Prevalence of hemolytic neonatal hyperbilirubinemia (NHB) is not well characterized, and economic burden at the population level is poorly understood. This study evaluated the prevalence, clinical characteristics, and economic burden of hemolytic NHB newborns receiving treatment in U.S. real-world settings.This cohort study used administrative claims from 01/01/2011 to 08/31/2017. The treated cohort had hemolytic NHB diagnosis and received phototherapy, intravenous immunoglobulin, and/or exchange transfusions. They were matched with non-NHB newborns who had neither NHB nor related treatments on the following: delivery hospital/area, gender, delivery route, estimated gestational age (GA), health plan eligibility, and closest date of birth within 5 years. Inferential statistics were reported.p = 0.003), vacuum extractor affecting newborn , and polycythemia neonatorum  than the matched non-NHB cohort. The treated hemolytic NHB cohort also had significantly longer mean birth hospital stays , higher level 2–4 neonatal intensive care admissions  and higher 30-day readmission .The annual NHB prevalence was 29.6 to 31.7%; hemolytic NHB, 1.8 to 2.4%; treated hemolytic NHB, 0.46 to 0.55%, between 2011 and 2016. The matched analysis included 1373 pairs ≥35 weeks GA. The treated hemolytic NHB cohort had significantly more birth trauma and hemorrhage  and $21,556 vs. $12,986 (p < 0.001), respectively. The average costs for 30-day readmission among newborns who readmitted were $13,593 for the treated hemolytic NHB cohort and $3638 for the matched non-NHB cohort, p < 0.001. The authors extrapolated GA-adjusted prevalence of treated hemolytic NHB in the U.S. newborn population ≥ 35 weeks GA and estimated an incremental healthcare expenditure of $177.0 million during the first month after birth in 2016.One-month and one-year average total costs of care were significantly higher for the treated hemolytic NHB cohort vs. the matched non-NHB cohort, $14,405 vs. $5527 (The prevalence of treated hemolytic NHB was 4.6–5.5 patients per 1000 newborns. This high-risk hemolytic NHB imposed substantial burdens of healthcare resource utilization and incremental costs on newborns, their caregivers, and the healthcare system. Neonatal hyperbilirubinemia (NHB), a common condition in newborn infants, results from elevated blood bilirubin levels. The excessive bilirubin manifests as yellowing of the skin and the normally white outer layer of the eyeballs –3. WhileThe origin of NHB may be physiologic or pathologic. Physiologic NHB may be caused by neonate immaturity and the resulting inability to cope with elevated levels of bilirubin . This beThe American Academy of Pediatrics (AAP) clinical practice guidelines address the assessment, screening, and treatment of NHB among infants at ≥35 weeks of gestation . Risk asWhen treatment is indicated, AAP guidelines recommend phototherapy as the initial treatment , 10. In To the best of our knowledge, the prevalence of hemolytic NHB newborns receiving treatment has not been well characterized, and economic burden at the population level is poorly understood. Our study aimed to address this knowledge gap. We focused on newborns with hemolytic NHB who received treatment because the receipt of intervention indicated that those neonates met the AAP guideline for the recommendation of intervention in order to prevent severe NHB and the spectrum of associated complications , 12–14.SM), a geographically dispersed managed-care repository with claims data on more than 45 million enrollees residing across all 50 states, to identify infants born from 01/01/2011 through 08/31/2017. The HIRD is one of the largest privately insured population databases in the U.S [This retrospective matched cohort study used the HealthCore Integrated Research Database  numbers. Mothers’ delivery dates were verified within 32 days of newborns’ dates of birth using delivery codes : Table 7NHB population was defined as newborns with ≥1 International Classification of Diseases (ICD)-9/10-CM diagnostic codes of NHB  during the first 30 days after birth. Newborns with ≥1 ICD-9/10-CM diagnosis codes of ICD-9-CM = 773.0, 773.1, 773.2, 773.4, 774.0, 774.1, 774.7 and ICD-10-CM = P55.x, P57.x, P58.0, P58.1, P58.8, P58.9 were selected for the population of NHB with hemolysis indicators or hemolytic NHB : Table 8Treated hemolytic NHB cohort were selected from the hemolytic NHB population if they were ≥ 35 weeks GA and received at least one NHB intervention including: phototherapy , IVIg treatment along with NHB diagnosis code on the same claim , or exchange transfusions .A non-NHB cohort was established using 1:1 matching with newborns in the treated hemolytic NHB cohort ≥35 weeks GA. Inclusion in the non-NHB cohort required the absence of NHB diagnostic codes, no NHB treatment and a minimum of 30-day health plan enrollment after birth. Exact matching was performed based on delivery hospital/provider, gender, delivery route , estimated GA, and post-index health plan continuous enrollment. When the matching of delivery hospital/provider was not possible, residence zip code (5-digit) was used instead. After all factors of interest were matched, newborns with the closest date of birth within 5 years were selected.We calculated the GA of a newborn from prenatal procedure testing dates, from a range of common prenatal tests in the mother’s medical claims, using the weighted procedure date-based average methodology, as described by Wallace et al. . This meThe annual prevalence of NHB, hemolytic NHB and treated hemolytic NHB were estimated for 2011 through 2016 as the number of newborns diagnosed with a disease divided by the total number of newborns after mother-infant linkage and health plan eligibility requirement during a particular calendar year.All-cause hospital measures included birth hospitalization, length of stay, NICU admissions, receipt of NHB treatments, and readmissions. The use of emergency department (ED) visits, physician office visits, other outpatient visits, and prescription fills were also presented. All healthcare resource utilization during the first 30 days and first year after birth were summarized.The effects of hyperbilirubinemia on the brain and neurodevelopmental status were examined by evaluating occurrences of kernicterus, cerebral palsy, encephalopathy, hearing and vision loss, motor dysfunction, and neurodevelopmental delay during the first year after birth. These clinical outcomes were identified using ICD-9/10-CM diagnosis codes, requiring ≥1 diagnosis for inpatient/ED settings or ≥ 2 diagnoses on distinct dates for physician office settings : Table 9Total all-cause costs during the first 30 days and first year after birth were reported. Since newborn care during birth hospitalization could be billed under their mothers’ plan ID, mothers’ delivery hospitalization costs were included to avoid any potential unequal underestimation between the newborn cohorts. These costs were the sum of the total paid amount by health plans, members’ out-of-pocket costs, and coordination of benefits. Total costs consisted of expenses incurred in inpatient, ED, office visits, other outpatient settings and pharmacy costs. Costs were adjusted for inflation using the Medical Care Consumer Price Index, and calculated in terms of 2017 U.S. dollars [Using U.S. Centers for Disease Control and Prevention (CDC) 2016 birth data by gestational age  and the All outcome measures were compared between the treated hemolytic NHB and matched non-NHB cohorts. Statistical differences between groups were assessed using McNemar or McNemar-Bowker tests for categorical variables and paired t-tests or Wilcoxon signed-rank tests for continuous variables, respectively. A conventional alpha of 0.05 with two-tailed level of significance was used to interpret statistical significance. Statistical analyses were performed with SAS EG 7.1 .Of the 1.4 million identified newborns, 365,937 were successfully linked to their birth mothers , region of residence, type of health plan, comorbidity and gestational diabetes were similar at time of delivery. Slightly less than one-third (29.1%) of births was delivered by C-section, and 18.2% of newborns were of 35–37 weeks GA in each cohort , delivery by vacuum extractor affecting newborn , and polycythemia neonatorum  compared to the matched non-NHB cohort , and a greater proportion were admitted to NICU  compared to matched non-NHB newborns (Table p < 0.001). Hospital readmissions and physician office visits were significantly higher for treated hemolytic NHB newborns than the matched non-NHB cohort, 8.7% vs. 1.7% (p < 0.001) and 90.8% vs. 82.6% (p < 0.001), respectively. No difference was reported for ED visits  and prescription fills  between the groups.Treated hemolytic NHB newborns had longer average length of stay during birth hospitalization  and $3,638  for the treated hemolytic NHB and non-NHB groups, respectively. The mean (SD) 30-day incremental total all-cause costs associated with treated hemolytic NHB newborns was $9,381  composed of $8,878  from newborns plus $503  from mothers’ delivery hospitalization.Mean (SD) total 30-day all-cause costs for the newborns were $14,405  for the treated hemolytic NHB group and $5,527  for the matched non-NHB cohort (p < 0.001). The treated hemolytic NHB group incurred mean (SD) total inpatient hospitalization costs of $13,794  compared to $5,216  in the matched non-NHB group, p < 0.001 and 69.7% vs. 63.5%, p = 0.009, respectively). The mean (SD) total one-year all-cause costs incurred by the treated hemolytic NHB cohort were $21,556  compared to $12,986  in the matched non-NHB cohort, p < 0.001. The average (SD) one-year incremental total all-cause costs associated with treated hemolytic NHB was $9,383 , consisting of $813  from mother’s delivery hospitalization and $8,570  from newborns  matched pairs with one-year follow-up were included in the analysis. There was no statistically significant difference between the two cohorts in inpatient admissions and ED visits during the period from 31 days to 1 year after birth. Physician office visits and prescription fills were slightly higher in the treated hemolytic NHB group compared to the matched non-NHB group  among 3.9 million newborns in the U.S. in 2016. Among newborns ≥35 weeks GA, the GA-adjusted prevalence of treated hemolytic NHB was 0.50% resulting in 18,872 newborns . The 18,872 treated hemolytic NHB newborns represent an estimated total healthcare expenditure of $271.9 million and