Cohort profile: The COPENHAGEN Minipuberty Study-A longitudinal prospective cohort of healthy full-term infants and their parents.

BACKGROUND: The hypothalamic-pituitary-gonadal (HPG) axis governs sexual maturation and reproductive function in humans. In early postnatal life, it is transiently active during which circulating sex steroids reach adult levels. While this so-called minipuberty represents a universal phenomenon in infants of both sexes, its role for early maturation and growth remains incompletely understood. OBJECTIVES: To provide normative data on auxology as well as serum and urinary hormone levels in healthy, full-term infants throughout the first year of life and to investigate associations of postnatal HPG axis dynamics as well as hormonal, genetic and environmental exposures with early genital development and growth. POPULATION: Healthy, Danish, full-term, singleton newborns including their parents. DESIGN: Single-centre, prospective, observational longitudinal pregnancy and birth cohort. METHODS: Newborns were followed with six repeated clinical examinations during a one-year follow-up period. An umbilical cord blood sample was drawn at birth. At each visit, infants underwent a clinical examination focusing on auxology and genital development. Further, blood (serum, plasma, DNA) and urine samples were collected at each visit. Mothers and fathers underwent a clinical examination and provided blood samples prior to and after birth. A subset of parents provided urine samples and breast milk samples. Pregnancy and obstetrical outcomes, and detailed parental questionnaires were compiled. PRELIMINARY RESULTS: Between August 2016 and August 2018, 2481 women with singleton pregnancies were invited to participate of which 298, including their partners, were enrolled (12.0%). A total of 268 healthy, full-term newborns born appropriate for gestational age (AGA) were included at birth, 233 newborns participated in the postnatal follow-up period and 186 completed the one-year follow-up period (9.4% and 7.5%, respectively). CONCLUSION: The COPENHAGEN Minipuberty Study provides detailed, longitudinal data on early genital development and growth including hormonal and genetic profiles and environmental exposure in healthy infants including additional data in their parents.

Why we succeed and fail in detecting fetal growth restriction: A population-based study.

INTRODUCTION: The objective of this study was to explore the association between detection of fetal growth restriction and maternal-, healthcare provider- and organizational factors. MATERIAL AND METHODS: A historical, observational, multicentre study. All women who gave birth to a child with a birthweight <2.3rd centile from 1 September 2012 to 31 August 2015 in Zealand, Denmark, were included. The population was identified through the Danish Fetal Medicine Database. Medical charts were reviewed to obtain data regarding maternal characteristics and information on the healthcare professionals. Date of authorization for the midwives and obstetricians involved was extracted from the Danish Health Authorization Registry. Multivariable Cox regression models were used to identify predictors of antenatal detection of fetal growth restriction, and analyses were adjusted for hospital, body mass index, parity, the presence of at least one risk factor and experience of the first midwife, number of midwife visits, number of visits to a doctor, the experience of the consultant midwife or the educational level of the doctor, the number of scans and gaps in continuity of midwife-care. Antenatal detection was defined as an ultrasound estimated fetal weight <2.3rd centile (corresponding to -2 standard deviations) prior to delivery. RESULTS: Among 78 544 pregnancies, 3069 (3.9%) had a fetal growth restriction. Detection occurred in 31% of fetal growth-restricted pregnancies. Clinical experience (defined as years since graduation) of the first consultation midwife was positively associated with detection, with a hazard ratio [HR] of 1.15, 95% confidence interval [CI] 1.03-1.28), for every 10 years of additional experience. The hazard of detection increased with the number of midwife consultations (HR 1.15, 95% CI 1.05-1.26) and with multiparity (HR 1.28, 95% CI 1.03-1.58). After adjusting for all covariates, an unexplained difference between hospitals (P = .01) remained. CONCLUSIONS: The low-risk nullipara may constitute an overlooked group of women at increased risk of antenatal non-detection of fetal growth restriction. Being screened by experienced midwives during early pregnancy and having access to multiple midwife consultations may improve future diagnosis.

Violence among pregnant women in Denmark from 2019 to 2021 - A hospital-based cross-sectional study.

