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ADC Online First, published on September 26, 2014 as 10.1136/archdischild-2014-306175 Original article
The burden of selected congenital anomalies amenable to surgery in low and middle-income regions: cleft lip and palate, congenital heart anomalies and neural tube defects Hideki Higashi,1,2 Jan J Barendregt,2 Nicholas J Kassebaum,1,3 Thomas G Weiser,4 Stephen W Bickler,5 Theo Vos1,2 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ archdischild-2014-306175). For numbered affiliations see end of article. Correspondence to Dr Hideki Higashi, Institute for Health Metrics and Evaluation, University of Washington, 2301 Fifth Ave, Suite 600, Seattle, WA 98121, USA; [email protected] Received 9 February 2014 Revised 25 August 2014 Accepted 30 August 2014
ABSTRACT Objective To quantify the burden of selected congenital anomalies in low and middle-income countries (LMICs) that could be reduced should surgical programmes cover the entire population with access to quality care. Design Burden of disease and epidemiological modelling. Setting LMICs from all global regions. Population All prevalent cases of selected congenital anomalies at birth in 2010. Main outcome measures Disability-adjusted life years (DALYs). Interventions and methods Surgical programmes for three congenital conditions were analysed: clefts (lip and palate); congenital heart anomalies; and neural tube defects. Data from the Global Burden of Disease 2010 Study were used to estimate the combination of fatal burden that could be addressed by surgical care and the additional long-term non-fatal burden associated with increased survival. Results Of the estimated 21.6 million DALYs caused by these three conditions in LMICs, 12.4 million DALYs (57%) are potentially addressable by surgical care among the population born with such conditions. Neural tube defects have the largest potential with 76% of burden amenable by surgery, followed by clefts (59%) and congenital heart anomalies (49%). Sub-Saharan Africa and South Asia have the greatest proportion of surgically addressable burden for clefts (68%), North Africa and Middle East for congenital heart anomalies (73%), and South Asia for neural tube defects (81%). Conclusions There is an important and neglected role surgical programmes can play in reducing the burden of congenital anomalies in LMICs.
INTRODUCTION
To cite: Higashi H, Barendregt JJ, Kassebaum NJ, et al. Arch Dis Child Published Online First: [ please include Day Month Year] doi:10.1136/ archdischild-2014-306175
Congenital anomalies constitute a major cause of infant mortality, and patients that survive often live with disabilities that continue into adulthood. Approximately 3% of live births are associated with some kind of birth defect. Findings from the Global Burden of Diseases, Injuries and Risk Factors Study (GBD) 2010 suggest that 302 000 infants die from causes attributable to congenital anomalies (6% of all infant deaths), 96% of which occur in low and middle-income countries (LMICs).1
What is already known on this topic? ▸ From the Global Burden of Disease 2010 Study, congenital anomalies account for 302 000 infant deaths, 96% of which occur in low and middle-income countries. ▸ Some congenital anomalies, including cleft lip and palate, congenital heart anomalies and neural tube defects, can be treated by specialised surgical procedures. ▸ Such surgical services require specialised skills and infrastructure that they are often provided as vertical programmes in low and middle-income countries.
What this study adds? ▸ Disease burden associated with cleft lip and palate, congenital heart anomalies and neural tube defects in low and middle-income regions could be halved by scaling up surgical care. ▸ Vertical surgical programmes, including training, deserve due attention so as not to leave an important cause of premature infant death and long-term disability unaddressed.
Certain congenital anomalies can be treated by specialised operations, in particular clefts, neural tube defects and congenital heart anomalies. While some tertiary referral hospitals in LMICs may provide surgical care for these conditions,2 the advanced skills required for the procedure often hinder its incorporation into the general healthcare system. Therefore these conditions have often been managed by establishing vertical programmes in LMICs, frequently supported by international funding and surgical missions.3–5 The Disease Control Priorities Project6 identified surgery as an essential component of public health, where congenital anomalies accounted for 9% of burden estimated to be amenable to surgical care.7 This work has been conducted as part of a systematic estimate of surgical burden for the updated Disease Control Priorities Project. We aim to quantify the degree by which the burden of congenital
Higashi H, et al. Arch 2014. Dis Child Produced 2014;0:1–6. doi:10.1136/archdischild-2014-306175 1 Copyright Article author (or their employer) by BMJ Publishing Group Ltd (& RCPCH) under licence.
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Original article anomalies could be reduced among children born with the conditions in LMICs in what we would consider a ‘hypothetical’ state where the entire population has access to safe, reliable, efficacious and high quality surgical care.
METHODS Selection of conditions for analysis We examined three surgical conditions: clefts (lip and palate); congenital heart anomalies; and neural tube defects. These conditions were selected from the GBD 2010 cause list because they constitute a major burden of congenital anomalies (58% of burden of congenital anomalies in GBD 2010; see table 1 for estimates),1 because a reasonable amount of data and knowledge on epidemiology are available, and because there are clearly corresponding and established surgical programmes. While there are other congenital conditions that are correctable by surgery, most of them fall within the heterogeneous category of ‘other congenital conditions’ in GBD 2010, and hence a reasonable analysis of the proportion amenable to surgery could not be made. Disease-specific background information for the selected conditions is provided in the online appendix section 1.
