.The exclusion criteria are 1) Multiple pregnancy; 2) foetal mal-presentation contraindicating vaginal delivery; 3) complicated pregnancy requiring close monitoring and restricted mobilization; 4) Caesarean delivery planned for this pregnancy; 5) any of the contraindication to use birth ball listed for each hospital (slightly varies due to different setting).We recognise that the use of a birth ball is a complex intervention that changes the women’s usual care in several ways that some may consider confounding factors. Research suggests that splitting complex non-pharmacological pain relief methods into specific and placebo components may not be meaningful and may even produce false negative results . Other nWomen in the intervention group are first offered and taught how to use the birth ball, followed by other non-pharmacological and pharmacological options, upon the women’s requests and advice from midwives. The existence and nature of placebo and the specific purpose of the trial is not disclosed at enrolment similar to other trials , 19.Midwives or physiotherapists with certified birth ball training  or who attended birth ball teaching classes, provide instructions on birth ball exercises and supervise the participants (and her labour support person if present) using a birth ball. Instructions on four groups of exercises adapted from the Taiwan trial  and locaWomen in the control group receive the usual midwifery care, without the midwives actively teaching and proactively suggesting women the use of the birth ball. Other non-pharmacological pain relief methods may include warm compresses, massage and transcutaneous electrical nerve stimulation. For ethical reasons, women in the control group can use the birth ball if they specifically request it. Their data remains in the control arm in intention-to-treat analysis.A Cochrane systematic review reported a list of core outcomes for labour pain control, agreed through a wide consultation with researchers and consumer groups . These oA simple and rapid visual analogue scale (VAS) of a 10-cm horizontal line, subdivided evenly with marks. Scores range from 0 (no pain) to 10 (extreme pain) are rounded to the nearest 0.1 cm, based on the women’s perceptions of pain at the time of assessment and during the peak of the last contraction at various time points: 1) on admission; 2) pre- and post-analgesia; 3) during labour, minimally every 2–4 h according to the phase of labour; 4) within 2 h of childbirth. This scale is the most widely used pain assessment scale in other birth ball studies , 14. OthSatisfaction with pain reliefModified satisfaction subscale from the American Pain Society – Patient Outcome Questionnaire (APS-POQ Modified)  is a 6-pAdditional questions on the willingness to use different analgesic methods in their next pregnancy and the most satisfied non-pharmacological method.Sense of control in labourSatisfaction with childbirth experienceA 29-item Chinese validated Labour Agentry Scale (c-LAS) , 22 is uSix Simple Questions (SSQ) , 24 asseOther data we collect as secondary outcomes include effect (negative) on mother-baby interaction , 26, breMothers’ demographic information is collected, such as maternal age, weight, height, socio-economic status, educational level, occupation, and marital status. Paternal age, occupation, and educational level are also noted. Other relevant obstetrical confounding factors of mothers on admission for labour – including parity, weeks of gestation, duration of labour prior to admission, degree of cervical dilation on admission and frequency of uterine contractions – are documented. During labour, information on any need for labour augmentation, foetal head position and status of amniotic fluid, are collected from medical records. Required infant data includes birth weight, gender, birth date, and body length. All the above information are recorded in the staff record form.Baseline characteristics of the two groups are compared by an ANOVA test for continuous variables and χ -test forTo control for potential cluster effect,  we will use a linear mixed model where the midwife is treated as a random effect. The basic model is a random intercept model with compound symmetry as the covariance structure. The data fitness is explored using alternative models, e.g., using different covariance structures, will be compared by the restricted maximum likelihood.P value of 0.05 or less is considered statistically significant. Objective measures and clinical outcomes are validated independently by two researchers. To minimise missing data, research officers ensure complete data collection prior to subjects’ hospital discharge and remind subjects that a follow-up assessment takes place at 6 to 8 weeks post-partum.Intention-to-treat analysis is adopted and performed by researchers masked to subjects’ group allocation. A two-sided This study draws data from five different sites across Hong Kong, which will increase the generalizability of results and enable easier systematic adoption of the intervention in other non-trial units. With the large sample size, single-blinded and stratified randomisation design, the results we have will provide reliable data. We are using stratified randomisation according to potential confounders of parity (nulliparous or non-nulliparous) and type of labour onset (spontaneous or induced) – two strata give four possible combinations.Taking