incremental costs of $177.0 million compared with their counterparts without NHB during the first month after birth in the U.S. in 2016.To the best of our knowledge, this is the first study to estimate the prevalence of high-risk hemolytic NHB newborns receiving intervention, and to quantify the burden of hemolytic NHB in the US. The proportions of newborns with hemolytic NHB who received treatment were 0.46 to 0.55% in a privately insured population in the US. Although not prevalent, those high-risk hemolytic NHB neonates who received treatment were associated with substantial healthcare resource utilization and incremental economic burden.NHB research in the U.S. has been limited, and prevalence estimates vary markedly in the handful of studies in the literature. In a systematic review that included 14 studies to examine the effects and outcomes of phototherapy, Woodgate and Jardine noted that about 50% of full-term and 80% preterm newborns developed jaundice . In a suOur study focused on NHB specifically with etiology of hemolytic diseases, and we found that approximately 7% of the NHB cases were hemolytic NHB. Our estimated prevalence of treated hemolytic NHB (ranging from 0.46–0.55%) was comparable to < 1% of significant hemolysis reported by Wagle and Deshpande . Chang eWe found that treated hemolytic NHB newborns had significantly longer length of stay during their birth hospitalization, higher 30-day readmission rates, higher NICU use and slightly higher rates of physician office visits, compared to their matched counterparts. Length of stay of mothers’ delivery hospitalizations were also slightly longer in the treated hemolytic NHB cohort . These findings suggest significant burden to patients, their caregivers, and the healthcare system. Prior studies have shown that NHB was as major cause of readmission. Approximately half (51%) of all readmissions occurring 2 weeks after birth were attributable to NHB . The incWe also found that hemolytic NHB newborns who received treatment incurred 2.6 times the average costs of their matched non-NHB counterparts during the first 30 days after birth. The majority of the incremental cost was derived from birth hospitalizations. Indirect costs associated with patients’ and caregivers’ quality of life as well as caregivers’ loss of productivity could not be evaluated using claims data. As of now, no prior study has examined the economic burden of hemolytic NHB. One earlier study estimated the average cost of childbirth via vaginal or caesarian at $18,329 or $27,866, respectively, in a private health plan [We extrapolated our findings to the entire U.S. newborn population in 2016. The extrapolation estimated total healthcare expenditure of $271.9 million and incremental costs of $177.0 million among 18,872 treated hemolytic NHB newborns as compared with their counterparts without NHB during the first month after birth. Our extrapolation assumed our estimates were applicable to the U.S. newborn population mainly insured by private insurance plans or Medicaid. This projection should be interpreted with caution as privately insured populations tend to have higher socioeconomic status and healthcare expenditures than the Medicaid population . FurtherWe did not observe significant difference in neurodevelopment delay, language disorders, motor dysfunction, cerebral palsy, abnormal behavior, encephalopathy, hearing and vision loss between treated hemolytic NHB newborns and the matched non-NHB cohort during the first year of birth. However, the observation period was likely too short as many of these conditions might not be identifiable nor noticeable in the first year of life. Kernicterus, a brain injury resulting from severe NHB, was found in nine newborns, approximately 1.2% of all treated hemolytic NHB newborns during the one-year follow up. Kernicterus has been reported from 1.0 to 3.7 cases per 100,000 live birth in the literature , 32, butEffective management of high-risk hemolytic NHB is critical to reduce the impact of disease burden on patients, their caregivers, and the healthcare system. Several studies have investigated comprehensive approaches, such as pre-discharge bilirubin screening for all newborns , or the Our results should be interpreted in light of certain limitations. Known risk factors such as family history, race and ethnicity, and breastfeeding status are not available in administrative claims data. Cases of mild NHB do not usually require intervention, and can be underdiagnosed and/or under-coded in administrative data leading to underestimation of NHB and hemolytic NHB. The use of phototherapy during hospitalization might not have been observed due to bundled payments and/or under-coding. Duration on phototherapy was also not captured. This study population was from a U.S. privately insured population, which may limit the generalizability of these results to other population segments, such as Medicaid.This is likely the first study estimating the prevalence of newborns with hemolytic NHB who received intervention in the U.S. This high-risk population imposes a substantial burden of healthcare resource utilization and incremental costs on newborns, their caregivers, and the healthcare system. Effective management protocols and emerging new treatments may help to mitigate the overall burden of hemolytic NHB.


The LNG IUS is one of the most effective forms of reversible contraception and has important noncontraceptive benefits but is currently not used at scale in any Family Planning 2020 focus country. A global working group developed a shared learning agenda to answer critical questions, harmonize approaches, avoid duplication, and facilitate introduction of the method within the context of informed choice. The LNG IUS is one of the most effective forms of reversible contraception and has important noncontraceptive benefits but is currently not used at scale in any Family Planning 2020 focus country. A global working group developed a shared learning agenda to answer critical questions, harmonize approaches, avoid duplication, and facilitate introduction of the method within the context of informed choice. We then describe an introduction coordination platform that was launched in 2015 to help address these challenges and answer critical questions about the LNG IUS through a shared global learning agenda. We also discuss some of the advantages and disadvantages of this type of method-specific coordination platform and provide a call to action for other organizations that are considering introducing or scaling up the LNG IUS.,–Historically, the high cost of LNG IUS commodities has been a primary barrier to public-sector procurement in international settings, and therefore to inclusion in the contraceptive method mix in national family planning programs.An unbranded LNG IUS product manufactured by Bayer Healthcare is available for free by application through donations made by the International Contraceptive Access (ICA) Foundation, a private-public partnership between Bayer Healthcare and the Population Council. Since 2005, approximately 125,000 units have been donated through this mechanism in 36 countries.The landscape may be changing as new LNG IUS products become more available globally . A new LNew, more affordable LNG IUS products are starting to become available in some FP2020 markets.A recent assessment of the direct service delivery costs of various family planning methods per couple-years of protection (CYP)  demonstrated that at US$15 per unit, the cost per CYP of the LNG IUS compared favorably with that of other contraceptive methods commonly procured in FP2020 countries.Despite this, past experience with other methods demonstrates that even if a method is cost-effective over its duration of use, high upfront commodity costs can still be a barrier to procurement by donors and governments.–The more affordable pricing for implants, which can be procured now by donors and governments for US$6.90 to $8.50 per unit in FP2020 countries, has set a new bar, which could impact expectations for pricing of the LNG IUS. In addition, copper IUDs are available for procurement for programs in FP2020 countries for less than US$0.50 per unit.,As stakeholders consider whether to procure the LNG IUS for public-sector programs and/or invest in a global price reduction strategy, additional evidence is needed regarding the potential value of adding the LNG IUS to the method mix within countries. Stakeholders recognize that contraceptive commodity costs are only one factor impacting access and use. In the case of the LNG IUS, awareness and demand for the method would need to increase and potential supply-side barriers would need to be addressed for availability and uptake to expand substantially.,,–Notably, while use of contraceptive implants has risen dramatically over recent years in sub-Saharan Africa, voluntary uptake of the copper IUD remains low with no country in the region having an IUD prevalence above 2%.The LNG IUS may face similar barriers to uptake as the copper IUD.There is an emerging body of evidence about use of the LNG IUS in LMICs. For example, a recent study of LNG IUS users in Kenya found high satisfaction and continuation rates. Among 671 postpartum women offered a range of methods, 16% chose the LNG IUS.Emerging evidence from several sub-Saharan African countries finds positive perceptions of the LNG IUS among users and providers.,Moving forward, additional evidence is needed to inform potential future introduction of the LNG IUS, especially to address the unresolved questions about demand. This will be particularly important given limited budgets and competing priorities as countries work to scale up the contraceptive methods they already have available. Specifically, questions remain about what demand generation and provider training strategies would be required to overcome potential barriers to uptake and whether the LNG IUS would be cost-effective compared with other long-acting reversible methods, especially if more resources are required to increase awareness and demand for the LNG IUS than are required for other methods. Governments and donors also want to know whether the method would primarily attract new users and/or “switchers.” Preliminary research in Kenya and Nigeria found that among switchers, a portion of LNG IUS users shifted from using short-acting resupply methods.Understand potential demand and use dynamics among different populations (such as new users and switchers), continuation