Puberty disorders among ART-conceived singletons: a Nordic register study from the CoNARTaS group.

STUDY QUESTION: Do ART-conceived children have an increased risk for puberty disorders? SUMMARY ANSWER: Both ART-conceived boys and girls had a higher risk of puberty disorders; early puberty was more common among girls and late puberty among boys. WHAT IS KNOWN ALREADY: Some physiological differences in growth and metabolism have been reported for ART-conceived children compared to non-ART-conceived children. Knowledge on pubertal development and disorders in ART-conceived children is limited. STUDY DESIGN, SIZE, DURATION: A register-based cohort study was carried out including data from 1985 to 2015. The Committee of Nordic Assisted Reproductive Technology and Safety (CoNARTaS) study population consists of all live and stillborn children, as well as their mothers, registered in the Medical Birth Registers during the study period in Denmark, Sweden, Finland and Norway. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 122 321 ART-conceived singletons and 6 576 410 non-ART singletons born in Denmark (1994-2014), Finland (1990-2014), Norway (2002-2015) and Sweden (1985-2015) were included. Puberty disorders were defined using International Classification of Diseases and Related Health Problems (ICD)-9/ICD-10 codes and classified in the following groups: late puberty (6268/E30.0), early puberty (2591 and 2958/E30.1 and E30.8) and unspecified disorders (V212 and V579/E30.9 and Z00.3 as well as Z51.80 for Finland). The results in Cox regression were adjusted for maternal age, parity, smoking, gestational diabetes, chronic hypertension, hypertensive disorders during pregnancy and country, and further for either gestational age, birthweight, small for gestational age or large for gestational age. MAIN RESULTS AND THE ROLE OF CHANCE: There were 37 869 children with diagnoses related to puberty disorders, and 603 of them were born after ART. ART-conceived children had higher risks for early (adjusted hazard ratio (aHR) 1.45, 95% CI: 1.29-1.64) and late puberty (aHR 1.47, 95% CI: 1.21-1.77). Girls had more diagnoses related to early puberty (aHR 1.46, 95% CI: 1.29-1.66) and boys with late puberty (aHR 1.55, 95% CI: 1.24-1.95). LIMITATIONS, REASONS FOR CAUTION: Using reported puberty disorders with ICD codes in health care registers might vary, which may affect the numbers of cases found in the registers. Register data may give an underestimation both among ART and non-ART-conceived children, especially among non-ART children, who may not be as carefully followed as ART-conceived children. Adjustment for causes and duration of infertility, mothers' own puberty characteristics and BMI, as well as children's BMI, was not possible because data were not available or data were missing for the early years. It was also not possible to compare ART to non-ART siblings or to study the pubertal disorders by cause of subfertility owing to a small number of discordant sibling pairs and a large proportion of missing data on cause of subfertility. WIDER IMPLICATIONS OF THE FINDINGS: This large, register-based study suggests that ART-conceived children have a higher risk for puberty disorders. However, the mechanisms of infertility and pubertal onset are complex, and ART is a rapidly advancing field with various treatment options. Studying the pubertal disorders of ART-conceived offspring is a continuing challenge. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Nordic Trial Alliance: a pilot project jointly funded by the Nordic Council of Ministers and NordForsk (71450), the Central Norway Regional Health Authorities (46045000), the Nordic Federation of Obstetrics and Gynaecology (NF13041, NF15058, NF16026 and NF17043), the Interreg Öresund-Kattegat-Skagerrak European Regional Development Fund (ReproUnion project), the Research Council of Norway's Centre of Excellence funding scheme (262700), the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-70940) and FLUX Consortium 'Family Formation in Flux-Causes, Consequences and Possible Futures', funded by the Strategic Research Council, Academy of Finland (DEMOGRAPHY 345130). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Risks of Adverse Perinatal Outcomes after Repeat Terminations of Pregnancy by their Methods: a Nationwide Register-based Cohort Study in Finland 1996-2013.

BACKGROUND: Repeat terminations of pregnancy (TOPs) are associated with an increased risk of adverse outcomes in the subsequent birth. The perinatal outcomes after repeat TOPs by their methods have not yet been properly studied. This study aimed to examine perinatal outcomes in subsequent pregnancy among the women with a singleton birth and a history of TOPs. METHODS: All the first-time mothers (n = 419 879) with a singleton birth during 1996-2013 in Finland were identified from the Medical Birth Register and linked to the Abortion Register. Adjusted multivariable logistic regression analysis was used to estimate risks of adverse perinatal outcomes. RESULTS: The increased incidence of adverse perinatal outcomes was found with increasing number of surgical TOPs. After adjusting for confounders, the women with one surgical TOP had slightly increased but significant odds of 1.07 (95% CI 1.02, 1.13) for being small for gestational age compared with the women having no TOP. A significantly high risk for extremely preterm birth (OR 1.51, 95% CI 1.03, 2.23) was found among the women having had repeat surgical TOPs when compared to the women with no TOP. Non-significant risks were found for adverse perinatal outcomes after women's repeat surgical TOPs than repeat medical TOPs. CONCLUSION: Information regarding the consequences of repeat induced TOPs will be significant in sexual health education as well as counselling women after first termination.

