The effect of three triterpene acids and sporidesmin on the enzyme activities of rat liver plasma membranes.

Vinyl chloride and vinyl benzene (styrene) are mutagenic in microbial tests, in Drosophila, in yeast, and in mammalian cells. Reports from various countries have shown an excess of chromosomal aberrations in the lymphocytes of workers exposed to vinyl chloride monomer when the workers were compared with controls. Workers occupationally exposed to styrene also revealed a clear increase in the rate of chromosome aberrations in their lymphocytes. Both chloroethylene oxide and styrene oxide, the primary biotransformation products of vinyl chloirde and styrene respectively, bind covalently to cellular macromolecules. Vinyl chloride is a carcinogen in both animals and man. Styrene is currently being tested in animals. These findings, the demonstration of mutagenic response via microbial and other test systems and with observations of significant excesses of chromosomal aberrations among workers exposed to these agents, raise scientific and health oriented concern about the possible genetic risks of vinyl chloride and styrene to man.     

Long-Term Survival of Individuals Born Small and Large for Gestational Age

Background

Little is known on long-term survival and causes of death among individuals born small or large for gestational age. This study investigates birth weight in relation to survival and causes of death over time.

Methods

A national cohort of 1.7 million live-born singletons in Denmark was followed during 1979–2011, using the Danish Civil Registration System, the Medical Birth Registry and the Cause of Death Registry. Cox proportional hazards were estimated for the impact of small (SGA) and large (LGA) gestation weight and mortality overall, by age group and birth cohort.

Results

Compared to normal weight children, SGA children were associated with increased risk of dying over time. Though most of the deaths occurred during the first year of life, the cumulative mortality risk was increased until 30 years of age. The hazard ratios [HR] for dying among SGA children ages <2 years were: 3.47 (95% CI, 3.30–3.64) and 1.06 (95% CI, 0.60–1.87) in 30 years and older. HR for dying among SGA adults (20–29 years) were: 1.20 (95% CI, 0.99–1.46) in years 1979–1982 and 1.61 (95% CI, 1.04–2.51) in years 1989–1994. The SGA born had increased risk of dying from infection, heart disease, respiratory disease, digestive disease, congenital malformation, perinatal conditions, and accidents, suicide, and homicide. Individuals born LGA were associated with decreased mortality risk, but with increased risk of dying from malignant neoplasm.

Conclusions

Survival has improved independently of birth weight the past 30 years. However, children born SGA remain at significantly increased risk of dying up till they turn 30 years of age. Individuals born LGA have lower mortality risk but only in the first two years of life.     

Effect of birth spacing on infant and child mortality in rural Nepal

This examination of the effect of birth spacing on infant and child mortality in rural Nepal is based on data from the Nepal Fertility Survey 1976 carried out by the Nepal Family Planning and Maternal Child Health Project in collaboration with the World Fertility Survey. The study confirms that the higher risk of infant death to 1st born children is mainly due to the higher proportion of younger women having 1st births, rather than due to their being 1st order births per se. The effect of maternal age on infant and child mortality is largely associated with birth interval. Previous birth interval, therefore, stands out as the most important factor affecting infant mortality; the next most important factor is the survival of the preceding child. A child born after an interval of less than 18 months since the previous live birth has a 31% higher risk of dying during infancy than 1 born after an interval of 1 1/2 to 2 years. The risk of the index child's dying is only 50% of that when its preceding sibling is dead. Neither education of mother nor education of father has a significant effect on infant mortality in rural Nepal.     

Excess mortality rate during adulthood among Danish adoptees

Background and objective

Adoption studies have been used to disentangle the influence of genes from shared familial environment on various traits and disease risks. However, both the factors leading to adoption and living as an adoptee may bias the studies with regard to the relative influence of genes and environment compared to the general population. The aim was to investigate whether the cohort of domestic adoptees used for these studies in Denmark is similar to the general population with respect to all-cause mortality and cause-specific mortality rates.

Methods

13,111 adoptees born in Denmark in 1917, or later, and adopted in 1924 to 1947 were compared to all Danes from the same birth cohorts using standardized mortality ratios (SMR). The 12,729 adoptees alive in 1970 were similarly compared to all Danes using SMR as well as cause-specific SMR.

Results

The excess in all-cause mortality before age 65 years in adoptees was estimated to be 1.30 (95% CI 1.26–1.35). Significant excess mortality before age 65 years was also observed for infections, vascular deaths, cancer, alcohol-related deaths and suicide. Analyses including deaths after age 65 generally showed slightly less excess in mortality, but the excess was significant for all-cause mortality, cancer, alcohol-related deaths and suicides.