rates, and client and provider perspectives of the method.Identify if and how the challenges that have impacted use of the copper IUD in many settings could be overcome by the LNG IUS, given the similarities and differences between the 2 methods.Identify effective strategies to generate awareness and demand for the LNG IUS including how to communicate method attributes in relation to attributes of other methods.Assess programmatic models in different service delivery channels.Evaluate willingness-to-pay for the LNG IUS among different market segments.Increase coordination among service delivery groups by sharing country introduction plans, service delivery approaches, and regulatory resources.Contribute to the global family planning community by making LNG IUS provider training materials, counseling materials, and job aids widely available.In 2015, a product introduction coordination platform, the LNG IUS Working Group, was convened by the United States Agency for International Development (USAID) with the goal of facilitating the introduction of high-quality, affordable LNG IUS products in developing countries in order to increase the range of highly effective contraceptive options available to women, within the context of informed choice. The LNG IUS coordination platform includes donors, suppliers, research agencies, and training and service delivery organizations that are currently supporting LNG IUS introduction and/or evaluation activities. The platform was formed to address the following objectives:As a first step, the group collaborated on development of a shared global learning agenda related to the LNG IUS. While the creation and use of a learning agenda is increasingly common in the development sector,Members of the LNG IUS Working Group developed a shared global learning agenda for the LNG IUS.BOX 2Learning Agenda QuestionsA. Client Demand1. What are the profile(s) of the clients who will use this product?a. Is there or would there be demand for this product among sub-populations with high unmet need for family planning ?b. Will introduction of the LNG IUS help reach new family planning users ?c. To what degree will introduction of the LNG IUS result in “switching” and from what other methods ?2. Does the LNG IUS have the potential to ‘revitalize’ the IUD market in FP2020 countries?a. Will demand for the LNG IUS be higher than demand for the copper IUD has been?3. Would introduction of the LNG IUS increase family planning use overall/increase contraceptive prevalence rate(s)?a. Can scale-up of this product help meet FP2020 goals?4. How do continuation rates of the LNG IUS compare to continuation rates of other LARCs in multiple contexts?5. Does immediate postpartum access to the LNG IUS increase use of postpartum family planning overall?B. Marketing6. What are effective demand creation strategies with different populations and in different sectors?7. How can promotion of family planning including the LNG IUS be integrated into other health sectors such as nutrition programs or menstrual hygiene management programs?C. Service Delivery8. How can we overcome barriers that have impacted provision of the copper IUD at the service delivery level when introducing the LNG IUS?9. What are health care providers' perceptions of this product?10.What are effective service delivery models for LNG IUS provision? How does it differ by context, channel, and/or user group?a. What are effective provider training strategies for the LNG IUS?D. Noncontraceptive Attributes11. How does knowledge of noncontraceptive attributes of the LNG IUS affect uptake and use?a. What noncontraceptive attributes are most attractive to women in different contexts?b. What noncontraceptive attributes are seen as most beneficial by providers in different contexts?12. What are perceptions of amenorrhea among providers and various clients segments?13. Can scale-up of the LNG IUS help reduce rates of anemia?E. Cost-Effectiveness and Pricing14. To what extent is the LNG IUS cost-effective compared to other family planning methods including other LARCs?15. What is the willingness-to-pay for the LNG IUS among different populations of clients and different stakeholder groups?Abbreviations: FP2020, Family Planning 2020; IUD, intrauterine device; LARCs, long-acting reversible contraceptives; LNG IUS, levonorgestrel-releasing intrauterine system.Learning agenda questions were prioritized by donors and implementing agencies and used to inform investment and programming decisions. The subcommittee of implementing agencies as well as donors involved with the LNG IUS Working Group each ranked the learning agenda questions in order of priority and relevance for their respective institutional strategies. This exercise was useful to identify how priorities differed among stakeholders and to facilitate further discussion among the group's members. The learning agenda also informed donor decisions for new research studies and maximized opportunities to leverage support among funders.Research and service delivery groups coordinated to support data collection in pilot programs. Members of the LNG IUS Working Group recognized that if all pilot programs introducing the LNG IUS could ask similar questions of women choosing the method as part of routine data collection, the impact of evaluation efforts could be increased. FHI 360 modified 3 questions that had been included in a research study in Kenya conducted by Hubacher and colleagues,Since its adoption in 2016, the LNG IUS learning agenda has been used in several ways:BOX 3,Can you briefly tell me the reasons you chose the LNG IUS today instead of another method?If the LNG IUS had not been available today, what method, if any, would you have chosen instead?How did you first find out about the LNG IUS?Three questions were adapted from a previous research study in KenyaVersions of these questions were administered by providers in Kenya, Madagascar, Nigeria, Zambia, and Zimbabwe. Data were then compiled by members of the LNG IUS Working Group in a single dashboard so results could be compared. The dashboard will be updated on an ongoing basis. The current version (as of November 2018) is available online in the IUD Toolkit on the Knowledge for Health platform.The LNG IUS Working Group brings together partners that are supporting introduction and evaluation of the LNG IUS in pilot settings such that information shared during the meetings can be used immediately. In addition to providing a forum to define and implement the global learning agenda, the LNG IUS Working Group offers a platform to share updates and lessons from the field, training resources, and regulatory materials. The group has also facilitated approved sharing of LNG IUS product stock in country and provided an opportunity for members to co-develop client-centered counseling materials, such as a new job aid for providers about menstrual bleeding changes.While the coordination platform has proved to be useful to participant organizations, it faces challenges that the group openly acknowledges. Suppliers with a product approved by a stringent regulatory authority are key partners in the LNG IUS Working Group, and they are not always able to share commercially sensitive information, especially among other suppliers. As such, some information and negotiation goes on in separate confidential meetings not open to the larger group. This limits the inclusion of all working group members in some planning activities; however, it ensures the continued involvement of manufacturers in this platform. The LNG IUS Working Group also includes service delivery and research partners that are potentially competing against each other for donor resources or a share of the LNG IUS market in countries. The donors involved have to be cognizant of the competitive nature of the work. For example, they must stay informed of when there are procurements being bid that may impact the working group participants' relationships while still holding partners accountable for coordination to ensure that LNG IUS introduction and evaluation efforts are as cost-effective and efficient as possible given limited resources.40 or other product introduction efforts.The implementation of a method-specific introduction coordination platform has allowed for the creation of a tailored learning agenda with input from diverse stakeholders. The LNG IUS is being introduced in contexts of informed choice, where it is one method among a range of contraceptives that country programs offer. There are learning gaps specific to the LNG IUS that have made coordination and collaboration useful for service delivery groups, research partners, manufacturers, and donors. Lessons from implementing this type of method-specific platform and global learning agenda model could be applied to other issuesAt the same time, this type of single-method introduction coordination platform comes with costs as well as benefits. There are other new contraceptive methods being introduced in FP2020 countries, and the level of effort required for a single-method coordination group may not be needed or warranted in all cases. In addition, while the LNG IUS Working Group aims to apply experiences with scaling up access to other underused methods—such as implants and subcutaneous injectables—a platform that focuses on more than one method could further increase coordination and learning.A single-method introduction coordination platform comes with costs as well as benefits.Given the positive attributes of the LNG IUS and the potential benefits of adding it to the contraceptive method mix in LMICs, country-level stakeholders should consider if and when to introduce the method into family planning programs. At the same time, considering the potential programmatic challenges as well as unanswered questions such as the potential demand for the method if price barriers were removed, the new global learning agenda for the LNG IUS is a call to action for other entities engaged in LNG IUS introduction or research. We encourage other implementers and researchers to document and publish LNG IUS introduction experiences in LMICs, including uptake data, and to administer standardized monitoring and evaluation questions where possible. Rigorous research and program evaluations are essential, as are coordinated country-level introduction efforts, to better understand the potential impact of expanding access to this highly effective, potentially popular—yet now largely unavailable—contraceptive option.