We examined the prevalence of lifetime physical and any recent violence and related maternal characteristics and health in pregnant women. We used Patient Reported Outcomes data retrieved from the Copenhagen Pregnancy Cohort (n = 7,361). The prevalence of lifetime physical and any recent violence was 4.0 % and 1.6 %, respectively. For both lifetime and any recent violence, the highest prevalence rates were seen among women aged 18-24, non-cohabiting, smokers, low levels of educational attainment, and women with chronic medical and psychiatric disease and lower psychological well-being. The prevalence may potentially be underestimated in this study, highlighting the need for improving screening for violence.

Use of fertility drugs and risk of uterine cancer: results from a large Danish population-based cohort study.

Some epidemiologic studies have indicated that uterine cancer risk may be increased after use of fertility drugs. To further assess this association, the authors used data from a large cohort of 54,362 women diagnosed with infertility who were referred to Danish fertility clinics between 1965 and 1998. In a case-cohort study, rate ratios and 95% confidence intervals were used to assess the effects of 4 groups of fertility drugs on overall risk of uterine cancer after adjustment for potentially confounding factors. Through mid-2006, 83 uterine cancers were identified. Ever use of any fertility drug was not associated with uterine cancer risk (rate ratio (RR) = 1.10, 95% confidence interval (CI): 0.69, 1.76). However, ever use of gonadotropins (follicle-stimulating hormone and human menopausal gonadotropin) increased uterine cancer risk (RR = 2.21, 95% CI: 1.08, 4.50); the risk was primarily observed after 10 years of follow-up. Furthermore, uterine cancer risk increased with number of cycles of use for clomiphene (for > or =6 cycles, RR = 1.96, 95% CI: 1.03, 3.72) and human chorionic gonadotropin (for > or =6 cycles, RR = 2.18, 95% CI: 1.16, 4.08) but not for other gonadotropins. Use of gonadotropin-releasing hormone analogs was not associated with risk. Gonadotropins, and possibly clomiphene and human chorionic gonadotropin, may increase the risk of uterine cancer, with higher doses and longer follow-up leading to greater risk.

Risk of breast cancer and gynecologic cancers in a large population of nearly 50,000 infertile Danish women.

Infertility is considered to influence the risk of breast cancer and gynecologic cancers. To assess this association, the authors used data from a large cohort of 54,362 women with a diagnosis of infertility who were referred to Danish fertility clinics between 1963 and 1998. Through 2003, 1,975 cancers were identified by linkage to the Danish Cancer Registry. Cancer risk was assessed through standardized incidence ratios (SIRs) and corresponding 95% confidence intervals, using general and parity-specific cancer incidence rates in the general population of Denmark as a reference. After adjustment for parity status, significantly increased SIRs were observed for breast (SIR = 1.08, 95% confidence interval: 1.01, 1.16) and ovarian (SIR = 1.46, 95% confidence interval: 1.24, 1.71) cancer. The risk of breast cancer increased with follow-up time. Similar risk patterns were observed for the different histologic types of breast cancer and all nonmucinous types of ovarian cancer, whereas the risk of mucinous ovarian cancers seemed not to be increased. These data thus suggest higher risks of breast and ovarian cancer among infertile women. However, since these results could not distinguish the effects of underlying infertility from the effects of fertility treatment, additional studies are needed to disentangle the effects of these two factors.

Risk of breast cancer after exposure to fertility drugs: results from a large Danish cohort study.

BACKGROUND: Few epidemiologic studies have examined the association between fertility drugs and breast cancer risk, and results have been contradicting. Using data from the largest cohort of infertile women to date, the aim of this study was to examine the effects of fertility drugs on breast cancer risk overall and according to histologic subtypes. METHOD: A cohort of 54,362 women with infertility problems referred to all Danish fertility clinics between 1963 and 1998 was established. A detailed data collection, including information of type and amount of treatment, was conducted. We used case-cohort techniques to calculate rate ratios (RR) of breast cancer associated with use of five groups of fertility drugs, after adjustment for parity status. RESULTS: Three hundred thirty-one invasive breast cancers were identified in the cohort during follow-up through 1998. Analyses within cohort showed no overall increased breast cancer risk after use of gonadotrophins, clomiphene, human chorionic gonadotrophin, or gonadotrophin-releasing hormone, whereas use of progesterone increased breast cancer risk (RR, 3.36; 95% confidence interval, 1.3-8.6). For all groups of fertility drugs, no relationships with number of cycles of use or years since first use of fertility drug were found. However, gonadotrophins may have a stronger effect on breast cancer risk among nulliparous women (RR, 1.69; 95% confidence interval, 1.03-2.77). Similar risk patterns were present for ductal, lobular, and tumors of other histologies, indicating identical etiologies. CONCLUSION: The results showed no strong association between breast cancer risk and use of fertility drugs. Follow-up is, however, needed to assess long-term breast cancer risk after use of progesterone and among nulliparous women exposed to gonadotrophins.