Approach and analysis The base population for the analysis was all prevalent cases of each congenital anomaly at birth in 2010. Disability-adjusted life year (DALY) was used as the metric of burden that combines fatal burden and non-fatal burden of a health condition into a single index: years of life lost; and years lived with disability (YLDs). The burden of congenital anomalies reported in GBD 2010 was split into burden that is amenable to surgery and burden that is not. We first estimated the DALYs that would remain if surgical coverage had been scaled up to a hypothetical state of comprehensive, high quality surgical coverage, and defined this as the burden not amenable to surgery. We then subtracted it from the burden reported in the GBD 2010 to derive the burden amenable to surgery. We obtained data from the GBD 2010.1 Key parameters included: population, standard life expectancy, cause-specific mortality, prevalence and disability weight.8–10 The GBD 2010 employed a Bayesian meta-regression programme, DisMod-MR, which is built on an age-integrating mixed-effects negativebinomial model for all epidemiological parameters.9 The model incorporates covariates that predict variation in true rates between regions and that predict systematic variation across different types and sources of data (measurement bias) to produce and extrapolate an internally consistent set of epidemiological parameters for all regions that are specific to age, sex and year. The GBD 2010 grouped the countries into 21 epidemiological
Table 1 Burden of selected congenital anomalies in low and middle-income countries, 2010
Death YLL YLD DALY
Clefts
Congenital heart anomalies
Neural tube defects
3660 314 241 254 160 555 094
207 202 14 262 481 563 385 14 755 312
69 914 5 561 143 754 470 6 294 486
Source: Global Burden of Diseases (GBD) 2010 Study.1 8 9 NB: uncertainty bounds are not reported here. DALY, disability-adjusted life year; YLD, years lived with disability; YLL, years of life lost.
2
regions and seven super-regions (of which six regions group LMICs). Our analysis was conducted at the super-region level. We first estimated the non-fatal burden of each condition for the hypothetical circumstance of surgical coverage in LMIC super-regions (see online appendix subsection 2.1 for details). We assumed that the difference in prevalence between a particular age-group and the next in the high-income super region reflects the excess mortality of congenital anomalies in case of the hypothetical surgical coverage. Such excess mortality includes deaths attributed to anomalies as well as deaths coded otherwise that contribute to higher all-cause mortality among those with congenital anomalies compared with those without. Beginning with the birth prevalence in each region, we applied this assumption to age 1 year and above to follow the agespecific prevalence. The resulting prevalence for each sex and age was then multiplied by the disability weights of each to derive the YLDs condition (see online appendix subsection 2.1 for the disability weights used). Next, we estimated the fatal burden attributable to congenital anomalies under the hypothetical situation (see online appendix subsection 2.2 for details). We assumed that the lowest mortality rates of congenital anomalies (ie, number of deaths attributable to each congenital condition per prevalent case) among the 21 epidemiological regions for each age and sex reflect 100% surgical coverage, and hence the difference of mortality rates between each region and the lowest as reflecting the gap of surgical coverage. The majority of lowest mortality rates were from high-income regions (ie, Asia Pacific High Income, Australasia, Europe Western and North America High Income). By applying the lowest mortality rates to the prevalence of a hypothetical state as estimated above, we calculated the number of deaths attributable to each congenital condition for the hypothetical situation. We then multiplied the number of deaths by the agespecific standard life expectancy used in GBD 2010.8 11 Finally, we summed up non-fatal burden and fatal burden to derive the DALYs for the hypothetical state. For clefts, we conducted an extra analysis. The years of life lost of clefts in GBD 2010 only included those deaths coded as clefts being the underlying cause under the age of 5 years. This is potentially an underestimation of the true burden at the age of 5 years and above. If we compare the two epidemiological models from DisMod-MR that were used to estimate the YLDs of clefts (one for surgically repaired cases and another one for non-repaired cases),9 we see a sharp decline in prevalence as the non-repaired cases age, while that among repaired cases remains fairly steady throughout the life course (see online appendix section 3). This implies that the excess mortality due to any cause among the non-repaired clefts is far more prominent than those that had undergone repair, suggesting extra opportunities for reducing the burden of clefts through surgical repairs. We conducted a separate analysis using the set of parameters produced by the DisMod-MR models reflecting the excess mortality due to any cause rather than merely accounting for deaths that are attributed to clefts (see online appendix section 4 for details).
RESULTS Of the three congenital anomalies studied, deaths could be reduced by 67% and the disease burden by 57% in the population born with those conditions in LMICs by scaling up surgical programmes and providing comprehensive, efficacious, high quality interventions (see table 2). Deaths coded as being attributable to clefts can be reduced by appropriate surgery to virtually zero. Deaths from congenital heart anomalies appear more Higashi H, et al. Arch Dis Child 2014;0:1–6. doi:10.1136/archdischild-2014-306175
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Original article Table 2 Burden of congenital anomalies amenable to surgery in low and middle-income regions East Europe and Central Asia Clefts Death
113 (100%) YLL 9348 (100%) YLD* −507 (0%) DALY 8841 (38%) Congenital heart anomalies Death 8772 (68%) YLL 687 909 (73%) YLD* −24 112 (0%) DALY 663 797 (68%) Neural tube defects Death 1462 (93%) YLL 115 052 (92%) YLD* −5155 (0%) DALY 109 897 (78%) Total of three congenital anomalies Death 10 347 (71%) YLL 812 309 (75%) YLD* −29 774 (0%) DALY 782 535 (68%)
Sub-Saharan Africa
North Africa and Middle East
South Asia
East Asia Pacific
Latin America and Caribbean
Total
726 (100%) 60 103 (100%) 2769 (9%) 62 872 (68%)
115 (100%) 9514 (100%) 6788 (22%) 16 302 (40%)
1470 (100%) 121 660 (100%) 6522 (10%) 128 182 (68%)
1061 (100%) 87 708 (100%) 6727 (8%) 94 435 (55%)
176 (100%) 14 573 (100%) 3662 (17%) 18 235 (51%)
3661 (100%) 302 906 (100%) 25 961 (10%) 328 867 (59%)
2131 (9%) 212 778 (11%) −149 176 (0%) 63 602 (3%)
21 538 (76%) 1 749 893 (77%) −57 165 (0%) 1 692 728 (73%)
39 136 (59%) 1 254 018 (38%) −274 853 (0%) 979 165 (29%)
34 392 (65%) 2 903 207 (70%) −128 972 (0%) 2 774 235 (64%)
15 255 (71%) 1 156 527 (72%) −33 367 (0%) 1 123 160 (68%)
121 225 (58%) 7 964 332 (56%) −667 645 (0%) 7 296 687 (49%)
12 315 (88%) 1 045 529 (88%) −62 463 (0%) 983 066 (79%)
1694 (70%) 137 851 (69%) −18 613 (0%) 119 238 (44%)
39 391 (92%) 3 006 287 (91%) −82 659 (0%) 2 923 628 (81%)
5388 (83%) 440 770 (82%) 3248 (2%) 444 018 (60%)
2508 (90%) 206 955 (90%) −3898 (0%) 203 057 (76%)
62 758 (90%) 4 952 444 (89%) −169 540 (0%) 4 782 904 (76%)
15 172 (39%) 1 318 410 (40%) −208 870 (0%) 1 109 540 (32%)
23 347 (75%) 1 897 258 (77%) −68 990 (0%) 1 828 268 (70%)
79 997 (72%) 4 381 965 (65%) −350 990 (0%) 4 030 975 (56%)
40 841 (68%) 3 431 685 (72%) −118 997 (0%) 3 312 688 (63%)
17 939 (73%) 1 378 055 (74%) −33 603 (0%) 1 344 452 (68%)
187 643 (67%) 13 219 682 (65%) −811 224 (0%) 12 408 458 (57%)
NB: Percentages in parentheses are the amenable proportion of total burden. *Negative values of YLDs reflect the added non-fatal burden due to increased survival. DALY, disability-adjusted life year; YLD, years lived with disability; YLL, years of life lost.
