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1.  Association between Prenatal Exposure to Antiretroviral Therapy and Birth Defects: An Analysis of the French Perinatal Cohort Study (ANRS CO1/CO11) 
PLoS Medicine  2014;11(4):e1001635.
Jeanne Sibiude and colleagues use the French Perinatal Cohort to estimate the prevalence of birth defects in children born to HIV-infected women receiving antiretroviral therapy during pregnancy.
Please see later in the article for the Editors' Summary
Background
Antiretroviral therapy (ART) has major benefits during pregnancy, both for maternal health and to prevent mother-to-child transmission of HIV. Safety issues, including teratogenic risk, need to be evaluated. We estimated the prevalence of birth defects in children born to HIV-infected women receiving ART during pregnancy, and assessed the independent association of birth defects with each antiretroviral (ARV) drug used.
Methods and Findings
The French Perinatal Cohort prospectively enrolls HIV-infected women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 y of age according to national guidelines.
We included 13,124 live births between 1994 and 2010, among which, 42% (n = 5,388) were exposed to ART in the first trimester of pregnancy. Birth defects were studied using both European Surveillance of Congenital Anomalies (EUROCAT) and Metropolitan Atlanta Congenital Defects Program (MACDP) classifications; associations with ART were evaluated using univariate and multivariate logistic regressions. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study. The prevalence of birth defects was 4.4% (95% CI 4.0%–4.7%), according to the EUROCAT classification. In multivariate analysis adjusting for other ARV drugs, maternal age, geographical origin, intravenous drug use, and type of maternity center, a significant association was found between exposure to zidovudine in the first trimester and congenital heart defects: 2.3% (74/3,267), adjusted odds ratio (AOR) = 2.2 (95% CI 1.3–3.7), p = 0.003, absolute risk difference attributed to zidovudine +1.2% (95% CI +0.5; +1.9%). Didanosine and indinavir were associated with head and neck defects, respectively: 0.5%, AOR = 3.4 (95% CI 1.1–10.4), p = 0.04; 0.9%, AOR = 3.8 (95% CI 1.1–13.8), p = 0.04. We found a significant association between efavirenz and neurological defects (n = 4) using the MACDP classification: AOR = 3.0 (95% CI 1.1–8.5), p = 0.04, absolute risk +0.7% (95% CI +0.07%; +1.3%). But the association was not significant using the less inclusive EUROCAT classification: AOR = 2.1 (95% CI 0.7–5.9), p = 0.16. No association was found between birth defects and lopinavir or ritonavir with a power >85% for an odds ratio of 1.5, nor for nevirapine, tenofovir, stavudine, or abacavir with a power >70%. Limitations of the present study were the absence of data on termination of pregnancy, stillbirths, tobacco and alcohol intake, and concomitant medication.
Conclusions
We found a specific association between in utero exposure to zidovudine and heart defects; the mechanisms need to be elucidated. The association between efavirenz and neurological defects must be interpreted with caution. For the other drugs not associated with birth defects, the results were reassuring. Finally, whatever the impact that some ARV drugs may have on birth defects, it is surpassed by the major role of ART in the successful prevention of mother-to-child transmission of HIV.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS and HIV infection are commonly treated with antiretroviral therapy (ART), a combination of individual drugs that work together to prevent the replication of the virus and further spread of the infection. Starting in the 1990s, studies have shown that ART of HIV-infected women can substantially reduce transmission of the virus to the child during pregnancy and birth. Based on these results, ART was subsequently recommended for pregnant women. Since 2004, ART has been standard therapy for pregnant women with HIV/AIDS in high-income countries, and it is now recommended for all HIV-infected women worldwide. Several different antiviral drug combinations have been shown to be effective and are used to prevent mother-to-infant transmission. However, as with any other drugs taken during pregnancy, there is concern that ART can harm the developing fetus.
Why Was This Study Done?
Several previous studies have assessed the risk that ART taken by a pregnant woman might pose to her developing fetus, but the results have been inconsistent. Animal studies suggested an elevated risk for some drugs but not others. While some clinical studies have reported increases in birth defects in children born to mothers on ART, others have shown no such increase.
The discrepancy may be due to differences between the populations included in the studies and the different methods used to diagnose birth defects. Additional large studies are therefore necessary to obtain more and better evidence on the potential harm of individual anti-HIV drugs to children exposed during pregnancy. So in this study, the authors conducted a large cohort study in France to assess the relationship between different antiretroviral drugs and specific birth defects.
What Did the Researchers Do and Find?
The researchers used a large national health database known as the French Perinatal Cohort that contains information on HIV-infected mothers who delivered infants in 90 centers throughout France. Pediatricians follow all children, whatever their HIV status, to two years of age, and health statistics are collected according to national health-care guidelines. Analyzing the records, the researchers estimated the rate at which birth defects occurred in children exposed to antiretroviral drugs during pregnancy.
The researchers included 13,124 children who were born alive between 1994 and 2010 and had been exposed to ART during pregnancy. Children exposed in the first trimester of pregnancy, and those exposed during the second or third trimester, were compared to a control group (children not exposed to the drug during the whole pregnancy). Using two birth defect classification systems (EUROCAT and MACDP—MACDP collects more details on disease classification than EUROCAT), the researchers sought to detect a link between the occurrence of birth defects and exposure to individual antiretroviral drugs.
They found a small increase in the risk for heart defects in children with exposure to zidovudine. They also found an association between efavirenz exposure and a small increase in neurological defects, but only when using the MACDP classification system. The authors found no association between other antiretroviral drugs, including nevirapine (acting similar to efavirenz); tenofovir, stavudine, and abacavir (all three acting similar to zidovudine); and lopinavir and ritonavir (proteinase inhibitors) and any type of birth defect.
What Do These Findings Mean?
These findings show that, overall, the risks of birth defects in children exposed to antiretroviral drugs in utero are small when considering the clear benefit of preventing mother-to-child transmission of HIV. However, where there are safe and effective alternatives, it might be appropriate to avoid use by pregnant women of those drugs that are associated with elevated risks of birth defects.
Worldwide, a large number of children are exposed to zidovudine in utero, and these results suggest (though cannot prove) that these children may be at a slightly higher risk of heart defects. Current World Health Organization (WHO) guidelines for the prevention of mother-to-child transmission no longer recommend zidovudine for first-line therapy.
The implications of the higher rate of neurological birth defects observed in infants exposed to efavirenz in the first trimester are less clear. The EUROCAT classification excludes minor neurological abnormalities without serious medical consequences, and so the WHO guidelines that stress the importance of careful clinical follow-up of children with exposure to efavirenz seem adequate, based on the findings of this study. The study is limited by the lack of data on the use of additional medication and alcohol and tobacco use, which could have a direct impact on fetal development, and by the absence of data on birth defects and antiretroviral drug exposure from low-income countries. However, the findings of this study overall are reassuring and suggest that apart from zidovudine and possibly efavirenz, other antiretroviral drugs are not associated with birth defects, and their use during pregnancy does not pose a risk to the infant.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001635.
This study is further discussed in a PLOS Medicine Perspective by Mofenson and Watts
The World Health Organization has a webpage on mother-to-child transmission of HIV
The US National Institutes of Health provides links to additional information on mother-to-child transmission of HIV
The Elizabeth Glaser Pediatric AIDS Foundation also has a webpage on mother-to-child transmission
The French Perinatal Cohort has a webpage describing the cohort and its main publications (in French, with a summary in English)
doi:10.1371/journal.pmed.1001635
PMCID: PMC4004551  PMID: 24781315
2.  Maternal age and birth defects after the use of assisted reproductive technology in Japan, 2004–2010 
Background
Older mothers are becoming more common in Japan. One reason for this is the widespread use of assisted reproductive technology (ART). This study assesses the relationship between maternal age and the risk of birth defects after ART.
Methods
Nationwide data on ART between 2004 and 2010 in Japan were analyzed. Diseases that were classified as code Q00-Q99 (ie, congenital malformations, deformations, and chromosomal abnormalities) in the International Classification of Diseases, tenth edition, were selected. There were 219,185 pregnancies and 153,791 live births in total ART. Of these, 1943 abortions, stillbirths, or live births with birth defects were recorded. Percentage of multiple birth defects in total birth defects, the prevalence, crude relative risk and 95% confidence interval per 10,000 pregnancies and per 10,000 live births were analyzed according to the maternal age class (ie, 25–29, 30–34 (reference), 35–39, and 40+ years).
Results
Multiple birth defects were observed among 14% of the 25–29 year old class, and 8% among other classes when chromosomal abnormalities were excluded. The prevalence of chromosomal abnormalities per pregnancy and per live birth became significantly and rapidly higher in mothers in the age classes of 30–35 and 40+ years. Nonchromosomal birth defects per pregnancy decreased linearly with advanced maternal age, while the number of nonchromosomal birth defects per live birth formed a gradual U-shaped distribution. The prevalence per pregnancy of congenital malformations of the nervous system was significantly lower with advanced maternal age. The relative risk per live birth was significant regarding congenital malformations of the circulatory system for a maternal age of 40+ years. Some other significant associations between maternal age and birth defects were observed.
Conclusion
Maternal age is associated with several birth defects; however, older maternal age in itself does not produce noticeable extra risk for nonchromosomal birth defects overall.
doi:10.2147/IJWH.S32296
PMCID: PMC3581291  PMID: 23450007
birth defects; assisted reproductive technology; maternal age; pregnancy; live births; epidemiologic prevalence study
3.  Predicting Live Birth, Preterm Delivery, and Low Birth Weight in Infants Born from In Vitro Fertilisation: A Prospective Study of 144,018 Treatment Cycles 
PLoS Medicine  2011;8(1):e1000386.
Using the HFEA database of all 144,018 live births in all IVF cycles in the UK between 2003 and 2007, Scott Nelson and Debbie Lawlor show that couple- and treatment-specific factors can be used to help predict successful outcome following IVF.
Background
The extent to which baseline couple characteristics affect the probability of live birth and adverse perinatal outcomes after assisted conception is unknown.
Methods and Findings
We utilised the Human Fertilisation and Embryology Authority database to examine the predictors of live birth in all in vitro fertilisation (IVF) cycles undertaken in the UK between 2003 and 2007 (n = 144,018). We examined the potential clinical utility of a validated model that pre-dated the introduction of intracytoplasmic sperm injection (ICSI) as compared to a novel model. For those treatment cycles that resulted in a live singleton birth (n = 24,226), we determined the associates of potential risk factors with preterm birth, low birth weight, and macrosomia. The overall rate of at least one live birth was 23.4 per 100 cycles (95% confidence interval [CI] 23.2–23.7). In multivariable models the odds of at least one live birth decreased with increasing maternal age, increasing duration of infertility, a greater number of previously unsuccessful IVF treatments, use of own oocytes, necessity for a second or third treatment cycle, or if it was not unexplained infertility. The association of own versus donor oocyte with reduced odds of live birth strengthened with increasing age of the mother. A previous IVF live birth increased the odds of future success (OR 1.58, 95% CI 1.46–1.71) more than that of a previous spontaneous live birth (OR 1.19, 95% CI 0.99–1.24); p-value for difference in estimate <0.001. Use of ICSI increased the odds of live birth, and male causes of infertility were associated with reduced odds of live birth only in couples who had not received ICSI. Prediction of live birth was feasible with moderate discrimination and excellent calibration; calibration was markedly improved in the novel compared to the established model. Preterm birth and low birth weight were increased if oocyte donation was required and ICSI was not used. Risk of macrosomia increased with advancing maternal age and a history of previous live births. Infertility due to cervical problems was associated with increased odds of all three outcomes—preterm birth, low birth weight, and macrosomia.
Conclusions
Pending external validation, our results show that couple- and treatment-specific factors can be used to provide infertile couples with an accurate assessment of whether they have low or high risk of a successful outcome following IVF.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than 10% of couples are infertile. Sometimes there is no obvious reason for a couple's inability to have children but, for many couples, problems with their eggs or sperm prevent “fertilization”—the union of an egg and a sperm that leads, eventually, to the birth of a baby. Until recently, little could be done to help infertile couples. Then, on the 25 July 1978, the world's first “test-tube baby” was born. Since then, 4 million babies have been born through in vitro fertilization (IVF). In IVF, mature eggs are collected from the woman (or from an egg donor if the woman cannot make her own eggs) after a course of special hormones, and they are mixed in a dish with her partner's sperm. If her partner has a low sperm count or abnormal sperm, a single sperm can be injected directly into the egg in a procedure called intracytoplasmic sperm injection (ICSI), which became widely available in the mid 1990s, or sperm from a donor can be used. Finally, a number (depending on the country) of embryos (eggs that have begun to divide and develop) are put back into the woman where, hopefully, they will establish a successful pregnancy.
Why Was This Study Done?