ethical concerns into consideration, we are not forbidding women in the control group to use the birth ball if they request them, and vice-versa; we will not forcefully limit their other pain relief options. All the subjects from control group will remain in the control arm in the intention-to-treat analysis. This is regarded as a major limitation of the study that is not likely to be solved. Furthermore, since we aim to examine the effectiveness of the birth ball intervention as a whole in real clinical settings, these possible confounders are not intentionally separated out, as they are integral parts of birth ball application and implementation. Different hospitals have different cultures and settings, and hence this can lead to deviation in practice and therefore bias. To standardise the research protocol and administering of the intervention, meetings and training are given to the midwives at all study sites before and periodically during recruitment. There will be subgroup analysis in each hospital.Other limitations of this study include the concomitant use of other non-pharmacological pain relief methods during labour. It is common for pregnant women to use several analgesic methods at the same time. Although the time and method of all the analgesic methods are noted, the outcome effects of using a birth ball would become difficult to measure. Besides, in a busy antenatal and labour ward, the completion of research data by midwives and staff would be less than expected. Our researchers follow-up each participant and ensure all the relevant information from the medical record is reviewed. Although it would be impossible to blind the midwives or physiotherapists who teach birth ball, all the researchers will not be disclosed the case or control status of participants in the ward and during data analysis.Currently, birth balls are widely adopted in the delivery units in public and private hospitals in Hong Kong. Results from this study provide rigorous scientific evidence for policy development. If the results are favourable, it will facilitate systematic implementation to promote birth ball use for women in labour. Additionally, if proven effective and safe for mothers and babies, this simple non-invasive and non-pharmacological method can be used in delivery suites around the world, especially in low-resource settings at low cost to the healthcare system. Study results will be disseminated in peer-reviewed journals, academic and press conferences, and community conventions.This study will be the largest RCT on birth ball use for pregnant women in the world, with a total of 512 subjects. Our primary research questions include the effect of using the birth ball on pain intensity, satisfaction with pain relief and childbirth experience, and sense of control in labour. Results will provide rigorous scientific evidence for clinical practice and policy development.


Inherited factors and maternal behaviors are thought to play an important role in the etiology of several congenital malformations. Twin studies can offer additional evidence regarding the contribution of genetic and lifestyle factors to common birth anomalies, but few large-scale studies have been reported.We included data from twins  from the population-based California Twin Program. We compared concordance in monozygotic (MZ) to dizygotic (DZ) twins for the following birth anomalies: clubfoot, oral cleft, spina bifida, muscular dystrophy, deafness, cerebral palsy, strabismus, and congenital heart defects. Each birth anomaly was also examined for the associations with birth characteristics (birthweight and birth order) and parental exposures .P = 0.043) and strabismus . Among the total 20,803 pairs, parental smoking was significantly associated with risk of spina bifida  and strabismus . A significant quadratic trend of increasing risk for clubfoot, spina bifida, and strabismus was found when examining whether father smoked, mother smoked, or both parents smoked relative to non-smoking parents .The overall prevalence of any selected birth anomaly in California twins was 38 per 1,000 persons, with a slightly decreasing trend from 1957–1982. For pairwise concordance in 6,752 MZ and 7,326 like-sex DZ twin pairs, high MZ:DZ concordance ratios were observed for clubfoot (CR 5.91; Our results provide evidence for a multifactorial etiology underlying selected birth anomalies. Further research is needed to understand the biological mechanisms. Advanced maternal age is associated with an increasing prevalence of birth anomalies ,5–7 and maternal smoking is linked to an increased risk of oral cleft, clubfoot, and congenital heart defects.8 Aside from age and maternal smoking, other risk factors, such as other maternal conditions, paternal smoking, parental education, or birth characteristics, have been linked to certain birth anomalies. However, those factors have seldom been tested for a wide breadth of birth anomalies in the same population simultaneously.Approximately 6% of total births worldwide and 3% of newborns in the United States are born with a structural or genetic birth anomaly annually.9,10 The excess of concordance for a disease among MZ twins comparing to DZ twins suggests a role for a genetic component in disease etiology.11 This is of increasing importance given that the birth rate for twins in the United States is increasing, with rates increasing from 18.9 per 1,000 