difficult to prevent (58%) while deaths from neural tube defects can be reduced by 90%. Sub-Saharan Africa and South Asia have the largest proportion of burden of clefts amenable to surgery (68%), and East Europe and Central Asia and North Africa and Middle East the least (38–40%). While some of the regions have similarly high proportions of burden of neural tube defects amenable to surgery (about 80%), North Africa and Middle East, and perhaps East Asia Pacific, have a relatively low proportion (44–60%). In comparison to congenital heart anomalies, the proportion of DALYs of neural tube defects amenable to surgery is smaller than the deaths avoidable by surgery (76% vs. 90%, respectively). The results of congenital heart anomalies are rather counterintuitive that sub-Saharan Africa and South Asia have the smallest proportion of burden amenable to surgery (3% and 29%, respectively). The results from the extra analysis we conducted for clefts where we have taken into account the excess mortality due to any cause experienced by non-repaired cases are provided in table 3. The results demonstrate a 15-fold difference in the burden amenable to surgery (5.1 million as opposed to 0.33 million). Figures 1–3 visualise the results for each condition.
The burden of the three conditions amenable to surgery accounts for 33.5% of burden of all congenital anomalies in LMICs (37 million DALYS). By comparing the 12.4 million DALYs that is amenable to surgery with other global health challenges, the burden is equivalent to 11% of burden of ischaemic heart disease in LMICs (109 million DALYs in 2010) or 15% of that of HIV/AIDS (80.6 million DALYs in 2010).1 As is evident from the extra analysis conducted for clefts, the burden amenable to surgery could be even greater if excess mortality due to any cause that may be associated with neural tube defects and congenital heart anomalies were also taken into account. Generally, the higher proportion of burden amenable to surgery implies that a relatively small portion of burden had been avoided prior to 2010. The large proportion of burden of clefts amenable to surgery in sub-Saharan Africa and South Asia therefore reflects the low coverage of surgical care in 2010. The international charity Smile Train has been the largest provider of cleft repairs in China since 1999, contributing to the high surgical coverage in East Asia Pacific (285 000 repairs in China to date).5 Recently the same charity has been accelerating its
Higashi H, et al. Arch Dis Child 2014;0:1–6. doi:10.1136/archdischild-2014-306175
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DISCUSSION
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Original article Table 3 Burden of clefts amenable to surgery in low and middle-income regions (with all-cause excess mortality)
Death YLL YLD DALY
East Europe and Central Asia
Sub-Saharan Africa
North Africa and Middle East
South Asia
East Asia Pacific
Latin America and Caribbean
Total
1915 (63%) 142 859 (76%) 4802 (33%) 147 661 (73%)
16 863 (78%) 1 421 707 (85%) 26 106 (78%) 1 447 813 (85%)
8330 (86%) 577 720 (90%) 23 286 (71%) 601 006 (89%)
21 905 (79%) 1 658 090 (85%) 47 269 (67%) 1 705 359 (85%)
13 631 (77%) 926 507 (84%) 38 525 (43%) 965 032 (81%)
3004 (76%) 199 644 (83%) 10 057 (45%) 209 701 (80%)
65 648 (79%) 4 926 527 (85%) 150 045 (57%) 5 076 572 (84%)
NB: Percentages in parentheses are the amenable proportion of total burden. DALY, disability-adjusted life year; YLD, years lived with disability; YLL, years of life lost.