Childhood tumor risk after treatment with ovulation-stimulating drugs.

OBJECTIVE: To assess childhood cancer risk among children conceived following the use of ovulation-stimulating drugs. DESIGN: Record linkage study. SETTING: Infertility patients and their offspring as identified through medical records. PATIENT(S): Cohort of 30,364 Danish women evaluated for infertility beginning in the early 1960s. MAIN OUTCOME MEASURE(S): Standardized incidence ratios (SIRs) compared cancer incidence in the children to the Danish population. Case-cohort techniques calculated rate ratios (RRs) according to prior maternal drug exposures. RESULT(S): A total of 51 cancers were identified among the study children, resulting in an SIR of 1.14 (95% confidence interval [CI] 0.8-1.5). Usage of any fertility drug was associated with an RR of 0.82 (95% CI 0.4-1.6) and clomiphene citrate with an RR of 0.77 (95% CI 0.4-1.6). Tumors occurring early in life and nonhematopoietic malignancies (including neuroblastomas) were not associated with drug usage. Nonsignificant elevations in the risk of cancers occurring later in life, especially childhood hematopoietic malignancies (RR for use of any ovulation-stimulating drugs of 2.30, 95% CI 0.8-6.6), may have been related to underlying reasons for medication usage. CONCLUSION(S): Although the findings of this study are reassuring, additional adequately powered studies should continue monitoring the effects of ovulation-stimulating drugs on specific tumors, including hematopoietic malignancies.

The FIB-PPH trial: fibrinogen concentrate as initial treatment for postpartum haemorrhage: study protocol for a randomised controlled trial.

BACKGROUND: Postpartum haemorrhage (PPH) remains a leading cause of maternal mortality worldwide. In Denmark 2% of parturients receive blood transfusion. During the course of bleeding fibrinogen (coagulation factor I) may be depleted and fall to critically low levels, impairing haemostasis and thus worsening the ongoing bleeding. A plasma level of fibrinogen below 2 g/L in the early phase of postpartum haemorrhage is associated with subsequent development of severe haemorrhage. Use of fibrinogen concentrate allows high-dose substitution without the need for blood type crossmatch. So far no publications of randomised controlled trials involving acutely bleeding patients in the obstetrical setting have been published. This trial aims to investigate if early treatment with fibrinogen concentrate reduces the need for blood transfusion in women suffering severe PPH. METHODS/DESIGN: In this randomised placebo-controlled double-blind multicentre trial, parturients with primary PPH are eligible following vaginal delivery in case of: manual removal of placenta (blood loss ≥ 500 ml) or manual exploration of the uterus after the birth of placenta (blood loss ≥ 1000 ml). Caesarean sections are also eligible in case of perioperative blood loss ≥ 1000 ml. The exclusion criteria are known inherited haemostatic deficiencies, prepartum treatment with antithrombotics, pre-pregnancy weight <45 kg or refusal to receive blood transfusion. Following informed consent, patients are randomly allocated to either early treatment with 2 g fibrinogen concentrate or 100 ml isotonic saline (placebo). Haemostatic monitoring with standard laboratory coagulation tests and thromboelastography (TEG, functional fibrinogen and Rapid TEG) is performed during the initial 24 hours.Primary outcome is the need for blood transfusion. To investigate a 33% reduction in the need for blood transfusion, a total of 245 patients will be included. Four university-affiliated public tertiary care hospitals will include patients during a two-year period. Adverse events including thrombosis are assessed in accordance with International Conference on Harmonisation (ICH) good clinical practice (GCP). DISCUSSION: A widespread belief in the benefits of early fibrinogen substitution in cases of PPH has led to increased off-label use. The FIB-PPH trial is investigator-initiated and aims to provide an evidence-based platform for the recommendations of the early use of fibrinogen concentrate in PPH. TRIAL REGISTRATION: ClincialTrials.gov NCT01359878.

[Reconvalescence following Caesarean section]. / Rekonvalescens efter kejsersnit.

