Previous studies from low-resource countries have highlighted concerns surrounding non-specific effects of whole-cell pertussis vaccination, particularly in females. We sought to examine the effects of sex and birth weight on health services utilization following first exposure to whole-cell pertussis vaccine. Using a self-controlled case series design and by calculating relative incidence ratios (RIRs), we compared the relative incidence of emergency department visits and/or hospital admissions between sexes and between birth weight quintiles. Females had a higher relative incidence of events following vaccination compared to males , which persisted after adjustment for birth weight . We also observed a trend of increasing relative incidence of events over decreasing quintiles of birth weight; infants in the lowest quintile had a 26% higher relative event rate compared to the highest quintile, which was robust to adjustment for sex . The risk of all-cause health services utilization immediately following vaccination, was elevated in female infants and infants having lower birth weight. Further study is warranted to determine if vaccine dosing should take infant weight into account. However, a World Health Organization commissioned review found no randomized clinical trials examining this question for the pertussis vaccine. The combined evidence from observational studies was deemed inconclusive, despite pointing on average towards increased mortality. 10Immunization is widely accepted as one of the most beneficial interventions in population health. While today’s vaccines are rigorously tested for safety and efficacy, there remains some uncertainty with respect to non-specific effects of vaccination, which are separate from the intended effect: protection against infectious disease. One routinely-administered childhood vaccine is designed to protect against pertussis, a highly contagious bacterial infection, and an important cause of infant illness and deaths worldwide. 11 as well as an increase in all-cause health services use in females in days 4 to 12 following the 12-month Measles, Mumps and Rubella vaccine. 12 Moreover, we have also found that birth weight, independent of preterm birth, has an important effect on the risk of health services use following exposure to the acellular pertussis vaccine at 2 months of age. 13 In this study, we sought to examine the effect of sex on all-cause health services utilization during the years in which the whole-cell pertussis vaccine was administered using population-based health administrative data. We hypothesized that the sex difference in risk of non-specific vaccine effects observed in previous studies may be partly mediated by birth weight. We investigated this hypothesis by analyzing the effects of both sex and birth weight on health services use following the 2-month whole-cell pertussis vaccination.In view of the low infant mortality rate in Canada, non-specific vaccine effects can be studied by examining health services utilization following vaccination as a proxy for general reactogenicity. In a series of studies in the province of Ontario, we have previously demonstrated an increase in all-cause health services utilization in the first 3 days following whole-cell Diphtheria, Tetanus, and Pertussis vaccination compared to the acellular version, Our analysis included data on 208,184 children born between April 1, 1994 and March 31, 1996 who received the whole-cell pertussis vaccine at 2 months of age . The daySupplementary Figure 2 graphically displays the frequency of events on each day relative to the date of vaccination by birth weight quintile. Among the infants with the lowest birth weight (quintile 5), the incidence of events in the first 3 days following vaccination was significantly higher than in the control period in both the unadjusted model, and in the model adjusted for birth weight . We obseMost of the observed events were ED visits (~80%). When examining hospital admissions alone, there was evidence of a similar pattern of increased relative incidence in female infants, and in those with the lowest birth weight, as was seen for ED visits and hospital admissions combined. However, these results were not statistically significant .Although 44% of the hospital admissions and ED visits observed in the risk period occurred within the first 24 hours following vaccination, the sex difference in relative incidence of events was only apparent when including events within 72 hours of vaccination in the analysis (Supplementary Table 1). Similar to our 2-month analysis, our 4- and 6-month analyses showed an increased relative incidence of events in females compared to males, but with attenuation of the RIR observed for the 2-month vaccination.In a post-hoc sensitivity analysis, we compared the relative incidence of events between infants having a birth weight <2500g and infants weighing 2500g or more at birth. There was no significant difference in relative incidence of events between the two groups in the unadjusted analysis, or in the analysis adjusted for sex .In this study, we demonstrate an increased risk of all-cause admissions and ED visits in female infants, immediately after the first exposure to the whole-cell pertussis vaccine at 2 months of age, compared to a control period. Although not statistically significant, there is a pattern of higher relative incidence of events in females compared to males. These findings persist after adjustment for birth weight, indicating that the sex effect is relatively independent of birth weight. We also demonstrate that infants in the lowest birth weight quintile have an increased relative incidence of events immediately following vaccination compared to the control period, and this relative incidence is trending toward a significant increase compared to the highest birth weight quintile, after adjustment for sex. Our post-hoc sensitivity analysis comparing infants born at <2500g vs ≥2500g found no significant difference in relative incidence of events between the two groups. The absence of a significant effect in this analysis is likely due to infants under 2500g being a highly select population with a high baseline rate of events, making it difficult to discern a signal from the reactogenicity of a vaccine. Taken together, our findings suggest there are independent effects of sex and, in particular, birth weight on the risk of admissions and ED visits following whole-cell pertussis vaccination at 2 months of age.8 One should note that the observation period in those studies lasted several months to over a year, thus including both our observation period of 0–72 hours post-vaccination, as well as our control period of 9 to 18 days post-vaccination. Therefore, it is unclear whether the effects observed in our high-resource, low-mortality and intensively monitored settings share the same potential etiology as the longer-term effects reported in the less closely monitored, low-resource and high-mortality settings. Our results are consistent with an earlier study conducted by members of our group that identified an increased risk of health services utilization with decreasing birth weight in term infants following the 2-month acellular pertussis vaccination. 13 Interestingly, our previous analysis of the impact of sex on the risk of events following the 2-month vaccination did not identify any effect with the acellular pertussis vaccine, 12 which is known to have a considerably lower reactogenicity profile compared with the whole cell pertussis vaccine.Several other studies have found evidence of an increased risk of non-specific vaccine effects in females compared to males. Similar to our results, the World Health Organization review of studies in low-resource countries found some evidence for differential increased mortality among girls, but the evidence was not significant. 14 We hypothesize that the observed effect of birth weight on risk of health services utilization following immunization could be partly attributable to the fact that the same dose of vaccine is administered to all infants regardless of weight, resulting in lower birth weight infants receiving more vaccine per unit of body weight as compared to higher birth weight infants. An animal study that found the risk of vaccine adverse events to be correlated with body weight supports this hypothesis. 15 Moreover, body weight is taken into account for dosing of other pharmaceuticals given to infants and children. 16Our use of birth weight as a proxy for weight at the time of vaccination at 2 months of age is based on the strong correlation between birth weight and infant weight at 2 months. 20 including those related to hormones levels. Variations in immune responses to vaccines by sex have been reported, both in immunogenicity21 and vaccine reactogenicity following the live-attenuated rubella, 22 and the high- and standard-titre measles vaccines. 25 Given this evidence, there may be a physiological and immunological basis to the sex effect we observed with the whole-cell pertussis vaccine in this study. We also hypothesized that the sex difference was partially mediated by birth weight, but since the effect of sex was robust to adjustment by birth weight, it appears that there are independent effects of both variables on the risk of health services use following whole-cell pertussis vaccination.Many studies have recognized the important physiological differences between sexes that affect their immunologic responses, 27 The use of RIRs to compare relative incidences of events between sexes allows us to adjust for confounding such as the healthy vaccinee effect. On the other hand, the use of RIRs can introduce other potential confounding as the resulting effect estimates are no longer within an individual. 28 We have taken steps to mediate this by adjusting for sex in the analysis of birth weight, and by adjusting for birth weight in the analysis of sex, but we cannot exclude the possibility of unmeasured confounding impacting our results. The use of all-cause health services utilization as an outcome represents both a strength and a weakness of our study. The use of all-cause events allowed us to capture non-specific vaccine effects, including events related to immunomodulation. The 5 most common diagnoses for the events, based on diagnosis codes, were: dyspnea and respiratory abnormalities, acute bronchiolitis, other and unspecified complications of medical care, fever and convulsions. On the other hand, less severe events that do not result in an ED visit would be missed.Strengths of our study include the examination of the impact of birth weight in term infants, the large sample size and the use of the self-controlled case series design, which allowed us to adjust for fixed confounders. By using a case-only design, where cases serve as their own controls, this design can reduce the impact of selection bias and unequal distribution of confounding variables between vaccinated and unvaccinated infants. This is particularly important in studying population-wide vaccinations as vaccinated infants are fundamentally different from unvaccinated infants. This is one of the reasons that the SCCS is a widely adopted study design in studying adverse events following vaccination. One limitation of the data is that only general vaccination codes were available. While we cannot be certain that the vaccination administered at 2 months of age was pertussis vaccine, we are confident in this assumption given the schedule of Ontario’s publicly-funded immunization program. As pertussis vaccine is administered as part of a combination vaccine, our study is unable to ascertain with certainty whether the effects we observed are due to pertussis or other components of the vaccine. However, previous studies have demonstrated that the whole cell pertussis component of the vaccine is the most reactogenic as the switch to acellular pertussis considerably reduced the adverse event profile.10 In our analysis we assume that the risk and control periods are consistent between males and females. Our analysis of RIRs further assumed that the healthy vaccinee effect manifested similarly in the compared subgroup (sex and birth weight). Conversely, studies that report RIs without attempting to account for the healthy vaccinee effect have likely underestimated effect sizes. 