Conclusion

Adoptees have an increased all-cause mortality compared to the general population. All major specific causes of death contributed, and the highest excess is seen for alcohol-related deaths.     

Are birth defects among Hispanics related to maternal nativity or number of years lived in the United States?

BACKGROUND: Literature on the risk of birth defects among foreign‐ versus U.S.–born Hispanics is limited or inconsistent. We examined the association between country of birth, immigration patterns, and birth defects among Hispanic mothers. METHODS: We used data from the National Birth Defects Prevention Study and calculated odds ratios (ORs) and 95% confidence intervals and assessed the relationship between mothers' country of birth, years lived in the United States, and birth defects among 575 foreign‐born compared to 539 U.S.–born Hispanic mothers. RESULTS: Hispanic mothers born in Mexico/Central America were more likely to deliver babies with spina bifida (OR = 1.53) than their U.S.–born counterparts. Also, mothers born in Mexico/Central America or who were recent United States immigrants (≤5 years) were less likely to deliver babies with all atrial septal defects combined, all septal defects combined, or atrial septal defect, secundum type. However, Hispanic foreign‐born mothers who lived in the United States for >5 years were more likely to deliver babies with all neural tube defects combined (OR = 1.42), spina bifida (OR = 1.89), and longitudinal limb defects (OR = 2.34). Foreign‐born mothers, regardless of their number of years lived in the United States, were more likely to deliver babies with anotia or microtia. CONCLUSIONS: Depending on the type of birth defect, foreign‐born Hispanic mothers might be at higher or lower risk of delivering babies with the defects. The differences might reflect variations in predisposition, cultural norms, behavioral characteristics, and/or ascertainment of the birth defects. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Using birth defects registry data to evaluate infant and childhood mortality associated with birth defects: an alternative to traditional mortality assessment using underlying cause of death statistics

BACKGROUND: Although birth defects are a leading cause of death in infancy and early childhood, the proportion of all deaths to children with clinically diagnosed birth defects is not well documented. The study is intended to measure the proportion of all deaths to infants and children under age 10 occurring to children with birth defects and how and why this proportion differs from the proportion of deaths due to an underlying cause of congenital anomalies using standard mortality statistics. METHODS: A linked file of Michigan livebirths and deaths was combined with data from a comprehensive multisource birth defects registry of Michigan livebirths born during the years 1992 through 2000. The data were analyzed to determine the mortality rate for infants and children with birth defects and for children with no reported birth defect. Mortality risk ratios were calculated. The underlying causes of death for children with birth defects were also categorized and compared to cause- specific mortality rates for the general population. RESULTS: Congenital anomalies were the underlying cause of death for 17.8% of all infant deaths while infants with birth defects were 33.7% of all infant deaths in the study. Almost half of all Michigan deaths to children aged 1 to 2 were within the birth defects registry, though only 15.0% had an underlying cause of death of a congenital anomaly based upon standard mortality statistics. The mortality experience among children with birth defects was significantly higher than other children throughout the first 9 years of life, ranging from 4.6 for 5 year olds to 12.8 for children 1 to 2. Mortality risk ratios examined by cause of death for infants with birth defects were highest for other endocrine (28.1), other CNS (28.1), and heart (21.9) conditions. For children 1 through 9, the highest differential risk was seen for other perinatal conditions (39.0), other endocrine (29.7), other CNS (24.5), and heart (21.4). CONCLUSIONS: Childhood mortality analyses that incorporate birth defects registry data provide a more comprehensive picture of the full burden of birth defects on mortality in infant and children and can provide an effective mechanism for monitoring the survival and mortality risks of children with selected birth defects on a population basis.     

Evaluation of preterm births and birth defects in liveborn infants of US military women who received smallpox vaccine