Recommendations for reconvalescence and restriction of physical activity after elective caesarean section are not consistent and there is a lack of evidence on the subject. Although physiological changes are rapidly normalized after the operation, the women experience an extended period characterized by fatigue caused by lack of sleep due to nursing and breastfeeding of the baby. This paper accounts for the effects of post-operative pain, breastfeeding, fatigue, sexuality and physical recovery in the period of reconvalecence following elective caesarean section.

Use of fertility drugs and risk of ovarian cancer: Danish Population Based Cohort Study.

OBJECTIVE: To examine the effects of fertility drugs on overall risk of ovarian cancer using data from a large cohort of infertile women. DESIGN: Population based cohort study. SETTING: Danish hospitals and private fertility clinics. PARTICIPANTS: 54,362 women with infertility problems referred to all Danish fertility clinics during 1963-98. The median age at first evaluation of infertility was 30 years (range 16-55 years), and the median age at the end of follow-up was 47 (range 18-81) years. Included in the analysis were 156 women with invasive epithelial ovarian cancer (cases) and 1241 subcohort members identified in the cohort during follow-up in 2006. MAIN OUTCOME MEASURE: Effect of four groups of fertility drugs (gonadotrophins, clomifene citrate, human chorionic gonadotrophin, and gonadotrophin releasing hormone) on overall risk of ovarian cancer after adjustment for potential confounding factors. RESULTS: Analyses within cohort showed no overall increased risk of ovarian cancer after any use of gonadotrophins (rate ratio 0.83, 95% confidence interval 0.50 to 1.37), clomifene (1.14, 0.79 to 1.64), human chorionic gonadotrophin (0.89, 0.62 to 1.29), or gonadotrophin releasing hormone (0.80, 0.42 to 1.51). Furthermore, no associations were found between all four groups of fertility drugs and number of cycles of use, length of follow-up, or parity. CONCLUSION: No convincing association was found between use of fertility drugs and risk of ovarian cancer.

Malignant melanoma risk after exposure to fertility drugs: results from a large Danish cohort study.

OBJECTIVE: The aim was to examine the effects of fertility drugs on malignant melanoma risk using data from the largest cohort of infertile women to date. METHODS: A cohort of 54,362 women with infertility problems referred to Danish fertility clinics in the period 1963-1998 was established. A detailed data collection including information about type and amount of treatment was conducted. Using case-cohort techniques, we calculated rate ratios (RRs) of malignant melanoma associated with different fertility drugs after adjustment for parity status. RESULTS: 112 malignant melanomas were identified during follow-up through 2000. Use of clomiphene, gonadotrophins, hCG or GnRH did not affect risk of malignant melanoma significantly. When stratifying for parity, however, use of gonadotrophins (RR = 2.29; CI: 1.16-4.52) or GnRH (RR = 3.26; 95% CI: 1.50-7.09) among parous women was associated with a significant increased risk. For all groups of fertility drugs, we found no association with number of cycles of use or years since first use (latency). CONCLUSIONS: Our findings showed no strong association between malignant melanoma risk and use of fertility drugs, although the results indicated that use of gonadotrophins or GnRH might increase risk in parous women. Longer follow-up is needed to confirm our findings.

Alcohol use as predictor for infertility in a representative population of Danish women.

BACKGROUND: Our aim was to examine the association between use of alcohol and subsequent incidence of primary infertility. METHODS: The study subjects were chosen from a population-based cohort of Danish women aged 20-29 years. Eligible women were nulliparous and not pregnant (n = 7760). Information on alcohol intake and potential confounders (age, education, marital status, diseases in the reproductive organs, and cigarette smoking) was assessed at enrollment. The incidence of fertility problems during follow-up was obtained by record linkage with the Danish Hospital Discharge Register and the Danish Infertility Cohort Register. Main outcome measures were hazard ratios of infertility according to alcohol intake at baseline estimated in a multivariate Cox proportional hazards model. RESULTS: During a mean follow-up of 4.9 years, 368 women had experienced infertility. Alcohol intake at baseline was unassociated with infertility among younger women, but was a significant predictor for infertility among women above age 30. In this age group, the adjusted hazard ratio for consuming seven or more drinks per week was 2.26 (95% confidence interval: 1.19-4.32) compared with women consuming less than one drink per week. CONCLUSIONS: These findings suggest that alcohol intake is a predictor for infertility problems among women in the later reproductive age group.