General estimated equation (GEE) models were used to address the correlation between fetuses when assessing SGA. A total of 866 eligible subjects were included in the analysis. In total, 460 pregnancies had placentas with different locations, and 406 had placentas with same locations. The gestational age at delivery was slightly younger in the same placental location group than in the different placental location group . Other maternal and fetal characteristics were comparable between the two study groups. There was no significant difference in BWD ≥20%  or SGA  between the same and different placental location groups. Neither the mean value nor the absolute difference in birth weight was associated with placental location combination . In conclusion, discordant birthweight is not affected by same location of diamniotic-dichorionic placentas.This retrospective cohort study aimed to investigate the effect of placental location on birthweight discordance among diamniotic-dichorionic twin pregnancies. Medical records and sonographic reports of 978 diamniotic-dichorionic twin pregnancies delivered at Foshan Maternal and Fetal Health Hospital were reviewed. Pregnancies with congenital malformation, intrauterine death or placenta previa were excluded. The placental location for each twin was determined by last sonographic examination before delivery, and the pregnancies were grouped by different versus same placental location in each pregnancy. Maternal and fetal characteristics were summarized. The primary outcome of interest was birthweight discordance (BWD) ≥20%, and secondary outcomes included small for gestational age (SGA) as a binary outcome and mean value and absolute difference in birthweight as continuous outcomes. Student’s  Twin gestations are associated with a series of adverse outcomes such as preterm birth, congenital anomalies, fetal loss, fetal growth restriction and neonatal death5. Accumulating evidence has shown that growth discordance with small for gestational age (SGA) among twin gestations is related to increased perinatal morbidity and mortality, as well as long-term adverse neuro-developmental outcomes7.In recent years, the number of twin pregnancies has been steadily growing with the increasing use of assisted reproductive technology (ART)9. In addition, because the placenta plays a key role in mediating the growth and development of twin fetuses, considerable efforts have been made to evaluate the effect of placental characteristics on fetal growth. Abnormal cord insertion  and placental volume were demonstrated to be associated with increased risks of growth retardation and discordance10. Venovenous anastomoses were proven to be associated with birth weight discordance in monochorionic-diamniotic twin pregnancies11.Identifying predictors of fetal growth is of great benefit in patients counseling and antepartum management. Previous studies have investigated predictors such as maternal and fetal factors, including maternal weight gain during pregnancy, maternal complications, methods of conception, chorionicity and neonatal sex14, mainly due to decreased blood supply to lateral and fundal placentas. Evidence for the role of placental location, nevertheless, among diamniotic-dichorionic twins is sparse. The mechanism of discordant growth among diamniotic-dichorionic twins (DC) is not clear. We hypothesized that, when both placentas were covering on the same area of the uterus wall, there exists an intertwin competition for blood supply, which might subsequently affect the fetal growth. Belogolovkin et al.15 retrospectively reviewed the medical records of a medium-sized population (292 pairs of diamniotic-dichorionic twins) and found no correlation between birth weight and placental location. This result, however, may be of limitedly utility because of the inclusion criteria for eligible participants. To the best of our knowledge, no other results from a different center have been reported.Placental location was reported to be related to birthweight among singleton pregnanciesIn this regard, we sought to investigate the association between placental location and birthweight discordance among diamniotic-dichorionic twins in a large population.The flowchart of the study group selection is represented in Fig. P = 0.067). There were no differences between the two study groups in maternal-fetal characteristics, including maternal age, use of ART, history of pregnancy loss, maternal complications, abnormal cord insertion and neonatal sex.Sonographic examinations were performed on the included participants at a median gestational age of 35.9 weeks (range: 26.8–38.2 weeks). The maternal-fetal characteristics by placental location are shown in Table P = 0.930) or SGA pregnancy  between the two study groups. Regarding continuous outcomes, the mean birth weight was slightly higher in the different placental location group  and the absolute difference in birthweight was significantly larger in the different placental location group .The overall prevalence of birth weight discordance ≥20% and SGA pregnancy was 10.7% and 6.8%, respectively. Neonatal outcomes by study groups in the univariate analysis are shown in Table P = 0.478) nor the absolute difference  in birth weight was correlated with placental location  or SGA   or fundal, as in previous studies17. We grouped cases according to whether the two placentas shared the same uterine wall. A large population (n = 866) of twin pregnancies with all types of placental locations, except placenta previa, were included. However, the results refuted our hypothesis, that was, placentas that shared the same uterine wall did not lead to a higher risk of severe discordant birthweight, or intrauterine growth restriction. This finding is similar to that of a previous study by Belogolovkin et al.15, although their inclusion criteria may have introduced some selection bias because they included only twin pairs with specific placental types (anterior and posterior placentas). Blickstein et al.18 reported a similar incidence of SGA and birth weight discordance between dichorionic twins with fused and separate placentas. This finding is in accordance with ours despite the use of different placental location categories. Based on existing evidence, one possible explanation is that a shared uterus wall shared by two placentas can provided the uteroplacental perfusion for both fetuses; otherwise, one or both would migrate towards a site providing better nourishment. As reported by prior studies, abnormal cord insertion has implications for fetal growth19. We detected trends in both SGA and discordance ≥20% when the pregnancies were complicated with abnormal cord insertion; nevertheless, these trends failed to achieve a customary level of statistical significance (data not shown), which may be due to the low incidence among our study population.While the placenta is a unique organ that delivers nutrition to the fetus, it is generally accepted that fetal growth retardation is associated with abnormal placentation, leading to decreased blood supply to the fetus. In singletons, fundal and lateral placentas are reported to be associated with a higher risk of SGA infants21. However, current evidence is still unable to provide a robust panel of biomarkers, partly due to a lack of statistical power and reproducible methods. On the other hand, the implementation of early serum markers in clinical practice has been hampered by their low sensitivity and specificity and their high cost22. Notably, previous evidence was predominantly based on singletons, rarely on diamniotic-dichorionic twins. Recently, Biesiada et al.23 found dysregulation of gene expression related to angiogenesis and growth factors in placentas of diamniotic-dichorionic twins with discordant growth. Because this study excluded intertwin competition for blood supply as a factor for discordant birthweight, we agreed with that a diamniotic-dichorionic twin pregnancy is a good model as both twins develop in the same maternal environment. Future evidence on this model may provide novel insight into placental biomarkers among SGA fetuses.A panel of biomarkers in combination with ultrasound finding and clinical characteristics for the early diagnosis of preeclampsia and fetal growth restriction, could offer an opportunity to optimize maternal and/or perinatal outcomes, which consists of controlling hypertension, preventing seizures, timely delivery and even prophylactic administration of aspirin. On one hand, increasing evidences in the recent years has identified the role of micro-RNA in pregnancies with these placenta-induced complications25. However, we were unable to obtain this information due to the retrospective nature of this study. Moreover, these limitations may hamper the extension of our conclusions to other circumstances where there are fewer ART-related pregnancies.Since ART procedure is increasingly used and the majority of ART-related multiple gestations are expected to be dizygotic, our results may be of interest to gynecologists and pediatricians for evaluating the risk of fetal growth restriction in diamniotic-dichorionic twins. While the strength of this study is the large population, several limitations should be noted in our study when interpreting results. First, the classification of placental location in our study may lack precision. Therefore, we believe that terms that describe whether both placentas receive blood supply from the same uterine artery, or the distance between the two placentas, may more clearly delineate the relationship between placental location and birthweight discordance. Second, information on placental location was obtained from examinations in the third trimester; thus, we could have missed cases of placental migration. Our results need to be confirmed by evidence with earlier ultrasound examinations. Third, a large proportion of ART-related twin pregnancies were included in our study. It is reasonable to believe that some of the mothers may have had endometriosis, which is reported to affect up to 50% of infertile women and is considered as a risk factor for SGA newbornsIn summary, discordant birthweight among diamniotic-dichorionic twins is not affected by the same or different placental locations. Future studies on ultrasound-based placental characteristics related to discordant growth among diamniotic-dichorionic twins are warranted.in vitro fertilization and embryo transfer (IVF-ET), artificial insemination (AI) and intracytoplasmic sperm injection (ICSI). The presence of abnormal cord insertion  was also recorded upon placental gross examinations. Placental location for each twin was determined in the last transabdominal sonographic examination before delivery and was recorded as anterior, posterior, left, right or fundal placenta when the placenta predominantly  covered the corresponding position of uterine wall. When a placenta located on one position  but entered another , combination terms were recorded. For example, if “anterior” and “right” were simultaneously indicated, the placental location was recorded as an anterior-right placenta. In this study, twin pregnancies were grouped by same or different placental location group according to whether the placental locations overlapped. Typically, same placental location was defined as both placentas clearly were located on the same uterine wall, such as anterior-anterior, posterior-posterior, left-left placentas or right-right. In addition, pregnancies were placed in the same placental location group when the combination term of one placenta overlapped the location of the other. For example, a pregnancy with an anterior-right placenta and an anterior placenta was placed in the same placental location group. Otherwise, pregnancies with differently located placentas were placed in the different placental location group.This retrospective cohort study was performed by analyzing the medical records and sonographic reports for diamniotic-dichorionic twin pregnancies who referred to and deliverd at Foshan Maternal and Fetal Health Hospital between July 2015 and June 2018. This study was approved by the Human Subjects Committee of the Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan. All the methods in the present study were performed in accordance with the approved guidelines. Informed consent was obtained from all participants. Eligible subjects were identified through a systematic review of medical records and sonographic reports. Pregnancies with viable twins born at a gestational age of ≥26 weeks were included if complete information on pregnancy outcomes and sonographic examination were available; otherwise, pregnancies were excluded if: (1) major congenital malformations or chromosomal anomalies were noted in medical records; (2) twin pregnancies were affected by intrauterine death or were terminated before gestation 26 weeks of gestational age; or (3) twin pregnancies were complicated by any type of placenta previa. Chorionicity was determined at the first sonographic examination (lambda-sign for monochorionicity and T-sign for diamnioticity) and was confirmed by placental pathologic findings after birth. The gestational age was calculated based on the last menstrual period and confirmed by sonography in the first trimester, if available. Maternal and fetal medical records were reviewed for the following