Associations of maternal age with maternity care use and birth outcomes in primiparous women: a comparison of results in 1991 and 2008 in Finland.

OBJECTIVE: To compare birth outcomes and maternity care use in 1991 and 2008 by age among primiparous Finnish women. DESIGN: Register-based study. SETTING: Nationwide Medical Birth Register. POPULATION: All primiparous women in 1991 (n = 24,765) and 2008 (n = 23,511). METHODS: Women aged 35-39 and ≥40 years were compared with women aged 20-34 years in 1991 and 2008, using logistic regression to adjust for women's background. MAIN OUTCOME MEASURES: Maternity care: prenatal visits, hospitalisation during pregnancy, labour induction, delivery mode, long postpartum hospital stay; and birth outcomes: birthweight, preterm birth, Apgar scores, intensive/observation unit, respiratory care, perinatal death. RESULTS: In both years, older women's deliveries were more often induced, instrumental, or by caesarean section. In 2008 compared with 1991, hospitalisations were lower and instrumental deliveries and labour induction were higher in older women. A significant decrease in adjusted odds ratios (OR, 95% confidence intervals) between 1991 and 2008 among women aged 35-39 was found for preterm birth (1.47, 1.18-1.84 versus 0.96, 0.86-1.07) and for intensive/observation unit (1.73, 1.47-2.05 versus 1.21, 1.07-1.37) and, among women aged ≥40 years, for intensive/observation unit (3.14, 2.30-4.29 versus 1.64, 1.31-2.07). The risk for perinatal death (1.66, 0.60-4.60 versus 2.69, 1.07-6.79) was higher in 2008 than in 1991 among women aged ≥40. CONCLUSIONS: In 2008, older primiparous women still used more maternity care, had more interventions, and poorer birth outcomes than younger women, regardless of care advances. Additional risks declined among women aged 35-39 but not among aged ≥40.

Birth outcomes after induced abortion: a nationwide register-based study of first births in Finland.

STUDY QUESTION: Is the perinatal health of first-born children affected by the mother's previous induced abortion(s) (IAs)? SUMMARY ANSWER: Prior IAs, particularly repeat IAs, are correlated with an increased risk of some health problems at first birth; even in a country with good health care quality. WHAT IS KNOWN ALREADY: A positive association between IA and risk of preterm birth or a dose-response effect has been found in some previous studies. Limited information and conflicting results on other infant outcomes are available. STUDY DESIGN, SIZE AND DURATION: Nationwide register-based study including 300 858 first-time mothers during 1996-2008 in Finland. PARTICIPANTS/MATERIALS, SETTING AND METHODS: All the first-time mothers with a singleton birth (obtained from the Medical Birth Register) in the period 1996-2008 (n = 300 858) were linked to the Abortion Register for the period 1983-2008. MAIN RESULTS AND THE ROLE OF CHANCE: Of the first-time mothers, 10.3% (n = 31 083) had one, 1.5% had two and 0.3% had three or more IAs. Most IAs were surgical (88%) performed before 12 weeks (91%) and carried out for social reasons (97%). After adjustment, perinatal deaths and very preterm birth (<28 gestational week) suggested worse outcomes after IA. Increased odds for very preterm birth were seen in all the subgroups and exhibited a dose-response relationship: 1.19 [95% confidence interval (CI) 0.98-1.44] after one IA, 1.69 (1.14-2.51) after two and 2.78 (1.48-5.24) after three IAs. Increased odds for preterm birth (<37 weeks) and low birthweight (<2500 g and <1500 g) were seen only among mothers with three or more IAs: 1.35 (1.07-1.71), 1.43 (1.12-1.84) and 2.25 (1.43-3.52), respectively. LIMITATIONS, REASONS FOR CAUTION: Observational studies like ours, however large and well-controlled, will not prove causality. WIDER IMPLICATIONS OF THE FINDINGS: In terms of public health and practical implications, health education should contain information of the potential health hazards of repeat IAs, including very preterm birth and low birthweight in subsequent pregnancies. Health care professionals should be informed about the potential risks of repeat IAs on infant outcomes in subsequent pregnancy. STUDY FUNDING/COMPETING INTEREST(S): National Institute for Health and Welfare and the Academy of Finland. No competing interests.

Cancer morbidity in a cohort of 9175 Finnish women treated for infertility.