28 A limitation of all self-controlled case series analyses is the possibility of coincident temporal exposures; however, to our knowledge there are no other routinely-administered interventions at 2 months of age.Further, previous studies have found that the risk of non-specific vaccine effects is altered by the sequence in which vaccines are given, which we could not address using general vaccination codes. Finally, our use of birth weight as a proxy for body weight at the time of the 2-month vaccination may have introduced measurement error due to imperfect correlation between birth weight and body weight at 2 months of age. However, this likely would have biased observed differences in relative incidences according to birth weight towards the null.In conclusion, we observed an increased risk of all-cause health services utilization following whole-cell pertussis vaccination in the first 3 days following immunization, in female vs. male infants, and in infants having a low birth weight. In a previous study conducted during the period in which the acellular Diphtheria, Tetanus, and Pertussis vaccine was used, we did not find any effect of sex following the 2-month vaccination. Further study is needed to explore the biological mechanisms surrounding this observed sex difference associated with the whole-cell version. Moreover, additional study is warranted to determine if vaccine dosing should take infant weight into account.29 Using this infrastructure, we examined the effects of sex and birth weight on rates of emergency department (ED) visits and/or hospital admissions within pre-defined risk periods following the standard pediatric immunizations administered at 2 months of age. We included all infants who were born in Ontario between April 1, 1994 and March 31, 1996 (when the whole-cell pertussis vaccine was in use), and who had follow-up data available until at least 6 months of age. In Ontario, vaccination against pertussis was administered as part of a combination vaccine, which also includes diphtheria, tetanus, polio, and Haemophilus influenza type b. This pentavalent formulation was the only vaccine administered at 2 months of age in Ontario during the study period.We conducted this study using VISION (Vaccine and Immunization Surveillance in Ontario), an analysis platform that was created using linked health administrative data to monitor vaccine safety and effectiveness in Ontario, Canada. All study datasets were linked using unique encoded identifiers and analyzed at the ICES. ICES data includes Ontario residents covered by the publicly-funded Ontario Health Insurance Plan, encompassing virtually all people living in the province, but may exclude recent immigrants. Pediatric vaccinations were identified using physician billing claims data from the Ontario Health Insurance Plan database. To ascertain the 2-month vaccinations, we identified Ontario Health Insurance Plan billing codes for general vaccination occurring on the exact due date (61 days assuming an average month length of 30.5 days) as well as any vaccinations 14 days before and up to 40 days after the due date to allow for variations in scheduling. All-cause acute care hospital admissions were identified using the Canadian Institute for Health Information’s Discharge Abstract Database, and Ontario Health Insurance Plan billing data was used to ascertain all-cause ED visits during the study period.26 For the 2-month vaccination, the at-risk period was 0 to 2 days following vaccination and the control period was 9 to 18 days post-vaccination. For infants with more than one vaccination in the database during the 2-month target period, the first vaccination was used as the index vaccination. If another vaccination occurred within the observation period (0 to 18 days after the index vaccination) for a given infant, then this individual was excluded from analysis. We calculated the relative incidence of ED visits and/or hospital admissions in the at-risk period versus the control period using a fixed-effects conditional Poisson regression model. By design, this type of regression model controls for non-time-varying individual-level characteristics, thereby allowing each individual to serve as his/her own control. To control for the dependence of multiple events occurring close together in time , each individual was classified as having “one or more events” or “no events” in each of the at-risk and control periods.To conduct our analysis of ED visits or hospitalizations following immunization, we utilized the self-controlled case series design in which individual study subjects serve as their own control. In this design, the analysis only includes individuals who were both vaccinated and had an event of interest during the observation period. For each individual in our study, the index date for the exposure was the date of the 2-month pertussis vaccination. The follow-up time was then divided into three distinct intervals: an exposed period (or at-risk period), an unexposed period (or control period), and a washout period between the exposed and unexposed periods. Our selection of the at-risk and control periods was based on our previous studies of ED visits and/or hospitalizations following 2-, 4-, and 6-month immunizations, and our previous study comparing whole-cell and acellular pertussis vaccines. 30 The parameter estimate from the interaction term can be exponentiated to yield a relative incidence ratio (RIR) which is equivalent to the ratio of relative incidence in females to the relative incidence in males: an intuitive measure of the magnitude of the difference in relative incidences for females versus males. To separate the effects of sex and birth weight, we also presented a model with adjustment for birth weight. Similarly, we tested a model that included an exposure time period by birth weight quintile interaction term in order to estimate the effect of lower birth weight on the relative incidence of events. This model was also adjusted for sex. This RIR has the added benefit of allowing us to overcome the impact of the ‘healthy vaccinee effect’, the decision by parents and health care providers to forgo vaccination when a child is acutely ill resulting in the administration of vaccines to children who are in a comparatively healthy state. 32 Such an effect results in a marked reduction in events prior to vaccination and can mask any adverse effect in the immediate post-vaccination period. Using the ratio of relative incidence in two subgroups  can largely cancel out the healthy vaccinee effect where it is expected to behave similarly in the two subgroups.In order to determine whether the relative incidence of the composite outcome varied between males and females, we included an exposure time period by sex interaction term in the self-controlled case series conditional Poisson model. A likelihood ratio test was used to compare the full model including the interaction term to the reduced model without the interaction term in order to test whether the interaction term was statistically significant. 13 we conducted a sensitivity analysis restricting the risk period to the first day post-vaccination. Lastly, to examine the effect of additional vaccine doses, we repeated our analysis for the 4- and 6-month vaccinations.We conducted several sensitivity analyses to evaluate the robustness of our conclusions. To estimate the effects of sex and birth weight on the risk of more severe events following immunization, we modeled the relative incidence of hospital admissions alone. Since we have previously observed that most adverse events following immunization occur within the first 24 hours,


Care for women during pregnancy, labour, birth and the postpartum period is essential to reducing maternal and neonatal mortality and morbidity, however the ideal place and organisation of care provision has not been established. The World Health Organization recommends a two-tier maternity care system involving first-level care in community facilities, with backup obstetric hospital care. However, evidence from high-income countries is increasingly showing benefits for low risk women birthing outside of hospital with skilled birth assistance and access to backup care, including lower rates of intervention. Indonesia is a lower middle-income country with a network of village based midwives who attend births at homes, clinics and hospitals, and has reduced mortality rates in recent decades while maintaining largely low rates of intervention. However, the country has not met its neonatal or maternal mortality reduction goals, and it is unclear whether greater improvements could be made if all women birthed in hospital.This paper reviewed the literature on birth outcomes by place of birth and/or caregiver for women considering their risk of complications in Indonesia. A systematic literature search of Pubmed, CINAHL, CENTRAL, Web of Science, Popline, WHOLIS and clinical trials registers in 2016 and updated in 2018 resulted in screening 2211 studies after removing duplicates. Twenty four studies were found to present outcomes by place of birth or caregiver and were included. The studies were varied in their findings with respect of the outcomes for women birthing at home and in hospital, with and without skilled care. The quality of most studies was rated as poor or moderate using the Effective Public Health Practice Project Quality Assessment Tool. Only one study gave an overall assessment of the risk status of the women included, making it impossible to draw conclusions about outcomes for low risk women specifically; other studies adjusted for various individual risk factors.From the studies in this review, it is impossible to assess the outcomes for low risk women birthing with health professionals within and outside of Indonesian hospitals. This finding is supported by reviews from other countries with developing maternity systems. Better evidence and information is needed before determinations can be made about whether attended birth outside of hospitals is a safe option for low risk