characteristics: maternal age, mode of conception method (spontaneous conception vs. ART), last menstrual period, nulliparity, history of spontaneous fetal loss, presence of maternal complications  and birth weight. ART included th percentile for gestation age and sex based on twin birth weight curves in Chinese twins27, and the mean value and absolute difference in birthweight, which were analyzed as continuous variables. The percentage of birth weight discordance was calculated by dividing the actual birth weight difference by the weight of the larger twin and multiplying by 100.The primary outcome of interest was birth weight discordance (BWD) defined as an intrapair difference of 20% or greater. The secondary outcomes were small for gestational age, defined as birthweight was below the 10P-values were two-sided, at a significance level of 0.05.PASS version 11 was used for sample size calculation, and Stata version 13.1 was used for the statistical analysis. The overall incidence of BWD in the different placental location group was presumed to be 10%. To detect a minimal increase of 7% in the same placental location group, with a statistical power of 80% and a confidence level of 95%, 373 pregnancies had to be included in each group. Data are presented as the mean ± SD or frequency and percentage. Study population characteristics and neonatal outcomes were compared between the two study groups  using a t test or the chi-square test. Multivariate logistic models and linear regression models were utilized to adjust for confounders of binary outcomes and continuous outcomes, respectively. Confounding variables included neonatal sex, abnormal placental insertion and maternal diabetes. Gestational age at delivery was also adjusted for when assessing birthweight as a continuous outcome. For SGA fetuses, the general estimated equation (GEE) was used in order to address the correlation between fetuses in a paired set. The results are represented as odds ratios for binary outcomes or as coefficients for continuous outcomes, with corresponding 95% confidence intervals. All Table S1, Table S2


Environmental pollution exposure during pregnancy has been identified as a risk factor for preterm birth. Most studies have evaluated exposures individually and in limited study populations.We examined the associations between several environmental exposures, both individually and cumulatively, and risk of preterm birth in Fresno County, California. We also evaluated early (< 34 weeks) and spontaneous preterm birth. We used the Communities Environmental Health Screening Tool and linked hospital discharge records by census tract from 2009 to 2012. The environmental factors included air pollution, drinking water contaminants, pesticides, hazardous waste, traffic exposure and others. Social factors, including area-level socioeconomic status (SES) and race/ethnicity were also evaluated as potential modifiers of the relationship between pollution and preterm birth.In our study of 53,843 births, risk of preterm birth was associated with higher exposure to cumulative pollution scores and drinking water contaminants. Risk of preterm birth was twice as likely for those exposed to high versus low levels of pollution. An exposure-response relationship was observed across the quintiles of the pollution burden score. The associations were stronger among early preterm births in areas of low SES.In Fresno County, we found multiple pollution exposures associated with increased risk for preterm birth, with higher associations among the most disadvantaged. This supports other evidence finding environmental exposures are important risk factors for preterm birth, and furthermore the burden is higher in areas of low SES. This data supports efforts to reduce the environmental burden on pregnant women.The online version of this article (10.1186/s12940-018-0414-x) contains supplementary material, which is available to authorized users. Preterm birth (before 37 weeks gestation) is estimated to impact 10% of U.S. births annually with resultant potential for developmental and long-term adverse health consequences . The estSeveral studies have identified important environmental risk factors for preterm birth including prenatal exposure to air pollution , 7, contStudies have also shown that exposures to pollutants differ by race/ethnicity and SES . In prevFresno County, in the San Joaquin Valley of California (CA), is an area of known environmental pollution burden  and a hiBirth outcome and maternal demographic information were collected from a linked hospital discharge birth cohort database maintained by the CA Office of Statewide Health Planning and Development (OSHPD) that includes linked information from the State of CA vital records and hospital discharge records (comorbidities were identified from codes in the form of ICD-9-CM diagnoses). From this linked dataset, the study includes race/ethnicity, infant sex, maternal age at delivery, years of education, participation in the Women, Infants, and Children (WIC) food and nutrition service , payer for delivery costs , place of mother’s birth, body mass index (BMI) calculated from maternal height and pre-pregnancy weight, preexisting diabetes (ICD-9 code 250 and 648.0), gestational diabetes (648.8), preexisting hypertension , gestational hypertension (642.3), preeclampsia/eclampsia , infection , anemia (648.2), mental illness (648.4), reported smoking, reported drug abuse, reported alcohol dependence, trimester when prenatal care began, parity, previous preterm birth, previous cesarean section, inter-pregnancy interval, premature rupture of membranes (658.1), mode of delivery , birth weight, birth date and gestational age at delivery (best obstetric estimate).The sample was restricted to live-born singleton births with known birth date, birth weight between three standard deviations of mean by week of gestation  and gestMethods and protocols for the study were approved by the Committee for the Protection of Human Subjects within the Health and Human Services Agency of the State of California.https://oehha.ca.gov/calenviroscreen).We used the California Communities Environmental Health Screening Tool  to estimate environmental exposures for each census tract in Fresno County . The CalCalEnviroScreen 2.0 consists of 19 environmental and population indicators in total, which are aggregated into a final, relative CalEnviroScreen Score .We merged the OSHPD birth records with CalEnviroScreen 2.0 data by 2010 census tract. When birth records contained 2000 census tracts, we used the relationship files for 2000 to 2010 census tracts to create area-weighted values for the CalEnviroScreen variables . If a ceOur primary outcome was preterm birth was defined as birth at less than 37 weeks gestation. We examined 24 exposure variables, which included the following scores and indicators from the CalEnviroScreen: Pollution Burden Score; Exposures score (component of Pollution Burden); Environmental Effects (component of Pollution Burden); 11 indicators ; and 10 subcategories of the drinking water indicator , demographic characteristics , obstetrical-related variables , and, among multiparous women, previous caesarean section, previous preterm birth, and inter-pregnancy interval from the previous live birth to the estimated conception of the index pregnancy. Inter-pregnancy interval was calculated from previous live birth (month and year) as reported in linked records and estimated as months to conception of the index pregnancy. Given that the day of previous live birth was not available, the middle of the month was used for calculation purposes . We explp < 0.05 in crude risk calculations.We used logistic regression to evaluate the association between each indicator and preterm birth (< 37 weeks) and early preterm birth (< 34 weeks), comparing each of the higher 4 quintiles to the lowest to allow for non-monotonic relationships across the pollution distribution. We ran three sets of models: crude, adjusted with a priori variables and a stepwise selection. The covariates determined a priori included maternal education, age, race/ethnicity, and payer of delivery costs. The stepwise procedure included a forward and backward algorithm to estimate the association between environmental factors with preterm birth that allowed inclusion of covariates listed above that had To explore the hypothesis that there is a double jeopardy when populations are vulnerable to both social and environmental stressors, we examined SES and race/ethnicity as potential modifiers in the relationship between environmental contaminants and preterm birth. We stratified analyses to examine the relationships between pollution and preterm birth by high and low SES of the census tract the woman lived in. The low SES group consisted of census tracts with below median levels of poverty, education, unemployment and linguistic isolation Fig. , Table 1In sensitivity analyses, we explored several alternative analytic decisions. We evaluated the pollutants continuously, both in individual models and a combined model with social factors. We chose more specific phenotypes of preterm birth including early preterm birth (< 34 weeks) and spontaneous preterm (i.e. premature labor or premature rupture of membranes) to restrict to preterm births that were not the consequence of a known cause or indication. We evaluated the raw scores of the exposure indicators (as opposed to the percentiles). Additionally, we mapped preterm birth prevalence across the county to visually observe the geographic variability.After applying our exclusion criteria, our final study population included 53,843 births Fig. . Our stu2.5, Diesel PM, Toxic Release, Traffic, Drinking Water Score, Cadmium, Nitrate, Uranium, Solid Waste and Pollution Burden Score were all higher among preterm births.Correlations were moderate between diesel PM, ozone and traffic, ranging from 0.53 to 0.79 . Additionally, Hispanic, African-American and Asian mothers were more likely to have preterm birth compared to white mothers. Mothers with Medi-Cal payer status had higher risk of preterm birth. Additional risk factors for preterm birth included underweight BMI, diabetes, hypertension without pre-eclampsia, infection, anemia, mental illness, previous cesarean delivery, and short (< 6 months) or long (> 59 months) inter-pregnancy interval. Conversely, mothers that participated in WIC were less likely to deliver preterm.We found that the mothers in the highest quintile of Exposures score were two times as likely to have preterm birth (< 37 weeks), compared to the lowest quintile in the a priori variable adjustment regardless of different statistical adjustment settings . We also found the highest three quintiles of Pollution Burden score had statistically higher odds of preterm birth Table .Table 4CWe found the highest quintile of drinking water contaminants was associated with higher odds of preterm birth Table , especiaThe Exposures score, diesel PM and drinking water contaminants were more strongly associated with increased risk of early preterm birth in the low socioeconomic areas compared to the high socioeconomic areas Table . SimilarWe also found the association between diesel PM and preterm birth was slightly higher among non-white and non-Hispanic women, particularly for early preterm birth after adjusting for age, education and payment for delivery costs Table .Table 6C2.5 and Pollution Burden Score were associated with 6% increases in odds of preterm birth after adjustment for education, payer of delivery, maternal age and race/ethnicity. Diesel PM, traffic density and Trichloroethylene concentration (in drinking water) were associated with 26.3% increased odds of early preterm birth  examining one indicator at a time continuously, two pollutant measures were statistically associated with preterm birth: interquartile range increases in PM2.5 and unemployment, maternal age > 34, Medi-Cal payer of delivery and African-American race were associated with preterm birth (data not shown). Results examining raw scores were comparable to those of the percentiles.When all individual environmental indicators and social factors were included in the same model, PMOverall, the current study found small but consistent associations between pollution exposure and preterm birth in Fresno County. Although many of the individual pollutants were not associated with preterm birth, the cumulative scores were consistently associated with preterm birth, including the Exposures score, drinking water contaminants and Pollution Burden score. Novel exposures, such as the toxic releases from facilities, were identified as a potential contributor to preterm birth in Fresno County. There was an exposure-response of increased risk of preterm birth across quintiles of Pollution Burden scores. Furthermore, the relationship between pollution and preterm birth was stronger among areas with lower SES., hypertension) [Some risk factors of preterm birth, such as hypertension, have large associations though only affect a small portion of the population. The associations found with pollution were smaller, but may affect a larger portion of births across the population. Pollution may be exacerbating diseases and health issues that lead to preterm birth (e.g.tension) , or opertension) .The results did not differ considerably when restricted to spontaneous