operations in India (335 000 repairs to date), which is likely reducing the burden in South Asia since 2010. Given that the extra analysis of clefts revealed a large number of deaths that may be associated with, yet not attributed to, clefts, surgical repair of clefts has the potential to further reduce the burden that has been attributed to other conditions. Surgical repair for congenital anomalies have often been accomplished through vertical programmes such as specialised clinics and medical missions. As the global health community looks beyond 2015 and the close of the Millennium Development Goals, the global health agenda is shifting towards a more systemic approach.12 Accordingly such surgical programmes should be incorporated in the general healthcare delivery framework through training and enhanced local infrastructure. Specialised surgical training programmes have been provided in Africa, Latin America, Asia and East and Central Europe, frequently by foreign charities that participate in clinical care and capacity development. However, the complex nature of these operations would likely be a non-trivial endeavour, at least in the short run, and vertical programmes could continue to fill in the gap until such time when local providers become capable of performing such operations, and providing training, on their own. This study is the most rigorous, data-driven estimation of burden of congenital anomalies amenable to surgery to date. As with any modelling and estimation exercise, assumptions were required that should be noted. The mortality data used in this study reflect those deaths where each of the three anomalies was coded as the underlying cause. There may be cases where deaths immediately following births due to congenital anomalies were coded elsewhere, such as ‘stillbirth’, causing underestimation of the burden. The counterintuitive results of the low proportion of burden of congenital heart anomalies amenable to surgery in sub-Saharan Africa and South Asia are likely due to coding practices. When comparing the infant mortality rates due to congenital heart anomalies between regions, sub-Saharan Africa and South Asia had substantially lower rates than other regions (9% and 29% as compared with an average of 68% in other LMIC regions). Given the sharp decline in prevalence between infants and the 1– 4 years age group, it is likely that a significant proportion of deaths were coded elsewhere. While verbal autopsy is frequently the source of data in determining the cause of death in these regions, congenital heart anomalies are not likely to be identified properly as the underlying cause. Should this be the case, the burden of congenital heart anomalies amenable to surgery estimated for these two regions is potentially underestimated. We assumed that the lowest fatality estimates from the 21 epidemiological regions reflect the ideal case of full surgical
coverage. A situation of full surgical coverage assumed here allows for timely access to surgical care, physically and financially, with sufficient quality when operation is warranted. Such a situation would potentially entail a mix of infrastructure, transport, appropriate skills and financing mechanisms. While most of the estimates were from high-income regions, it is not clear if those figures are applicable to other settings. Even if vertical programmes with foreign support, such as surgical missions, are able to reach the entire population, health-seeking behaviour may vary between regions and cultures. Some cases may need follow-up support leading to different long-term health outcomes, which depends on the total health system rather than the surgical care alone. These issues may have resulted in an overestimation of burden amenable to surgery. Another limitation is the absence of uncertainty intervals in the results. While the GBD 2010 study reported the uncertainty intervals of the estimated disease burden, only point estimates are reported in our analysis. The main sources of uncertainty in our study are the assumptions we had to make. Doing uncertainty analysis based on the uncertainty interval (credible or Bayesian CI) in the GBD 2010 estimates provides a false sense of precision because it does not include this main source of uncertainty. Finally, this analysis was conducted at the regional level due to the nature of GBD 2010, while results at the country level would have been more useful for policy making. The occurrence of neural tube defects is known to be preventable by appropriate folic acid intake in early pregnancy, and so the potential of surgical operations in reducing disease burden should not be interpreted as discouraging such critical interventions. In the global context, interventions for child health in LMICs have been largely targeting infectious diseases and nutritional conditions through vaccination, nutrition supplementation, water and sanitation, etc. While our analysis alludes to the magnitude of impact surgical operations could contribute to global health, we did not investigate the relative efficiency of surgical care in comparison to those other priority agenda. Therefore we are not able to suggest whether limited resources should be reallocated from those traditional child health interventions to paediatric surgery with a view of maximising health outcomes. While a number of studies have examined the cost-effectiveness of different surgical procedures in LMICs,13 future studies investigating the cost-effectiveness of these particular procedures would complement our study.
4
Higashi H, et al. Arch Dis Child 2014;0:1–6. doi:10.1136/archdischild-2014-306175
CONCLUSIONS There are substantial opportunities for specialised surgical interventions to reduce the burden of congenital anomalies in
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Original article Figure 1 Surgical burden of clefts in six LMIC super regions ((A) coded deaths only; (B) including all-cause excess mortality). DALY, disability-adjusted life year; LMICs, low and middle-income countries.
Figure 2 Surgical burden of congenital heart anomalies in six LMIC super regions. DALY, disability-adjusted life year. LMICs, low and middle-income countries.
Higashi H, et al. Arch Dis Child 2014;0:1–6. doi:10.1136/archdischild-2014-306175
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Original article Figure 3 Surgical burden of neural tube defects in six LMIC super regions. DALY, disability-adjusted life year. LMICs, low and middle-income countries.
LMICs. Such programmes may not become immediately available through general healthcare delivery systems due to the associated complexity, and hence may be overlooked in planning essential health services packages. Governments of LMICs and donor communities should pay due attention to these essential surgical programmes so as not to leave an important cause of premature infant death and long-term disability unaddressed. Author affiliations 1 Institute for Health Metrics and Evaluation, University of Washington, Seattle, Washington, USA 2 School of Population Health, University of Queensland, Brisbane, Queensland, Australia 3 Division of Anesthesiology & Pain Medicine, Seattle Children’s Hospital, Seattle, Washington, USA 4 Department of Surgery, School of Medicine, Stanford University, Stanford, California, USA 5 Department of Surgery, School of Medicine, University of California, San Diego, California, USA Contributors HH participated in conceptualising and designing of the study, performed primary analyses, and drafted the initial manuscript. JJB and TV participated in conceptualising and designing of the study, provided analytical expertise, and critically reviewed the manuscript. NJK, TGW and SWB participated in conceptualising and designing of the study, provided technical expertise of surgery, and critically reviewed the manuscript. All authors approved the final manuscript as submitted. Funding This research was supported by the Bill and Melinda Gates Foundation under the Disease Control Priorities Network Project. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed.
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Murray CJL, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2197–223. Bickler SW, Sanno-Duanda B. Epidemiology of paediatric surgical admissions to a government referral hospital in the Gambia. Bull World Health Organ 2000;78:1330–6. International Children’s Heart Foundation. Medical mission trips. Memphis: International Children’s Heart Foundation, 2013. http://babyheart.co/ babyheart-missions/medical-mission-trips/ (accessed 3 Nov 2013). CURE International. Uganda. Pennsylvania: CURE International, 2013. http://cure.org/ hospitals/uganda/ (accessed 3 Nov 2013). Smile Train. Our work around the world. New York: Smile Train, 2013. http://www. smiletrain.org/around-the-world/ (accessed 3 Nov 2013). Jamison D, Breman J, Measham A, et al. Disease control priorities in developing countries. 2nd edn. Washington, DC: The World Bank, 2006. Debas H, Gosselin R, McCord C, et al. Surgery. In: Jamison D, Breman J, Measham A, et al, eds. Disease control priorities in developing countries. 2nd edn. Washington, DC: The World Bank, 2006:1245–59. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2095–128. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2163–96. Salomon JA, Vos T, Hogan DR, et al. Common values in assessing health outcomes from disease and injury: disability weights measurement study for the Global Burden of Disease Study 2010. Lancet 2012;380:2129–43. Murray CJL, Ezzati M, Flaxman AD, et al. GBD 2010: design, definitions, and metrics. Lancet 2012;380:2063–6. World Health Organization. WHO discussion paper: positioning health in the post-2015 development agenda. Geneva: World Health Organization, 2012. Grimes C, Henry J, Maraka J, et al. Cost-effectiveness of surgery in low-and middle-income countries: a systematic review. World J Surg 2014;38:252–63.