live births in 1980 to 33.3 per 1,000 in 2009.12 However, there are limited epidemiological studies that investigate birth anomalies in twins; most were conducted in Europe and focused on genetic rather than environmental factors.13–17Twin studies offer a unique opportunity to investigate the potential roles of genetics and shared early exposures. Identical (monozygotic [MZ]) twins share 100% and fraternal (dizygotic [DZ]) twins share, on average, 50% of their genome. A comparison of disease concordance between MZ and DZ twin pairs can crudely estimate heritability.Here we examine the prevalence of various birth anomalies, estimate the crude heritability, and investigate the association between selected birth characteristics and parental exposures and risk using data from the population-based California Twin Program (CTP).18,19 This study was based on information from a subset of twins born between 1957 and 1982, who were identified through birth records and California Department of Motor Vehicles (DMV) and returned and completed an updated 16-page questionnaire that included more detailed information on development and medical history, such as congenital conditions during the period of 1998 to 2001. A total of 28,050 individuals completed this questionnaire, representing 20,803 twin pairs, including both members of 7,247 pairs (double-respondent pairs), and one member of 13,556 pairs (single-respondent pairs). The crude overall response rate was 45.2%, which is comparable with or higher than similar cohort studies.20 In comparison with census data and California multiple birth records, the responding participants were representative of native California twins regarding to age, sex, zygosity, and residential distribution.18,19 The CTP was approved by the Institutional Review Board at the University of Southern California.The CTP is a population-based cohort of twins born in California between 1908 and 1982. The development and representativeness of CTP have been described elsewhere.The CTP questionnaire included a section on “Congenital Conditions”, listing 10 congenital conditions. In this study, we focused on eight anomalies: clubfoot, oral cleft, deafness, cerebral palsy, muscular dystrophy, spina bifida, strabismus (lazy eye), and congenital heart defects. Down syndrome and mental retardation were excluded from the analyses. Individuals were asked to report the presence of their own conditions (self-report) as well as those of their twins, brothers/sisters, and mothers/fathers (proxy-report). For double-respondent twin pairs, the disease condition was based on self-reports from both twins, whereas for single-respondent twin pairs, the disease condition was based on self- and proxy-report from the respondent twin. Concordant disease pairs were defined as those in which both twins had the same condition, and discordant disease pairs were those in which only one twin had the condition.st birth, 2nd birth, 3rd birth, or 4th or later birth. For the comparison within twin pairs, relative birthweight (“Which twin weighted more at birth?”) was coded as a binary variable: “1” for a twin member who indicated lower birth weight vs “0” for the co-twin with higher birth weight.Participants’ characteristics  were obtained based on the self-reported questionnaires validated using birth records. Self-reported zygosity from the questionnaire was adjusted based on gender, similarity questions  and confirmed by co-twins in double respondent-twin pairs, if available. Birth order was defined as the birth of the twin pair among all of their mother’s pregnancies that resulted in live births, and was categorized as 1All parental exposures, including maternal age, mother’s and father’s smoking history, and mother’s and father’s education, were reported by the twins completing the questionnaire. Maternal age was grouped as 29 years or younger vs 30 years or older. Parent smoking history (not necessarily during the pregnancy) was summarized as neither parent smoked, only father smoked, only mother smoked, or both parent smoked. Parent’s (mother or father) education was treated as a dichotomous variable for each parent with 12 or less years’ education versus 13 or more years’ education.In order to test the validity of the proxy responses from single-respondent twins’ questionnaires about their twins, agreement on shared factors  was evaluated, comparing self-reports to proxy reports in double-respondent twin pairs. Proxy responses from single-respondent twins were included when agreement on the variable of interest was high (>70%). Responses from double-respondent twin pairs with consistent responses between members of the pair were included, but those with inconsistent responses were excluded from the analysis.All 20,803 twin pairs were considered in the analyses unless specified. The characteristics of study population were shown separately by affected twin pairs  and unaffected twin pairs . For each birth anomaly, the frequency and percentage of concordant, discordant, and unaffected twin pairs were described by zygosity  and in total.Pairwise concordance is the proportion of the pairs in which both twins are affected (concordant) among the pairs in which at least one twin is affected (concordant + discordant). The measure is used to predict the disease status of the co-twin given that one twin is affected. It was calculated as follows:2 test were calculated using