women outside of high income countries.The online version of this article (10.1186/s12978-019-0724-7) contains supplementary material, which is available to authorized users. Women need care by a skilled health professional during pregnancy and childbirth to identify, prevent and treat health issues for her and her baby if they should arise. We do not know if providing that care at home is as safe as in a hospital, particularly in poorer and developing countries. In wealthy countries, attended homebirth is a rare option but found to be safe if the woman choosing it is at low risk of complications and has access to a hospital if needed. In Indonesia, women birth at home, in health centres and in hospitals, and most with a health professional, unlike most lower and middle income countries, making Indonesia a good place to study the safety of birth in these different settings. This paper thoroughly searched for and summarised existing studies on this topic in Indonesia. Twenty four studies were found, most were of low quality and they found conflicting results. Some said homebirth was the safest option, others found hospital was safer. Most did not assess whether the women birthing at home were well or had complications which would have meant hospital birth was a better option for those women. We conclude that more research is needed to assess whether attended home birth is a safe option in Indonesia, particularly for low risk women.Countries vary widely in their approaches to maternity care. In high income countries birth occurs mostly within a hospital environment with care supervision by obstetricians and midwives or nurse-midwives. Aside from a few exceptions such as The Netherlands, birth at home is often controversial, rare and not well supported by governments, insurers or private health institutions. Outside of high income countries, birth outside of hospitals is more common, and access to medical facilities and obstetricians may be restricted by a lack of many factors such as recognition of need, availability, transport, finances, or culturally or socially appropriate care , 2. CareEnsuring that every woman has a skilled birth attendant (SBA) is a key part of international recommendations for improving maternal and neonatal outcomes. An SBA is defined as “an accredited health professional — such as a midwife, doctor or nurse — who has been educated and trained to proficiency in the skills needed to manage normal (uncomplicated) pregnancies, childbirth and the immediate postnatal period, and in the identification, management and referral of complications in women and newborns” . The MilThere is no decisive evidence on whether birth setting – where, by whom and with what facilities - influences pregnancy outcomes for low risk women in low income countries. The World Health Organization has for over a decade advocated a two tier approach; first level care in district health centres located near to women’s homes and back-up care at centrally located tertiary referral hospitals . The proIn high income countries, evidence is increasingly showing benefits for women at low risk of complications who choose to birth outside of hospital and are attended by skilled carers. These women experience lower rates of vacuum or forceps birth , 10, caeDebate still exists over the safety of planned, low risk home birth in high-income countries, though there has been no consistency of negative findings. Importantly, in a meta-analysis conducted in 2010 which included 7 studies reporting on neonatal mortality, this was found to be higher in planned home births compared with hospital births  . HoweverHowever, the overall positive outcomes are supporting increased acceptability for home birth in many high income countries. Women in The Netherlands, New Zealand and Canada are publicly financially supported in their choice of birth setting and care provider including home birth , 13, 26,plans to birth, especially if this is different to where she actually births, though collecting this data is fraught with difficulties, contributing to reasons for a lack of studies from low resource settings.The vast majority of this literature and the subsequent policy decisions about home birth focus on low risk women, though no international definition of what constitutes risk of birth complications exists. Women are, however, routinely assessed to determine their risk of complications during birth and therefore the type of care which best suits them . CompariIndonesia is potentially a useful case study to investigate whether attended low risk homebirth is safe in lower income, higher mortality contexts. Indonesia is one of the few countries which has developed their maternal health system by including efforts to provide skilled birth care in communities and homes, unlike most other countries where skilled birth care is limited to hospitals or health centres. The backbone of the Indonesian system is thousands of village based midwives who provide reproductive, maternal and child health services, often including birthing at home, or in clinics in villages . These Ibidan di desa) was started in 1989 by the government and supported by international aid agencies. At the time, most women birthed at home with the help of a traditional birth attendant (dukun bayi) who had little or no health training. An increase from 13,000 midwives to over 50,000 by the end of the 1996/97 budget year providing birth assistance to 96% of villages in Indonesia [The village midwife program , caesarean section, postpartum haemorrhage, labour augmentation or induction, episiotomy, position of birth, analgesia/anaesthesia for labour or birth, known support person present for labour and birth, maternal views of care, neonatal admission to intensive care, Apgar scores, and breastfeeding rates at any point of time. These outcomes were adapted from the Cochrane Review on alternative versus conventional birth settings  and was The methodology of this review was developed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . No protArticles were restricted to 1997 or later, as this is when the majority of women in Indonesia had at least access to skilled birth assistance through the village midwife program. Articles were removed if they were duplicates, did not provide a comparison of at least one outcome (listed below) by birth setting or caregiver, and if they did not include some measure of pregnancy risk status, where risk factors for complication at birth have been identified and accounted for, either through segregation (low and high risk grouping) or through analysis . A list of risk factors  Quality Assessment Tool . This toCitations for each database searched were imported into reference software (Zotero) which was then used to sort and exclude articles by title and abstract. Crude data were extracted by two authors and entered directly into Microsoft excel to create a comparison table. The data were clearly too different to attempt meta-analyses.An initial search in 2016 revealed 2125 studies and four were identified through references of key documents, 407 of which were removed as duplicates. A second search to update the review was conducted in 2018 and identified 653 articles and an additional one was found through relevant bibliographies. The resulting studies were screened by title and abstract and 119 were considered to potentially meet the inclusion criteria and were assessed by full text, with 24 being included in the final review. These studies are listed in Additional file Assessment of quality and risk of bias in the studies was undertaken by one author (KH) using the Effective Public Health Practise Project Quality Rating Tool . Only onThe 24 studies included represent the breadth of literature which considers the impact of birth caregiver and birth setting on birth outcomes in Indonesia  include no measure of risk of complications at birth as defined in Table % includeThe studies are varied in their methodology, though 13 of the 24 sourced their data from the Indonesian Demographic Health Survey (IDHS). Neonatal mortality is the most common outcome and crude results were able to be extracted and presented in Fig. Twelve studies report neonatal mortality as their outcome. Two include only caregiver as their exposure while the rest consider both caregiver and birth setting. Two of the studies find that SBA is associated with decreased risk of neonatal death , 44, andFigure n = 9) making it difficult to interpret whether the increase in mortality was associated with home birth or a lack of SBA.Interestingly, the one study that did find a significant association between birth at home and neonatal mortality  is a casincreased risk of neonatal mortality. While in urban areas, birthing in a health facility resulted in a protective factor if the mother had complications at birth. This could be pointing to a tendency for women in rural areas to seek help too late for their babies to be saved, or a tendency for only high risk women birthing in rural areas to have health professionals present.Titaley, Dibley and Roberts  highlighFive studies report on maternal mortality outcomes. One compares private and public facility birth  and the Of those comparing caregiver, one found no statistically significant association  while twAdisasmita et al.  reports Three studies assessed caesarean section and all compared private with public hospitals –62. Two Four studies compared breastfeeding outcomes; three were concerned with exclusive breastfeeding –65 and oIt was impossible to determine from the included studies outcomes specifically for low risk women. Five of the 24 studies included no risk factors, another 14 adjusted for either one or two risk factors and the other five considered between three and seven risk factors. The risk factors included were most commonly maternal age and neonatal size but other factors such as anemia, history of previous pregnancies or twins were sometimes considered (see appendix for details). However, none could be said to have been comprehensive when compared with the list in Table Of those which did include antenatal risk factors for complications at birth, nearly all found one or more of them to be association with the outcomes assessed. This shows the impact of risk factors on birth outcomes and the importance of their consideration when determining the impact of birth settings and caregivers on neonatal and maternal mortality in particular.While the outcomes and findings of this review included studies are diverse, they paint an overall picture that the impact of birth setting and caregiver on birth outcomes is not as clear as many policies imply. Most of the included studies find that birth setting and caregiver are not statistically significant in their associations with neonatal mortality or breastfeeding. Two studies found an increased risk of maternal mortality with SBA as opposed to no SBA, but both found this among populations where uptake was low (more remote and poorer women). SBA was found to improve neonatal mortality among just two studies yet also two studies found an increase in risk of neonatal death among facility births when compared with home births. These findings are particularly