Not every attempt at IVF is successful. In the US and the UK, IVF is successful in about a third of women under 35 years old but in only 5%–10% of women over the age of 40. It would be useful to have a way to predict the likelihood of a live birth after IVF for individual couples. Such a “prediction model” would facilitate patient counseling, clinical decision making, and the allocation of IVF resources. In this study, the researchers use information on IVF cycles collected by the Human Fertilisation and Embryology Authority (HFEA), which regulates IVF in the UK, to assess the extent to which the characteristics of infertile couples and the treatment they receive can be used to predict live birth after IVF. They also use these data to identify which factors are associated with preterm delivery, low birthweight, and macrosomia (the birth of an unusually large baby), three undesirable birth characteristics.
What Did the Researchers Do and Find?
Between 2003 and 2007, 163,425 IVF cycles were completed in the UK, 23.4% of which resulted in at least one live birth. The researchers used the data collected by the HFEA on 144,018 of these cycles (the other cycles had missing data) to develop a multivariable logistic regression prediction model (a type of statistical model) for the outcome of IVF. According to this model, a decreased chance of at least one live birth was associated with several factors including increasing maternal age, increasing duration of infertility, and the use of the woman's own oocytes. By contrast, a previous IVF live birth and the use of ICSI were associated with increased chances of success. Importantly, compared with an established multivariable prediction model, which was developed before the introduction of ICSI, the researchers' new prediction model predicted the chance of a live birth following IVF with greater accuracy. Finally, the researchers report that the chances of preterm and low birthweight after IVF were increased if donor eggs were required and ICSI was not used, that an increased risk of macrosomia was associated with increasing maternal age and with a history of previous live births, and that all three undesirable birth characteristics were associated with infertility due to cervical problems.
What Do These Findings Mean?
These findings indicate that couple- and treatment-specific factors can be used to provide infertile couples with an accurate assessment of whether they have a low or high chance of a successful outcome following IVF. The prediction model developed here provides a more accurate assessment of likely outcomes after IVF than a previously established model. Furthermore, because the new model considers the effect of ICSI on outcomes, it should be more useful in contemporary populations than the established model, which does not consider ICSI. However, before this new prediction model is used to guide clinical decisions and to counsel patients, it needs to be validated using independent IVF data. To facilitate the external validation of their model, the researchers are currently generating a free web-based prediction tool and iPhone application (IVFpredict).
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000386.
The Human Fertilisation and Embryology Authority provides information on IVF and IVF statistics for the UK
The UK National Health Service Choices website provides information for patients on infertility and on IVF
The American Pregnancy Association has information for patients on infertility and on IVF
MedlinePlus has links to further resources on infertility and IVF (in English and Spanish)
The history of the development of IVF is described on the Nobel Prize website
The prediction tool that was used in this study is at http://www.IVFpredict.com
doi:10.1371/journal.pmed.1000386
PMCID: PMC3014925  PMID: 21245905
4.  Congenital malformations in Ecuadorian children: urgent need to create a National Registry of Birth Defects 
Aim
This study sets out (a) to estimate the prevalence of admissions by birth defects, using the official database of hospitals of Ecuador; and (b) to set the basis for a new National Register of Birth Defects in Ecuador that works as a program for the clinical and epidemiological investigation of risk factors in the etiology of congenital anomalies in Ecuadorian hospitals, using a case-control methodological approach. This is the first report in their class.
Methods
The data used in this study are derived from the National Register of Hospital Admission/Discharges of the Instituto Nacional de Estadísticas y Censos; data of the Ministry of Public Health were also used. Ecuador does not have an official Medical Birth Registry or a Congenital Malformations Registry.
Results
A total of 51,375 discharges by congenital malformations were registered in a 7-year period. Of these, 16,679 admissions were of children aged less than 1 year of age, with a birth prevalence rate (BPR) of 72.33/10,000 births. 77% of the congenital defects registered comprise the 50 most common birth defects observed in this age group. Cleft lip was the most prevalent birth defect in children less than 1 year of age and the second most common defect in children 1 to 5 years of age. Unilateral cleft lip shows a BPR of 4.57/10,000 births; cardiac birth defects as a group have a BPR of 4.2; hydrocephalus a BPR of 3.77; and Down’s syndrome a BPR of 3.70. Undescended testicle was the most prevalent birth defect in children between 1 to 5 years. 9384 children under 1 year of age were male (55.9%) and 7053 were female (42.1%). BPR in males was 40.45 and in females 30.40.
Conclusion
This report documents the prevalence estimates for birth defects reported in the hospital discharge data. These estimates are important to 1) plan for health-care and education needs of the Ecuadorian population, 2) identify increased occurrences of birth defects in specific geographic regions, 3) serve as a reference point for assessment of provincial surveillance systems, 4) evaluate national public health interventions, 5) compare Ecuador prevalence estimates with those of other countries, and 6) help determine the appropriate allocation of resources for basic and public health research. There is an urgent need to establish a National Registry of Birth Defects involving different sources of information such as prenatal medical records, birth records and medical records during the first year of life at an early stage, and surveys on cytogenetic prenatal diagnostic surveys and cytogenetics of therapeutic abortions.
PMCID: PMC3681162  PMID: 23776361
Ecuador; genetics; birth defects surveillance; database; prevalence; epidemiology; congenital malformations
5.  Major Radiodiagnostic Imaging in Pregnancy and the Risk of Childhood Malignancy: A Population-Based Cohort Study in Ontario 
PLoS Medicine  2010;7(9):e1000337.
In a record-linkage study, Joel Ray and colleagues examine the association between diagnostic imaging during pregnancy and later childhood cancers.
Background
The association between fetal exposure to major radiodiagnostic testing in pregnancy—computed tomography (CT) and radionuclide imaging—and the risk of childhood cancer is not established.
Methods and Findings
We completed a population-based study of 1.8 million maternal-child pairs in the province of Ontario, from 1991 to 2008. We used Ontario's universal health care–linked administrative databases to identify all term obstetrical deliveries and newborn records, inpatient and outpatient major radiodiagnostic services, as well as all children with a malignancy after birth. There were 5,590 mothers exposed to major radiodiagnostic testing in pregnancy (3.0 per 1,000) and 1,829,927 mothers not exposed. The rate of radiodiagnostic testing increased from 1.1 to 6.3 per 1,000 pregnancies over the study period; about 73% of tests were CT scans. After a median duration of follow-up of 8.9 years, four childhood cancers arose in the exposed group (1.13 per 10,000 person-years) and 2,539 cancers in the unexposed group (1.56 per 10,000 person-years), a crude hazard ratio of 0.69 (95% confidence interval 0.26–1.82). After adjusting for maternal age, income quintile, urban status, and maternal cancer, as well as infant sex, chromosomal or congenital anomalies, and major radiodiagnostic test exposure after birth, the risk was essentially unchanged (hazard ratio 0.68, 95% confidence interval 0.25–1.80).
Conclusions
Although major radiodiagnostic testing is now performed in about 1 in 160 pregnancies in Ontario, the absolute annual risk of childhood malignancy following exposure in utero remains about 1 in 10,000. Since the upper confidence limit of the relative risk of malignancy may be as high as 1.8 times that of an unexposed pregnancy, we cannot exclude the possibility that fetal exposure to CT or radionuclide imaging is carcinogenic.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In industrialized countries, childhood cancer (any form of cancer in a child aged 14 years or under) remains a major cause of death. With the exception of a few known risk factors, such as acquired genetic predisposition to cancer, which accounts for about 10% of all childhood cancers, the etiology of most childhood cancer remains unknown. There is thought to be an association between exposure to ionizing radiation in pregnancy and the subsequent risk of development of cancer in the exposed mother's child, but the evidence base to support this association is conflicting. For example, studies examining maternal exposure to plain radiographs in pregnancy and subsequent childhood cancer are inconsistent. Furthermore, although their use has dramatically increased over the past two decades, little is known about the cancer risk related to certain types of radiodiagnostic tests, such as CT and radionuclide imaging, both of which expose the fetus to considerably higher doses of radiation than plain radiographs administered at the same anatomical level.
Why Was This Study Done?
Many women could be exposed to major radiodiagnostic tests, such as those used in emergency situations, before they are aware that they are pregnant, as almost 50% of pregnancies are unplanned. This situation means that it is important to determine the subsequent cancer risk to any child exposed to maternal radiodiagnostic tests before birth.
What Did the Researchers Do and Find?
The researchers conducted a retrospective population-based cohort study of women who delivered a live infant in Ontario, Canada between April 1, 1992 and March 31, 2008. The basis of the research was an anonymized database for the whole province of Ontario, where universal health care, including prenatal care and radiodiagnostic testing, is available to all residents. Database characteristics allowed the researchers to link maternal radiation exposure (a major radiodiagnostic test performed on the mother up to one day before her delivery date) in a specific (index) pregnancy to a subsequent malignancy in the child. After birth, maternal-infant pairs were only followed up if the infant was delivered at term, weighed 2,500 g or more, and survived for at least 30 days.
The researchers were able to follow up 1,835,517 maternal-child pairs. The overall rate of exposure to major radiodiagnostic testing in pregnancy was 3.0 per 1,000 and occurred at an estimated mean gestational age of 15.7 weeks. A total of four childhood cancers occurred in the exposed group and 2,539 cancers in the unexposed group corresponding to a crude hazard ratio of 0.69, which did not significantly change after adjustments were made for potential confounding factors, such as maternal age, sex, and the presence of any chromosomal or congenital anomalies in the infant. The overall prevalence of childhood cancer following exposure to CT or radionuclide imaging in pregnancy is under 0.07%, giving an incidence rate of 1.13 per 10,000 person-years.
What Do These Findings Mean?
These findings can help inform clinicians and mothers about the risk of childhood malignancy following major radiodiagnostic testing in pregnancy. The absolute risk appears to be low, while the relative risk is not materially higher than that of unexposed controls. However, as the upper confidence limit of the relative risk of malignancy may be a maximum of 1.8 times that of an unexposed pregnancy, the possibility that fetal exposure to CT or radionuclide imaging is carcinogenic cannot be excluded. Because this finding means that a very slight risk may exist, beta hCG testing should continue to be done in all potentially pregnant women before undergoing major radiodiagnostic testing, and lead apron shielding used in all women of reproductive age, whether or not known to be pregnant. In addition, nonradiation-emitting imaging, such as MRI and ultrasonography, should be considered first, when clinically appropriate. However, some pregnant women will still be faced with the decision to undergo CT or nuclear imaging because the test is clinically warranted. The findings of this study suggest that when clinically indicated, major radiodiagnostic testing in pregnancy should be performed, along with brief counseling to help lessen the anxiety experienced by an expectant mother before and after the birth of her child.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000337.
For information for patients and caregivers on radiodiagnostic testing, see The Royal College of Radiologists
The National Cancer Institute provides information about childhood cancer
CureSearch for Children's Cancer provides additional information about research into childhood cancer
doi:10.1371/journal.pmed.1000337
PMCID: PMC2935460  PMID: 20838660
6.  Birth defects, season of conception, and sex of children born to pesticide applicators living in the Red River Valley of Minnesota, USA. 
Environmental Health Perspectives  2002;110(Suppl 3):441-449.
We previously demonstrated that the frequency of birth defects among children of residents of the Red River Valley (RRV), Minnesota, USA, was significantly higher than in other major agricultural regions of the state during the years 1989-1991, with children born to male pesticide applicators having the highest risk. The present, smaller cross-sectional study of 695 families and 1,532 children, conducted during 1997-1998, provides a more detailed examination of reproductive health outcomes in farm families ascertained from parent-reported birth defects. In the present study, in the first year of life, the birth defect rate was 31.3 births per 1,000, with 83% of the total reported birth defects confirmed by medical records. Inclusion of children identified with birth or developmental disorders within the first 3 years of life and later led to a rate of 47.0 per 1,000 (72 children from 1,532 live births). Conceptions in spring resulted in significantly more children with birth defects than found in any other season (7.6 vs. 3.7%). Twelve families had more than one child with a birth defect (n = 28 children). Forty-two percent of the children from families with recurrent birth defects were conceived in spring, a significantly higher rate than that for any other season. Three families in the kinships defined contributed a first-degree relative other than a sibling with the same or similar birth defect, consistent with a Mendelian inheritance pattern. The remaining nine families did not follow a Mendelian inheritance pattern. The sex ratio of children with birth defects born to applicator families shows a male predominance (1.75 to 1) across specific pesticide class use and exposure categories exclusive of fungicides. In the fungicide exposure category, normal female births significantly exceed male births (1.25 to 1). Similarly, the proportion of male to female children with birth defects is significantly lower (0.57 to 1; p = 0.02). Adverse neurologic and neurobehavioral developmental effects clustered among the children born to applicators of the fumigant phosphine (odds ratio [OR] = 2.48; confidence interval [CI], 1.2-5.1). Use of the herbicide glyphosate yielded an OR of 3.6 (CI, 1.3-9.6) in the neurobehavioral category. Finally, these studies point out that (a) herbicides applied in the spring may be a factor in the birth defects observed and (b) fungicides can be a significant factor in the determination of sex of the children of the families of the RRV. Thus, two distinct classes of pesticides seem to have adverse effects on different reproductive outcomes. Biologically based confirmatory studies are needed.