BACKGROUND: Women serving in the US military have some unique occupational exposures, including exposure to vaccinations that are rarely required in civilian professions. When vaccinations are inadvertently given during pregnancy, such exposures raise special concerns. These analyses address health outcomes, particularly preterm births and birth defects, among infants who appear to have been exposed to maternal smallpox vaccination in pregnancy. METHODS: This retrospective cohort study included 31,420 infants born to active‐duty military women during 2003–2004. We used Department of Defense databases to define maternal vaccination and infant health outcomes. Multivariable regression models were developed to describe associations between maternal smallpox vaccination and preterm births and birth defects in liveborn infants. RESULTS: There were 7,735 infants identified as born to women ever vaccinated against smallpox, and 672 infants born to women vaccinated in the first trimester of pregnancy. In multivariable modeling, maternal smallpox vaccination in pregnancy was not associated with preterm or extreme preterm delivery. Maternal smallpox vaccination in the first trimester of pregnancy was not significantly associated with overall birth defects (OR 1.40; 95% CI: 0.94, 2.07), or any of seven specific defects individually modeled. CONCLUSIONS: Results may be reassuring that smallpox vaccine, when inadvertently administered to pregnant women, is not associated with preterm delivery or birth defects in liveborn infants. Birth Defects Research (Part A) 2008. © 2008 Wiley‐Liss, Inc.     

Infant mortality in Zambia: socioeconomic and demographic correlates

Trends in infant mortality in Zambia suggest a reversal of the decline experienced between the 1960s and the late 1970s. From a high of about 140, infant mortality rate declined to about 90 in the late 1970s only to rise again to 100 by 1996. Data on 5,600 births born between 1987 and 1992, and 6,630 births between 1991 and 1996 from the Zambian DHS are analyzed to identify socioeconomic and demographic correlates of infant mortality. Demographic factors such as small size at birth and short birth intervals are associated with higher neonatal mortality. In the post-neonatal period, urban children from poorer households had the highest mortality between 1991-1996. Also, differences in infant mortality rates between provinces narrowed. Children born in the most developed province of Lusaka had as high of risk of dying as those from Luapula, a province with a history of extremely high mortality rates in Zambia.     

Determinants of survival in children with congenital abnormalities: a long-term population-based cohort study

BACKGROUND: Today more children with birth defects survive early childhood because of improved medical care; however, little information is available about patterns of long-term mortality and survival in this population. In particular, it is not clear whether other birth characteristics, apart from birth defects, have any role in their mortality. METHODS: Two large cohorts of children with and without birth defects were followed for up to 17 years. More than 45,000 children with birth defects, and 45,000 matched children without birth defects born in Ontario between 1979 and 1986 were followed. Throughout the study period long-term survival rates and the risk of death were compared between the 2 cohorts. Birth characteristics were also examined to determine their effect on the risk of death. RESULTS: During the study the deaths of 3620 and 301 children with and without birth defects, respectively, were recorded, indicating that those with birth defects had a 13 times higher rate of mortality (relative risk [RR], 12.9, 95% confidence interval [CI], 12.1-13.7). Mortality rates in the birth-defects cohort remained higher even after 10-15 years. In both groups children of low gestational age and low birth weight had a higher risk of death. There was a strong dose-response relationship between the number of defects and the risk of death. CONCLUSIONS: Children born with abnormalities face many challenges throughout their lifetimes. If they survive the high mortality risk of the first year of life, they still have to face the considerably higher risk of death in the years to come. In addition to birth defects, other birth characteristics play an independent role in their mortality. These indicators could be used to identify high-risk children.     

Sex differential patterns in perinatal deaths in Italy

In industrialized countries, male excess is generally found in early deaths, despite the overall decrease in mortality. We studied the association between sex and some factors generally considered crucial for babies' survival, such as mother's age and education, birth order, and gestational age, in order to gain insight into the causes underlying the persisting higher vulnerability of male sex in early life. The analysis was performed on babies dying during the perinatal period. These were subdivided into those who were stillborn and those who died during the first week of extrauterine life. A higher male excess among babies dying during the neonatal period than among those who were stillborn was always found in all classes of all factors. The finding of such generalized male overmortality in the early extrauterine period of life, together with the patterns shown by the temporal sex ratio in stillbirths and in early deaths, supports the hypothesis of a postponement of male risk from late fetal into neonatal life.     

Absence of effects from immunocontraception on seasonal birth patterns and foal survival among barrier island wild horses

Despite a large body of safety data, concern exists that porcine zonae pellucidae (PZP) immunocontraception--used to manage wild horse populations--may cause out-of-season births with resulting foal mortality. Our study at Assateague, Maryland indicated the effects of immunocontraception on season of birth and foal survival between 1990 and 2002 on wild horses from Assateague Island. Among 91 mares never treated, 69 (75.8%) of foals were born in April, May, and June (in season). Among 77 treated mares, 50 (64.9%) were born in season. Of 29 mares foaling within 1 year after treatment (contraceptive failures), 20 (68.9%) were born in season. Of 48 mares treated for greater than 2 years then withdrawn from treatment, 30 (62.5%) of 48 foals were born in season. There were no significant differences (p <.05) between either treatment group or untreated mares. Survival did not differ significantly among foals born in or out of season or among foals born to treated or untreated mares. Data indicate a lack of effect of PZP contraception on season of birth or foal survival on barrier island habitats.     