BACKGROUND: Results of earlier studies on cancer risk in infertile women are inconsistent for many cancer types. Our goal was to study cancer incidence among a cohort of women treated with IVF, including ICSI and frozen embryo transfer (FET), compared with that of a control population. METHODS: A cohort of women who purchased drugs for IVF (including ICSI and FET treatments, n= 9175) in the period 1996-1998 in Finland (later called IVF women) and their age and residence-matched controls further adjusted for socio-economic position and marital status were linked to the Finnish Cancer Registry 1996-2004. RESULTS: The overall cancer incidence and combined incidence of hormonal-related breast, uterine and invasive ovarian cancers were similar among IVF women and controls. IVF women had statistically significantly less cervical cancer [odds ratio (OR): 0.51, 95% confidence interval (CI): 0.30-0.85], but more skin cancers other than melanoma (OR: 3.11, 95% CI: 1.02-9.6). IVF women had three times more invasive ovarian cancers than controls, but this difference was not statistically significant, possibly due to the small number of cases. IVF women had slightly fewer breast cancers but difference was likewise not statistically significant. All cases of pulmonary cancer were diagnosed among controls (P= 0.03). CONCLUSIONS: General cancer risk or risk of hormonal-related cancers in women was not increased by IVF. The differences in certain cancers suggest a healthy patient effect or may be partly caused by residual socio-economic differences. More large studies and reanalysis of existing studies are needed to evaluate cancer risk among infertile women by subgroups regarding the cause of infertility. When evaluating risk of cancer after drug exposure, dosage and the use of different medicaments should be taken into consideration.

Psychiatric disorders leading to hospitalization before and after infertility treatments.

BACKGROUND: This study aimed at determining the psychiatric morbidity of women undergoing infertility treatments, before and after treatment as compared with control women. METHODS: The number of women hospitalized because of psychiatric disorders was obtained from the Hospital Discharge Register (1969-2006) in a cohort of women who purchased drugs for in vitro fertilization, intra-cytoplasmic sperm injection or frozen embryo transfer treatments (n = 9175) in 1996-1998 in Finland and their controls (n = 9175). The age- and residence-matched controls were further adjusted in the analysis for socio-economic position and marital status. RESULTS: Women with infertility treatments had fewer hospitalizations due to depression, psychotic disorders, personality disorders, anxiety disorders, bipolar disorder or mania, eating disorders, adjustment disorders and alcohol or other intoxicant abuse before their treatments than did controls. However, the difference was statistically significant only for psychotic disorders [Odds ratios (OR) 0.38, 95% confidence intervals (CI) 0.20-0.72]. Differences in hospitalization remained similar also during the 10-year post-treatment follow-up. The exceptions were increased risk of hospitalizations due to adjustment disorders (OR 3.43, 95% CI 1.03-11.4) and decreased risk of alcohol or other intoxicant abuse (OR 0.44, 95% CI 0.25-0.75) among the women with infertility treatments. The infertile women who gave birth had fewer hospitalizations for all psychiatric diagnoses than did infertile women who did not have a baby. The difference was statistically significant for anxiety disorders (OR 0.38, 95% CI 0.18-0.81), depression (OR 0.63, 95% CI 0.41-0.96) and alcohol or other intoxicant abuse (OR 0.38, 95% CI 0.18-0.80). Hospitalizations among infertile women who did not have a baby and controls were similar, with the exception of significantly more hospitalizations for psychotic disorders among controls (OR 0.38, 95% CI 0.19-0.77). CONCLUSIONS: Women treated for infertility had less serious psychiatric morbidity leading to hospitalization than did the controls, both before and after treatments, suggesting a healthy patient effect. After treatments, the risk of hospitalization due to adjustment disorders was increased among the infertile women. Having a baby after infertility treatments was associated with fewer hospitalizations following psychiatric diagnosis.

Cognitive development following ART: effect of choice of comparison group, confounding and mediating factors.

BACKGROUND: Epidemiological studies have examined the health of children born after assisted reproductive technology (ART), with contradictory results. In this article, we address the question 'Do singletons born after ART have a poorer cognitive developmental outcome at 3 years of age?' We assess the implications of using different comparison groups, and discuss appropriate analytical approaches for the control of confounding and mediating variables. METHODS: Data were drawn from the Millennium Cohort Study. Interviews captured sociodemographic, behavioural and pregnancy information. Developmental assessments conducted at age three included the British Ability Scales II Naming Vocabulary (BAS-NV) instrument. We compared ART infants (born after IVF or ICSI) to four comparison groups: a 'matched' group; a 'subfertile' group (time to conception >12 months); a 'fertile' group (time to conception <12 months); and an 'any spontaneous conceptions' group. Linear regression provided estimates of the difference in mean BAS-NV scores in the ART and comparison groups; both unadjusted estimates and those adjusted for confounding and mediating factors are presented. RESULTS: In the unadjusted analyses, ART children gained significantly better BAS-NV test results than did the comparison group children. When converted to an estimate of developmental age gap, ART children were 2.5, 2.7, 3.6 and 4.5 months ahead of the 'matched', 'subfertile', 'fertile' and 'spontaneous conception' children, respectively. After adjusting for confounding and mediating factors, the differences were reduced, and were not statistically significant. CONCLUSIONS: ART is not associated with poorer cognitive development at 3 years. We have highlighted methodological considerations for researchers planning to study the effect of infertility and ART on childhood outcomes.