PMCID: PMC1241196  PMID: 12060842
7.  Quantifying the Number of Pregnancies at Risk of Malaria in 2007: A Demographic Study 
PLoS Medicine  2010;7(1):e1000221.
By combining data from the Malaria Atlas Project with country-specific data, Feiko ter Kuile and colleagues provide the first contemporary global estimates of the annual number of pregnancies at risk of malaria.
Background
Comprehensive and contemporary estimates of the number of pregnancies at risk of malaria are not currently available, particularly for endemic areas outside of Africa. We derived global estimates of the number of women who became pregnant in 2007 in areas with Plasmodium falciparum and P. vivax transmission.
Methods and Findings
A recently published map of the global limits of P. falciparum transmission and an updated map of the limits of P. vivax transmission were combined with gridded population data and growth rates to estimate total populations at risk of malaria in 2007. Country-specific demographic data from the United Nations on age, sex, and total fertility rates were used to estimate the number of women of child-bearing age and the annual rate of live births. Subregional estimates of the number of induced abortions and country-specific stillbirths rates were obtained from recently published reviews. The number of miscarriages was estimated from the number of live births and corrected for induced abortion rates. The number of clinically recognised pregnancies at risk was then calculated as the sum of the number of live births, induced abortions, spontaneous miscarriages, and stillbirths among the population at risk in 2007. In 2007, 125.2 million pregnancies occurred in areas with P. falciparum and/or P. vivax transmission resulting in 82.6 million live births. This included 77.4, 30.3, 13.1, and 4.3 million pregnancies in the countries falling under the World Health Organization (WHO) regional offices for South-East-Asia (SEARO) and the Western-Pacific (WPRO) combined, Africa (AFRO), Europe and the Eastern Mediterranean (EURO/EMRO), and the Americas (AMRO), respectively. Of 85.3 million pregnancies in areas with P. falciparum transmission, 54.7 million occurred in areas with stable transmission and 30.6 million in areas with unstable transmission (clinical incidence <1 per 10,000 population/year); 92.9 million occurred in areas with P. vivax transmission, 53.0 million of which occurred in areas in which P. falciparum and P. vivax co-exist and 39.9 million in temperate regions with P. vivax transmission only.
Conclusions
In 2007, 54.7 million pregnancies occurred in areas with stable P. falciparum malaria and a further 70.5 million in areas with exceptionally low malaria transmission or with P. vivax only. These represent the first contemporary estimates of the global distribution of the number of pregnancies at risk of P. falciparum and P. vivax malaria and provide a first step towards a more informed estimate of the geographical distribution of infection rates and the corresponding disease burden of malaria in pregnancy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria, a mosquito-borne parasitic disease, is a major global public-health problem. About half of the world's population is at risk of malaria, which kills about one million people every year. Most of these deaths are caused by Plasmodium falciparum, which thrives in tropical and subtropical regions. However, the most widely distributed type of malaria is P. vivax malaria, which also occurs in temperate regions. Most malaria deaths are among young children in sub-Saharan Africa, but pregnant women and their unborn babies are also very vulnerable to malaria. About 10,000 women and 200,000 babies die annually because of malaria in pregnancy, which can cause miscarriages, preterm births, and low-birth-weight births. Over the past decade, a three-pronged approach has been developed to prevent and control malaria in pregnancy. This approach consists of intermittent preventative treatment of pregnant women with antimalarial drugs, the use of insecticide-treated bed nets to protect pregnant women from the bites of infected mosquitoes, and management of malarial illness among pregnant women.
Why Was This Study Done?
This strategy has begun to reduce the burden of malaria among pregnant women and their babies but the resources available for its introduction are very limited in many of the developing countries where malaria is endemic (always present). Policy makers in these countries need to know the number of pregnancies at risk of malaria so that they can use their resources wisely. However, although the World Health Organization recently estimated that more than 30 million African women living in malaria endemic areas become pregnant and are at risk for malaria each year, there are no comprehensive and contemporary estimates of the number of pregnancies at risk of malaria for endemic areas outside Africa. In this study, the researchers derive global estimates of the number of women who became pregnant in 2007 in areas with P. falciparum and P. vivax transmission.
What Did the Researchers Do and Find?
The researchers estimated the sizes of populations at risk of malaria in 2007 by combining maps of the global limits of P. vivax and P. falciparum transmission with data on population densities. They used data from various sources to calculate the annual number of pregnancies (the sum of live births, induced abortions, miscarriages, and still births) in each country. Finally, they calculated the annual number of pregnancies at risk of malaria in each country by multiplying the number of pregnancies in the entire country by the fraction of the population living within the spatial limits of malaria transmission in that country. In 2007, they calculate, 125.2 million pregnancies occurred in areas with P. falciparum and/or P. vivax transmission. These pregnancies—60% of all pregnancies globally—resulted in 82.6 million live births. 77.4 million at-risk pregnancies occurred in Southeast Asia and the Western Pacific (India had the most pregnancies at risk of both P. falciparum and P. vivax malaria), 30.3 million in Africa, 13.1 million in Europe and the Eastern Mediterranean, and 4.3 million in the Americas. 54.7 million at-risk pregnancies occurred in regions with stable P. falciparum transmission (more than one case of malaria per 10,000 people per year), whereas 70.5 million occurred in areas with low malaria transmission or P. vivax transmission only.
What Do These Findings Mean?
These findings are the first contemporary estimates of the global distribution of the number of pregnancies at risk of P. falciparum and P. vivax malaria. They do not provide any information on the actual incidence of malaria during pregnancy or the health burden on mothers and unborn babies. They simply represent “any risk” of exposure. So, for example, the researchers calculate that only about 5,000 actual malaria infections may occur annually among the 70.5 million at-risk pregnancies in areas with very low malaria transmission or with P. vivax transmission only. Furthermore, these findings do not allow for the seasonality of malaria—pregnancies that occur outside of the transmission season may be at no or very low risk of malaria. Nevertheless, the estimates reported in this study are an important first step towards a spatial map of the burden of malaria in pregnancy and should help policy makers allocate resources for research into and control of this important public-health problem.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000221.
Information is available from the World Health Organization on malaria and on malaria in pregnancy (in several languages)
The US Centers for Disease Control and Prevention also provides information on malaria and on malaria in pregnancy (in English and Spanish)
Information is available from the Roll Back Malaria Partnership on all aspects of global malaria control, including information on malaria in pregnancy
The Malaria in Pregnancy Consortium is undertaking research into the prevention and treatment of malaria in pregnancy and also provides a comprehensive bibliographic database of published and unpublished literature relating to malaria in pregnancy
The Malaria Atlas Project provides maps of malaria transmission around the world
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1000221
PMCID: PMC2811150  PMID: 20126256
8.  Racial/Ethnic Variations in the Prevalence of Selected Major Birth Defects, Metropolitan Atlanta, 1994–2005 
Public Health Reports  2012;127(1):52-61.
SYNOPSIS
Objectives
Birth defects are the leading cause of infant mortality and are responsible for substantial child and adult morbidity. Documenting the variation in prevalence of birth defects among racial/ethnic subpopulations is critical for assessing possible variations in diagnosis, case ascertainment, or risk factors among such groups.
Methods
We used data from the Metropolitan Atlanta Congenital Defects Program, a population-based birth defects registry with active case ascertainment. We estimated the racial/ethnic variation in prevalence of 46 selected major birth defects among live births, stillbirths, and pregnancy terminations at >20 weeks gestation among mothers residing in the five central counties of metropolitan Atlanta between 1994 and 2005, adjusting for infant sex, maternal age, gravidity, and socioeconomic status (SES). We also explored SES as a potential effect measure modifier.
Results
Compared with births to non-Hispanic white women, births to non-Hispanic black women had a significantly higher prevalence of five birth defects and a significantly lower prevalence of 10 birth defects, while births to Hispanic women had a significantly higher prevalence of four birth defects and a significantly lower prevalence of six birth defects. The racial/ethnic disparities in the prevalence of some defects varied by SES, but no clear pattern emerged.
Conclusions
Racial/ethnic disparities were suggested in 57% of included birth defects. Disparities in the prevalence of birth defects may result from different underlying genetic susceptibilities; exposure to risk factors; or variability in case diagnosis, ascertainment, or reporting among the subpopulations examined. Policies that improve early diagnosis of birth defects could reduce associated morbidity and mortality.
PMCID: PMC3234397  PMID: 22298922
9.  The Effect of Changing Patterns of Obstetric Care in Scotland (1980–2004) on Rates of Preterm Birth and Its Neonatal Consequences: Perinatal Database Study 
PLoS Medicine  2009;6(9):e1000153.
Jane Norman and colleagues analyzed linked perinatal surveillance data in Scotland and find that between 1980 and 2004 increases in spontaneous and medically induced preterm births contributed equally to the rising rate of preterm births.
Background
Rates of preterm birth are rising worldwide. Studies from the United States and Latin America suggest that much of this rise relates to increased rates of medically indicated preterm birth. In contrast, European and Australian data suggest that increases in spontaneous preterm labour also play a role. We aimed, in a population-based database of 5 million people, to determine the temporal trends and obstetric antecedents of singleton preterm birth and its associated neonatal mortality and morbidity for the period 1980–2004.
Methods and Findings
There were 1.49 million births in Scotland over the study period, of which 5.8% were preterm. We found a percentage increase in crude rates of both spontaneous preterm birth per 1,000 singleton births (10.7%, p<0.01) and medically indicated preterm births (41.2%, p<0.01), which persisted when adjusted for maternal age at delivery. The greater proportion of spontaneous preterm births meant that the absolute increase in rates of preterm birth in each category were similar. Of specific maternal complications, essential and pregnancy-induced hypertension, pre-eclampsia, and placenta praevia played a decreasing role in preterm birth over the study period, with gestational and pre-existing diabetes playing an increasing role. There was a decline in stillbirth, neonatal, and extended perinatal mortality associated with preterm birth at all gestation over the study period but an increase in the rate of prolonged hospital stay for the neonate. Neonatal mortality improved in all subgroups, regardless of obstetric antecedent of preterm birth or gestational age. In the 28 wk and greater gestational groups we found a reduction in stillbirths and extended perinatal mortality for medically induced but not spontaneous preterm births (in the absence of maternal complications) although at the expense of a longer stay in neonatal intensive care. This improvement in stillbirth and neonatal mortality supports the decision making behind the 34% increase in elective/induced preterm birth in these women. Although improvements in neonatal outcomes overall are welcome, preterm birth still accounts for over 66% of singleton stillbirths, 65% of singleton neonatal deaths, and 67% of infants whose stay in the neonatal unit is “prolonged,” suggesting this condition remains a significant contributor to perinatal mortality and morbidity.
Conclusions
In our population, increases in spontaneous and medically induced preterm births have made equal contributions to the rising rate of preterm birth. Despite improvements in related perinatal mortality, preterm birth remains a major obstetric and neonatal problem, and its frequency is increasing.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last about 40 weeks but increasing numbers of babies are being born preterm, before they reach 37 weeks of gestation (gestation is the period during which a baby develops in its mother). Nowadays in the US, for example, more than half a million babies arrive earlier than expected every year (1 in 8 babies). Although improvements in the care of newborn babies (neonatal care) mean that preterm babies are more likely to survive than in the past, preterm birth remains the single biggest cause of infant death in many developed countries, and many preterm babies who survive have long-term health problems and disabilities, particularly those born before 32 weeks of gestation. Preterm births can be spontaneous or medically induced. At present, it impossible to predict which mothers will spontaneously deliver early and there is no effective way to prevent these preterm births; medically induced early labor is undertaken when either the unborn baby or mother would be at risk if the pregnancy continued to full term.
Why Was This Study Done?
Preterm birth rates need to be reduced, but before this can be done it is important to know how the causes of preterm birth, the numbers of preterm stillbirths, and the numbers of preterm babies who die at birth (neonatal deaths) or soon after (perinatal deaths) are changing with time. If, for example, the rise in preterm births is mainly due to an increase in medically induced labor and if this change in practice has reduced neonatal deaths, it would be unwise to try to reduce the preterm birth rate by discouraging medically induced preterm births. So far, data from the US and Latin America suggest that the increase in preterm births in these countries is solely due to increased rates of medically induced preterm births. However, in Europe and Australia, the rate of spontaneous preterm births also seems to be increasing. In this study, the researchers examine the trends over time and causes of preterm birth and of neonatal death and illness in Scotland over a 25-year period.