Higashi H, et al. Arch Dis Child 2014;0:1–6. doi:10.1136/archdischild-2014-306175
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The burden of selected congenital anomalies amenable to surgery in low and middle-income regions: cleft lip and palate, congenital heart anomalies and neural tube defects Hideki Higashi, Jan J Barendregt, Nicholas J Kassebaum, et al. Arch Dis Child published online September 26, 2014
doi: 10.1136/archdischild-2014-306175
Updated information and services can be found at: http://adc.bmj.com/content/early/2014/09/26/archdischild-2014-306175.full.html
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References
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ADC Online First, published on September 26, 2014 as 10.1136/archdischild-2014-306175 Original article
The burden of selected congenital anomalies amenable to surgery in low and middle-income regions: cleft lip and palate, congenital heart anomalies and neural tube defects Hideki Higashi,1,2 Jan J Barendregt,2 Nicholas J Kassebaum,1,3 Thomas G Weiser,4 Stephen W Bickler,5 Theo Vos1,2 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ archdischild-2014-306175). For numbered affiliations see end of article. Correspondence to Dr Hideki Higashi, Institute for Health Metrics and Evaluation, University of Washington, 2301 Fifth Ave, Suite 600, Seattle, WA 98121, USA; [email protected] Received 9 February 2014 Revised 25 August 2014 Accepted 30 August 2014
ABSTRACT Objective To quantify the burden of selected congenital anomalies in low and middle-income countries (LMICs) that could be reduced should surgical programmes cover the entire population with access to quality care. Design Burden of disease and epidemiological modelling. Setting LMICs from all global regions. Population All prevalent cases of selected congenital anomalies at birth in 2010. Main outcome measures Disability-adjusted life years (DALYs). Interventions and methods Surgical programmes for three congenital conditions were analysed: clefts (lip and palate); congenital heart anomalies; and neural tube defects. Data from the Global Burden of Disease 2010 Study were used to estimate the combination of fatal burden that could be addressed by surgical care and the additional long-term non-fatal burden associated with increased survival. Results Of the estimated 21.6 million DALYs caused by these three conditions in LMICs, 12.4 million DALYs (57%) are potentially addressable by surgical care among the population born with such conditions. Neural tube defects have the largest potential with 76% of burden amenable by surgery, followed by clefts (59%) and congenital heart anomalies (49%). Sub-Saharan Africa and South Asia have the greatest proportion of surgically addressable burden for clefts (68%), North Africa and Middle East for congenital heart anomalies (73%), and South Asia for neural tube defects (81%). Conclusions There is an important and neglected role surgical programmes can play in reducing the burden of congenital anomalies in LMICs.
INTRODUCTION
To cite: Higashi H, Barendregt JJ, Kassebaum NJ, et al. Arch Dis Child Published Online First: [ please include Day Month Year] doi:10.1136/ archdischild-2014-306175
Congenital anomalies constitute a major cause of infant mortality, and patients that survive often live with disabilities that continue into adulthood. Approximately 3% of live births are associated with some kind of birth defect. Findings from the Global Burden of Diseases, Injuries and Risk Factors Study (GBD) 2010 suggest that 302 000 infants die from causes attributable to congenital anomalies (6% of all infant deaths), 96% of which occur in low and middle-income countries (LMICs).1
What is already known on this topic? ▸ From the Global Burden of Disease 2010 Study, congenital anomalies account for 302 000 infant deaths, 96% of which occur in low and middle-income countries. ▸ Some congenital anomalies, including cleft lip and palate, congenital heart anomalies and neural tube defects, can be treated by specialised surgical procedures. ▸ Such surgical services require specialised skills and infrastructure that they are often provided as vertical programmes in low and middle-income countries.
What this study adds? ▸ Disease burden associated with cleft lip and palate, congenital heart anomalies and neural tube defects in low and middle-income regions could be halved by scaling up surgical care. ▸ Vertical surgical programmes, including training, deserve due attention so as not to leave an important cause of premature infant death and long-term disability unaddressed.
Certain congenital anomalies can be treated by specialised operations, in particular clefts, neural tube defects and congenital heart anomalies. While some tertiary referral hospitals in LMICs may provide surgical care for these conditions,2 the advanced skills required for the procedure often hinder its incorporation into the general healthcare system. Therefore these conditions have often been managed by establishing vertical programmes in LMICs, frequently supported by international funding and surgical missions.3–5 The Disease Control Priorities Project6 identified surgery as an essential component of public health, where congenital anomalies accounted for 9% of burden estimated to be amenable to surgical care.7 This work has been conducted as part of a systematic estimate of surgical burden for the updated Disease Control Priorities Project. We aim to quantify the degree by which the burden of congenital
Higashi H, et al. Arch 2014. Dis Child Produced 2014;0:1–6. doi:10.1136/archdischild-2014-306175 1 Copyright Article author (or their employer) by BMJ Publishing Group Ltd (& RCPCH) under licence.
Downloaded from adc.bmj.com on October 1, 2014 - Published by group.bmj.com
Original article anomalies could be reduced among children born with the conditions in LMICs in what we would consider a ‘hypothetical’ state where the entire population has access to safe, reliable, efficacious and high quality surgical care.
METHODS Selection of conditions for analysis We examined three surgical conditions: clefts (lip and palate); congenital heart anomalies; and neural tube defects. These conditions were selected from the GBD 2010 cause list because they constitute a major burden of congenital anomalies (58% of burden of congenital anomalies in GBD 2010; see table 1 for estimates),1 because a reasonable amount of data and knowledge on epidemiology are available, and because there are clearly corresponding and established surgical programmes. While there are other congenital conditions that are correctable by surgery, most of them fall within the heterogeneous category of ‘other congenital conditions’ in GBD 2010, and hence a reasonable analysis of the proportion amenable to surgery could not be made. Disease-specific background information for the selected conditions is provided in the online appendix section 1.