preterm birth. In some cases, results were stronger among the more severe early preterm birth (less than 34 weeks). The drinking water contaminant, THM, was associated with a decrease in preterm birth; however, it can be inversely correlated with other contaminants because it is a disinfection by-product commonly found in metropolitan areas.Our findings add to the literature on environmental risk factors and preterm birth. For example, in previous studies in CA, we found small but consistent effects of air pollution on risk of preterm birth using air pollution measurements at the geocoded residence , 36, 37.Consistent with previous work on environmental justice, we observed higher pollution burden among those who were non-White and of lower education and income. Additionally, we found stronger, though not statistically different, associations between some environmental indicators and preterm birth in low SES areas. This is consistent with the concept of ‘double jeopardy’ of environmental and socioeconomic stressors . FurtherNotably, WIC participation, which was associated with high pollution burden and requires low SES, was protective against preterm birth. This is an example of a program that may be having a positive effect on reducing preterm birth in Fresno county. The addition of similar programs, which provide access to supplemental foods, healthcare referrals and nutritional education for pregnant women, may further reduce preterm birth in low-income areas.Despite the large inclusion of the population, our study did have several limitations. One limitation is the imprecise exposure assessment both geographically and temporally. In some cases, the linkage between the birth records and the census tract were not available and this may have resulted in bias, given changes in census tracts are often a result of population growth. The exposure assessment was at the census tract level and the years were pooled for most data sources. Additionally, the CalEnviroScreen was designed as a screening level tool and does not include specific pollutants or chemical exposures that may be affecting this study population. We examined many indicators of pollution that included nested summary measures, which led to many comparisons. Although we did not adjust for multiple comparisons, we present these results as exploratory. Some women may have had two or possibly more births during this time period (2009–2012); however, we were unable to link them and control for these correlated events. Lastly, we assumed that mothers lived constantly throughout their pregnancy in the maternal residence recorded in the birth certificate without relocating from other regions and did not account for time activity patterns or time spent in other geographical areas.The CalEnviroScreen is a unique tool devised to identify areas of high pollution burden and vulnerable populations and has the benefit of informing epidemiologic studies. Strengths of this study include our ability to include a large set of pollution indicators both individually and cumulatively across a broad geographic area. Additionally, we were able to include all singleton births in Fresno County with detailed demographic and medical information from medical discharge records. Further, our results find a stronger association with the Exposures score, which makes sense as this score consists of monitoring data that is likely to be more representative of actual exposures in the population.Our study provides an initial investigation of the CalEnviroScreen as an epidemiologic tool to help elucidate a host of environmental and social factors that contribute to preterm birth. As a screening tool designed to discern communities that assume disproportionate environmental burdens in California, the CalEnviroScreen provides data for environmental justice research. Future studies could expand to the entire state of California and aim to include additional sources of data such as biomonitoring and genomics that could confirm exposure levels and identify pathways by which environmental pollutants contribute to preterm birth.Additional file 1:Appendix 1a. Pearson Correlation Matrix of Exposures from CalEnviroScreen 2.0. Appendix 1b. Correlation Matrix of Drinking Water Contaminants from CalEnviroScreen 2.0. Appendix 2. Crude and adjusted relative risk of early (< 34 weeks) preterm birth across quintiles of CalEnviroScreen indicators and scores in Fresno County, 2009–2012 . Appendix 3. Crude and adjusted relative risk of early (< 34 weeks) preterm birth comparing above versus below the median of environmental exposure by census tract-level socioeconomic status (SES) in Fresno County, 2009–2012 . Appendix 4. Crude and adjusted relative risk of early (< 34 weeks) preterm birth comparing above versus below the median of environmental exposure by race/ethnicity in Fresno County, 2009–2012 . (DOCX 88 kb)


Kagami–Ogata syndrome is also known as paternal uniparental disomy 14 and related disorders and is caused by abnormal genomic imprinting in the long arm of the chromosome 14q32.2 region. Its clinical manifestations include polyhydramnios in the fetal stage, respiratory insufficiency because of a small thorax, abdominal wall abnormalities, and peculiar facial features after birth.de novo microdeletion in a differentially methylated region.A 38-year-old Japanese primigravida woman was referred to our hospital in the 19th week of pregnancy for suspected omphalocele. She had a history of hypothyroidism but was prescribed orally administered levothyroxine (50 μg/day) prior to conception and was euthyroid. Her ultrasound scan prior to visiting our hospital revealed fetal omphalocele, heavy for date, and polyhydramnios. The mother was advised to be admitted for observation from 28 weeks of gestation for threatened premature delivery. She required amniodrainage at 29 and 32 weeks of gestation. At 35 weeks of gestation, the fetal membrane prematurely ruptured and she gave birth after an emergency Cesarean section. The infant was a male child with a birth weight of 3188 g, and was suspected to have Kagami–Ogata syndrome after birth based on thoracic hypoplasia, swallowing function abnormalities, and peculiar facial features. A definitive diagnosis was established by performing genetic testing of the infant after obtaining informed written consent from both the parents; the results of the genetic testing revealed hypermethylated intergenic-differentially methylated region and maternally expressed gene 3-differentially methylated region in the corresponding chromosome 14 region. Both the parents were genetically tested after adequate genetic counseling, which revealed a Kagami–Ogata syndrome should have been suspected because of the presence of polyhydramnios and omphalocele during pregnancy. Respiratory insufficiency soon after birth, because of a small thorax, is expected in this disease and a diagnosis during pregnancy may have enabled appropriate care after birth. MEG3)-DMR is established after fertilization. Normally, these regions are hypermethylated in the case of paternally expressed genes and hypomethylated in the case of maternally expressed genes; as a result, RTL1 expression is suppressed in the maternal disomy of chromosome 14. However, in the paternal disomy of chromosome 14, two alleles of DMR are hypermethylated, resulting in overexpression of RTL1, which is responsible for clinical phenotypes. Other known causes apart from disomy are epigenetic mutations and microdeletions, including DMR of maternal origin [Kagami–Ogata syndrome is caused by abnormal genomic imprinting in the long arm of the chromosome 14q32.2 region. Genes are normally passed on to the offspring equally from both the parents; however, in genomic imprinting, genes are inherited from either the father  or mother  [The clinical phenotypes of cases have been reported previously. Specific facial gestalt , thoracic hypoplasia , abdominal wall abnormalities , polyhydramnios, placental hyperplasia, overweight at birth, psychomotor retardation, and feeding dysphagia, among other phenotypes, have been reported . The diaAlthough this was a very rare case, Kagami–Ogata syndrome can reportedly be diagnosed at the fetal stage. We, retrospectively, investigated this case to evaluate the clues for fetal diagnosis of this syndrome.Our patient was a 38-year-old Japanese primigravida woman referred to this hospital in the 19th week of pregnancy for suspected omphalocele. Her blood pressure was normal, height was 169 cm, body weight was 58 kg, body mass index (BMI) was 22, and she had no lower limb edema. She had a history of hypothyroidism but was prescribed orally administered levothyroxine (50 μg/day) prior to conception and was euthyroid. An ultrasound (US) scan prior to her referral to this hospital revealed fetal omphalocele. The estimated fetal weight was 365 g (+ 2.0 SD), which was large for date, and amniotic fluid was 130 cm, indicating polyhydramnios. Middle cerebral artery (MCA) and umbilical artery (UA) Doppler studies revealed an MCA-resistance index (RI) of 0.89, MCA-peak systolic velocity (PSV) of 49.07 cm/second, and UA-impedance index (II) of 0.49. The 75 g glucose tolerance test was conducted and the result was found to be normal. The mother was advised to be admitted for observation from 28 weeks of gestation for threatened premature delivery. She had a feeling of abdominal tightness but had no breathing difficulty; the cervical length was 15 mm. She was given betamethasone  because of the likelihood of preterm delivery at 31 weeks of gestation because of difficulty in controlling uterine contractions. In addition, because of aggravation of pressure symptoms due to polyhydramnios, we performed transabdominal amniocentesis and amniodrainage at 29.4 and 32.4 weeks without complications and removed 1535 mL and 1126 mL of amniotic fluid, respectively. She suffered premature rupture of the fetal membrane at 35.1 weeks and gave birth on the same day by emergency Cesarean section.The infant was a male child with a birth weight of 3188 g, Apgar scores of 3 at 1 minute and 6 at 5 minutes, and UA pH of 7.383. Spontaneous respiration of the infant was poor, and we performed intratracheal intubation at 9 minutes after birth and started artificial ventilation for respiratory care. A chest X-ray taken at 3 hours after birth  to naturally reduce into the abdominal cavity. Thereafter, at 10 days of age, we performed a radical surgery for the omphalocele.At 13 days of age, we performed endotracheal extubation and the infant was moved to bi-level positive airway pressure. Thereafter, he gradually stopped requiring positive pressure, and spontaneous respiration was established using nasal oxygen administration alone. Enteral feeding was started at 12 days of age. Thereafter, upon trying to feed milk orally, swallowing dysfunction was detected. Enteral feeding (full feeding) was established at 20 days of age along with commencement of swallowing training.Because the infant showed omphalocele, polyhydramnios, overweight, and abnormalities identified after birth, that is, thoracic hypoplasia morphological abnormality of the ribs, abnormal swallowing function, and peculiar facial features, we suspected Kagami–Ogata syndrome. After obtaining informed written consent from both the parents, chromosomal banding and genetic testing was performed for the infant.MEG3-DMR in the corresponding chromosome 14 imprinted regions. He was, therefore, diagnosed as having Kagami–Ogata syndrome. Furthermore, genetic testing of both the parents was performed after adequate explanation and genetic counseling. Although the alleles in the infant patient originated from both the parents, a comparative genomic hybridization (CGH) array showed microdeletion in the imprinted region. Analyses of both the parents revealed no deletion; thus, the deletion in the infant patient was considered de novo.Chromosome G-banding showed 46 normal XY karyotypes. Genetic testing revealed hypermethylated IG-DMR and The infant was discharged at 90 days of age with domiciliary oxygen therapy. After leaving the hospital, he used home oxygen therapy until he was 1 year and 3 months old, and after that, his breathing condition calmed down. He was able to walk alone at the age of 1 year and 8 months. A delay in language development was noticed and at the age of 2 years and 5 months, no meaningful speech could be recognized.Literature on fetal diagnosis reveals that seven or eight cases of death occur in premature infants . PolyhydIn this case, we retrospectively examined the points at which fetal diagnosis could have been established. In this case, omphalocele, polyhydramnios, and overweight were observed in the fetal stage. Re-examination of the three-dimensional/four-dimensional ultrasonogram revealed that the forehead and nose shape were characteristic of Kagami–Ogata syndrome Fig. . US examIn conclusion, cases presenting with abnormalities of the abdominal wall, such as polyhydramnios and omphalocele, and abnormality of the costal arch must be medically examined to rule out Kagami–Ogata syndrome. If diagnosed during pregnancy, the neonatal department can be consulted, information can be provided to both the parents, and the infant can be provided with continuous medical treatment after birth. Prenatal diagnosis may also be helpful for proactive treatment for threatened premature delivery.