Sudden infant death syndrome and postneonatal mortality in immigrants in England and Wales.

To examine ethnic differences in postneonatal mortality and the incidence of sudden infant death in England and Wales during 1982-5 records were analysed, the mother''s country of birth being used to determine ethnic group. Postneonatal mortality was highest in infants of mothers born in Pakistan (6.4/1000 live births) followed by infants of mothers born in the Caribbean (4.5) and the United Kingdom and Republic of Ireland (4.1). Crude rates were lower in infants of mothers born in India (3.9/1000), east and west Africa (3.0), and Bangladesh (2.8) than in infants of mothers born in the United Kingdom despite less favourable birth weights. Mortality ratios standardised separately for maternal age, parity, and social class were significantly higher in infants of mothers born in Pakistan and lower in those of mothers born in Bangladesh. The ratio for infants of Caribbean mothers was significantly higher when adjusted for maternal age. Ratios for infants of Indian and east African mothers did not show significant differences after standardisation. An important finding was a low incidence of sudden infant death in infants of Asian origin. This was paralleled by lower mortality from respiratory causes. During 1975-85 postneonatal mortality in all immigrant groups except Pakistanis fell to a similar or lower rate than that in the United Kingdom group; Pakistanis showed a persistent excess. During 1984-5 several immigrant groups (from the Republic of Ireland, India, west Africa, and the Caribbean) recorded an increase in postneonatal mortality. Surveillance of postneonatal mortality among ethnic communities should be continued, and research is needed to identify the causes underlying the differences.     

Deaths from cerebrovascular diseases correlated to month of birth: elevated risk of death from subarachnoid hemorrhage among summer-born

It has been suggested that maternal nutrition, and fetal and infant growth have an important effect on the risk of cardiovascular disease in adult life. We investigated the population-based distribution of deaths from cerebrovascular diseases (ICD9 codes 430, 431, or 434) in Japan in 1986–1994 as a function of birth month, by examining death-certificate records. For a total of 853 981 people born in the years 1900–1959, the distribution of the number of deaths according to the month of birth was compared with the distribution expected from the monthly numbers of all births for each sex and for the corresponding birth decade. For those born between 1920 and 1949, there were significant discrepancies between the actual numbers of deaths from subarachnoid hemorrhage (ICD9 430) and the numbers expected, and these differences were related to the month of birth. Those born in summer, June–September, consistently had an elevated risk of death, particularly men, where the excess risk was 8%–23%. This tendency was also observed, less distinctly but significantly, for deaths from intracerebral hemorrhage (ICD9 431), but was not observed for those dying from occlusion of the cerebral arteries (ICD9 434). The observation that the risk of dying from subarachnoid hemorrhage was more than 10% higher among those born in the summer implies that at least one in ten deaths from subarachnoid hemorrhage has its origin at a perinatal stage. Although variations in hypertension in later life, which could possibly be ”programmed” during the intra-uterine stages, could be an explanation for this observation, the disease-specific nature of the observation suggests the involvement of aneurysm formation, which is a predominant cause of subarachnoid hemorrhage. Received: 22 October 1999 / Revised: 8 May 2000 / Accepted: 10 May 2000     

Housing quality and child mortality in the rural Philippines

Factors influencing child survival to age 5 are investigated for a rural sample in lloilo Province, Philippines. Considered are construction materials in walls, doors, windows, and floors and the typpes of toilet facilities. 707 women were asked how many children they had borne alive; the sexes and dates of each live birth; whether each child was still living; and if not at what age the child had died. This study focused retrospectively on mortality among 2359 children born between 1960 and 1973. About 4.9% had died before age 5. This is 1/2 of what was observed nationally for rural children in the 1978 fertility survey. Health conditions in rural Iloilo Province may have been more favorable than in other rural parts of the nation. Income generated from shipping, lumbering, and fish culture may have also contributed to the lower rate of child mortality observed in this sample. The sex ratio of the children was 102, well within the range regarded as typical. A logit regression was employed. Of the 207 girls with low demographic risk and worse quality housing, 249 were estimated to survive to age 5 and 18 to die before age 5. Sex was not an important factor in child mortality. Boys and girls had about equal chances of surviving. A social-demographic risk factor commonly linked with infant mortality is breast feeding. Breastfed infants from a number of developing countries have had lower rates of infant mortality. A slightly larger % of nonbreastfed children (96.9%) survived to age 5 than did breastfed children. Living in a poorly constructed dwelling reduced the odds of a child's survival. Estimates from the Brass method showed that the expected probability of children dying before age 5 was .073 and .035, representing life expectancies at birth of 63.4 and 69.9 years.     