What Did the Researchers Do and Find?
By searching a Scottish database of linked maternity records and infant health and death records, the researchers identified 1.49 million singleton births that occurred between 1980 and 2004 of which nearly 90,000 were preterm births. Over the study period, the rates of spontaneous and of medically induced preterm births per 1,000 births increased by 10.7% and 41.2%, respectively, but because there were more spontaneous preterm births than medically induced preterm births, the absolute increase in the rates of each type of birth was similar. Several maternal complications including preeclampsia (a condition that causes high blood pressure) and placenta previa (covering of the opening of the cervix by the placenta) played a decreasing role in preterm births over the study period, whereas gestational and preexisting diabetes played an increasing role. Finally, there was a decline in stillbirths and in neonatal and perinatal deaths among preterm babies, although more babies remained in the hospital longer than 7 days after birth. More specifically, after 28 weeks of gestation, stillbirths and perinatal deaths decreased among medically induced preterm births but not among spontaneous preterm births.
What Do These Findings Mean?
These findings indicate that in Scotland between 1980 and 2004, increases in spontaneous and medically induced preterm births contributed equally to the rising rate of preterm births. Importantly, they also show that the increase in induced preterm births helped to reduce stillbirths and neonatal and perinatal deaths, a finding that supports the criteria that clinicians currently use to decide whether to induce an early birth. Nevertheless, preterm births still account for two-thirds of all stillbirths, neonatal deaths, and extended neonatal stays in hospital and thus cause considerable suffering and greatly increase the workload in neonatal units. The rates of such births consequently need to be reduced and, for Scotland at least, ways will have to be found to reduce the rates of both spontaneous and induced preterm births to achieve this goal while continuing to identify those sick babies who need to be delivered early to give them the best chance of survival.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000153
Tommys is a nonprofit organization that funds research and provides information on the causes and prevention of miscarriage, premature birth, and stillbirth
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on maternal and infant health (in English and Spanish)
The US National Women's Health Information Center has detailed information about pregnancy, including a section on pregnancy complications
MedlinePlus provides links to other information on premature babies and to information on pregnancy (in English and Spanish)
doi:10.1371/journal.pmed.1000153
PMCID: PMC2740823  PMID: 19771156
10.  Severe birth defects in children perinatal exposed to HIV from a “real-world” setting: Infectious Diseases National Institute, Bucharest, Romania 
Journal of the International AIDS Society  2014;17(4Suppl 3):19699.
Introduction
The shift in epidemic trends in recent years in Romania shows new problems in regard of HIV vertical transmission, firstly in intravenous drug user's mothers co-infected with hepatitis viruses and with social problems, and secondly the children of young mothers with an old HIV infection and long antiretroviral therapy history.
Materials and Methods
We studied all HIV perinatal exposed children routinely followed up in the Paediatric Department of the National Institute of Infectious Diseases, since January 1st 2006 till December 31st 2012. The analyses consisted of describing the birth defects and association with certain risk factors: gender, mother's age at birth and exposure to antiretrovirals in the first trimester of pregnancy.
Results
We analyzed 244 children born to HIV-infected mothers. The incidence of HIV infection was 16.39%. The rate of birth defects was 39.34% (96/244 cases). The most frequent findings were cardiac malformations (47/96), followed by musculoskeletal defects (24/96), neurologic defects (20/96), urogenital malformations (13/96), digestive tract defects (3/93), metabolic disorders (2/96) and genetic disorders (2/96). We found nine cases of severe congenital anomalies: complex heart defect, total congenital aganglionic megacolon, anal imperforation, Dandy-Walker syndrome, gangliosidosis, Niemann-Pick syndrome, Down syndrome, true hermaphroditism and cleft palate. Two children died during first year of life due to severe malformations. 9% of cases had associated malformations. The gender rate was in favour of males in group with birth defects (58/38) and with no birth defects (82/66). The median age at birth in mothers was 22 years, similar in both groups. The highest mean age at birth was in offspring's mothers with neurologic congenital defects 25, 15 years old, but is not statistically significant (p=0.1). In the studied period the highest number of birth defects were found in 2012, 37 children, compared with less than 15 in previous years (not statistically significant, p=0.07). In our studied patients the risk of birth defects was not statistically associated with HIV transmission or with exposure to antiretrovirals before and in first trimester of pregnancy (p=0.88).
Conclusion
The rate of birth defects among HIV-exposed children was not significantly associated with antiretroviral exposure, but we identify very rare and severe congenital conditions. We have noticed also a trend to increasing number of birth defects in 2012 among studied patients compared to previous years.
doi:10.7448/IAS.17.4.19699
PMCID: PMC4225364  PMID: 25397447
11.  National, Regional, and Global Trends in Infertility Prevalence Since 1990: A Systematic Analysis of 277 Health Surveys 
PLoS Medicine  2012;9(12):e1001356.
Gretchen Stevens and colleagues use information from demographic reproductive health surveys to estimate the global, regional, and country levels, patterns, and trends in infertility between 1990 and 2010.
Background
Global, regional, and national estimates of prevalence of and tends in infertility are needed to target prevention and treatment efforts. By applying a consistent algorithm to demographic and reproductive surveys available from developed and developing countries, we estimate infertility prevalence and trends, 1990 to 2010, by country and region.
Methods and Findings
We accessed and analyzed household survey data from 277 demographic and reproductive health surveys using a consistent algorithm to calculate infertility. We used a demographic infertility measure with live birth as the outcome and a 5-y exposure period based on union status, contraceptive use, and desire for a child. We corrected for biases arising from the use of incomplete information on past union status and contraceptive use. We used a Bayesian hierarchical model to estimate prevalence of and trends in infertility in 190 countries and territories. In 2010, among women 20–44 y of age who were exposed to the risk of pregnancy, 1.9% (95% uncertainty interval 1.7%, 2.2%) were unable to attain a live birth (primary infertility). Out of women who had had at least one live birth and were exposed to the risk of pregnancy, 10.5% (9.5%, 11.7%) were unable to have another child (secondary infertility). Infertility prevalence was highest in South Asia, Sub-Saharan Africa, North Africa/Middle East, and Central/Eastern Europe and Central Asia. Levels of infertility in 2010 were similar to those in 1990 in most world regions, apart from declines in primary and secondary infertility in Sub-Saharan Africa and primary infertility in South Asia (posterior probability [pp] ≥0.99). Although there were no statistically significant changes in the prevalence of infertility in most regions amongst women who were exposed to the risk of pregnancy, reduced child-seeking behavior resulted in a reduction of primary infertility among all women from 1.6% to 1.5% (pp = 0.90) and a reduction of secondary infertility among all women from 3.9% to 3.0% (pp>0.99) from 1990 to 2010. Due to population growth, however, the absolute number of couples affected by infertility increased from 42.0 million (39.6 million, 44.8 million) in 1990 to 48.5 million (45.0 million, 52.6 million) in 2010. Limitations of the study include gaps in survey data for some countries and the use of proxies to determine exposure to pregnancy.
Conclusions
We analyzed demographic and reproductive household survey data to reveal global patterns and trends in infertility. Independent from population growth and worldwide declines in the preferred number of children, we found little evidence of changes in infertility over two decades, apart from in the regions of Sub-Saharan Africa and South Asia. Further research is needed to identify the etiological causes of these patterns and trends.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Reproductive health is a priority global health area: the target for Millennium Development Goal 5B is to provide universal access to reproductive health by 2015. The indicators for monitoring progress in reaching this target are contraceptive prevalence rate, adolescent birth rate, antenatal care coverage, and the unmet need for family planning. Infertility, the inability to conceive after a prolonged period (the length of time varies in different definitions) of unprotected intercourse, is a critical but much neglected aspect of reproductive health. The inability to have children affects couples worldwide and causes emotional and psychological distress in both men and women. Many factors—including physiological, genetic, environmental, and social— contribute to infertility. According to the World Health Organization, infertility resulting from sexually transmitted diseases or reproductive tract infections is particularly problematic in Africa and Latin America.
Why Was This Study Done?
The researchers used a uniform measure of infertility that incorporated live birth as the outcome of interest (as this information is more commonly reported than pregnancies), a five-year “exposure period,” that is, a five-year period of being in an intimate relationship, not using contraceptives, and wanting a child (as the researchers calculated that this period was necessary to accommodate the time it takes to become pregnant and have a child, and to allow for incomplete information on frequency of unprotected intercourse). The researchers used a statistical model (Bayesian hierarchical model) to generate estimates for levels and trends of infertility in 190 countries over the time period 1990 to 2010 using information collected from national demographic and reproductive health surveys. The most data was available for South Asia and Sub-Saharan Africa.
What Did the Researchers Do and Find?
The researchers found that in 2010, 1.9% of women aged 20–44 years who wanted to have children were unable to have their first live birth (primary infertility), and 10.5% of women with a previous live birth were unable to have an additional live birth (secondary infertility). The researchers found that the levels of infertility were similar in 1990 and 2010, with only a slight overall decrease in primary infertility (0.1%, but with a more pronounced drop in Sub-Saharan Africa and South Asia) and a modest overall increase in secondary infertility (0.4%). Age affected infertility rates: the prevalence of primary infertility was higher among women aged 20–24 years than among older women. The age pattern was reversed and even more pronounced for secondary infertility. And primary infertility rates among women wanting children also varied by region, from 1.5% in Latin America and the Caribbean in 2010, to 2.6% in North Africa and the Middle East. With a few exceptions, global and country patterns of secondary infertility were similar to those of primary infertility.
What Do These Findings Mean?
These findings suggest that in 2010, an estimated 48.5 million couples worldwide were unable to have a child after five years. However, these findings also suggest that global levels of primary and secondary infertility hardly changed between 1990 and 2010. It is important to note that an infertility measure based on ability to become pregnant (rather than having a live birth—the outcome used in this study) may show different levels of infertility, and using an exposure period shorter than the five years used in this study would produce higher rates of infertility. However, because of the lack of widespread data collection on time to pregnancy, the methods used and results shown in this study provide useful insights into global, regional, and country patterns and trends in infertility.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001356.
The World Health Organization has information on reproductive health
Wikipedia defines infertility and gives some useful information (note that Wikipedia is a free online encyclopedia that anyone can edit)
Patient friendly information on infertility can be found at PubMed Health and NHS Choices
doi:10.1371/journal.pmed.1001356
PMCID: PMC3525527  PMID: 23271957
12.  East Ireland 1980-1994: epidemiology of neural tube defects 
STUDY OBJECTIVE: The objective of the study was to describe the epidemiology of neural tube defects (NTD) in the eastern region of Ireland using the EUROCAT register of congenital malformations. DESIGN, SETTING AND PATIENTS: EUROCAT registries monitor the prevalence of congenital anomalies in defined populations using multiple sources for case ascertainment. All cases of NTD on the Dublin EUROCAT register born between 1980 and 1994 were extracted and analysed. The crude birth prevalence rate for all NTD, spina bifida, anencephaly and encephalocoele were calculated for each year. Parameters measured were: sex ratio, stillbirth rate, proportion of low birth-weight babies (< 2500 g) and the proportion who were premature (< 37 weeks gestation). MAIN RESULTS: Of 821 NTD cases, 419 (51.0%) had spina bifida, 322 (39.2%) had anencephaly, 69 (8.4%) had encephalocoele and 11 (1.3%) were iniencephalic. The crude birth prevalence of NTD decreased fourfold from 46.9/10,000 births in 1980 to 11.6/10,000 in 1994. The downward trend ceased during the early 1990's. Younger mothers had significantly higher rates of NTD affected births. Twenty two per cent of NTD cases had additional non-central nervous system anomalies. In 40 cases, there was a previous family history of NTD in siblings. Seasonal effects in birth prevalence were observed. Birth notification was the most frequent mechanism of ascertainment. CONCLUSION: There was a marked fall in the birth prevalence of NTD during the 15 year period. This change was real and not accounted for by pre-natal screening and diagnostic practises with termination of pregnancy, which is not legally permissible in Ireland. Dietary factors may have had an influence. Rates of NTD in this region are still higher than many other parts of Europe. Primary prevention strategies through increased folic acid intake are necessary to further reduce NTD affected births.
 
PMCID: PMC1756811  PMID: 10656087
13.  US Birth Weight/Gestational Age-Specific Neonatal Mortality: 1995–1997 Rates for Whites, Hispanics, and Blacks 
Pediatrics  2003;111(1):e61-e66.