interesting given that a key message from the World Health Organization is that skilled care at birth is essential to save maternal and neonatal lives.The poor clarity of maternal risk status in the included studies suggests that assumptions were made by the authors about their outcomes. For example, where studies found higher mortality rates in hospitals or when births were attended by trained health professionals, compared with at home without trained assistance, the authors concluded that women were probably seeking care when they became ill and could be reaching assistance too late to be saved , 55, 57.Without any clear pregnancy and birth risk assessment, it is impossible to conclude if the appropriate women are being transferred to hospital, arriving too late to be saved, or if these deaths are due to some other factor. For example, perhaps the care being provided by health professionals in hospitals is leading to iatrogenic effects and poorer outcomes, or women who live further away from hospitals may have a poorer underlying health status and therefore more prone to adverse outcomes outside of hospitals.The issue of risk status and other confounding factors likely contribute to the inconsistent, and sometimes contradictory findings of the 24 included studies assessing the impact of birth carers and settings. Ideally, any study attempting to ascertain the impact of birth setting or caregiver needs to take into consideration the appropriateness of the setting and carer for that woman, i.e. risk status at the point of labour onset and ongoing, as well as the woman’s preferences and the options available to her. Assessing maternal intentions and whether the actual place of birth was the intended place of birth allows for accurate assessment of the impact of transfers in labour, and the effectiveness of the health system.This finding that risk of complications is not adequately considered is reflected in previous systematic reviews. Scott and Ronsmans  conducteSimilarly, Tura et al.  conducteThe studies included in this review were all but one given a quality rating of weak or moderate using the EPHPP tool. This is in part due to the difficulty in acquiring data which allow important potential confounders such as risk status to be taken into consideration. Data is frequently sourced from hospital records, excluding birth in communities, or from survey data such as the IDHS, which is open to recall bias and does not ask for enough details to permit accurate assessment.While language was not specifically restricted in the search strategy, terminology in Indonesian language was not searched, therefore some articles may not have been found. It is standard practice, however, for Indonesian research to provide an abstract translated into English, which should have been found in the search. Another limitation was that only one author undertook review of the quality of studies using the EPHPP tool.Studies which attempt to assess outcomes of birth by setting and caregiver in Indonesia and other low resource countries are conflicting in their results, making it difficult to draw conclusions. The studies fail to stratify by or adequately control for risk status of women, skill of caregiver and intended place of birth. Without these controls in place it is impossible to comment on the direct impact of a program which supports attended homebirth outside of high income countries. This ambiguity has implications on maternity health systems development, policies and funding priorities which impact women’s and babies’ health outcomes.Additional file 1:Appendix 1. Table of characteristics of included studies. (DOCX 43 kb)Additional file 2:Appendix 2. Search terms. (DOCX 51 kb)


This month, newspapers and websites released the news referring to the birth of twin girls by the world's oldest mother. A 74-year-old Indian woman and an 82-year-old Indian man, who have been married for 57 years were treated after 30 years of postmenopause. She became pregnant using donated eggs at an infertility clinic in Guntur, India. This treatment resulted in delivery of twin girls .This news disseminated confusion and received blame from medical policy makers, ethicists, lawyers and physicians, that why third-party infertility treatment should be ordered to such aged couple and debates about the future of children. Interestingly, and perhaps unfortunately, the report states that one day after the birth of these babies, her husband had heart attack, admitted to intensive care unit, besides the mother who was at special care in this unit due to the complications of pregnancy and twin delivery.In addition, numerous extremely old cases have been reported to give birth to live babies previously; for example, in 2008, a pregnant woman, named Omkari Panwar, in India aged 70 or 72 years had live birth. However, her age was not confirmed due to the lack of a formal birth certificate. In 2016, another Indian woman, Daljinder Kaur, delivered a boy at the age of 72 (1). According to literature, an egg donation pregnancy resulted in multiple gestations at age 50. Immediately following delivery, hypertension was observed with nausea and vomiting. A few hours later, the case was diagnosed with HELLP syndrome and died of cerebral hemorrhage .In fact, these grandparents, who are now parents of children, are unable to supply the psychological, economic, and physical demands of these children and maintain long-term parenting relationships. In addition, in most cases reported these children lost one or both parents before they reached adolescence which is the most stressful event of life that is beyond the endurance of children and adolescents. In addition, another problem with these pregnancies is the advanced paternal age, which is associated with increased birth anomalies and congenital disabilities due to genetic defects, as well as an increased risk of autism and schizophrenia .Therefore, egg and embryo donations should be discouraged for older women who are also suffering from medical problems by providing extensive counseling that these risks are exacerbated by pregnancy and childbirth. Since the large numbers of medical problems are pregnancy-related, especially following multiple pregnancies, elective single embryo transfer (eSET) should be an unchanging rule for all ART services for pregnancy at advanced age.The menopausal practitioner and obstetricians should provide more realistic insights about the evidence-based facts of maternal, fetal and neonate risks in pregnancy at advanced age. Clinicians should also advise the couples that you are at risk of not having a baby whenever you decide to delay your pregnancy and childbirth.There is no comprehensive guideline for maternal health of over aged candidates for pregnancy, although the American Society for Reproductive Medicine (ASRM) has stated that healthy women over 50 who have conceived through egg donation are at high gestational risks. Therefore, it is recommended that over aged women be prohibited from receiving this service .Although we recognize the obvious complications of pregnancy and childbirth of very old mothers as well as some of complications in their infants, we have no knowledge or prognosis of the long-term health consequences of these children at adulthood and geriatric era.Finally, in the creation of universe, the restriction of women’s reproductive period provided wisdom and rational reasons, but we have come to the war of nature with the tools of science and technology. However, we must consider the fact that in similar cases, such as damaging the nature and environment ecology, we have witnessed the consequences of such activities for a long time which make us to contemplate and regret for all previous deed. Thus we need to respect the rules of nature and limit our challenges.


The link between Zika virus infection during pregnancy and microcephaly and other neurodevelopmental defects in infants, referred to as congenital Zika syndrome (CZS), was recently discovered. One key question that remains is whether such neurodevelopmental abnormalities are limited to the recently evolved Asiatic ZIKV strains or if they can also be induced by endemic African strains. Thus, we examined birth registries from one particular hospital from a country in West Africa, where ZIKV is endemic. Results showed a seasonal pattern of birth defects that is consistent with potential CZS, which corresponds to a range of presumed maternal infection that encompasses both the peak of the warm, rainy season as well as the months immediately following it, when mosquito activity is likely high. While we refrain from definitively linking ZIKV infection and birth defects in West Africa at this time, in part due to scant data available from the region, we hope that this report will initiate broader surveillance efforts that may help shed light onto mechanisms underlying CZS. The overall risk of Zika-linked birth defects has been estimated at ~10% and 15% for infections during the 1st trimester10, potentially impacting thousands of infants in the US and US territories alone. Concerns exist that ZIKV-related outcomes are underreported, particularly when ZIKV infections result in neurodevelopmental abnormalities without visible microcephaly . Such outcomes are likely not recorded, particularly if the causative infection was asymptomatic14. Further, a recent CDC report that examined birth defect records from 15 US jurisdictions showed a statistically significant increase in prevalence of birth defects potentially consistent with CZS in areas with documented local ZIKV transmission in the second half of 201615. Notably, the majority of infants and fetuses with birth defects potentially related to ZIKV infection in this report lacked ZIKV infection testing, which may be in part attributed to lack of known maternal exposure or other such indicators16. Nonetheless, these findings are alarming and underscore not only the need for continued monitoring and surveillance, but also the need to better understand the full extent – as well as mechanisms – of neurodevelopmental defects associated with CZS.Since 2015, when an initial link between Zika Virus (ZIKV) and microcephaly was discovered in Brazil17. One key question is whether ZIKV-mediated birth defects are associated with a specific strain of ZIKV, which, for example, could have evolved after ZIKV migrated from South East Asia to French Polynesia and Brazil18 and now spread to North America, including the US15. However, other studies suggest that African strains are likely to be as pathogenic as the Asiatic strains ). Despite this, there exists negligible data regarding CZS across the African Continent; nevertheless, lack of evidence should not be taken as definitive proof of absence19. Thus, here we examine birth registries from one particular hospital in West Africa from a country considered by the WHO to be at medium risk of a ZIKV outbreak29. The study was approved by the Committee on Administration of the hospital where the data was collected in lieu of a functioning Ethics Committee. But as there are ongoing security concerns in this location, that committee required that the hospital name and location be kept anonymous to ensure