methods developed by Witte et al.21 An excess in pairwise concordance among MZ compared to DZ twin pairs suggests that heritable factors contributed to the birth anomaly. Under random or complete twin ascertainment, such as the population-based CTP, pairwise concordance is unbiased and sufficient to estimate the disease concordance.21 In this analysis, only MZ  and like-sex DZ  pairs were included for fair comparisons, since factors other than inheritable factors  in unlike-sex DZ pairs could contribute to the different outcomes.The standard error (SE) and χst birth, 2nd birth, or 3rd birth to 4th birth or later) on the selected birth anomaly, trend tests with the corresponding contrasts were used to test for linear, quadratic, or cubic trends.In order to examine the effects of birth characteristics or parental exposures on each birth anomaly, two analytic approaches were used. First, a within-pair case-control study was performed in which the affected (case) and unaffected (control) twin’s characteristics were compared using conditional logistic regression. Since the twin pairs share all parental and demographic factors, no confounder was adjusted in the model. Second, for shared birth characteristics and parental exposures, a between-pair analysis was performed with the pair as the unit. Due to small numbers, birth anomaly discordant and concordant pairs were combined as “affected pairs” and were compared to unaffected control pairs using a logistic regression model. Based on prior knowledge and any significant association with each outcome from univariate tests, the between-pair analyses were adjusted for zygosity, gender, maternal age at the twins’ birth, parental education, and birth order when the adjusted variable was not tested as the main effect. Because there were too few affected pairs in the categories other than white for each anomaly, race/ethnicity was excluded from the analyses due to inadequate power. To further address the potential trend for the effect of parental smoking  and birth order .All effects are reported as odds ratios (ORs) with 95% confidence intervals (CIs). If the cell number was less than 5, a Fisher’s exact test was used; otherwise, the likelihood ratio χThe overall prevalence of any birth anomaly in California twins was 38 per 1,000 persons. From 1957 to 1982, when the study twins were born, there was a general declined trend for each selected anomaly, except for cerebral palsy, the rate of which decreased in the 1960s and then slightly increased in the 1980s . The concordance ratio for strabismus was 2.52 (P = 0.0001), given that 17.01%  concordance in MZ versus 6.75%  concordance in DZ like-sex. The concordance for oral cleft in MZ twins was 4.9 times that of DZ like-sex twins; however, the statistical test was insignificant (P = 0.224), probably due to the low prevalence. These findings were consistently reported using probandwise concordances or structural equation modelling methods  and strabismus  was significantly associated with the decreasing risk of spina bifida  and congenital deafness  . No sign2nd vs 1st 0.99; 95% CI, 0.79–1.24; OR3rd vs 1st 0.76; 95% CI, 0.57–1.01; OR≥4th vs 1st 0.75; 95% CI, 0.57–0.99; Quadratic trend P = 0.008; We also examined the effect of birth weight (within pairs) and birth order (between pairs) on the risk of birth anomalies. The occurrence of deafness , cerebral palsy , and congenital heart defects  were significantly associated with lower birth weight . Twin paIn this large population-based twin cohort, the overall prevalence of birth anomalies decreased slightly from 1957 to 1982. We observed strong evidence of an inherited susceptibility for various birth anomalies. The concordance for clubfoot in MZ twins was 5.9 times that of DZ like-sex twins, and that for strabismus was 2.5 times. In terms of parental exposures, parental smoking was associated with an increased risk of spina bifida and strabismus. Interestingly, advanced maternal age significantly decreased the risk of spina bifida and congenital deafness. A decreased risk of strabismus was found among twins who were not the first born in family or whose fathers had higher education. Comparing within twin pairs, twin member who had lower birth weight than the co-twin was more likely to have deafness, cerebral palsy, and congenital heart defects.14–17,22–25 although some population-based studies have found no excess risk among twins compared to singletons .14 In this twin study, the overall prevalence rates for congenital heart defects  and oral cleft  are comparable to the global rates in 2006 ,26 indicating no excess risk of the two birth anomalies in California twins compared to the general population. However, the prevalence of clubfoot  is close to that from the other twin study,27 about 2-fold higher than that of the general population.4 In addition, California twins appeared at a substantially greater risk for spina bifida  comparing to the 2004–2006 general United States’ populations .1 The large difference is probably due to the introduction of folate use during pregnancy in 1990s, which was after our twins were born. We found significant excess of MZ compared to DZ concordance for clubfoot and strabismus, suggesting an underlying genetic predisposition.28 Family-based studies and linkage studies have identified several candidate genes for clubfoot and strabismus, including PITX129 and STBMS1,30,31 