Objective
In recent years, gains in neonatal survival have been most evident among very low birth weight, preterm, and low birth weight (LBW) infants. Most of the improvement in neonatal survival since the early 1980s seems to be the consequence of decreasing birth weight-specific mortality rates, which occurred during a period of increasing preterm and LBW rates. Although the decline in neonatal mortality has been widely publicized in the United States, research suggests that clinicians may still underestimate the chances of survival of an infant who is born too early or too small and may overestimate the eventuality of serious disability. So that clinicians may have current and needed ethnic- and race-specific estimates of the “chances” of early survival for newborn infants, we examined birth weight/gestational age-specific neonatal mortality rates for the 3 largest ethnic/racial groups in the United States: non-Hispanic whites, Hispanics, and non-Hispanic blacks. Marked racial variation in birth weight and gestational age-specific mortality has long been recognized, and growing concerns have been raised about ongoing and increasing racial disparities in pregnancy outcomes. Our purpose for this investigation was to provide an up-to-date national reference for birth weight/gestational age-specific neonatal mortality rates for use by clinicians in care decision making and discussions with parents.
Methods
The National Center for Health Statistics linked live birth-infant death cohort files for 1995–1997 were used for this study. Singleton live births to US resident mothers with a reported maternal ethnicity/race of non-Hispanic white, non-Hispanic black, or Hispanic (n = 10 610 715) were selected for analysis. Birth weight/gestational age-specific neonatal mortality rates were calculated using 250 g/2-week intervals for each ethnic/racial group.
Results
The overall neonatal mortality rates for whites, Hispanics, and blacks were 3.24, 3.45, and 8.16 neonatal deaths per 1000 live births, and the proportion of births <28 weeks was 0.35%, 0.45%, and 1.39%, respectively. Newborns who weighed <1500 g comprised <2.5% of all births in each racial/ethnic group but accounted for >50% of neonatal deaths. For whites, Hispanics, and blacks, >50% of newborns 24 to 25 weeks of gestational age survived. For most combinations of birth weights <3500 g and gestational ages of <37 weeks, the neonatal mortality rate was lowest among blacks, compared with whites or Hispanics. At these same gestational age/birth weight combinations, Hispanics have slightly lower mortality rates than whites. For combinations of birth weights >3500 g and gestational ages of 37 to 41 weeks, Hispanics had the lowest neonatal mortality rate. In these birth weight/gestational age combinations, where approximately two thirds of births occur, blacks had the highest neonatal mortality rate.
Conclusions
Compared with earlier reports, these data suggest that a substantial improvement in birth weight/gestational age-specific neonatal mortality has occurred in the United States. Regardless of ethnicity/race, the risk of a neonatal death does not exceed 50% (the suggested definition for the limit of viability), except for birth weights below 500 g and gestational ages <24 weeks. Notwithstanding, ethnic/racial variations in neonatal mortality rates continue to persist, both in overall rates and within birth weight/gestational age categories. Blacks continue to have higher proportions for preterm and LBW births, compared with either whites or Hispanics. At the same time, blacks experience lower risks of neonatal mortality for preterm and LBW infants, while having higher risks of mortality among term, postterm, normal birth weight, and macrosomic births.
doi:10.1542/peds.111.1.e61
PMCID: PMC1382183  PMID: 12509596
VLBW, very low birth weight; LBW, low birth weight; BG-NMR, birth weight/gestational age-specific neonatal mortality rate; NCHS, National Center for Health Statistics; LMP, last normal menstrual period
14.  Preterm Birth and Childhood Wheezing Disorders: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(1):e1001596.
In a systematic review and meta-analysis, Jasper Been and colleagues investigate the association between preterm birth and the development of wheezing disorders in childhood.
Please see later in the article for the Editors' Summary
Background
Accumulating evidence implicates early life factors in the aetiology of non-communicable diseases, including asthma/wheezing disorders. We undertook a systematic review investigating risks of asthma/wheezing disorders in children born preterm, including the increasing numbers who, as a result of advances in neonatal care, now survive very preterm birth.
Methods and Findings
Two reviewers independently searched seven online databases for contemporaneous (1 January 1995–23 September 2013) epidemiological studies investigating the association between preterm birth and asthma/wheezing disorders. Additional studies were identified through reference and citation searches, and contacting international experts. Quality appraisal was undertaken using the Effective Public Health Practice Project instrument. We pooled unadjusted and adjusted effect estimates using random-effects meta-analysis, investigated “dose–response” associations, and undertook subgroup, sensitivity, and meta-regression analyses to assess the robustness of associations.
We identified 42 eligible studies from six continents. Twelve were excluded for population overlap, leaving 30 unique studies involving 1,543,639 children. Preterm birth was associated with an increased risk of wheezing disorders in unadjusted (13.7% versus 8.3%; odds ratio [OR] 1.71, 95% CI 1.57–1.87; 26 studies including 1,500,916 children) and adjusted analyses (OR 1.46, 95% CI 1.29–1.65; 17 studies including 874,710 children). The risk was particularly high among children born very preterm (<32 wk gestation; unadjusted: OR 3.00, 95% CI 2.61–3.44; adjusted: OR 2.81, 95% CI 2.55–3.12). Findings were most pronounced for studies with low risk of bias and were consistent across sensitivity analyses. The estimated population-attributable risk of preterm birth for childhood wheezing disorders was ≥3.1%.
Key limitations related to the paucity of data from low- and middle-income countries, and risk of residual confounding.
Conclusions
There is compelling evidence that preterm birth—particularly very preterm birth—increases the risk of asthma. Given the projected global increases in children surviving preterm births, research now needs to focus on understanding underlying mechanisms, and then to translate these insights into the development of preventive interventions.
Review Registration
PROSPERO CRD42013004965
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last around 40 weeks, but worldwide, more than 11% of babies are born before 37 weeks of gestation (the period during which a baby develops in its mother's womb). Preterm birth is a major cause of infant death—more than 1 million babies die annually from preterm birth complications—and the number of preterm births is increasing globally. Multiple pregnancies, infections, and chronic (long-term) maternal conditions such as diabetes can all cause premature birth, but the cause of many preterm births is unknown. The most obvious immediate complication that is associated with preterm birth is respiratory distress syndrome. This breathing problem, which is more common in early preterm babies than in near-term babies, occurs because the lungs of premature babies are structurally immature and lack pulmonary surfactant, a unique mixture of lipids and proteins that coats the inner lining of the lungs and helps to prevent the collapse of the small air sacs in the lungs that absorb oxygen from the air. Consequently, preterm babies often need help with their breathing and oxygen supplementation.
Why Was This Study Done?
Improvements in the management of prematurity mean that more preterm babies survive today than in the past. However, accumulating evidence suggests that early life events are involved in the subsequent development of non-communicable diseases (non-infectious chronic diseases). Given the increasing burden of preterm birth, a better understanding of the long-term effects of preterm birth is essential. Here, the researchers investigate the risks of asthma and wheezing disorders in children who are born preterm by undertaking a systematic review (a study that uses predefined criteria to identify all the research on a given topic) and a meta-analysis (a statistical method for combining the results of several studies). Asthma is a chronic condition that is caused by inflammation of the airways. In people with asthma, the airways can react very strongly to allergens such as animal fur and to irritants such as cigarette smoke. Exercise, cold air, and infections can also trigger asthma attacks, which can sometimes be fatal. The symptoms of asthma include wheezing (a high-pitched whistling sound during breathing), coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
What Did the Researchers Do and Find?
The researchers identified 30 studies undertaken between 1995 and the present (a time span chosen to allow for recent changes in the management of prematurity) that investigated the association between preterm birth and asthma/wheezing disorders in more than 1.5 million children. Across the studies, 13.7% of preterm babies developed asthma/wheezing disorders during childhood, compared to only 8.3% of babies born at term. Thus, the risk of preterm babies developing asthma or a wheezing disorder during childhood was 1.71 times higher than the risk of term babies developing these conditions (an unadjusted odds ratio [OR] of 1.71). In analyses that allowed for confounding factors—other factors that affect the risk of developing asthma/wheezing disorders such as maternal smoking—the risk of preterm babies developing asthma or a wheezing disorder during childhood was 1.46 times higher than that of babies born at term (an adjusted OR of 1.46). Notably, compared to children born at term, children born very early (before 32 weeks of gestation) had about three times the risk of developing asthma/wheezing disorders in unadjusted and adjusted analyses. Finally, the population-attributable risk of preterm birth for childhood wheezing disorders was more than 3.1%. That is, if no preterm births had occurred, there would have been more than a 3.1% reduction in childhood wheezing disorders.
What Do These Findings Mean?
These findings strongly suggest that preterm birth increases the risk of asthma and wheezing disorders during childhood and that the risk of asthma/wheezing disorders increases as the degree of prematurity increases. The accuracy of these findings may be affected, however, by residual confounding. That is, preterm children may share other, unknown characteristics that increase their risk of developing asthma/wheezing disorders. Moreover, the generalizability of these findings is limited by the lack of data from low- and middle-income countries. However, given the projected global increases in children surviving preterm births, these findings highlight the need to undertake research into the mechanisms underlying the association between preterm birth and asthma/wheezing disorders and the need to develop appropriate preventative and therapeutic measures.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001596.
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
Nemours, another nonprofit organization for child health, also provides information (in English and Spanish) on premature babies and on asthma (including personal stories)
The UK National Health Service Choices website provides information about premature labor and birth and a real story about having a preterm baby; it provides information about asthma in children (including real stories)
The MedlinePlus Encyclopedia has pages on preterm birth, asthma, asthma in children, and wheezing (in English and Spanish); MedlinePlus provides links to further information on premature birth, asthma, and asthma in children (in English and Spanish)
doi:10.1371/journal.pmed.1001596
PMCID: PMC3904844  PMID: 24492409
15.  Birth Defects Data from Surveillance Hospitals in Hubei Province, China, 200l – 2008 
Background:
To determine the prevalence and characteristics of birth defects in perinatal infants in Hubei Province during 200l–2008.
Methods:
The prevalence of birth defects in perinatal infants delivered after 28 weeks or more was analyzed in Hubei surveillance hospitals during 200l–2008.
Results:
The incidence of birth defects in perinatal infants from 200l to 2008 was 120.0 per 10,000 births, and was increased by about 41% from 81. 1 in 2001 to 138.5 per 10,000 births in 2008. The incidence in the first 4 years (2005–2008) was much higher than the latter four (2001–2004) (χ2=77.64, P <0.05). The difference in prevalence between urban and rural was of no significance in 2008 (χ2=0.03, P >0.05), but that between male and female was significant (χ2=5.24, P <0.05), as the former prevalence was much higher. The prevalence of birth defects was slightly higher among mothers over 35 years old than those under 35 years old, but with no significance (χ2=1.98, P >0.05). The two leading birth defects were cleft lip and/or palate and polydactyly, followed by congenital heart disease, hydrocephaly, external ear malformation and neural tube defects. The prevalence of congenital heart disease was rising.
Conclusions:
Eight years’ birth defects data indicate that the birth defect rate was on the rise and the birth defects prevalence in Hubei province should be valued.
PMCID: PMC3481713  PMID: 23113146
Birth defect; Prevalence; Perinatal infants; Surveillance; Prevention
16.  Triple-Antiretroviral Prophylaxis to Prevent Mother-To-Child HIV Transmission through Breastfeeding—The Kisumu Breastfeeding Study, Kenya: A Clinical Trial 
PLoS Medicine  2011;8(3):e1001015.
Timothy Thomas and colleagues report the results of the Kisumu breastfeeding study (Kenya), a single-arm trial that assessed the feasibility and safety of a triple-antiretroviral regimen to suppress maternal HIV load in late pregnancy.
Background
Effective strategies are needed for the prevention of mother-to-child HIV transmission (PMTCT) in resource-limited settings. The Kisumu Breastfeeding Study was a single-arm open label trial conducted between July 2003 and February 2009. The overall aim was to investigate whether a maternal triple-antiretroviral regimen that was designed to maximally suppress viral load in late pregnancy and the first 6 mo of lactation was a safe, well-tolerated, and effective PMTCT intervention.
Methods and Findings
HIV-infected pregnant women took zidovudine, lamivudine, and either nevirapine or nelfinavir from 34–36 weeks' gestation to 6 mo post partum. Infants received single-dose nevirapine at birth. Women were advised to breastfeed exclusively and wean rapidly just before 6 mo. Using Kaplan-Meier methods we estimated HIV-transmission and death rates from delivery to 24 mo. We compared HIV-transmission rates among subgroups defined by maternal risk factors, including baseline CD4 cell count and viral load.