Low birth weight (LBW) newborns present different health outcomes when classified in different birth weight strata. This study evaluated the relationship of birth weight with Infant mortality (IM) through the influence of biological, social, and health care factors in a time series.Retrospective cohort study with data collected from Information Systems . The mortality trends were performed for each birth weight stratum: extremely low, < 1000 g; very low, 1000–1499 g; low, 1500–2499 g; insufficient, 2500–2999 g; adequate, 3000–3900 g; and macrosomia, > 4000 g. Chi-square tests analyzed IM rates. Sequential Poisson regression analyzed the impact of the determinant factors.A total of 277,982 newborns were included in the study and 2088 died before their first year. There was a tendency for a decrease in mortality in all strata of weight. With the exception of macrosomics, all other strata had a higher risk for IM when compared with adequate birth weight. Extremely LBW newborns presented higher risk for mortality when born in a public hospital. A higher percentage of infant deaths were associated with lower maternal age and lower schooling for all strata. Prenatal care with less than three visits demonstrated a risk for IM in low, insufficient, and adequate birth weight strata. The cesarean section was a protective factor for IM in Extremely and Very LBW strata and it was a risk factor in adequate birth weight stratum.LBW had a greater association with IM, especially those children of younger mothers and those born in public hospitals. Birth weight is an important indicator and prognostic factor for the health of newborns, as it reflects the nutritional and metabolic conditions of the mother, as well as fetal development during pregnancy. The World Health Organization (WHO)  defines Birth weight, besides the gestational age and sex of the newborn, has a close relationship with infant mortality and its components . The lower the birth weight and the gestational age, the greater the chance of death in the first year of life .Newborns weighing less than 2500 g have a higher risk of neonatal morbidity and mortality, malnutrition in the first year of life, susceptibility to infections, respiratory distress and traumas during childbirth, and development of chronic non-communicable diseases (NCDs) . The estIn this context, a better understanding of the risk factors and outcomes associated with low birth weight allows a more qualified care to pregnant women and the newborn using more appropriately the new technologies developed in the area of prenatal, perinatal, and neonatal care. Lin et al.  highlighDespite these technological advances, maternal and child health conditions are related to the social reality and public care provided to this type of population. In this sense, health determinants that involve the various biological, social, and care-related aspects should be considered. Differences in exposure and vulnerability to health conditions such as living conditions, work conditions, food availability, types of behaviors, lifestyle, and the health system itself—especially when there is no access to protection factors such as prenatal care—are considered important determinants of health .To investigate these several factors in Brazil, several researchers have used the Health Information Systems (SIS), such as the Live Birth Information System (SINASC) and the Mortality Information System (SIM). These provide information on vital statistics (birth and death) that are relevant for assessing the health conditions of a given population.Low birth weight alone can be considered an important predictor of child mortality risk, and its temporal evaluation at a given location is relevant for the monitoring, planning, and execution of public policies in the field of maternal and child health. Thus, the purpose of this study was to analyze the association of the various birth weight strata of newborns, especially LBW and its categories, with infant mortality, observing the influence of the main determining factors in the municipality of Porto Alegre, the state capital located in the extreme south of Brazil.This study is characterized as a retrospective cohort study with secondary data on live births and deaths in the first year of life, from 2000 to 2015 in Porto Alegre, capital of the state of Rio Grande do Sul. The population of the municipality, according to the latest Brazilian Institute of Geography and Statistics (IBGE) Census, held in 2010, totaled 1,409,351 inhabitants, with an estimated 1,484,941 inhabitants for 2017 [Information on all single live births of mothers residing in the municipality of Porto Alegre was collected from the Live Birth Information System from 2000 to 2014. Those newborns weighing less than 500 g, multiple births or with congenital anomalies were excluded from the analysis.Birth weight was categorized into strata, based on the WHO definitions with the following denominations: extremely low birth weight (ELBW), 500–999 g; very low birth weight (VLBW), 1000–1499 g; low birth weight (LBW), 1500–2499 g; insufficient birth weight (IBW), 2500–2999 g; adequate weight (ABW), 3000–3999 g; and macrosomic (MACR), 4000 g or more [1, were investigated through the Mortality Information System. The databases, in the annual format, of these systems were provided by the Coordinator-General of Health Surveillance of the Municipal Health Department of Porto Alegre.For this survey, the biological, social, and health care determinants were categorized in order to analyze the relationship between birth weight and infant death. As for biological determinants, five variables were used: maternal age , gender of the newborn ; gestational age ; the 5-min Apgar Index ; and skin color of the mother (white or black/brown/Asian/indigenous). Regarding the social determinants, three variables were used: maternal schooling ; number of previous living children ; and number of previous deceased children . For the care determinants, three variables were considered: number of prenatal visits ; type of delivery ; and type of hospital . In addition to the information obtained from the Live Birth Information System, the data on the occurrence and death period, from 2000 to 2015Through the number of the Live Birth Statement (LBS), present in both information systems, a linkage was developed. The non-convergent data by the LBS number was manually linked by the mother’s name and date of birth. Data that did not present convergence of information was considered as missing values and excluded from the survey.Based on the number of live births and annual deaths presented in these two databases, a temporal analysis of the mortality trends for each weight stratum in the period studied (2000–2015) was performed. Preliminarily, the Average Annual Percentage Change (AAPC) was calculated, with a 95% confidence interval. This temporal trend was performed through the Join Point program (version 4.1.1.1). Subsequently, chi-square tests for trend were carried out to evaluate infant mortality rates.In order to evaluate the impact of the determinants in each weight stratum on the outcome studied , univariate robust Poisson regression was performed considering all the available data. The reference categoriesP < 0.20 were included in the model, with a 95% confidence interval, to evaluate the impact of the determinants and the incidence ratio (IR), for each of the weight strata, on infant mortality.Afterwards, multivariable analysis was conducted using Poisson regression with robust variance. All variables that presented The database processing and analyses were performed by the Statistical Package for the Social Sciences (SPSS) - version 18.From January 1, 2000, to December 31, 2014, there were 291,039 live births, born to mothers living in the municipality of Porto Alegre, according to Live Birth Information System data, and from 2000 to 2015, there were 3393 deaths of children under 1 year of age, according to the Mortality Information System. From this list, 129 (0.04%) birth records did not allow linkage with the death records and, therefore, were considered losses. A total of 13,057 newborns were excluded thus distributed among the exclusion criteria of the study: 280 who had a birth weight of less than 500 g, 7045 multiple births, and 5732 had congenital anomalies. The losses and exclusions included 13,186 newborns, corresponding to 4.53% of all births occurred during the study period. Thus, the final sample totaled 277,982 newborns, of which 2088 (0.75%) died before completing their first year of life.During the study period, with the exception of macrosomic newborns, there was a tendency for infant mortality rates to decrease in all strata. The lowest annual variation pattern (Average Annul Percent Change = 2.4) occurred among the newborns with extremely low birth weight (500–999 g), while the highest (AAPC = 7.9) occurred among those with insufficient birth weight (2500–2999 g) Figs.  and 2.FRegarding the risk for infant mortality, with the exception of macrosomic, all other newborns with strata weighing less than 3000 g presented higher risk when compared with those of adequate birth weight (3000–3999 g). Newborns with extremely low birth weight were 200 times more likely to die in the first year of life. As the birth weight stratum increased, as predicted, the incidence ratio for the risk of death gradually decreased Table .Table 1Subsequently, the relationship between infant deaths and health care determinants was analyzed considering all the available data Table . Among tRegarding gestational age, newborns younger than 22 weeks with extreme low birth weight (500–999 g) had a 92.5% death rate, which decreased to 63.2% with an increase in gestational age from 22 to 27 weeks. Among newborns in this same weight stratum, when presenting a gestation age of 28–31 weeks, there was a greater drop in the percentage of death, indicating a 35.6% mortality. Very low birth weight infants (1000–1499 g) presented a variation in gestational age between 22 weeks and, as a maximum, 36 weeks, and those born at 22–27 weeks had a risk of 1.9  times greater of death in the first year of life, when compared with the reference category (32–36 weeks).The male gender showed an association with infant mortality in newborns of extremely low birth weight and adequate birth weight strata. Among the biological determinants, the offspring of mothers with color/race in the black/brown/Asian/indigenous category, after the adjusted analysis, presented a higher risk of infant mortality when compared with white in the strata of newborns with insufficient birth weight and ABW. Infants with an Apgar score lower than 7 in the fifth minute of life had a significant association with death before the first year of life in all birth weight strata. A score less than 7 in the fifth minute of life increased proportionally with the birth weight increase of newborns.Regarding the social determinants, children of mothers with a maternal education of less than 8 years of schooling  had a higher percentage of infant death in the first year of life in all strata of newborns. This low maternal schooling presented a risk of 2.3  for infant mortality even among newborns with adequate birth weight (3000–3999 g). Regarding the number of living children, children of mothers with two, three, or more previous living children, when compared with the reference category, did not present a risk for infant mortality when the newborns were found in the lower extremely low birth weight strata. The