Approach and analysis The base population for the analysis was all prevalent cases of each congenital anomaly at birth in 2010. Disability-adjusted life year (DALY) was used as the metric of burden that combines fatal burden and non-fatal burden of a health condition into a single index: years of life lost; and years lived with disability (YLDs). The burden of congenital anomalies reported in GBD 2010 was split into burden that is amenable to surgery and burden that is not. We first estimated the DALYs that would remain if surgical coverage had been scaled up to a hypothetical state of comprehensive, high quality surgical coverage, and defined this as the burden not amenable to surgery. We then subtracted it from the burden reported in the GBD 2010 to derive the burden amenable to surgery. We obtained data from the GBD 2010.1 Key parameters included: population, standard life expectancy, cause-specific mortality, prevalence and disability weight.8–10 The GBD 2010 employed a Bayesian meta-regression programme, DisMod-MR, which is built on an age-integrating mixed-effects negativebinomial model for all epidemiological parameters.9 The model incorporates covariates that predict variation in true rates between regions and that predict systematic variation across different types and sources of data (measurement bias) to produce and extrapolate an internally consistent set of epidemiological parameters for all regions that are specific to age, sex and year. The GBD 2010 grouped the countries into 21 epidemiological
Table 1 Burden of selected congenital anomalies in low and middle-income countries, 2010
Death YLL YLD DALY
Clefts
Congenital heart anomalies
Neural tube defects
3660 314 241 254 160 555 094
207 202 14 262 481 563 385 14 755 312
69 914 5 561 143 754 470 6 294 486
Source: Global Burden of Diseases (GBD) 2010 Study.1 8 9 NB: uncertainty bounds are not reported here. DALY, disability-adjusted life year; YLD, years lived with disability; YLL, years of life lost.
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regions and seven super-regions (of which six regions group LMICs). Our analysis was conducted at the super-region level. We first estimated the non-fatal burden of each condition for the hypothetical circumstance of surgical coverage in LMIC super-regions (see online appendix subsection 2.1 for details). We assumed that the difference in prevalence between a particular age-group and the next in the high-income super region reflects the excess mortality of congenital anomalies in case of the hypothetical surgical coverage. Such excess mortality includes deaths attributed to anomalies as well as deaths coded otherwise that contribute to higher all-cause mortality among those with congenital anomalies compared with those without. Beginning with the birth prevalence in each region, we applied this assumption to age 1 year and above to follow the agespecific prevalence. The resulting prevalence for each sex and age was then multiplied by the disability weights of each to derive the YLDs condition (see online appendix subsection 2.1 for the disability weights used). Next, we estimated the fatal burden attributable to congenital anomalies under the hypothetical situation (see online appendix subsection 2.2 for details). We assumed that the lowest mortality rates of congenital anomalies (ie, number of deaths attributable to each congenital condition per prevalent case) among the 21 epidemiological regions for each age and sex reflect 100% surgical coverage, and hence the difference of mortality rates between each region and the lowest as reflecting the gap of surgical coverage. The majority of lowest mortality rates were from high-income regions (ie, Asia Pacific High Income, Australasia, Europe Western and North America High Income). By applying the lowest mortality rates to the prevalence of a hypothetical state as estimated above, we calculated the number of deaths attributable to each congenital condition for the hypothetical situation. We then multiplied the number of deaths by the agespecific standard life expectancy used in GBD 2010.8 11 Finally, we summed up non-fatal burden and fatal burden to derive the DALYs for the hypothetical state. For clefts, we conducted an extra analysis. The years of life lost of clefts in GBD 2010 only included those deaths coded as clefts being the underlying cause under the age of 5 years. This is potentially an underestimation of the true burden at the age of 5 years and above. If we compare the two epidemiological models from DisMod-MR that were used to estimate the YLDs of clefts (one for surgically repaired cases and another one for non-repaired cases),9 we see a sharp decline in prevalence as the non-repaired cases age, while that among repaired cases remains fairly steady throughout the life course (see online appendix section 3). This implies that the excess mortality due to any cause among the non-repaired clefts is far more prominent than those that had undergone repair, suggesting extra opportunities for reducing the burden of clefts through surgical repairs. We conducted a separate analysis using the set of parameters produced by the DisMod-MR models reflecting the excess mortality due to any cause rather than merely accounting for deaths that are attributed to clefts (see online appendix section 4 for details).