Among 487 live-born, singleton, or first-born infants, cumulative HIV-transmission rates at birth, 6 weeks, and 6, 12, and 24 mo were 2.5%, 4.2%, 5.0%, 5.7%, and 7.0%, respectively. The 24-mo HIV-transmission rates stratified by baseline maternal CD4 cell count <500 and ≥500 cells/mm3 were 8.4% (95% confidence interval [CI] 5.8%–12.0%) and 4.1% (1.8%–8.8%), respectively (p = 0.06); the corresponding rates stratified by baseline maternal viral load <10,000 and ≥10,000 copies/ml were 3.0% (1.1%–7.8%) and 8.7% (6.1%–12.3%), respectively (p = 0.01). None of the 12 maternal and 51 infant deaths (including two second-born infants) were attributed to antiretrovirals. The cumulative HIV-transmission or death rate at 24 mo was 15.7% (95% CI 12.7%–19.4%).
Conclusions
This trial shows that a maternal triple-antiretroviral regimen from late pregnancy through 6 months of breastfeeding for PMTCT is safe and feasible in a resource-limited setting. These findings are consistent with those from other trials using maternal triple-antiretroviral regimens during breastfeeding in comparable settings.
Trial registration
ClinicalTrials.gov NCT00146380
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, about half a million children become infected with human immunodeficiency virus (HIV), which causes acquired immunodeficiency syndrome (AIDS). Nearly all these newly infected children live in resource-limited countries and most acquire HIV from their mother, so-called mother-to-child transmission (MTCT). Without intervention, 25%–50% of babies born to HIV-positive mothers become infected with HIV during pregnancy, delivery, or breastfeeding. This infection rate can be reduced by treating mother and child with antiretroviral (ARV) drugs. A single dose of nevirapine (a “non-nucleoside reverse transcriptase inhibitor” or NNRTI) given to the mother at the start of labor and to her baby soon after birth nearly halves the risk of MTCT. Further reductions in risk can be achieved by giving mother and baby three ARVs—an NNRTI and two nucleoside reverse transcriptase inhibitors (NRTIs such as zidovudine and lamivudine)—during pregnancy and perinatally (around the time of birth).
Why Was This Study Done?
Breastfeeding is crucial for child survival in poor countries but it is also responsible for up to half of MTCT. Consequently, many researchers are investigating how various ARV regimens given to mothers and/or their infants during the first few months of life as well as during pregnancy and perinatally affect MTCT. In this single-arm trial, the researchers assess the feasibility and safety of using a triple-ARV regimen to suppress the maternal HIV load (amount of virus in the blood) from late pregnancy though 6 months of breastfeeding among HIV-positive women in Kisumu, Kenya, and ask whether this approach achieves a lower HIV transmission rate than other ARV regimens that have been tested in resource-limited settings. In a single-arm trial, all the participants are given the same treatment. By contrast, in a “randomized controlled” trial, half the participants chosen at random are given the treatment under investigation and the rest are given a control treatment. A randomized controlled trial provides a better comparison of treatments than a single-arm trial but is more costly.
What Did the Researchers Do and Find?
In the Kisumu Breastfeeding Study (KiBS), HIV-infected pregnant women took a triple-ARV regimen containing zidovudine and lamivudine and either nevirapine or the protease inhibitor nelfinavir from 34–36 weeks of pregnancy to 6 months after delivery. They were advised to breastfeed their babies (who received single-dose nevirapine at birth), and to wean them rapidly just before 6 months. The researchers then used Kaplan-Meier statistical methods to estimate HIV transmission and death rates among 487 live-born infants from delivery to 24 months. The cumulative HIV transmission rate rose from 2.5% at birth to 7.0% at 24 months. The cumulative HIV transmission or death rate at 24 months was 15.7%; no infant deaths were attributed to ARVs. At 24 months, 3.0% of babies born to mothers with a low viral load were HIV positive compared to 8.7% of babies born to mothers with a high viral load, a statistically significant difference. Similarly, at 24 months, 8.4% of babies born to mothers with low baseline CD4 cell counts (CD4 cells are immune system cells that are killed by HIV; CD4 cell counts indicate the level of HIV-inflicted immune system damage) were HIV positive compared to 4.1% of babies born to mothers with high baseline CD4 cell counts, although this difference did not achieve statistical significance.
What Do These Findings Mean?
Although these findings are limited by the single-arm design, they support the idea that giving breastfeeding women a triple-ARV regimen from late pregnancy to 6 months is a safe, feasible way to reduce MTCT in resource-limited settings. The HIV transmission rates in this study are comparable to those recorded in similar trials in other resource-limited settings and are lower than MTCT rates observed previously in Kisumu in a study in which no ARVs were used. Importantly, the KiBS mothers took most of the ARVs they were prescribed and most stopped breastfeeding by 6 months as advised. The intense follow-up employed in KiBS may be partly responsible for this good adherence to the trial protocol and thus this study's findings may not be generalizable to all resource-limited settings. Nevertheless, they suggest that a simple triple-ARV regimen given to HIV-positive pregnant women regardless of their baseline CD4 cell count can reduce MTCT during pregnancy and breastfeeding in resource-limited setting.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001015.
The accompanying PLoS Medicine Research article by Zeh and colleagues describes the emergence of resistance to ARVs in KiBS
Information on HIV and AIDS is available from the US National Institute of Allergy and Infectious Diseases
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children, HIV, and AIDS and on preventing mother-to-child transmission of HIV (in English and Spanish)
UNICEF also has information about children and HIV and AIDS (in several languages)
The World Health organization has information on mother-to-child transmission of HIV http://www.who.int/hiv/topics/mtct/en/index.html (in several languages)
doi:10.1371/journal.pmed.1001015
PMCID: PMC3066129  PMID: 21468300
17.  Birth Size and Breast Cancer Risk: Re-analysis of Individual Participant Data from 32 Studies 
PLoS Medicine  2008;5(9):e193.
Background
Birth size, perhaps a proxy for prenatal environment, might be a correlate of subsequent breast cancer risk, but findings from epidemiological studies have been inconsistent. We re-analysed individual participant data from published and unpublished studies to obtain more precise estimates of the magnitude and shape of the birth size–breast cancer association.
Methods and Findings
Studies were identified through computer-assisted and manual searches, and personal communication with investigators. Individual participant data from 32 studies, comprising 22,058 breast cancer cases, were obtained. Random effect models were used, if appropriate, to combine study-specific estimates of effect. Birth weight was positively associated with breast cancer risk in studies based on birth records (pooled relative risk [RR] per one standard deviation [SD] [= 0.5 kg] increment in birth weight: 1.06; 95% confidence interval [CI] 1.02–1.09) and parental recall when the participants were children (1.02; 95% CI 0.99–1.05), but not in those based on adult self-reports, or maternal recall during the woman's adulthood (0.98; 95% CI 0.95–1.01) (p for heterogeneity between data sources = 0.003). Relative to women who weighed 3.000–3.499 kg, the risk was 0.96 (CI 0.80–1.16) in those who weighed < 2.500 kg, and 1.12 (95% CI 1.00–1.25) in those who weighed ≥ 4.000 kg (p for linear trend = 0.001) in birth record data. Birth length and head circumference from birth records were also positively associated with breast cancer risk (pooled RR per one SD increment: 1.06 [95% CI 1.03–1.10] and 1.09 [95% CI 1.03–1.15], respectively). Simultaneous adjustment for these three birth size variables showed that length was the strongest independent predictor of risk. The birth size effects did not appear to be confounded or mediated by established breast cancer risk factors and were not modified by age or menopausal status. The cumulative incidence of breast cancer per 100 women by age 80 y in the study populations was estimated to be 10.0, 10.0, 10.4, and 11.5 in those who were, respectively, in the bottom, second, third, and top fourths of the birth length distribution.
Conclusions
This pooled analysis of individual participant data is consistent with birth size, and in particular birth length, being an independent correlate of breast cancer risk in adulthood.
Editors' Summary
Background.
Last year, more than one million women discovered that they had breast cancer. In the US, nearly 200,000 women will face the same diagnosis this year and 40,000 will die because of breast cancer. Put another way, about one in eight US women will have breast cancer during her lifetime. Like all cancers, breast cancer begins when cells acquire genetic changes that allow them to divide uncontrollably and to move around the body (metastasize). This uncontrolled division leads to the formation of a lump that can be detected by mammography (a breast X-ray) or by manual examination of the breasts. Breast cancer is treated by surgical removal of the lump or, if the cancer has started to spread, by removal of the whole breast (mastectomy). Surgery is usually followed by radiotherapy, chemotherapy, and other treatments designed to kill any remaining cancer cells. Unlike some cancers, the outlook for women with breast cancer is good. In the US, for example, nearly 90% of affected women are still alive five years after their diagnosis.
Why Was This Study Done?
Scientists have identified several factors that increase a woman's risk of developing breast cancer by comparing the characteristics of populations of women with and without breast cancer. Well-established risk factors include increasing age, not having children, and having a late menopause, but another potential risk factor for breast cancer is birth size. A baby's weight, length, and head circumference at birth (three related measures of birth size) depend on the levels of hormones (including estrogen, a hormone that often affects breast cancer growth) and other biological factors to which the baby is exposed during pregnancy—its prenatal environment. The idea that prenatal environment might also affect breast cancer risk in later life was first proposed in 1990, but the findings of studies that have tried to investigate this possibility have been inconsistent. Here, the researchers re-analyze individual participant data from a large number of studies into women's health conducted in Europe, Northern America, and China to get more precise information about the association between birth size and breast cancer risk.
What Did the Researchers Do and Find?
The researchers identified 32 published and unpublished studies that had collected information on birth size and on the occurrence of breast cancer. They then obtained the individual participant data from these studies, which involved more than 22,000 women who had developed breast cancer and more than 600,000 women who had not. Their analyses of these data show that birth weight was positively associated with breast cancer risk in those studies where this measurement was recorded at birth or based on parental recall during the study participant's childhood (but not in those studies in which birth weight was self-reported or maternally recalled during the participant's adulthood). For example, women with recorded birth weights of more than 4 kg or more had a 12% higher chance of developing breast cancer than women who weighed 3–3.5 kg at birth. Birth length and head circumference were also positively associated with breast cancer risk, but birth length was the strongest single predictor of risk. Finally, the amount by which birth size affected breast cancer risk was not affected by allowing for other established risk factors.
What Do These Findings Mean?
These findings provide strong evidence that birth size—in particular, birth length—is a marker of a woman's breast cancer risk in adulthood although the mechanisms underlying this association are unclear. The researchers note that the observed effect of birth size on breast cancer risk is of a similar magnitude to that of other more established risk factors and estimate that 5% of all breast cancers in developed countries could be caused by a high birth size. Because practically all the studies included in this pooled analysis were done in developed countries, these findings may not hold for developing countries. Further investigations into how the prenatal environment may affect breast cancer risk might identify new ways to prevent this increasingly common cancer.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050193.
This study is further discussed in a PLoS Medicine Perspective by Trichopoulos and Lagiou
The US National Cancer Institute provides detailed information for patients and health professionals on all aspects of breast cancer, including information on risk factors for breast cancer (in English and Spanish)
The MedlinePlus Encyclopedia provides information for patients about breast cancer; Medline Plus also provides links to many other breast cancer resources (in English and Spanish)
The UK charity Cancerbackup also provides detailed information about breast cancer
Cancer Research UK is the UK's leading charity dedicated to cancer research
doi:10.1371/journal.pmed.0050193
PMCID: PMC2553821  PMID: 18828667
18.  Prevalence of and factors associated with daily smoking among Inner Mongolia medical students in China: a cross-sectional questionnaire survey 
Background
To date, no study on smoking behavior of medical students in Inner Mongolia has been reported. The aim of the present study was to determine the 1-month prevalence of and factors associated with daily smoking among medical students in Inner Mongolia of China, to assist interventions designed to reduce the smoking behavior of medical college students in this region.
Methods
During December 2010 and January 2011 a cross-sectional survey was conducted among medical students at the Inner Mongolia Medical College using a self-administered questionnaire. The questionnaire consisted of three sections: students’ basic information, attitude on smoking behavior, and smoking status of the student daily smokers. Students who smoked every day in the last 30 days were regarded as daily smokers. Factors associated with smoking were identified using binary logistic regression analysis.
Results
A total of 6044 valid surveys were returned. The overall prevalence of daily smoking was 9.8% while the prevalence of daily smoking among males and females were 29.4% and 1.7%, respectively. Males in the Faculty of Medicine Information Management had the highest daily smoking rate (48.9%). Logistic regression models found that the main factors associated with daily smoking among male medical students were highest year of study (OR = 3.62; CI: 1.18–11.05); attitude towards smoking behavior Do not care about people smoking around you (OR = 2.75; CI: 2.08–3.64); and Smoking is harmful to their health (OR = 4.40; CI: 2.21–8.75). The main factor associated with daily smoking among female medical students was attitude towards smoking behavior Eliminate smoking on campus (OR = 0.11; CI: 0.06–0.23). Both for male and female medical students, there was no association between ethnicity and cigarette daily smoking. In regard to smoking status, more than 60% of daily smokers began smoking in high school, 61.3% smoked less than 5 cigarettes per day, 62.9% of the daily smokers’ families opposed their smoking behavior, and after an hour of not smoking 74.6% daily smokers did not feel uncomfortable.