the safety of the hospital and staff. The chosen hospital has a full service maternity/OB department, staffed by well-trained qualified obstetricians, midwives, and obstetric nurses. It handled about 2000 births per year during the studied period; reports compiled from the hospital data are routinely used by the country’s government.Earlier studies from the African Continent – where ZIKV is endemic – have documented a relatively high prevalence of ZIKV antibodies in human populations, including in West Africa 33 and Kenya (East Africa)34, where Rift Valley Fever epizootics were associated with heavy rainfalls. Our hypothesis was further informed by the temporal relationships between the number of ZIKV infections and microcephaly cases reported in Brazil35. We expected that the peak of CZS-type birth defects  would coincide with vertical ZIKV transmission at around 12-weeks post-conception during the peak of the rainy season, assuming an approximate 3-week lag between maternal infection and vertical transmission36, as suggested by data from Brazil in 201537.Risk of major neurodevelopmental defects, such as microcephaly, appears to be particularly high if vertical transmission occurs during the first trimester, especially within a “vulnerability window” around 12 weeks (10 to 14 weeks) post-conception4  from a non-governmental hospital in West Africa were examined to determine whether we could identify a seasonal pattern of birth defects potentially attributable to ZIKV infection . The number of births and respective outcomes  and reported complications  were collated by month/year. Reporting standards for birth complications varied between years; thus, we focused exclusively on visible neurodevelopmental complications  and pregnancy losses (such as stillbirth) that could be attributed to potential CZS4 . To infeWe also considered national average monthly temperature and rainfall data for the study years, collected from the World Bank Climate Change Knowledge Portal database. These values were treated as proxy indicators for mosquito activity in the hospital catchment area at time of maternal infection. To visualize any relevant trends, we plotted these data, as well as the average percentage of birth defects consistent with potential CZS by month.As shown in38.With this in mind, the early months of the cool, dry season (October–December) are likely hospitable enough for mosquito vectors to thrive and spread pathogens, including ZIKV; this may explain why the range of our presumed maternal month of infection (August–December) extends past the rainy season, given that mosquitoes require a balanced environment for survival, including both moderate rainfall and optimal temperatures35), our findings stop short of definitively linking ZIKV infection and birth defects in the study region, in part due to scant data. Instead, by reviewing the potential limitations of the data analyzed here, we hope that this report will initiate broader surveillance efforts – of both the infectious agents, including ZIKV, as well as that of birth defects - that may help shed light onto mechanisms that underlie CZS, including utilization of data that might already be available across various African countries where ZIKV is endemic and/or competent vectors exist . For example, a recent WHO Bulletin on Outbreaks and Other Emergencies41 reported a number of microcephaly cases from Angola (a country listed in the High risk category29) that appear to be linked to ZIKV infection, despite the lack of direct PCR confirmation from the specimens. Due to only recent implementation of active surveillance in the country, the true magnitude of the event is not yet clearly understood. Nonetheless, it is important for insights into a broader pattern of potential CZS defects, despite the lack of experimental ZIKV infection confirmation or lack of evidence of ongoing active ZIKV transmission in Angola (i.e. only two ZIKV cases were reported from Angola in early 201742).Our results suggest that a seasonal pattern exists with respect to CZS-type birth defects reported in the study region , where t44, often due to inability to pay for testing  as a CZS-type birth defect, would likely lead to underestimation of potential trends, if any. We also assumed that the available birth records were representative of the pregnancy/birth patterns that occur across the entire region. Other limitations of the available data are related to the standard of care that is feasible in much of West Africa, including (i) lack of family history and/or genetic testing for mutations in loci responsible for primary microcephaly; (ii) lack of laboratory evidence or testing for ZIKV and/or other infections, including TORCH agentsng e.g.,; and .10.6084/m9.figshare.5387029. Data are available under the terms of theCreative Commons Attribution 4.0 International license (CC-BY 4.0).Figshare : Data for The authors have addressed my concerns adequately.I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The  authors addressed all my concerns, and have no further comments.I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The authors present an analysis of birth defects by season from a single hospital in an unnamed West African country relative to a purported mosquito season. Their conclusion is that the seasonality of certain types of birth defects, consistent with CZS, could be explain by Zika virus transmission in the area. This is an interesting attempt to use available data to speculate about the impact of Zika virus on congenital defects in an endemic area. Although this is certainly thought-provoking and supports the authors recommendation to improve surveillance for Zika virus in endemic areas, there is insufficient discussion of all of the limitations to this particular analysis which, if included, would cast doubt on their proposed conclusion. The limitation that the data are from a single hospital in an un-named location make it impossible to make any generalizable conclusions  and to understand any limitations completely. Data do not exist on the underlying sero-prevalence of Zika virus infection in this population (I assume). However, given that Zika virus infection likely results in lifelong immunity, one might not expect to see any change in CZS-like defects simply due to a low number of susceptible pregnant women. Were the women with infants with birth defects generally younger and therefore less likely to have been previously infected? And why wouldn't we expect children to have a high rate of infection resulting in immunity as they reach child-bearing age? Again, although difficult to determine given the lack of geographic specificity provided, there is minimal discussion in the paper of other potential causes of microcephaly; most notably rubella and malnutrition. Although rubella-related birth defects might not be expected to show any seasonality, malnutrition might. As might toxoplasmosis. The time period covered by this report encompasses both the Ebola outbreak and significant Yellow fever activity; both of these could cause confounding in the data. Mosquito species are quite variable in their feeding habits, optimal climactic conditions and in their vectorial capacity. Relying on patterns of malarial disease to represent what is likely to happen with a flavivirus like Zika which is transmitted by different species of mosquitoes should be considered to be a limitation. What about using Yellow fever or dengue disease patterns? Lastly, while I understand the argument the authors are making, I found the assertion that the maternal infection period of August through October encompassed the peak and latter half of the warm, rainy season confusing. Based on the presented data, August through October had minimal rain and lower than average temperatures. October through December was described as the cool, dry season although temperatures peak for the year in November through January (according to the data presented by the authors).I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. >>>The limitation that the data are from a single hospital in an un-named location make it impossible to make any generalizable conclusions and to understand any limitations completely.We appreciate these limitations, and they were requirements for us to access the data. Specifically, the Committee on Administration of the hospital required us not to name the hospital or the country. We added a statement clarifying this. Our goal was to spur further discussion and further research from larger sample sizes in multiple locations in order to access the generality of this pattern.>>> Data do not exist on the underlying sero-prevalence of Zika virus infection in this population (I assume). However, given that Zika virus infection likely results in lifelong immunity, one might not expect to see any change in CZS-like defects simply due to a low number of susceptible pregnant women. Were the women with infants with birth defects generally younger and therefore less likely to have been previously infected? And why wouldn't we expect children to have a high rate of infection resulting in immunity as they reach child-bearing age?It is still unclear whether in humans (versus non-human primates) Zika infection confers life-long immunity . However, age distribution of mothers of infants with CZS-like birth defects indicates that such birth defects appear across multiple age cohorts, from 15 to 37, with the mean number of CZS-like cases per each age group of 2.39 (± standard error of 0.42). Further research of larger cohorts across different locations is needed to definitively test whether there are any maternal-age related effects.>>> Again, although difficult to determine given the lack of geographic specificity provided, there is minimal discussion in the paper of other potential causes of microcephaly; most notably rubella and malnutrition. Although rubella-related birth defects might not be expected to show any seasonality, malnutrition might. As might toxoplasmosis. The time period covered by this report encompasses both the Ebola outbreak and significant Yellow fever activity; both of these could cause confounding in the data.We agree that there are many human health issues that could display seasonality. This underscores the need for widespread comprehensive test for infectious agents and prenatal care, although implementation of such tests in Africa will require significant investments to be feasible.