Mads Melbye

Maternal age and fetal loss: population based register linkage study

Abstract Objective: To estimate the association between maternal age and fetal death (spontaneous abortion, ectopic pregnancy, stillbirth), taking into account a womans reproductive history. Design: Prospective register linkage study. Subjects: All women with a reproductive outcome (live birth, stillbirth, spontaneous abortion leading to admission to hospital, induced abortion, ectopic pregnancy, or hydatidiform mole) in Denmark from 1978 to 1992; a total of 634 272 women and 1 221 546 pregnancy outcomes. Main outcome measures: Age related risk of fetal loss, ectopic pregnancy, and stillbirth, and age related risk of spontaneous abortion stratified according to parity and previous spontaneous abortions. Results: Overall, 13.5% of the pregnancies intended to be carried to term ended with fetal loss. At age 42 years, more than half of such pregnancies resulted in fetal loss. The risk of a spontaneous abortion was 8.9% in women aged 20–24 years and 74.7% in those aged 45 years or more. High maternal age was a significant risk factor for spontaneous abortion irrespective of the number of previous miscarriages, parity, or calendar period. The risk of an ectopic pregnancy and stillbirth also increased with increasing maternal age. Conclusions: Fetal loss is high in women in their late 30s or older, irrespective of reproductive history. This should be taken into consideration in pregnancy planning and counselling.

The Danish National Birth Cohort - its background, structure and aim

Background: It is well known that the time from conception to early childhood has importance for health conditions that reach into later stages of life. Recent research supports this view, and diseases such as cardiovascular morbidity, cancer, mental illnesses, asthma, and allergy may all have component causes that act early in life. Exposures in this period, which infl uence fetal growth, cell divisions, and organ functioning, may have long-lasting impact on health and disease susceptibility. Methods: To investigate these issues the Danish National Birth Cohort (Better health for mother and child) was established. A large cohort of pregnant women with long-term follow-up of the offspring was the obvious choice because many of the exposures of interest cannot be reconstructed with sufficient validity back in time. The study needs to be large, and it is aimed to recruit 100,000 women early in pregnancy, and to continue follow-up for decades. The Nordic countries are better suited for this kind of research than most other countries because of their population-based registers on diseases, demography and social conditions, linkable at the individual level by means of the unique ID-number given to all citizens. Exposure information is mainly collected by computer-assisted telephone interviews with the women twice during pregnancy and when their children are six and 18 months old. Participants are also asked to fill in a self-administered food frequency questionnaire in mid-pregnancy. Furthermore, a biological bank has been set up with blood taken from the mother twice during pregnancy and blood from the umbilical cord taken shortly after birth. Data collection started in 1996 and the project covered all regions in Denmark in 1999. By August 2000, a total of 60,000 pregnant women had been recruited to the study. It is expected that a large number of gene-environmental hypotheses need to be based on case-control analyses within a cohort like this.

Effects of family history and place and season of birth on the risk of schizophrenia.

BACKGROUND Although a family history of schizophrenia is the best-established risk factor for schizophrenia, environmental factors such as the place and season of birth may also be important. METHODS Using data from the Civil Registration System in Denmark, we established a population-based cohort of 1.75 million persons whose mothers were Danish women born between 1935 and 1978. We linked this cohort to the Danish Psychiatric Central Register and identified 2669 cases of schizophrenia among cohort members and additional cases among their parents. RESULTS The respective relative risks of schizophrenia for persons with a mother, father, or sibling who had schizophrenia were 9.31 (95 percent confidence interval, 7.24 to 11.96), 7.20 (95 percent confidence interval, 5.10 to 10.16), and 6.99 (95 percent confidence interval, 5.38 to 9.09), as compared with persons with no affected parents or siblings. The risk of schizophrenia was associated with the degree of urbanization of the place of birth (relative risk for the capital vs. rural areas, 2.40; 95 percent confidence interval, 2.13 to 2.70). The risk was also significantly associated with the season of birth; it was highest for births in February and March and lowest for births in August and September. The population attributable risk was 5.5 percent for a history of schizophrenia in a parent or sibling, 34.6 percent for urban place of birth, and 10.5 percent for the season of birth. CONCLUSIONS Although a history of schizophrenia in a parent or sibling is associated with the highest relative risk of having the disease, the place and season of birth account for many more cases on a population basis.

Genome-partitioning of genetic variation for complex traits using common SNPs

We estimate and partition genetic variation for height, body mass index (BMI), von Willebrand factor and QT interval (QTi) using 586,898 SNPs genotyped on 11,586 unrelated individuals. We estimate that ∼45%, ∼17%, ∼25% and ∼21% of the variance in height, BMI, von Willebrand factor and QTi, respectively, can be explained by all autosomal SNPs and a further ∼0.5–1% can be explained by X chromosome SNPs. We show that the variance explained by each chromosome is proportional to its length, and that SNPs in or near genes explain more variation than SNPs between genes. We propose a new approach to estimate variation due to cryptic relatedness and population stratification. Our results provide further evidence that a substantial proportion of heritability is captured by common SNPs, that height, BMI and QTi are highly polygenic traits, and that the additive variation explained by a part of the genome is approximately proportional to the total length of DNA contained within genes therein.

Sexually Transmitted Infection as a Cause of Anal Cancer

Interviews were carried out with 423 women and 93 men with invasive or in situ anal cancer in Denmark and Sweden in a search for clues to the aetiology of this neoplasm. Patients with rectal adenocarcinoma (n = 534) and persons drawn from the background population (n = 554) served as controls. Multivariate logistic regression analyses confirmed previous observations of a strong association between either male homosexual experience or a history of anogenital warts and the risk for anal cancer. Moreover, hitherto unknown, but strong and consistent associations were observed between measures of high heterosexual activity and the risk for anal cancer among both sexes. Polymerase chain reaction analysis revealed human papilloma-virus DNA in the majority (88%) of anal cancer specimens but in none of 20 examined rectal adenocarcinomas. It is concluded that most anal cancers appear to be caused by sexually transmitted types of human papillomaviruses and, consequently, that anal cancer is a potentially preventable neoplasm.