Induced abortions previous to IVF: an epidemiologic register-based study from Finland.

BACKGROUND: The purpose of this study was to identify how many women treated for infertility had an abortion history, as well as when those abortions were carried out, and for what reasons. METHODS: Data on all women treated in Finland from 1996-1998 for infertility either with IVF (n = 9175) or ovulation induction (OI, n = 10,254) and the age-matched controls of IVF women were linked to the Abortion and Hospital Discharge Registers for the period 1969-2000. RESULTS: A notable proportion of IVF women (12%) and OI women (11%) had previous induced abortion(s). Practically all abortions were for social or age reasons. Most IVF women (72% of n = 1099) had their most recent abortion more than 10 years previous to fertility treatment, but more recently among OI women (45% of n = 1123 of the most recent abortions were in the preceding 10 years). Many IVF- and OI women were young and single at the time of the most recent abortion. At the time of IVF treatment most women were aged over 30 and married; OI women were also frequently married, but 42% of them were aged younger than 30. CONCLUSIONS: At different points in their life, women may rely on opposite fertility regulation strategies. Health care professionals providing IVF need to consider the possibility of a previous abortion. Young women need information on the possibility of future infertility in later age.

Health and life style among infertile men and women.

OBJECTIVE: Lifetime prevalence of infertility among couples is approximately 10-15%, but studies addressing their health behavior are few. Our aim was to describe health and life style of Finnish men and women who had experienced infertility. DESIGN: Cross-sectional survey. SETTING: Finland. POPULATION AND METHODS: Data from a population-based survey (n=7021) was utilized. Life style of infertile men (n=289) and women (n=155) were compared to other men and fertile women. MAIN OUTCOME MEASURES: Life style (dietary factors, use of alcohol, physical activity), reproductive factors, other diseases and symptoms. RESULTS: After adjusting for age, area and education, infertile women under 50 years consumed more polyunsaturated fat (OR 1.23, 95% CI 1.03-1.46), less saturated fat (OR 0.83, 95% CI 0.74-0.92) and had experienced more hangovers during previous year (OR 1.02, 95% CI 1.00-1.05) than fertile women. Infertile men under 50 years consumed more total fat (OR 1.06, 95% CI 1.03-1.10), polyunsaturated fat (OR 1.20, 95% CI 1.05-1.37) and monounsaturated fat (OR 1.17, 95% CI 1.06-1.28) compared to other men. Infertile men did not consume more alcohol nor smoke more cigarettes but reported more often allergies than fertile men. Infertile women also had Chlamydia trachomatis infection, benign tumor in their uterus and intestinal disease more often than fertile women. Infertile women over 50 years were more often current smokers than fertile women, but the differences in other age-groups were not significant. CONCLUSIONS: Women with infertility experience reported more diseases and less use of oral contraceptives than other women, possibly reflecting reasons to infertility. Since both infertility and unhealthy use of alcohol are an increasing public health issues in western societies, more attention should be paid towards life style, especially alcohol use of infertile women.

Health care costs resulting from IVF: prenatal and neonatal periods.

BACKGROUND: The use of expensive infertility treatments is increasing rapidly. To compare the prenatal and neonatal health care costs after IVF and spontaneous conception, we conducted a study based on a cohort of IVF and control pregnancies and neonates. METHODS: A cohort of 215 IVF mothers and 255 IVF neonates were compared with a cohort of 662 control mothers and 388 control children, randomly chosen from the Finnish Medical Birth Register and matched for sex, year of birth, area of residence, parity, maternal age, socioeconomic status and plurality. The analyses on prenatal and neonatal costs were performed by plurality. Singletons were also compared with twins. The cost calculations were based on the known level of utilization of maternal and neonatal health care services. RESULTS: The total health care costs for an IVF singleton until the end of the neonatal period were 5780 and 15 580 for an IVF twin. The health care costs were 1.3-fold for IVF singletons and 1.1-fold for IVF twins compared to control singletons and twins. The costs for twins were approximately 3-fold compared to singletons. CONCLUSIONS: The health care costs of an IVF singleton neonate were higher than those of a spontaneously conceived control neonate with similar backgrounds. For twins the health care costs were equal. Multiple births increase the health care costs and therefore the reduction of multiple pregnancies is the most effective way to reduce the health care costs resulting from IVF.