>>> Mosquito species are quite variable in their feeding habits, optimal climactic conditions and in their vectorial capacity. Relying on patterns of malarial disease to represent what is likely to happen with a flavivirus like Zika which is transmitted by different species of mosquitoes should be considered to be a limitation. What about using Yellow fever or dengue disease patterns?In our inferences we did not rely on the malaria pattern to infer seasonality; instead, it was referenced to indicate consistency in the inferred activities from the temperature and rainfall data. Regretfully, no data regarding yellow fever or dengue infections were available. However, the temperature ranges of the peak transmission of malaria and dengue are overlapping . Therefore, we expect that the transmission patterns would be similar.PLoS One8(11): e79276.Beck-Johnson, L. M., et al. (2013). "The effect of temperature on Anopheles mosquito population dynamics and the potential for malaria transmission."PLoS Negl Trop Dis11(4): e0005568.Mordecai, E. A., et al. (2017). "Detecting the impact of temperature on transmission of Zika, dengue, and chikungunya using mechanistic models.">>> Lastly, while I understand the argument the authors are making, I found the assertion that the maternal infection period of August through October encompassed the peak and latter half of the warm, rainy season confusing. Based on the presented data, August through October had minimal rain and lower than average temperatures. October through December was described as the cool, dry season although temperatures peak for the year in November through January (according to the data presented by the authors).We revised the figure 1 legend to make it clear that the bottom axis corresponds with the birth month (depicted with yellow bars) and therefore with the left Y axis that shows % CZS-type birth defects, while the top axis corresponds with the month of maternal infection .  We have also added color guides to the figure to make it visually clear. 1The following important reference is missing from the article, please include: Rasmussen et al. (2016)Authors should mention that Zika migrated not only to Brazil but to the Americas.What are the characteristics of the chosen hospital? Why only one hospital was chosen? Does the hospital has a good reliable birth defect registry?There is no description of the birth defects taken into account for the paper; which CZS-type birth defects were chosen form the hospital registry? Were the birth defects confirmed? Was any description available in medical records? Were X-rays available for review? I agree with the authors on the importance to have birth defects surveillance systems in place. I hope that this article will contribute to the awareness of public health authorities regarding this important issue. Birth defects surveillance is needed to identify Zika related defects. As the authors mention, the majority of infected pregnant women are asymptomatic.I think it will be important to differentiate in the article between Zika virus surveillance and birth defects surveillance, and the difficulties of implementing them in Africa.Thank you for the opportunity to review this article. I have the following questions/suggestions for the consideration of the authors:I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. >>> 1.  The following important reference is missing from the article, please include: Rasmussen et al. (2016)Thank you for pointing out our oversight. We added this important reference to the paper.>>>> 2. Authors should mention that Zika migrated not only to Brazil but to the Americas.Done.  >>>> 3. What are the characteristics of the chosen hospital? Why only one hospital was chosen? Does the hospital has a good reliable birth defect registry?Additional identifiable characteristics were not included in order to protect the identity of the hospital; however, we now added several broad characteristics of the hospital to the manuscript.These were the only data that were available to us, and we are confident in the quality of the birth defect registry. We are excited that we were able to demonstrate this trend even with the relatively small sample available to us. We hope this study will spur further comprehensive analyses of larger datasets.>>> 4.  There is no description of the birth defects taken into account for the paper; which CZS-type birth defects were chosen form the hospital registry? Were the birth defects confirmed? Was any description available in medical records? Were X-rays available for review?The description of birth complications that we categorize as a CZS-type  are listed in the Supplementary table 1, while Supplementary table 2 lists the non-CZS-type complications. We did not have access to individuals' medical records beyond the descriptions listed in Supplementary tables. The hospital does not routinely perform X-rays on newborns with birth defects; thus, no further description of cases or X-rays were available to us.>>> 5. I agree with the authors on the importance to have birth defects surveillance systems in place. I hope that this article will contribute to the awareness of public health authorities regarding this important issue.6. Birth defects surveillance is needed to identify Zika related defects. As the authors mention, the majority of infected pregnant women are asymptomatic.Thank you, we completely agree.>>> 7.  I think it will be important to differentiate in the article between Zika virus surveillance and birth defects surveillance, and the difficulties of implementing them in Africa.We agree, and have added statements to that effect. Enhanced birth defect surveillance within hospitals are potentially feasible with the current resources, although they may require additional personnel and/or training. However, the surveillance of birth defects outside of hospital settings would be problematic, though potentially possible. On the other hand, Zika virus surveillance per se, as well as surveillance of other viral diseases, would require substantial financial investments globally, as well as overcoming other challenges related to the implementation of such surveillance. I understand the need for security and thus not naming the hospital but would naming the country truly jeopardize security?While I agree that it is possible that African ZIKV has always had the capability of causing CZS and that it is likely underreported or unrecognized, an alternative explanation is that in Africa where ZIKV is endemic girls and women are exposed early in life and subsequent immunity provides protection against CZS during child bearing years. Is there any age distribution that can be associated with the outcomes presented here?Throughout comparisons are made to Malaria which is transmitted by Anopheles mosquitoes, whereas, ZIKV is likely transmitted by an Aedes species mosquito. Therefore, the same environmental factors may not drive transmission of both equally. Do the authors have any data on, for example, dengue cases that were reported at the same hospital during the study period? The data are from a country that is at "medium risk for a Zika outbreak". I believe it is more important to know what the estimated seroprevalence of Zika exposure is in this country. This suggests that perhaps Zika is not endemic in the country.The authors have produced a paper speculating that African lineage Zika virus has the same capacity to cause congenital Zika syndrome (CZS) as more recent Asian/American outbreak isolates. This was accomplished by analyzing birth outcome reports from one hospital in West Africa and temporally linking outcomes consistent with CZS to seasonal patterns when mosquito populations would be abundant. The paper is well written and certainly addresses an outstanding question in the field. In sum, this article's major purpose is to create a discussion and provide a rationale for broader Zika surveillance activities in Africa, which I I believe has been accomplished, however, there are a few minor details that could be changed to facilitate understanding by the reader.I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. >>> 1. I understand the need for security and thus not naming the hospital but would naming the country truly jeopardize security?We agree with you in principle; however, the Committee on Administration of the hospital required us not to name the hospital or the country. We added a statement clarifying this.  >>> 2. While I agree that it is possible that African ZIKV has always had the capability of causing CZS and that it is likely underreported or unrecognized, an alternative explanation is that in Africa where ZIKV is endemic girls and women are exposed early in life and subsequent immunity provides protection against CZS during child bearing years. Is there any age distribution that can be associated with the outcomes presented here?We agree with the reviewer that the question of whether early exposure to ZIKV and/or other flaviviruses may offer subsequent long-term protection against CZS during childbearing years warrants further attention. CZS-type defects analyzed in our study were found in women of ages 15-37 years old; the average number of cases per maternal age class is 2.39 (± standard error of 0.42). Thus, these data are not well suited to test this hypothesis, which we hope can be tested in the future with appropriate power.  >>> 3. Throughout comparisons are made to Malaria which is transmitted by Anopheles mosquitoes, whereas, ZIKV is likely transmitted by an Aedes species mosquito. Therefore, the same environmental factors may not drive transmission of both equally. Do the authors have any data on, for example, dengue cases that were reported at the same hospital during the study period?There are no data on dengue cases available from the hospital. However, the temperature ranges of the peak transmission of malaria and dengue are overlapping . Therefore, we expect that the transmission patterns would be similar.Beck-Johnson, L. M., et al. (2013). "The effect of temperature on Anopheles mosquito population dynamics and the potential for malaria transmission." PLoS One 8(11): e79276.Mordecai, E. A., et al. (2017). "Detecting the impact of temperature on transmission of Zika, dengue, and chikungunya using mechanistic models." PLoS Negl Trop Dis 11(4): e0005568.>>> 4. The data are from a country that is at "medium risk for a Zika outbreak". I believe it is more important to know what the estimated seroprevalence of Zika exposure is in this country. This suggests that perhaps Zika is not endemic in the country.Unfortunately, there are relatively scant data available from the region, most of which comes from the decades-old studies. Specifically, antibodies to ZIKV were found in human blood samples collected in 1960-ies in Senegal, Burkina Faso, Cote D'Ivoire, Guinea-Bissau, Cameroon, Mali, Niger, Benin, Gabon (Brès 1970), in Senegal  and Nigeria (Adekolu-John and Fagbami 1983) in 1970-ies and 1980-ies, supporting the premise that ZIKV is present across multiple countries in West Africa region ). We hope that this study will motivate the collection of such data in the future. We added these references to the manuscript, to the "Can we expect to find cases of congenital Zika syndrome in the African Continent?" section.Trans R Soc Trop Med Hyg77(2): 149-151.Adekolu-John, E. O. and A. H. Fagbami (1983). "Arthropod-borne virus antibodies in sera of residents of Kainji Lake Basin, Nigeria 1980."Bulletin of the World Health Organization43(2): 223-267.Brès, P. (1970). "Données récentes apportées par les enquêtes sérologiques sur la prévalence des arbovirus en Afrique, avec référence spéciale à la fièvre jaune ."Bull World Health Organ171082.Kindhauser, M. K., et al. (2016). "Zika: the origin and spread of a mosquito-borne virus."Bull Soc Pathol Exot Filiales71(2): 131-140.Renaudet, J., et al. (1978). "[A serological survey of arboviruses in the human population of Senegal]."