Disruption of an AP-2α binding site in an IRF6 enhancer is associated with cleft lip

Previously we have shown that nonsyndromic cleft lip with or without cleft palate (NSCL/P) is strongly associated with SNPs in IRF6 (interferon regulatory factor 6). Here, we use multispecies sequence comparisons to identify a common SNP (rs642961, G>A) in a newly identified IRF6 enhancer. The A allele is significantly overtransmitted (P = 1 × 10−11) in families with NSCL/P, in particular those with cleft lip but not cleft palate. Further, there is a dosage effect of the A allele, with a relative risk for cleft lip of 1.68 for the AG genotype and 2.40 for the AA genotype. EMSA and ChIP assays demonstrate that the risk allele disrupts the binding site of transcription factor AP-2α and expression analysis in the mouse localizes the enhancer activity to craniofacial and limb structures. Our findings place IRF6 and AP-2α in the same developmental pathway and identify a high-frequency variant in a regulatory element contributing substantially to a common, complex disorder.

Growth patterns and the risk of breast cancer in women

Adult height and body mass index (BMI) influence the risk of breast cancer in women. Whether these associations reflect growth patterns of the fetus or growth during childhood and adolescence is unknown. We investigated the association between growth during childhood and the risk of breast cancer in a cohort of 117,415 Danish women. Birth weight, age at menarche, and annual measurements of height and weight were obtained from school health records. We used the data to model individual growth curves. Information on vital status, age at first childbirth, parity, and diagnosis of breast cancer was obtained through linkages to national registries. During 3,333,359 person-years of follow-up, 3340 cases of breast cancer were diagnosed. High birth weight, high stature at 14 years of age, low BMI at 14 years of age, and peak growth at an early age were independent risk factors for breast cancer. Height at 8 years of age and the increase in height during puberty (8-14 years of age) were also associated with breast cancer. The attributable risks of birth weight, height at 14 years of age, BMI at 14 years of age, and age at peak growth were 7%, 15%, 15%, and 9%, respectively. No effect of adjusting for age at menarche, age at first childbirth, and parity was observed. Birth weight and growth during childhood and adolescence influence the risk of breast cancer.

A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4

Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635–0.778, P = 1.44 × 10−11; and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292–1.587, P = 5.01 × 10−12) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes remained similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24, whereas Asian families showed stronger evidence for association with MAFB and ABCA4. Expression studies support a role for MAFB in palatal development.

Consistent high viral load of human papillomavirus 16 and risk of cervical carcinoma in situ: a nested case-control study

BACKGROUND Persistent infection with certain types of human papillomavirus (HPV) is believed to be a prerequisite for the development of cervical neoplasia. Persistence may depend on certain characteristics, such as viral load, which has so far been given little attention. We investigated the association between HPV 16 viral load and cervical carcinoma in situ. METHODS We did a nested case-control study of women participating in cytological screening in Sweden. We used a sensitive quantitative PCR assay to estimate HPV 16 load in multiple smears for each woman, taken during a period of up to 26 years before diagnosis. We calculated C, values, which decrease as the number of viral DNA copies increases. FINDINGS 2081 smears from 478 cases and 1754 smears from 608 controls were tested. Among cases, we found a consistently increased load of HPV 16 already 13 years or more before diagnosis, and when many smears were still cytologically normal. Women with high HPV 16 viral loads were at least 30 times the relative risk of HPV-16-negative women more than a decade before diagnosis. The increase in relative risk was constant over time. About 25% of women (95% CI 0.12-0.32) infected with a high viral load before age 25 years developed cervical carcinoma in situ within 15 years. INTERPRETATION Cervical carcinoma in situ associated with HPV 16 occurs mainly in HPV-16-positive women who have consistently high viral loads long term. Women at high risk could be identified by use of a quantitative HPV test in addition to cytological screening.

Factors influencing the effect of age on prognosis in breast cancer: population based study

Abstract Objective To investigate whether young age at diagnosis is a negative prognostic factor in primary breast cancer and how stage of disease at diagnosis and treatment influences such an association. Design: Retrospective cohort study based on a population based database of patients with breast cancer containing detailed information on tumour characteristics, treatment regimens, and survival. Setting: Denmark. Subjects: 10 356 women with primary breast cancer who were less than 50 years old at diagnosis. Main outcome measures: Relative risk of dying within the first 10 years after diagnosis according to age at diagnosis after adjustment for known prognostic factors and expected mortality. Results: Overall, young women with low risk disease who did not receive adjuvant treatment had a significantly increased risk of dying; risk increased with decreasing age at diagnosis (adjusted relative risk: 45-49 years (reference): 1; 40-44 years: 1.12 (95% confidence interval 0.89 to 1.40); 35-39 years: 1.40 (1.10 to 1.78); <35 years: 2.18 (1.64 to 2.89). However, no similar trend was seen in patients who received adjuvant cytotoxic treatment. The increased risk in younger women who did not receive adjuvant treatment compared with those who did remained when women were grouped according to presence of node negative disease and by tumour size. Conclusion The negative prognostic effect of young age is almost exclusively seen in women diagnosed with low risk disease who did not receive adjuvant cytotoxic treatment. These results suggest that young women with breast cancer, on the basis of age alone, should be regarded as high risk patients and be given adjuvant cytotoxic treatment.