number of previous deceased children was not related to infant death in the first year of life in the offspring of mothers of all birth weight strata studied.Among the determinants of care, the lack of prenatal care is a risk factor for infant mortality in newborns weighing 1500 g or more. The performance of one to three prenatal consultations, when compared with mothers who completed seven or more visits (reference category), demonstrated a risk for infant mortality in the very low birth weight, low birth weight, insufficient birth weight, and adequate birth weight strata. These results reveal a risk of death in the first year of life for most of the birth weight strata when the number of prenatal consultations is below that established by the Brazilian Ministry of Health and WHO, i.e., seven or more visits. Regarding the type of delivery, cesarean delivery, among infants with extremely low birth weight, was a protective factor of 0.7  for infant mortality when compared with vaginal delivery, and 0.7  among newborns in the VLBW stratum. In contrast, among newborns of ABW, cesarean delivery showed a risk of 1.3  times for infant death in the first year of life in relation to vaginal delivery. Birth in a public hospital showed a risk of 1.8 for infant mortality  only among newborns of the LBW stratum. Throughout the study period, newborns in private hospitals had a 26.7% occurrence of deaths in the first year of life in the ELBW stratum. This scenario rises to 47.7% in hospitals considered to be mixed and to 65.9% in public hospitals.The study focused on investigating the relation of birth weight in its various strata, especially in the cases of extreme low weight, very low weight, and low weight, with infant mortality, subject to the influence of the main biological, social, and care-related determinants of health within a time temporal series in a capital in the extreme south of Brazil.Low birth weight and prematurity are universally recognized as the most important risk factors for neonatal mortality. This research confirmed the importance of specialized assistance to newborns with LBW, as the percentage of deaths in the first year of life among them was high: 55% for children under 1000 g (extremely low birth weight) and 11 % among those from 1000 to 1499 g (very low birth weight). These data are similar to other studies in Brazil, which have shown that infant mortality in these groups is still very high, especially among newborn infants less than 750 g [Different associations between the determinants investigated with infant mortality among newborns of the various birth weight strata during the study period were observed. Those with adequate birth weight (3000–3999 g) had only 0.30% death in the first year of life. Regarding biological determinants, in this same stratum, a lower maternal age (17 years or less) revealed risk, whereas an older age (35 years or more) indicated protection for infant mortality. It should be noted that, among newborns in the ABW stratum, there was an inversely proportional relationship between maternal age and infant death in the first year of life.The 5-min Apgar Index was shown to be a risk factor for infant mortality in newborns in all birth weight strata, confirming that it is an important indicator of the viability of the newborn during perinatal care. In this context, it should be noted that, among infants in the extremely low birth weight and very low birth weight strata, as well as in the others, an Apgar Index of the fifth minute of life of less than seven meant that birth weight is directly proportional to the risk of infant mortality. Thus, the higher the birth weight, paradoxically, the greater the likelihood of death. As a possible hypothesis of this result, in the conditions of birth weight considered adequate, newborns with an Apgar score of less than seven in the fifth minute of life will have a greater influence of the other determinants of health. In this perspective, a study conducted in the same state in Brazil in 2012, also based on Live Birth Information System, showed that there was a relationship between the prenatal coverage of the pregnant woman and the vitality of the newborn (Apgar Index in the fifth minute of life), as a low number of consultations by the pregnant woman reflected in a low Apgar score for the newborn .In addition to the greater risk for mortality, newborns weighing less than 1000 g, physiologically, present a high risk of visual loss and blindness due to retinopathy of prematurity, pulmonary dysplasia (35–45% of cases), and heart disease . There iThe risk factors for neonatal survival and neonatal mortality in a cohort of live births with birth weight up to 1500 g (corresponding to the low birth weight and very low birth weight scores in the present study) were investigated in the city of São Paulo, the most populous city in Brazil . An ApgaMaternal education, number of prenatal consultations, and type of hospital, considered as social determinants, have been shown to influence the relationship between birth weight and infant mortality. This result indirectly reflects the socioeconomic conditions that are related to the quality of perinatal care. In this perspective, some studies pointed out that women with higher levels of education tend to be more prone to taking care of themselves, since, given their greater access to information, they are more aware of the care that must be taken both in the gestational and postpartum periods , 15. AccRegarding the determinants of care, prenatal care was an extremely important factor, since, as the number of consultations increased, there was a decrease in the incidence rate for infant mortality, except for newborns in the strata of extremely low birth weight. The importance of prenatal care has already been demonstrated in several studies. The adequate follow-up during pregnancy can assist in the early identification of problems in the fetus, making it possible to act in time to reduce the impact of possible complications, as well as to prevent the births of very low birth weight infants (less than 1500 g)  and has Another aspect in the scope of care analyzed by this study is the type of delivery. Among the newborns in the strata of extremely low birth weight and very low birth weight, cesarean delivery showed a protective effect for infant mortality. Differently, for newborns in the adequate birth weight stratum, cesarean delivery demonstrated a risk for infant mortality. Regarding the type of delivery, it has been demonstrated in other studies in Brazil that cesarean had a protective effect for neonatal mortality among newborns of VLBW , 13. AccRegarding the type of hospital, the results showed a risk for infant mortality among newborns in the extremely low birth weight stratum, which revealed an 85% higher likelihood of death in public hospitals than in private ones, and a 46% higher likelihood of this outcome when compared with mixed and private hospitals. Moreover, newborns weighing less than 1500 g born in public hospitals had a higher risk for infant mortality in the period studied. It should be noted that, in particular, a small increase in newborns in this birth weight stratum has previously been observed in the municipality . In thisIt is important to highlight a peculiar and interesting situation that occurs in some major cities of Brazil. More recently, as a way to improve neonatal care, some authors have warned about the increase of judicial decisions to obtain vacancies in neonatal intensive care unit . AccordiIn this study, the analysis of a health indicator such as infant mortality (outcome), considering the birth weight distributed among the different strata, allowed an interesting evaluation of the different determinants of health related to infant death. The studies usually aimed only at low birth weight infants (less than 2500 g), not discriminated according to their subcategories (extremely low weight and very low weight), which may induce misinterpretations regarding their association with infant mortality. Therefore, an evaluation of this detailed relationship in the different low birth weight strata, coupled with an analysis of the determining factors, also considered as mediators, should be interpreted as a strong point of this study. In addition, the use of two official health information systems ratified by the Ministry of Health of Brazil , available across the national territory and with a high level of quality –27 with Some of the limitations of the study that may be pointed out include the low number of newborns in some strata of weight, especially among those with over 4000 g; the use of categorical maternal variables such as gestational age, which, from 2012 onwards, became continuous, and the degree of maternal schooling classified in the Live Birth Information System, at intervals of years of study; and the lack of information about maternal smoking and other gestational diseases and obstetric indication for cesarean delivery that could contribute to the understanding of causal relationships on low birth weight.Therefore, fundamentally, prenatal care programs should develop effective actions to promote health and strengthen the importance of care during pregnancy. The development of effective strategies promotes fetal growth and development, thus contributing to an adequate birth weight of newborns, and should prioritize the follow-up and management of risk pregnancies and early detection of maternal-fetal diseases.The infant mortality rate has shown a declining trend in recent years, but low birth weight infants are still at increased risk for mortality.Among the determinants of health, lower age and maternal schooling are associated with a higher percentage of infant deaths for all birth weight strata. Insufficient prenatal (less than three visits) demonstrated a higher risk for infant mortality among low birth weight, insufficient, and adequate birth weight infants. The delivery performed in a public hospital presented a higher risk for mortality for the extremely low birth weight infants. Cesarean section was a protective factor for mortality among extremely low and very low birth weight infants and, on the contrary, was a risk factor for newborns with adequate birth weight.Some of the determinants of health investigated in this study have shown an influence on the birth weight, which is therefore closely related to infant mortality. The determinants of care have proved to be more representative and are liable to a more direct and punctual intervention by the public authorities. Consequently, it is necessary to ensure a more targeted and specific look at newborns weighing less than 2500 g in order to expand and qualify the care focus in prenatal, perinatal, and neonatal care, as well as the preparation and application of efficient policies in the field of maternal and infant health. In this way, it may be possible to reduce the rates of low birth weight, with a subsequent increase in the survival of these infants.Finally, although low birth weight continues to be an important risk factor for infant mortality, it is necessary to evaluate, individually, the different strata of LBW under the view of the different determinants of health involved. In this way, more effective and specific measures can be performed in the health care of the different LBW categories.Additional file 1: Database originated from the link between the two health information systems used . It contains all the variables used in the sixteen year period evaluated. (SAV 83644 kb)