To determine whether moderate neonatal hypoglycemia in otherwise healthy infants is associated with adverse neurodevelopmental outcome in pre-school children. Population-based cohort study with prospectively collected register data from Sweden. All singletons born July 1st 2008 through December 31st 2012  in the region were included. Infants with congenital malformations, infants treated in neonatal intensive care unit, infants with inborn errors of metabolism and infants to mothers with diabetes were excluded. Infants were followed-up until 2014, at 2–6 years of age. Exposure was neonatal moderate hypoglycemia. Main outcomes were a compiled neurological or neurodevelopmental outcome; any developmental delay; motor developmental delay; and cognitive developmental delay. In adjusted regression analyses, the odds ratio (OR) of any neurological or neurodevelopmental outcome was 1.48  in hypoglycemic compared to normoglycemic infants. The adjusted risk of any developmental delay was more than doubled (OR 2.53 [1.71–3.73]), the adjusted risk of motor developmental delay was almost doubled (OR: 1.91 [1.06–3.44]) and the adjusted risk of cognitive developmental delay was almost tripled (OR 2.85 [1.70–4.76]). Infants with early neonatal hypoglycemia (< 6 h) had a double risk (OR 1.94 [1.30–2.89]) of any neurological or neurodevelopmental outcome and a tripled risk of cognitive developmental delay (OR 3.17 [1.35–7.43]), compared to normoglycemic infants. In the first population-based study on this topic, we show that moderate neonatal hypoglycemia is associated with increased risks of impaired neurodevelopment. Current treatment routines for uncomplicated hypoglycemia should be followed. Hypoglycemic episodes requiring treatment during the first days of life are common 5–15%) [5% [1]. WThe general assumption is that asymptomatic infants with transient hypoglycemia are at very low risk of neurologic complications , 10 and There is a lack of studies of healthy, term and near-term infants with moderate hypoglycemia, without need for intravenous glucose fluids or admission to the neonatal intensive care unit , 15. We We performed a population-based cohort study with prospectively collected data. Information on mother, pregnancy, delivery and infant was obtained from computerized antenatal, obstetrical and neonatal electronic medical records including births in the counties of Stockholm and Gotland, Sweden (the Stockholm-Gotland Obstetric Cohort ). WithinVia the individual Swedish National Registration Number assigned to each Swedish resident at birth or immigration , data frThe study was approved by the regional ethics board in Stockholm, Sweden (2009/275-31 and 2012/365-32). Patient information was retrieved from a computerized medical record system and national health registries and there was no informed consent prior to inclusion in the study.From July 1st 2008 through December 31st 2012, 112 256 singleton infants  were born in the Stockholm-Gotland county. The purpose of this study was to examine otherwise healthy infants and therefore, all infants admitted to a neonatal care unit (n = 9 852) were excluded before analyses. We then excluded infants (n = 170) who received one or more of the following ICD-10 diagnoses of inborn errors of metabolism before end of follow-up: E03; E25; E53.8; E70; E71; E72; E74; E75; E76; E77; E78; and E79. Information on maternal pre-gestational diabetes was collected at the first attendance to antenatal care, generally at 8–12 gestational weeks. Gestational diabetes was screened for by blood glucose test at the antenatal booking and at gestational weeks 25, 29, 32/33 and 37/38, respectively. Infants whose mothers had pre-gestational (n = 484) or gestational diabetes (n = 690) were then excluded because maternal diabetes was considered a possible mediator on the association between neonatal hypoglycemia and neurological outcome. After these operations, 101 060 infants were included in the study cohort.Exposure was defined as having a diagnosis of transitory neonatal hypoglycemia  at discharge from the postnatal ward. Blood glucose was measured by bed-side analyses. The unexposed group consisted of all other infants discharged from the postnatal ward. Exposure was categorized into hypoglycemia within the first 6 h after birth (ICD-10: P70.4A); hypoglycemia after the first 6 h after birth (ICD-10: P70.4B); and any neonatal hypoglycemia . Iatrogenic neonatal hypoglycemia (ICD-10: P70.3) was not included in the exposure group. Among included high-risk infants , extra feeding was initiated within 1 h after birth and blood glucose was routinely measured just before the newborn’s second meal or before 4 h of age. Blood glucose was then followed-up until there were two consecutive normal values over 47 mg/dL and additional feedings provided when necessary. In low-risk infants, blood glucose was measured only if symptoms of hypoglycemia were present. Infants in need of intravenous glucose infusions were admitted to a neonatal care unit and thereby excluded from the study cohort.All infants were followed-up until end of 2014, by the time they were 2–6 years of age. Outcome was defined by pre-specified neurologic and developmental diagnoses in the Swedish National Patient Registry or the Swedish Cause of Death Registry. Main outcome was defined as one or more of the pre-specified diagnoses. Secondary outcome was defined as any developmental delay; motor developmental delay; cognitive developmental delay; autism spectrum disorders and attention-deficit/hyperactivity syndromes; tics and stereotypic disorders; and/or epilepsy or febrile seizures. Detailed definitions with ICD-10 codes of the main and secondary outcomes are presented in Table BMI was calculated as weight in kilograms (measured by a midwife) divided by the square of body height (self-reported) in square meters. Mode of delivery was recorded in standardized delivery records. Gestational age, birth weight and Apgar scores were registered in the neonatal record. In 94.3% of pregnancies, gestational age was based on ultrasound examination, offered to all women in early second trimester. If data on ultrasound was not available, last menstrual period was used for pregnancy dating. Information on maternal body-mass index (BMI) and parity were collected at the first attendance to antenatal care. Self-reported data on smoking was collected at 32 gestational weeks. Birth weight by gestational age was calculated using the sex-specific Swedish reference curve for normal fetal growth . ApproprP value < 0.05 was considered statistically significant. For statistical analyses, SAS version 9.4 was used.Mode of delivery, gestational age, birth weight for gestational age, infant sex, Apgar score and birth year were a priori considered possible confounders or mediators and were considered by stratification, restriction and/or adjustment in the multivariable analyses. Early pregnancy BMI, parity and smoking in gestational week 32 did not affect the relationship between neonatal hypoglycemia and neurological or neurodevelopmental outcome, and thus, these variables were not included in the final regression models. A logistic regression model was used to determine crude odds ratios and 95% confidence intervals. Analyses started with the main outcome and then secondary outcomes were evaluated one by one. Co-variates were first tested separately and, if contributing to the association between exposure and outcome, they were added into a stepwise multivariable regression model. Parity, mode of delivery, gestational age and Apgar score were a priori considered possible effect modifiers on the association between neonatal hypoglycemia and subsequent neurodevelopmental outcome. Effect modification was tested by stratification and insertion of an interaction variable in the regression models. A In the study population, 1 500 infants (1.5%) had a hypoglycemia diagnosis at discharge from the postnatal ward. Risk factors associated with a high proportion ≥ 2.0%) of hypoglycemia diagnosis were: being a first-born, maternal BMI ≥ 30, maternal smoking, elective Cesarean delivery, emergency Cesarean delivery, preterm birth < 37 gestational weeks, term birth at 37–38 weeks (as compared to term birth at 39–40 weeks), SGA, LGA, and Apgar score less than 7 at 5 min  and 1 013 had the diagnosis P704.B . The remainder of hypoglycemic infants (n = 104) were not specified according to timing and these infants were excluded from analyses stratified by timing of hypoglycemia. Infants with early neonatal hypoglycemia had a 2-5 fold increased risk of affected neurodevelopment compared to normoglycemic infants in crude analyses. After adjustments, the specified risks of any neurological or neurodevelopmental outcome, any developmental delay and cognitive developmental delay were doubled to tripled. Infants with neonatal hypoglycemia after 6 h of age had a more than doubled to tripled risk of any developmental delay, motor developmental delay and cognitive developmental delay compared to their normoglycemic peers. In adjusted analyses, the risk of any developmental delay was more than doubled and the risk of cognitive developmental delay was more than doubled  infants were SGA, and 10 688 (10.6%) infants were LGA. Crude risks of any neurological or neurodevelopmental outcome among hypoglycemic infants by birth weight percentiles are shown in Table We did not detect any effect modification from parity, mode of delivery, gestational age, or 5-min Apgar score on the association between neonatal hypoglycemia and neurological diagnoses at follow-up.In this population-based cohort study including 101 060 infants followed-up until 2-6 years of age, moderate neonatal hypoglycemia was associated to increased risks