Do infants with major congenital anomalies have an excess of macrosomia?

BACKGROUND: Infants that develop congenital anomalies may also have an excess prevalence of macrosomia (birth weight > or =4,000 g). This may indicate that abnormalities of glycemic control play a role in the etiology of birth defects. This study was undertaken to determine whether all infants with congenital anomalies have an excess of macrosomia and whether it is confined to specific types of anomalies. METHODS: A case-control study was conducted, comparing the birth weights of 8,226 infants with congenital anomalies ascertained by the Texas Birth Defects Monitoring Division with those of 965,965 infants without birth defects. Odds ratios were calculated to determine the association between birth weight and congenital anomalies, for 45 specific defects, and for all these defects combined. RESULTS: For all 45 defects combined, a significant association occurred only in the highest birth weight category. Infants with congenital anomalies were more likely than infants without birth defects to have a birth weight > or =4,500 g (OR = 1.65; 95% CI = 1.39-1.96). Infants born with ventricular septal defects, atrial septal defects, ventricular hypertrophy, or anomalies of the great vessels were 1.5-2.5 times more likely to weigh > or =4,000 g than were infants without birth defects. Based on small numbers, a stronger excess of macrosomia was observed for infants with encephalocele, holoprosencephaly, anomalies of the corpus callosum, preaxial polydactyly, and omphalocele. CONCLUSIONS: Our data suggest that infants with specific congenital anomalies are more likely to be macrosomic than are infants without an anomaly. If these findings are confirmed, associations between macrosomia and specific types of birth defects may help to identify birth defects that are caused by alterations in glycemic control.     

Are there ethnic disparities in risk of preterm birth among infants born with congenital heart defects?

BACKGROUND: Birth defects and preterm birth (PTB) are leading causes of infant morbidity and mortality in the United States. Infants with birth defects are more likely to be born preterm (<37 weeks), yet the roles of maternal ethnicity and fetal growth in this relationship are unclear. This study aimed to assess the risk of PTB among non-Hispanic (NH) Black, NH-White, and Hispanic infants with congenital heart defects (CHD), adjusting for fetal growth. METHODS: Florida Birth Defects Registry data were used to conduct a retrospective cohort study on 14,319 live-born infants with CHDs born January 1, 1998 to December 31, 2002. ORs and 95% CIs were computed for each growth category (small-for-gestational age [SGA], appropriate-for-gestational-age [AGA], and large-for-gestational-age [LGA]) by ethnicity and adjusted for maternal and infant covariates using logistic regression. RESULTS: After adjusting for potential confounders, SGA and AGA NH-Black infants with CHDs had increased risk of PTB compared to NH-White infants with CHDs (OR 1.79; 95% CI: 1.40, 2.30 and OR 1.89; 95% CI: 1.68, 2.13, respectively). Hispanic SGA, AGA, and infants with CHDs had no increased risk of PTB compared to NH-White infants. CONCLUSIONS: The increased risk of PTB among SGA and AGA NH-Black infants with CHDs is not explained by the overall disparities in risk of PTB between NH-Blacks and NH-Whites. Additional studies are needed to determine the specific subtypes of CHD for which these relationships are present and if these findings are seen among infants with other birth defects.     

Trends in All-Cause Mortality across Gestational Age in Days for Children Born at Term

Background

Term birth is a gestational age from 259 days to 293 days. However trends in mortality according to gestational ages in days have not yet been described in this time period.

Methods and Findings

Based on nation-wide registries, we conducted a population-based cohort study among all children born at term in Denmark from 1997 to 2004 to estimate differences in mortality across gestational ages in days among singletons born at term. We studied early-neonatal mortality, neonatal mortality, infant mortality, and five-year mortality. Children were followed from birth up to the last day of the defined mortality period or December 31, 2009. A total of 360,375 singletons born between 259 and 293 days of gestation were included in the study. Mortality decreased with increasing gestational age in days and the highest mortality was observed among children born at 37 week of gestation. A similar pattern was observed when analyses were restricted to children born to by mothers without pregnancy complications.