Conclusions
Antismoking education should be further promoted in Inner Mongolia medical students, with consideration given to the factors associated with daily smoking behavior found in the present study.
doi:10.1186/1747-597X-7-20
PMCID: PMC3419670  PMID: 22591602
Daily smoking; Behavior; Medical students; Prevalence
19.  Birth defects in a cohort of infants born to HIV-infected women in Spain, 2000-2009 
BMC Infectious Diseases  2014;14(1):700.
Background
Antiretroviral therapy (ART) in pregnancy has resulted in a marked impact on reducing the risk of mother-to-child transmission (MCT) of HIV. However the safety of in utero ART exposure in newborns remains a concern.
Methods
A multicenter prospective observational study of HIV-infected mother and their infants was performed in Madrid, Spain, from 2000 to 2009. Children had regular visits with clinical examination according to protocol until the age of 24 months. An abdominal ultrasound and an echocardiogram were scheduled during follow up. Birth defects (BDs) were registered according to European Surveillance of Congenital Anomalies (EUROCAT).
Results
A total of 897 live births from 872 mothers were included. Overall the birth defects prevalence observed was 6.9% (95% CI 5.4-9.1).The most commonly reported birth defects types were in genital organs and urinary system (19 cases, 30.6%) and cardiovascular system (17 cases, 27.4%). There was no increased risk for infants exposed in the first trimester to ARVs compared with unexposed infants. No significant associations were observed between exposure to any individual antiretroviral agent during pregnancy and birth defects
Conclusion
A higher prevalence of BDs was observed, higher than previously reported. In utero exposure to ART was not proved to be a major risk factor of birth defects in infants. However the relatively small number of patients is a major limitation of this study.
doi:10.1186/s12879-014-0700-3
PMCID: PMC4297442
Antiretrovirals; Birth defects; HIV
20.  Birth Defects in Singleton versus Multiple ART Births in Japan (2004–2008) 
Journal of Pregnancy  2011;2011:285706.
The purpose of the present study was to evaluate the relative risk (RR) of multiple births for birth defects after assisted reproductive technology (ART) using Japanese nationwide data from 2004 to 2008 with singletons as the reference group. In multiples compared to singletons, the percentage of birth defects per pregnancy were significantly higher (RR = 1.88, 95% confidence interval (CI) 1.60–2.13), the percentage of birth defects per live birth was not significantly higher (RR = 0.90, 95% CI 0.78–1.05 or RR = 0.94, 95% CI 0.81–1.10), and the early neonatal mortality rate was significantly higher (RR = 2.68, 95% CI 1.52–4.70 or RR = 2.80, 95% CI 1.60–4.92). The early neonatal mortality per 10,000 live births was slightly higher in ART (5.09) than in the general population (3.86). We concluded that the impact of birth defects after ART would be larger in families with multiples compared to families with singletons, since the mean number of children would be larger in the former.
doi:10.1155/2011/285706
PMCID: PMC3228342  PMID: 22175021
21.  Morbidity due to acute lower respiratory infection in children with birth defects: a total population-based linked data study 
BMC Pediatrics  2014;14:80.
Background
Acute lower respiratory infections (ALRIs) are leading causes of hospitalisation in children. Birth defects occur in 5% of live births in Western Australia (WA). The association between birth defects and ALRI hospitalisation is unknown.
Methods
We conducted a retrospective cohort study of 245,249 singleton births in WA (1996-2005). Population-based hospitalisation data were linked to the WA Register of Developmental Anomalies to investigate ALRI hospitalisations in children with and without birth defects. We used negative binomial regression to estimate associations between birth defects and number of ALRI hospitalisations before age 2 years, adjusting for known risk factors.
Results
Overall, 9% of non-Aboriginal children and 37% of Aboriginal children with birth defects had at least one ALRI admission before age 2 years. Aboriginal children (IRR 2.3, 95% CI: 1.9-2.8) and non-Aboriginal children (IRR 2.0, 95% CI: 1.8-2.2) with birth defects had higher rates of hospitalisation for an ALRI than children with no birth defects. Rates of ALRI hospitalisation varied by type of defect but were increased for all major birth defects categories, the highest rate being for children with Down syndrome (IRR 8.0, 95% CI: 5.6-11.5). The rate of ALRI hospitalisation was 3 times greater in children with multiple birth defects than in those with isolated defects.
Conclusions
Children with birth defects experience higher rates of hospitalisation for ALRIs before age 2 years than children with no birth defects. Optimal vaccination coverage and immunoprophylaxis for specific categories of birth defects would assist in reducing hospitalisation rates for ALRI.
doi:10.1186/1471-2431-14-80
PMCID: PMC3987821  PMID: 24661413
Acute lower respiratory infections; Birth defects; Aboriginal Australian children; Linked population health data; Hospitalisations
22.  Gene-Environment Interaction in the Onset of Eczema in Infancy: Filaggrin Loss-of-Function Mutations Enhanced by Neonatal Cat Exposure  
PLoS Medicine  2008;5(6):e131.
Background
Loss-of-function variants in the gene encoding filaggrin (FLG) are major determinants of eczema. We hypothesized that weakening of the physical barrier in FLG-deficient individuals may potentiate the effect of environmental exposures. Therefore, we investigated whether there is an interaction between FLG loss-of-function mutations with environmental exposures (pets and dust mites) in relation to the development of eczema.
Methods and Findings
We used data obtained in early life in a high-risk birth cohort in Denmark and replicated the findings in an unselected birth cohort in the United Kingdom. Primary outcome was age of onset of eczema; environmental exposures included pet ownership and mite and pet allergen levels. In Copenhagen (n = 379), FLG mutation increased the risk of eczema during the first year of life (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.27–4.00, p = 0.005), with a further increase in risk related to cat exposure at birth amongst children with FLG mutation (HR 11.11, 95% CI 3.79–32.60, p < 0.0001); dog exposure was moderately protective (HR 0.49, 95% CI 0.24–1.01, p = 0.05), but not related to FLG genotype. In Manchester (n = 503) an independent and significant association of the development of eczema by age 12 mo with FLG genotype was confirmed (HR 1.95, 95% CI 1.13–3.36, p = 0.02). In addition, the risk increased because of the interaction of cat ownership at birth and FLG genotype (HR 3.82, 95% CI 1.35–10.81, p = 0.01), with no significant effect of the interaction with dog ownership (HR 0.59, 95% CI 0.16–2.20, p = 0.43). Mite-allergen had no effects in either cohort. The observed effects were independent of sensitisation.
Conclusions
We have demonstrated a significant interaction between FLG loss-of-function main mutations (501x and 2282del4) and cat ownership at birth on the development of early-life eczema in two independent birth cohorts. Our data suggest that cat but not dog ownership substantially increases the risk of eczema within the first year of life in children with FLG loss-of-function variants, but not amongst those without. FLG-deficient individuals may need to avoid cats but not dogs in early life.
In two independent cohorts of children, Hans Bisgaard and colleagues show an association between mutations in the filaggrin gene (FLG) and ownership of cats, but not dogs, with development of eczema.
Editors' Summary
Background.
Eczema is a skin condition characterized by dry, red, and itchy patches on the skin. Eczema is associated with asthma and allergy, though allergy rarely plays a role in development or severity of eczema. Eczema usually begins during infancy, typically on the face, scalp, neck, extensor sides of the forearms, and legs. Up to one in five infants develops eczema, but in more than half of them, the condition improves or disappears completely before they are 15 years old. If eczema persists into adulthood, it usually affects the face and the skin inside the knees and elbows. There is no cure for eczema but it can be controlled by avoiding anything that makes its symptoms worse. These triggers include irritants such as wool, strong soaps, perfumes, and dry environments. A good skin-care routine and frequent moisturizing can also help to keep eczema under control, but in many cases, corticosteroid creams and ointments may be necessary to reduce inflammation.
Why Was This Study Done?
Eczema tends to run in families. This suggests that eczema is caused by genetic factors as well as by environmental factors. Recently, researchers discovered that two common “loss-of-function” variants in the gene encoding filaggrin (FLG) predispose people to eczema. People who inherit one or two defective genes make no filaggrin, a protein that normally forms a physical barrier in the skin that protects the body from potentially harmful substances in the environment. Might the weakening of this barrier in filaggrin-deficient individuals affect their responses to environmental substances to which the skin is exposed? In this study, the researchers test this potential explanation for how genetic and environmental factors (in particular, exposure to pets) might interact to determine an individual's chances of developing eczema.
What Did the Researchers Do and Find?
To test their hypothesis, the researchers studied two independent groups of infants during their first year of life—a high-risk group consisting of infants born in Copenhagen, Denmark to mothers with asthma and a group of infants born to women from the general population in Manchester, United Kingdom. The researchers determined which FLG variants each child had inherited and classified those with either one or two defective copies of FLG as having an FLG mutation. They determined pet exposure in early life by asking whether a dog or a cat was living in the parental home when the child was born (“pet ownership”) and then analyzed how these genetic and environmental factors affected the age of onset of eczema. In both groups, children with FLG mutations were twice as likely to develop eczema during the first year of life as children without FLG mutations. For children without FLG mutations, cat ownership at birth had no effect on eczema risk but for children with FLG mutations, cat ownership at birth (but not dog ownership) further increased the risk of developing eczema.
What Do These Findings Mean?
These findings show that FLG mutations and cat ownership at birth interact to determine the chances of a child developing eczema during the first year of life. They provide support, therefore, for the researchers' suggestion that the weakening of the skin's protective barrier that is caused by filaggrin deficiency increases the child's susceptibility to factors associated with cat exposure. Only a small number of children in this study carried FLG mutations and were exposed to cats from birth, so these findings need confirming in independent studies. In addition, it is still not clear how exposure to cats drives the development of eczema. Allergy was not the mechanism as the FLG-deficient children exposed to cat and who developed eczema did not develop cat-specific immunoglobin E antibodies. Nevertheless, these findings suggest that, to reduce their risk of developing eczema, filaggrin-deficient individuals should avoid cats (but not dogs) during the first few months of life.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050131.
The MedlinePlus Encyclopedia has a page on eczema (in English and Spanish); links to further information are provided by MedlinePlus
EczemaNet is a comprehensive online information resource about eczema provided by the American Academy of Dermatologists
The US National Institute of Arthritis and Musculoskeletal and Skin Diseases provides information on eczema
The UK National Health Service Direct health encyclopedia provides information for patients on eczema (in several languages)
The Copenhagen Studies on Asthma in Childhood (COPSAC) and Manchester Asthma and Allergy Study (MAAS) Web sites provide more information about the children involved in this research
doi:10.1371/journal.pmed.0050131
PMCID: PMC2504043  PMID: 18578563
23.  Neural Tube Defects in Native Fars Ethnicity in Northern Iran 
Iranian Journal of Public Health  2010;39(3):116-123.
Background:
Neural tube defects (NTD) are one of the leading causes of infant mortality worldwide. This study was designed to determine the prevalence of NTDs among native Fars ethnic groups during 1998–2005, and to identify maternal and demographic factors associated with NTDs.
Methods:
We performed a descriptive cross-sectional hospital-based study in Dezyani Hospital, Gorgan, North of Iran, since January 1998 until December 2005. The design was based on a sample of 30,639 births of native Fars ethnic groups. Data were analyzed by using spss V13.5 software and were compared with the chi-square test.
Results:
The prevalence of NTDs in Native Fars during the 8-year period was 25.4 per 10000 births (95% confidence interval: 20.1–31.8). The prevalence of NTDs was 20.6/10000 and 30.6/10000 in males and females respectively but this difference was not significant. The prevalence of spina bifida, anencephaly and encephalocele were 12.7, 11.4 and 1.3 per 10000 respectively. The rate of NTD was 48.9/10000 in newborns with mothers aged > 35 years. The highest rate of NTDs and spina bifida was in 2002. The highest and lowest rate of anencephaly was in 2005 and 2003 respectively. Twenty eight percent of the parents had consanguineous marriages. Degree relatedness 3, 4, 5 and 6 of consanguineous marriages were 12.8%, 9%, 3.8%, 2.5%, respectively. Also 47.5% of the parents resided in rural areas.
Conclusion:
This investigation showed that the rate of NTDs in Native Fars was higher in Iran. In addition, this rate is higher than the Canada and Ukraine and lower than Chinese people.
PMCID: PMC3481631  PMID: 23113030
Neural tube defects; Ethnicity; Epidemiology; Iran
24.  In Vitro Fertilization and Multiple Pregnancies 
Executive Summary
Objective
The objective of this health technology policy assessment was to determine the clinical effectiveness and cost-effectiveness of IVF for infertility treatment, as well as the role of IVF in reducing the rate of multiple pregnancies.