of later neurological diagnoses. More specifically, the risks were increased for developmental delay and risk estimates were robust through multivariable analyses adjusting for confounding factors.In publications from the New Zealand CHYLD cohort, high-risk infants  were extensively followed-up at 2 n = 404) and 4.5 years n = 477) 7 7, 11]11]. At 204 and 4.11]. At 2Our results on birth weight for gestational age percentiles were unexpected. The rates of the compiled neurological or neurodevelopmental outcome were of a similar magnitude in SGA and AGA infants, whereas risks of developmental delay were increased in AGA but not in SGA infants. This may be due to chance or insufficient power. It may also be a variant of the Low Birth Weight Paradox, as suggested by Wilcox , where lIn our cohort, we were able to analyze 1500 otherwise healthy cases of moderate neonatal hypoglycemia and to compare them with 99,560 healthy reference infants. This is the largest study on moderate neonatal hypoglycemia so far. The Stockholm-Gotland cohort has provided us with population-based , high-quThere are several limitations to our study; the first is that we have used discharge diagnoses as the exposure. Diagnosis status is a blunt instrument and there may be missed cases of moderate hypoglycemia where the diagnosis was not entered by the doctor at discharge. There may also be an unknown number of infants who were in fact hypoglycemic but went undetected. However, exposure misclassification is not associated with how the outcome was measured, suggesting non-differential misclassification. This bias would thus dilute the effects and not exaggerate them. Second, we did not have data on blood glucose levels. We were able to exclude all infants treated in the neonatal intensive care unit. These were infants with very low blood glucose levels (< 27 mg/dL), with prolonged hypoglycemia or where oral treatment failed. This exclusion provided a study population of otherwise healthy newborns who were at low risk of complications. The exclusions of severe hypoglycemia and infants of mothers with diabetes also resulted in a low percentage of hypoglycemia in the cohort . Nevertheless, results should be generalizable to most newborn infants of non-diabetic mothers that we see and treat in the clinical setting. Third, we had a follow-up of two to 6 years of age, which is enough only to detect major adverse neurodevelopmental outcomes. Infants and toddlers in Sweden are routinely screened with standardized developmental tests by a trained pediatric nurse at 2; 4; 6; 8; 10; 12; and 18 months of age and at 3, 4 and 5 years of age. Concern for a delayed development will lead to a referral to a pediatrician or a pediatric neurologist. Almost all Swedish children participate in the screening programme. Due to the large study population, it was not possible to measure neurodevelopment in all included children. Children who develop problems later in life than 2–6 years of age, will be misclassified as healthy in this study. This situation is similar for both the exposed and unexposed group. It would be interesting to see the results of a longer follow-up, perhaps with more detailed data on cognitive development and capacity. Fourth, our study has an observational design that cannot prove a causal relationship between moderate neonatal hypoglycemia and adverse neurodevelopment, and reversed causality cannot be completely ruled out. Fifth, we did not have data on heredity or the occurrence of neuropsychiatric, neurological or neurodevelopmental diagnoses in the parents. For these factors to act as confounders, they would have to be associated to both the exposure and the outcome. This may be the case in some instances, thus introducing a differential misclassification, which in most cases would exaggerate the risk. We do not believe that this is sufficiently common to affect our results to any significant degree. We also lacked data on other socio-economic factors than maternal BMI and smoking habits, which were found to have no influence on the study results. Parent education, housing status and income may have confounder status. Due to lack of data on these variables in the study, we used maternal smoking and BMI as proxys for other life-style factors, but there may still be some residual confounding. Sixth, our outcomes and co-variates were pre-defined based on previous studies and clinical experience. However, we did not perform any statistical test to rule out multiple test errors and there is, as always, a potential for chance findings in our results especially among the smaller groups of specific neurological outcomes and some caution should be taken when interpreting those results. Even though the risk for adverse neurodevelopmental outcome is clearly higher in the hypoglycemic group, the absolute risk of having any neurological or neurodevelopmental outcome is still relatively small (prevalence of 5.1% in the moderately hypoglycemic group versus 3.3% in the normoglycemic group. Nevertheless, the finding of relatively high and consistent risk measures, lack of the above mentioned biases and the support from previous studies imply that part of the association may be causal.Our study contributes to the dispute on moderate neonatal hypoglycemia and the possibility of adverse long-term outcome, by providing a large population-based study of low-risk infants who showed increased risks of neurological and neurodevelopmental outcomes. Our results support the current treatment practice of blood glucose sampling as an immediate action in symptomatic infants, also in low-risk infants, as well as the routines of extra oral feeding in infants with moderate hypoglycemia and preventive feedings to high-risk infants. Contrary to general belief, we found a significantly elevated risk of developmental delay in infants with moderate neonatal hypoglycemia starting before 6 h of age. In this time span, a decrease of blood glucose is considered to be physiologic. Our findings indicate that hypoglycemia during the first 6 h of age may be associated to a negative impact on the newborn brain and that treatment could be equally important in this early phase.We conclude that moderate neonatal hypoglycemia is associated with increased risks of impaired neurodevelopment in pre-school children. Our data do not support the notion that moderate neonatal hypoglycemia is a harmless physiologic state, or that early hypoglycemia is less damaging than later onset hypoglycemia. Clinical guidelines with screening of symptomatic and high-risk infants should be followed and immediate treatment of hypoglycemia should be provided.


Previously we found that certain fetal imprinted genes represented as an allele score are associated with maternal pregnancy glucose concentrations. Recently it was reported that fetal polymorphisms with strong associations with birth weight tend to mediate these independently of increases in maternal pregnancy glucose concentrations. We therefore investigated whether potential associations between the fetal allele score and birth weight were related to maternal glucose concentrations in the Cambridge Baby Growth Study.−3, n = 405). This association was partially attenuated by adjusting for maternal glucose concentrations (β = 50 (4–95) g/risk allele, β′ = 0.089, p = 0.03, n = 405). The allele score was also positively associated with risk of being large for gestational age at birth (odds ratio 1.60 (1.19–2.15) per risk allele, p = 2.1 × 10−3, n = 660) and negatively associated with risk of being small for gestational age at birth (odds ratio 0.65 (0.44–0.96) per risk allele, p = 0.03, n = 660). The large for gestational age at birth association was also partially attenuated by maternal glucose concentrations. These results suggest that associations between the fetal imprinted gene allele score and size at birth are mediated through both glucose-dependent and glucose-independent mechanisms.The fetal imprinted gene allele score was positively associated with birth weight (β = 63 (17–109) g/risk allele, β′ = 0.113, p = 7.6 × 10 Fetal exposure to glucose is thought to be one of the principal stimulators of growth in utero –3. It isGenetics can have roles in regulating both maternal glucose concentrations in pregnancy and fetal growth expressed as offspring birth weight. We recently reported associations between fetal imprinted genes represented as an allele score and both gestational diabetes and maternal glucose concentrations in late pregnancy . In a biThe first phase of the prospective, longitudinal Cambridge Baby Growth Study recruited mothers (and their partners and offspring) attending early pregnancy ultrasound clinics at the Rosie Maternity Hospital, Cambridge, UK between the years 2001–2009 , 10. At 2 test) and had a repeat genotyping discordancy rate of < 1.0%. The unweighted fetal allele score was formulated as previously described   1.60 1.19–2.15) per risk allele, p = 2.1 × 10.15 per rIn this study the fetal imprinted gene allele score that we had previously shown to be associated with both maternal glucose concentrations and gestational diabetes risk , was addINS-IGF2 rs10770125 and rs2585, and maternally-transmitted KCNQ1 rs231841 and rs7929804 [The main strengths of this study are its prospective nature and the use of a novel fetal imprinted gene allele score that we found to be robustly associated with maternal glucose concentrations, even to genome wide significance levels by meta-analysis of three different birth cohorts . Its cons7929804 , 10), arThe study has a modest (and variable) sample size which restricted its statistical power.The lack of validation of the associations in additional cohorts.The lack of adjustment of the p-values for multiple testing.