RESULTS Of the three congenital anomalies studied, deaths could be reduced by 67% and the disease burden by 57% in the population born with those conditions in LMICs by scaling up surgical programmes and providing comprehensive, efficacious, high quality interventions (see table 2). Deaths coded as being attributable to clefts can be reduced by appropriate surgery to virtually zero. Deaths from congenital heart anomalies appear more Higashi H, et al. Arch Dis Child 2014;0:1–6. doi:10.1136/archdischild-2014-306175
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Original article Table 2 Burden of congenital anomalies amenable to surgery in low and middle-income regions East Europe and Central Asia Clefts Death
113 (100%) YLL 9348 (100%) YLD* −507 (0%) DALY 8841 (38%) Congenital heart anomalies Death 8772 (68%) YLL 687 909 (73%) YLD* −24 112 (0%) DALY 663 797 (68%) Neural tube defects Death 1462 (93%) YLL 115 052 (92%) YLD* −5155 (0%) DALY 109 897 (78%) Total of three congenital anomalies Death 10 347 (71%) YLL 812 309 (75%) YLD* −29 774 (0%) DALY 782 535 (68%)
Sub-Saharan Africa
North Africa and Middle East
South Asia
East Asia Pacific
Latin America and Caribbean
Total
726 (100%) 60 103 (100%) 2769 (9%) 62 872 (68%)
115 (100%) 9514 (100%) 6788 (22%) 16 302 (40%)
1470 (100%) 121 660 (100%) 6522 (10%) 128 182 (68%)
1061 (100%) 87 708 (100%) 6727 (8%) 94 435 (55%)
176 (100%) 14 573 (100%) 3662 (17%) 18 235 (51%)
3661 (100%) 302 906 (100%) 25 961 (10%) 328 867 (59%)
2131 (9%) 212 778 (11%) −149 176 (0%) 63 602 (3%)
21 538 (76%) 1 749 893 (77%) −57 165 (0%) 1 692 728 (73%)
39 136 (59%) 1 254 018 (38%) −274 853 (0%) 979 165 (29%)
34 392 (65%) 2 903 207 (70%) −128 972 (0%) 2 774 235 (64%)
15 255 (71%) 1 156 527 (72%) −33 367 (0%) 1 123 160 (68%)
121 225 (58%) 7 964 332 (56%) −667 645 (0%) 7 296 687 (49%)
12 315 (88%) 1 045 529 (88%) −62 463 (0%) 983 066 (79%)
1694 (70%) 137 851 (69%) −18 613 (0%) 119 238 (44%)
39 391 (92%) 3 006 287 (91%) −82 659 (0%) 2 923 628 (81%)
5388 (83%) 440 770 (82%) 3248 (2%) 444 018 (60%)
2508 (90%) 206 955 (90%) −3898 (0%) 203 057 (76%)
62 758 (90%) 4 952 444 (89%) −169 540 (0%) 4 782 904 (76%)
15 172 (39%) 1 318 410 (40%) −208 870 (0%) 1 109 540 (32%)
23 347 (75%) 1 897 258 (77%) −68 990 (0%) 1 828 268 (70%)
79 997 (72%) 4 381 965 (65%) −350 990 (0%) 4 030 975 (56%)
40 841 (68%) 3 431 685 (72%) −118 997 (0%) 3 312 688 (63%)
17 939 (73%) 1 378 055 (74%) −33 603 (0%) 1 344 452 (68%)
187 643 (67%) 13 219 682 (65%) −811 224 (0%) 12 408 458 (57%)
NB: Percentages in parentheses are the amenable proportion of total burden. *Negative values of YLDs reflect the added non-fatal burden due to increased survival. DALY, disability-adjusted life year; YLD, years lived with disability; YLL, years of life lost.
difficult to prevent (58%) while deaths from neural tube defects can be reduced by 90%. Sub-Saharan Africa and South Asia have the largest proportion of burden of clefts amenable to surgery (68%), and East Europe and Central Asia and North Africa and Middle East the least (38–40%). While some of the regions have similarly high proportions of burden of neural tube defects amenable to surgery (about 80%), North Africa and Middle East, and perhaps East Asia Pacific, have a relatively low proportion (44–60%). In comparison to congenital heart anomalies, the proportion of DALYs of neural tube defects amenable to surgery is smaller than the deaths avoidable by surgery (76% vs. 90%, respectively). The results of congenital heart anomalies are rather counterintuitive that sub-Saharan Africa and South Asia have the smallest proportion of burden amenable to surgery (3% and 29%, respectively). The results from the extra analysis we conducted for clefts where we have taken into account the excess mortality due to any cause experienced by non-repaired cases are provided in table 3. The results demonstrate a 15-fold difference in the burden amenable to surgery (5.1 million as opposed to 0.33 million). Figures 1–3 visualise the results for each condition.
The burden of the three conditions amenable to surgery accounts for 33.5% of burden of all congenital anomalies in LMICs (37 million DALYS). By comparing the 12.4 million DALYs that is amenable to surgery with other global health challenges, the burden is equivalent to 11% of burden of ischaemic heart disease in LMICs (109 million DALYs in 2010) or 15% of that of HIV/AIDS (80.6 million DALYs in 2010).1 As is evident from the extra analysis conducted for clefts, the burden amenable to surgery could be even greater if excess mortality due to any cause that may be associated with neural tube defects and congenital heart anomalies were also taken into account. Generally, the higher proportion of burden amenable to surgery implies that a relatively small portion of burden had been avoided prior to 2010. The large proportion of burden of clefts amenable to surgery in sub-Saharan Africa and South Asia therefore reflects the low coverage of surgical care in 2010. The international charity Smile Train has been the largest provider of cleft repairs in China since 1999, contributing to the high surgical coverage in East Asia Pacific (285 000 repairs in China to date).5 Recently the same charity has been accelerating its
Higashi H, et al. Arch Dis Child 2014;0:1–6. doi:10.1136/archdischild-2014-306175
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DISCUSSION
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Original article Table 3 Burden of clefts amenable to surgery in low and middle-income regions (with all-cause excess mortality)
Death YLL YLD DALY
East Europe and Central Asia
Sub-Saharan Africa
North Africa and Middle East
South Asia
East Asia Pacific
Latin America and Caribbean
Total
1915 (63%) 142 859 (76%) 4802 (33%) 147 661 (73%)
16 863 (78%) 1 421 707 (85%) 26 106 (78%) 1 447 813 (85%)
8330 (86%) 577 720 (90%) 23 286 (71%) 601 006 (89%)
21 905 (79%) 1 658 090 (85%) 47 269 (67%) 1 705 359 (85%)
13 631 (77%) 926 507 (84%) 38 525 (43%) 965 032 (81%)
3004 (76%) 199 644 (83%) 10 057 (45%) 209 701 (80%)
65 648 (79%) 4 926 527 (85%) 150 045 (57%) 5 076 572 (84%)
NB: Percentages in parentheses are the amenable proportion of total burden. DALY, disability-adjusted life year; YLD, years lived with disability; YLL, years of life lost.