Conclusions

This study demonstrates heterogeneity in mortality rates even among singletons born at term. The highest mortality was observed among children born 37 weeks of gestation, which call for cautions when inducing labor in term pregnancies just reaching 37 weeks of gestation. The findings support that 37 weeks of gestation should be defined as early term.     

Effects of BRCA1 and BRCA2 mutations on female fertility

Women with BRCA1/2 mutations have a significantly higher lifetime risk of developing breast or ovarian cancer. We suggest that female mutation carriers may have improved fitness owing to enhanced fertility relative to non-carriers. Here we show that women who are carriers of BRCA1/2 mutations living in natural fertility conditions have excess fertility as well as excess post-reproductive mortality in relation to controls. Individuals who tested positive for BRCA1/2 mutations who linked into multi-generational pedigrees within the Utah Population Database were used to identify putative obligate carriers. We find that women born before 1930 who are mutation carriers have significantly more children than controls and have excess post-reproductive mortality risks. They also have shorter birth intervals and end child-bearing later than controls. For contemporary women tested directly for BRCA1/2 mutations, an era when modern contraceptives are available, differences in fertility and mortality persist but are attenuated. Our findings suggest the need to re-examine the wider role played by BRCA1/2 mutations. Elevated fertility of female mutation carriers indicates that they are more fecund despite their elevated post-reproductive mortality risks.     

Incidence of Neoplasms in Children Born after Influenza Epidemics

Following a recent report that neoplasia of the lymphatic and haematopoietic tissues is commoner than average in children whose mothers have had influenza in pregnancy, the incidence of neoplasms in 1954-68 in children of the Manchester Hospital Region was examined in relation to date of birth. There were no significant differences between cohorts born in different quinquennia. Incidence among children born after six influenza epidemics in 1951-68 was no higher than among other children born in these years. It is concluded that if there is an association between maternal influenza and childhood neoplasia it is probably due to factors such as immunological deficiencies which may predispose independently to both conditions.     

Cancer in children born after frozen-thawed embryo transfer: A cohort study

BackgroundThe aim was to investigate whether children born after assisted reproduction technology (ART), particularly after frozen-thawed embryo transfer (FET), are at higher risk of childhood cancer than children born after fresh embryo transfer and spontaneous conception.Methods and findingsWe performed a registry-based cohort study using data from the 4 Nordic countries: Denmark, Finland, Norway, and Sweden. The study included 7,944,248 children, out of whom 171,774 children were born after use of ART (2.2%) and 7,772,474 children were born after spontaneous conception, representing all children born between the years 1994 to 2014 in Denmark, 1990 to 2014 in Finland, 1984 to 2015 in Norway, and 1985 to 2015 in Sweden. Rates for any cancer and specific cancer groups in children born after each conception method were determined by cross-linking national ART registry data with national cancer and health data registries and population registries. We used Cox proportional hazards models to estimate the risk of any cancer, with age as the time scale.After a mean follow-up of 9.9 and 12.5 years, the incidence rate (IR) of cancer before age 18 years was 19.3/100,000 person-years for children born after ART (329 cases) and 16.7/100,000 person-years for children born after spontaneous conception (16,184 cases). Adjusted hazard ratio (aHR) was 1.08, 95% confidence interval (CI) 0.96 to 1.21, p = 0.18. Adjustment was performed for sex, plurality, year of birth, country of birth, maternal age at birth, and parity. Children born after FET had a higher risk of cancer (48 cases; IR 30.1/100,000 person-years) compared to both fresh embryo transfer (IR 18.8/100,000 person-years), aHR 1.59, 95% CI 1.15 to 2.20, p = 0.005, and spontaneous conception, aHR 1.65, 95% CI 1.24 to 2.19, p = 0.001. Adjustment either for macrosomia, birth weight, or major birth defects attenuated the association marginally. Higher risks of epithelial tumors and melanoma after any assisted reproductive method and of leukemia after FET were observed.The main limitation of this study is the small number of children with cancer in the FET group.ConclusionsChildren born after FET had a higher risk of childhood cancer than children born after fresh embryo transfer and spontaneous conception. The results should be interpreted cautiously based on the small number of children with cancer, but the findings raise concerns considering the increasing use of FET, in particular freeze-all strategies without clear medical indications.Trial registrationTrial registration number: ISRCTN 11780826.

Nona Sargisian and colleagues investigate the risk of childhood cancer in children born after Frozen-Thawed Embryo Transfer in Denmark, Finland, Norway, and Sweden.