respectively. Moreover, the further different MZ:DZ concordance ratios comparing twins whose parents smoked to those with non-smoking parents provided potential evidence of gene-environment interactions for clubfoot, strabismus, and congenital heart defects. More research is needed to examine the molecular mechanisms.Previous studies have suggested an increased risk among twins for a number of different birth anomalies,32 Consistent evidence is available for an effect of maternal smoking during pregnancy on an increased risk of oral cleft,33,34 clubfoot,35–41 strabismus,31,42,43 and congenital heart defects.8,32 A previous systematic review that included 17 studies found no association between maternal smoking and spina bifida.8 Paternal smoking during preconception has been linked to an increased risk of offspring anomalies, potentially as a result of sporadic DNA mutations in sperm or maternal secondhand smoke exposure.44 However, only borderline associations between paternal/secondhand smoking and clubfoot 45 and spina bifida 46 have been previously reported. In our study, we did not find any association between any birth anomaly and smoking status of either mother or father alone. However, when both parents smoked, the risks of spina bifida and strabismus in offspring were significantly increased. An quadratically increasing trend was also observed for the risk of clubfoot, spina bifida, and strabismus among offspring who had only father smoked, only mother smoked, and both parents smoked, suggesting that paternal smoking might have synergistic effect on the etiology of these three anomalies. One possible explanation for our failure to detect the significant association between maternal or paternal smoking alone and selected birth anomaly is potential misclassification of parental smoking measures from twins with no information of smoking level or time, such as during pregnancy. However, the agreement between offspring assessment of parental smoking status and parental self-report has been reported to be high (97%).47 Among our twins, who had limited prior knowledge of the relationship between birth anomaly and parental smoking at completion of questionnaires, more than 80% consistency was reported about which parent smoked, suggesting that any bias is likely to be non-differential, possibly leading to the attenuated effects.Parental exposures, particularly maternal smoking, have been well-studied in relation to the risk of birth anomalies. Smoking may interfere with normal fetal development through a variety of mechanisms, including DNA damage, loss of essential nutrients, teratogenic effects, or fetal hypoxia.5 Our study found decreased risk of spina bifida and congenital deafness among twins whose mothers were older than 29 years at delivery compared to younger mothers. There have been five studies that have investigated the associations between different types of birth anomalies and maternal age.48–52 One large population-based study in the Metropolitan Atlanta Congenital Defects Program (MACDP) involving in a total of 1,050,616 singleton infants found that young maternal age (14–19 years) was significantly associated with the elevated risk of anencephaly/spina bifida  and ear defects .52 Advanced maternal age was also associated with adverse pregnancy outcomes, such as low birth weight or infertility, possibly caused by the more frequent DNA mutations in germline cells and detrimental effects on decidual and placental development.7 On the other hand, advanced maternal age for first live birth correlated with higher income, better health care, higher socioeconomic status, and parental employment, which effects we may lack of power to test seperately.It is well-documented that advanced maternal age increases birth prevalence of chromosomal abnormalities.19,53,54 All together, the misclassifications from self-reports are more likely to be non-differential, leading the results towards the null. And our major findings have been repeated in analyses conducted only using consistent measures within double-respondent twin pairs. Second, potential selection bias may arise from DMV linkage for twin identification in the CTP. Some conditions in birth anomalies, such as physical disability or intellectual delays, could affect the capability to be in the DMV records or complete the questionnaires, thus resulting in less likelihood of being included in the study and a subsequently lower prevalence or attenuation of the concordance ratios, since the concordant affected twin pairs usually have more severe conditions than the discordant affected pairs. As a result, Down syndrome, the most affected anomaly was excluded from this study, despite the popular interest in this condition. Third, in a classic twin study, MZ and DZ twins are assumed to share unmeasured environmental factors equally , so excess concordance among MZ over DZ twins suggests heritable influences. However, any violation of this assumption, for example, a different uterine environment in DZ comparing to MZ twins, could result in an exaggerated genetic contribution to the selected birth anomaly observed in this study. Lastly, because twins are uncommon and most of birth anomalies have low prevalence in the general population, this study suffers an inadequate power to separate the concordant and discordant affected twin pairs in association studies or test other interesting factors (eg