Clinical Need: Target Population and Condition
Typically defined as a failure to conceive after a year of regular unprotected intercourse, infertility affects 8% to 16% of reproductive age couples. The condition can be caused by disruptions at various steps of the reproductive process. Major causes of infertility include abnormalities of sperm, tubal obstruction, endometriosis, ovulatory disorder, and idiopathic infertility. Depending on the cause and patient characteristics, management options range from pharmacologic treatment to more advanced techniques referred to as assisted reproductive technologies (ART). ART include IVF and IVF-related procedures such as intra-cytoplasmic sperm injection (ICSI) and, according to some definitions, intra-uterine insemination (IUI), also known as artificial insemination. Almost invariably, an initial step in ART is controlled ovarian stimulation (COS), which leads to a significantly higher rate of multiple pregnancies after ART compared with that following natural conception. Multiple pregnancies are associated with a broad range of negative consequences for both mother and fetuses. Maternal complications include increased risk of pregnancy-induced hypertension, pre-eclampsia, polyhydramnios, gestational diabetes, fetal malpresentation requiring Caesarean section, postpartum haemorrhage, and postpartum depression. Babies from multiple pregnancies are at a significantly higher risk of early death, prematurity, and low birth weight, as well as mental and physical disabilities related to prematurity. Increased maternal and fetal morbidity leads to higher perinatal and neonatal costs of multiple pregnancies, as well as subsequent lifelong costs due to disabilities and an increased need for medical and social support.
The Technology Being Reviewed
IVF was first developed as a method to overcome bilateral Fallopian tube obstruction. The procedure includes several steps: (1) the woman’s egg is retrieved from the ovaries; (2) exposed to sperm outside the body and fertilized; (3) the embryo(s) is cultured for 3 to 5 days; and (4) is transferred back to the uterus. IFV is considered to be one of the most effective treatments for infertility today. According to data from the Canadian Assisted Reproductive Technology Registry, the average live birth rate after IVF in Canada is around 30%, but there is considerable variation in the age of the mother and primary cause of infertility.
An important advantage of IVF is that it allows for the control of the number of embryos transferred. An elective single embryo transfer in IVF cycles adopted in many European countries was shown to significantly reduce the risk of multiple pregnancies while maintaining acceptable birth rates. However, when number of embryos transferred is not limited, the rate of IVF-associated multiple pregnancies is similar to that of other treatments involving ovarian stimulation. The practice of multiple embryo transfer in IVF is often the result of pressures to increase success rates due to the high costs of the procedure. The average rate of multiple pregnancies resulting from IVF in Canada is currently around 30%.
An alternative to IVF is IUI. In spite of reported lower success rates of IUI (pregnancy rates per cycle range from 8.7% to 17.1%) it is generally attempted before IVF due to its lower invasiveness and cost.
Two major drawbacks of IUI are that it cannot be used in cases of bilateral tubal obstruction and it does not allow much control over the risk of multiple pregnancies compared with IVF. The rate of multiple pregnancies after IUI with COS is estimated to be about 21% to 29%.
Ontario Health Insurance Plan Coverage
Currently, the Ontario Health Insurance Plan covers the cost of IVF for women with bilaterally blocked Fallopian tubes only, in which case it is funded for 3 cycles, excluding the cost of drugs. The cost of IUI is covered except for preparation of the sperm and drugs used for COS.
Diffusion of Technology
According to Canadian Assisted Reproductive Technology Registry data, in 2004 there were 25 infertility clinics across Canada offering IVF and 7,619 IVF cycles performed. In Ontario, there are 13 infertility clinics with about 4,300 IVF cycles performed annually.
Literature Review
Royal Commission Report on Reproductive Technologies
The 1993 release of the Royal Commission report on reproductive technologies, Proceed With Care, resulted in the withdrawal of most IVF funding in Ontario, where prior to 1994 IVF was fully funded. Recommendations of the Commission to withdraw IVF funding were largely based on findings of the systematic review of randomized controlled trials (RCTs) published before 1990. The review showed IVF effectiveness only in cases of bilateral tubal obstruction. As for nontubal causes of infertility, there was not enough evidence to establish whether IVF was effective or not.
Since the field of reproductive technology is constantly evolving, there have been several changes since the publication of the Royal Commission report. These changes include: increased success rates of IVF; introduction of ICSI in the early 1990’s as a treatment for male factor infertility; and improved embryo implantation rates allowing for the transfer of a single embryo to avoid multiple pregnancies after IVF.
Studies After the Royal Commission Report: Review Strategy
Three separate literature reviews were conducted in the following areas: clinical effectiveness of IVF, cost-effectiveness of IVF, and outcomes of single embryo transfer (SET) in IVF cycles.
Clinical effectiveness of IVF: RCTs or meta-analyses of RCTs that compared live birth rates after IVF versus alternative treatments, where the cause of infertility was clearly stated or it was possible to stratify the outcome by the cause of infertility.
Cost effectiveness of IVF: All relevant economic studies comparing IVF to alternative methods of treatment were reviewed
Outcomes of IVF with SET: RCTs or meta-analyses of RCTs that compared live birth rates and multiple birth rates associated with transfer of single versus double embryos.
OVID MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Library, the International Agency for Health Technology Assessment database, and websites of other health technology assessment agencies were searched using specific subject headings and keywords to identify relevant studies.
Summary of Findings
Comparative Clinical Effectiveness of IVF
Overall, there is a lack of well composed RCTs in this area and considerable diversity in both definition and measurement of outcomes exists between trials. Many studies used fertility or pregnancy rates instead of live birth rates. Moreover, the denominator for rate calculation varied from study to study (e.g. rates were calculated per cycle started, per cycle completed, per couple, etc...).
Nevertheless, few studies of sufficient quality were identified and categorized by the cause of infertility and existing alternatives to IVF. The following are the key findings:
A 2005 meta-analysis demonstrated that, in patients with idiopathic infertility, IVF was clearly superior to expectant management, but there were no statistically significant differences in live birth rates between IVF and IUI, nor between IVF and gamete-intra-Fallopian transfer.
A subset of data from a 2000 study showed no significant differences in pregnancy rates between IVF and IUI for moderate male factor infertility.
In patients with moderate male factor infertility, standard IVF was also compared with ICSI in a 2002 meta-analysis. All studies included in the meta-analysis showed superior fertilization rates with ICSI, and the pooled risk ratio for oocyte fertilization was 1.9 (95% Confidence Interval 1.4-2.5) in favour of ICSI. Two other RCTs in this area published after the 2002 meta-analysis had similar results and further confirmed these findings. There were no RCTs comparing IVF with ICSI in patients with severe male factor infertility, mainly because based on the expert opinion, ICSI might only be an effective treatment for severe male factor infertility.
Cost-Effectiveness of IVF
Five economic evaluations of IVF were found, including one comprehensive systematic review of 57 health economic studies. The studies compared cost-effectiveness of IVF with a number of alternatives such as observation, ovarian stimulation, IUI, tubal surgery, varicocelectomy, etc... The cost-effectiveness of IVF was analyzed separately for different types of infertility. Most of the reviewed studies concluded that due to the high cost, IVF has a less favourable cost-effectiveness profile compared with alternative treatment options. Therefore, IVF was not recommended as the first line of treatment in the majority of cases. The only two exceptions were bilateral tubal obstruction and severe male factor infertility, where an immediate offer of IVF/ICSI might the most cost-effective option.
Clinical Outcomes After Single Versus Double Embryo Transfer Strategies of IVF
Since the SET strategy has been more widely adopted in Europe, all RCT outcomes of SET were conducted in European countries. The major study in this area was a large 2005 meta-analysis, followed by two other published RCTs.
All of these studies reached similar conclusions:
Although a single SET cycle results in lower birth rates than a single double embryo transfer (DET) cycle, the cumulative birth rate after 2 cycles of SET (fresh + frozen-thawed embryos) was comparable to the birth rate after a single DET cycle (~40%).
SET was associated with a significant reduction in multiple births compared with DET (0.8% vs. 33.1% respectively in the largest RCT).
Most trials on SET included women younger than 36 years old with a sufficient number of embryos available for transfer that allowed for selection of the top quality embryo(s). A 2006 RCT, however, compared SET and DET strategies in an unselected group of patients without restrictions on the woman’s age or embryo quality. This study demonstrated that SET could be applied to older women.
Estimate of the Target Population
Based on results of the literature review and consultations with experts, four categories of infertile patients who may benefit from increased access to IVF/ICSI were identified:
Patients with severe male factor infertility, where IVF should be offered in conjunction with ICSI;
Infertile women with serious medical contraindications to multiple pregnancy, who should be offered IVF-SET;
Infertile patients who want to avoid the risk of multiple pregnancy and thus opt for IVF-SET; and
Patients who failed treatment with IUI and wish to try IVF.
Since, however, the latter indication does not reflect any new advances in IVF technology that would alter existing policy, it was not considered in this analysis.
Economic Analysis
Economic Review: Cost–Effectiveness of SET Versus DET
Conclusions of published studies on cost-effectiveness of SET versus DET were not consistent. While some studies found that SET strategy is more cost-effective due to avoidance of multiple pregnancies, other studies either did not find any significant differences in cost per birth between SET and DET, or favoured DET as a more cost-effective option.
Ontario-Based Economic Analysis
An Ontario-based economic analysis compared cost per birth using three treatment strategies: IUI, IVF-SET, and IVF-DET. A decision-tree model assumed three cycles for each treatment option. Two separate models were considered; the first included only fresh cycles of IVF, while the second had a combination of fresh and frozen cycles. Even after accounting for cost-savings due to avoidance of multiple pregnancies (only short-term complications), IVF-SET was still associated with a highest cost per birth. The approximate budget impact to cover the first three indications for IVF listed above (severe male factor infertility, women with medical contraindications to multiple pregnancy, and couples who wish to avoid the risk of multiple pregnancy) is estimated at $9.8 to $12.8 million (Cdn). Coverage of only first two indications, namely, ICSI in patients with severe male factor infertility and infertile women with serious medical contraindications to multiple pregnancy, is estimated at $3.8 to $5.5 million Cdn.
Other Considerations
International data shows that both IVF utilization and the average number of embryos transferred in IVF cycles are influenced by IVF funding policy. The success of the SET strategy in European countries is largely due to the fact that IVF treatment is subsidized by governments.
Surveys of patients with infertility demonstrated that a significant proportion (~40%) of patients not only do not mind having multiple babies, but consider twins being an ideal outcome of infertility treatment.
A women’s age may impose some restrictions on the implementation of a SET strategy.
Conclusions and Recommendations
A review of published studies has demonstrated that IVF-SET is an effective treatment for infertility that avoids multiple pregnancies.
However, results of an Ontario-based economic analysis shows that cost savings associated with a reduction in multiple pregnancies after IVF-SET does not justify the cost of universal IVF-SET coverage by the province. Moreover, the province currently funds IUI, which has been shown to be as effective as IVF for certain types of infertility and is significantly less expensive.
In patients with severe male factor infertility, IVF in conjunction with ICSI may be the only effective treatment.
Thus, 2 indications where additional IVF access should be considered include:
IVF/ICSI for patients with severe male factor infertility
IVF-SET in infertile women with serious medical contraindications to multiple pregnancy
PMCID: PMC3379537  PMID: 23074488
25.  Prevalence of Birth Defects in Korean Livebirths, 2005-2006 
Journal of Korean Medical Science  2012;27(10):1233-1240.
We investigated the livebirths prevalence and occurrence pattern of birth defects in Korea. After the survey on birth defects was done in 2,348 medical institutions around the nation, the birth defect prevalence of livebirths in 2005-2006 was calculated. This study was based on the medical insurance claims database of the National Health Insurance Corporation. The number of livebirths in Korea was 883,184 from 2005-2006, and 25,335 cases of birth defects were notified to our study, equivalent to a prevalence of 286.9 per 10,000 livebirths. Anomalies of the circulatory system were the most common defects, accounting for 43.4% of birth defects with a prevalence of 124.5 per 10,000 livebirths. It was followed by the musculoskeletal system anomalies, the digestive system anomalies, and the urinary system anomalies. The five major birth defects based on the ranking of prevalence were atrial septal defect, ventricular septal defect, hydronephrosis, patent ductus arteriosus, and cleft lip/palate. Birth defects in livebirths were associated with a high proportion of low birthweight, prematurity, multiple births and advanced maternal age. The prevalence of birth defects in Korea is similar to or lower than those reported in developed countries. Our study suggests baseline data to explain the current status of birth defects and to establish a registry system of birth defects in Korea.
doi:10.3346/jkms.2012.27.10.1233
PMCID: PMC3468762  PMID: 23091323
Prevalence; Birth Defects; Korea

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