operations in India (335 000 repairs to date), which is likely reducing the burden in South Asia since 2010. Given that the extra analysis of clefts revealed a large number of deaths that may be associated with, yet not attributed to, clefts, surgical repair of clefts has the potential to further reduce the burden that has been attributed to other conditions. Surgical repair for congenital anomalies have often been accomplished through vertical programmes such as specialised clinics and medical missions. As the global health community looks beyond 2015 and the close of the Millennium Development Goals, the global health agenda is shifting towards a more systemic approach.12 Accordingly such surgical programmes should be incorporated in the general healthcare delivery framework through training and enhanced local infrastructure. Specialised surgical training programmes have been provided in Africa, Latin America, Asia and East and Central Europe, frequently by foreign charities that participate in clinical care and capacity development. However, the complex nature of these operations would likely be a non-trivial endeavour, at least in the short run, and vertical programmes could continue to fill in the gap until such time when local providers become capable of performing such operations, and providing training, on their own. This study is the most rigorous, data-driven estimation of burden of congenital anomalies amenable to surgery to date. As with any modelling and estimation exercise, assumptions were required that should be noted. The mortality data used in this study reflect those deaths where each of the three anomalies was coded as the underlying cause. There may be cases where deaths immediately following births due to congenital anomalies were coded elsewhere, such as ‘stillbirth’, causing underestimation of the burden. The counterintuitive results of the low proportion of burden of congenital heart anomalies amenable to surgery in sub-Saharan Africa and South Asia are likely due to coding practices. When comparing the infant mortality rates due to congenital heart anomalies between regions, sub-Saharan Africa and South Asia had substantially lower rates than other regions (9% and 29% as compared with an average of 68% in other LMIC regions). Given the sharp decline in prevalence between infants and the 1– 4 years age group, it is likely that a significant proportion of deaths were coded elsewhere. While verbal autopsy is frequently the source of data in determining the cause of death in these regions, congenital heart anomalies are not likely to be identified properly as the underlying cause. Should this be the case, the burden of congenital heart anomalies amenable to surgery estimated for these two regions is potentially underestimated. We assumed that the lowest fatality estimates from the 21 epidemiological regions reflect the ideal case of full surgical
coverage. A situation of full surgical coverage assumed here allows for timely access to surgical care, physically and financially, with sufficient quality when operation is warranted. Such a situation would potentially entail a mix of infrastructure, transport, appropriate skills and financing mechanisms. While most of the estimates were from high-income regions, it is not clear if those figures are applicable to other settings. Even if vertical programmes with foreign support, such as surgical missions, are able to reach the entire population, health-seeking behaviour may vary between regions and cultures. Some cases may need follow-up support leading to different long-term health outcomes, which depends on the total health system rather than the surgical care alone. These issues may have resulted in an overestimation of burden amenable to surgery. Another limitation is the absence of uncertainty intervals in the results. While the GBD 2010 study reported the uncertainty intervals of the estimated disease burden, only point estimates are reported in our analysis. The main sources of uncertainty in our study are the assumptions we had to make. Doing uncertainty analysis based on the uncertainty interval (credible or Bayesian CI) in the GBD 2010 estimates provides a false sense of precision because it does not include this main source of uncertainty. Finally, this analysis was conducted at the regional level due to the nature of GBD 2010, while results at the country level would have been more useful for policy making. The occurrence of neural tube defects is known to be preventable by appropriate folic acid intake in early pregnancy, and so the potential of surgical operations in reducing disease burden should not be interpreted as discouraging such critical interventions. In the global context, interventions for child health in LMICs have been largely targeting infectious diseases and nutritional conditions through vaccination, nutrition supplementation, water and sanitation, etc. While our analysis alludes to the magnitude of impact surgical operations could contribute to global health, we did not investigate the relative efficiency of surgical care in comparison to those other priority agenda. Therefore we are not able to suggest whether limited resources should be reallocated from those traditional child health interventions to paediatric surgery with a view of maximising health outcomes. While a number of studies have examined the cost-effectiveness of different surgical procedures in LMICs,13 future studies investigating the cost-effectiveness of these particular procedures would complement our study.
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Higashi H, et al. Arch Dis Child 2014;0:1–6. doi:10.1136/archdischild-2014-306175
CONCLUSIONS There are substantial opportunities for specialised surgical interventions to reduce the burden of congenital anomalies in
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Original article Figure 1 Surgical burden of clefts in six LMIC super regions ((A) coded deaths only; (B) including all-cause excess mortality). DALY, disability-adjusted life year; LMICs, low and middle-income countries.
Figure 2 Surgical burden of congenital heart anomalies in six LMIC super regions. DALY, disability-adjusted life year. LMICs, low and middle-income countries.
Higashi H, et al. Arch Dis Child 2014;0:1–6. doi:10.1136/archdischild-2014-306175
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Original article Figure 3 Surgical burden of neural tube defects in six LMIC super regions. DALY, disability-adjusted life year. LMICs, low and middle-income countries.
LMICs. Such programmes may not become immediately available through general healthcare delivery systems due to the associated complexity, and hence may be overlooked in planning essential health services packages. Governments of LMICs and donor communities should pay due attention to these essential surgical programmes so as not to leave an important cause of premature infant death and long-term disability unaddressed. Author affiliations 1 Institute for Health Metrics and Evaluation, University of Washington, Seattle, Washington, USA 2 School of Population Health, University of Queensland, Brisbane, Queensland, Australia 3 Division of Anesthesiology & Pain Medicine, Seattle Children’s Hospital, Seattle, Washington, USA 4 Department of Surgery, School of Medicine, Stanford University, Stanford, California, USA 5 Department of Surgery, School of Medicine, University of California, San Diego, California, USA Contributors HH participated in conceptualising and designing of the study, performed primary analyses, and drafted the initial manuscript. JJB and TV participated in conceptualising and designing of the study, provided analytical expertise, and critically reviewed the manuscript. NJK, TGW and SWB participated in conceptualising and designing of the study, provided technical expertise of surgery, and critically reviewed the manuscript. All authors approved the final manuscript as submitted. Funding This research was supported by the Bill and Melinda Gates Foundation under the Disease Control Priorities Network Project. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed.
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Higashi H, et al. Arch Dis Child 2014;0:1–6. doi:10.1136/archdischild-2014-306175
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The burden of selected congenital anomalies amenable to surgery in low and middle-income regions: cleft lip and palate, congenital heart anomalies and neural tube defects Hideki Higashi, Jan J Barendregt, Nicholas J Kassebaum, et al. Arch Dis Child published online September 26, 2014
doi: 10.1136/archdischild-2014-306175
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References
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