ethnicity or birth places), which also leads to difficulty in investigating gene-environment interactions using more sophiscated twin models, although the CTP is a large population-based cohort.This study was based on data collected from cross-sectional questionnaires and has several limitations and assumptions. First, sole reliance on self-reports can be a concern for this study. However, for a birth cohort before the 1980s, when no related registry was available, the conditions at birth could only be reported using self responses or the proxy . Since the CTP questionnaire is a general survey designed decades ago with no specific study purpose and at a time when there was limited knowledge on birth anomalies, recall bias is likely to be limited. More than 75% agreements on exposures of interest in this study within our twin pairs suggest that the measures from self-report or proxy-report when self response was missing are reasonably valid and reliable. In addition, self-reported zygosity has shown more than 95% consistency with genetically determined zygosity in several studies, including a study with 600 pairs of the CTP twins.55,56,57 In addition, the self-reported information in twins can be validated by the co-twin, providing more confidence than a standard study of unrelated persons. Finally, the most current knowledge of birth anomalies in twins were from published studies in the Europe, where the population is relatively homogeneous and very different from the United States’ population. This study is the first twin study in the United States to explore various types of birth anomalies, to examine the heritable contributions, as well as to provide evidence of their associations with a set of birth characteristics and parental exposures. The unique twin study design may provide valuable clues to further understand the etiology, thus directing future studies.Using twins as the study population to investigate birth anomaly has the unique strengths over a traditional observational study. The major advantage of a twin study is to disentangle the genetic factors, shared and unshared environmental factors for a disease.


Echinococcus granulosus. Infection is transferred through the oral-fecal pathway by eggs of the parasite and more by eating vegetables and food contaminated with dog stool containing eggs of the parasite. Hydatid cyst can be made in liver, lung and rarely in heart, breast, thyroid, soft tissue of neck and kidney. Hydatid cyst of the kidney is a rare disease which may have no symptoms for years. In this case report, the patient has had a typical cyst in the left kidney for years that it seems to be silent for long time in a woman with ambiguous left flank pain whom went to a physician, and after complementary examinations, finally a typical hydatid cyst was diagnosed with the size of 93 × 120 mm in left kidney.Hydatid cyst is one of the most important zoonotic diseases that is caused by  Echinococcus, especially Echinococcus granulosus. The final hosts of the parasite are dogs and Canidae and the intermediate hosts are the livestock such as cows, sheep and goats. The infection is caused by oral-fecal route and transferred by parasite eggs, mostly due to consuming infected vegetables and food by stool of dog containing the parasite egg. The eggs are splitted in the intestinal duct; the larva enters to the blood through the intestinal mucosa. The disease is endemic in different parts of the world in which animal husbandry is common such as India, south of America, the Middle East, Mediterranean Australia and New Zealand [Hydatid cyst is one of the most important zoonotic diseases made by Cestoda  Zealand –4. Larva Zealand . Hydatid Zealand . The symA 26-year-old woman, resident of Mehdi Abad (Ilam province) with vague abdominal pain, was referred to urology department. In physical examination, low blood pressure and pervasive tenderness with the priority of left lower quadrant of the abdomen were found, and other vital signs were normal, and the patient did not have any apparent history. With regard to the symptoms and the involved organs, general tests such as the analysis of blood and biochemistry factors and also the urine analysis were prescribed for the patient. The analysis of blood and biochemistry factors was normal, but in urine analysis, a little mucus, epithelial cell and a high amount of RBC were seen and then sonography of kidneys was prescribed for the patient. Sonography of right kidney showed the normal dimension of 121 mm and parenchyma thickness of 23 mm, without any stone or obstruction but in left kidney with a dimension of 165 mm and parenchyma thickness of 18 mm, one typical cyst with a dimension of 120 × 93 mm was seen. Computed tomography scan illustrated the cyst in details , lung (15%) and other organs are less involved [Echinococcosis is a zoonotic disease and created by the larva of er about 5 %, lunginvolved . Renal hinvolved . Renal hAccording to this study and similar studies, it seems that diagnosis of hydatid cyst of the kidney, needs combination of methods such as laparoscopy, imaging, disease history, serology, hematology, and urinary analysis. Of course for removing the cyst scolicidal drugs must be used before surgery, and so involved organ, status and size of the hydatid cyst should be regarded to minimize the possibility of hydatid cyst tearing and consequently double pollution in other organs.