Background. Recently three large-scale epidemiological registry-based Scandinavian studies examined the association between use of hormonal contraception and the risk of developing depression or use of antidepressants. They reached surprisingly divergent results. Objectives: The aim of this study was to explain why these three recent studies from Denmark and Sweden could achieve quite different results, interpretations, and conclusions. Methods: Search strategi and selection. The three existing large scale Scandinavian studies examining associations between exposure to different types of hormonal contraception and risk of depression or use of antidepressants were examined according to chosen design, exclusion criteria, and included confounders. Methodological choices were considered, and the validity of these methodological choices tested. Main results. First, the assumption that differences between studies are due to residual confounding is proven unlikely, already because confounder control beyond age, year and education rarely change estimates materially. More likely basic differences in chosen study groups, exclusions from the study groups, exposure definitions, chosen reference populations, and interpretation of the results seem to explain the differences between the studies. Conclusion. The detailed review of the three Scandinavian studies reveals methodological choices as the main explanation for their different findings. Residual confounding was found unlikely to explain the divergent results, while ideological circumstances might have a main responsibility for the different chosen methods and for the interpretation of the results. Funding. None.

Objectives. To investigate the obstetrical management of cancer in pregnancy and to determine adverse pregnancy and neonatal outcomes. Design. A register-based nationwide historical prospective cohort study. Setting and population. We assessed all pregnancies (N = 4,071,848) in Denmark from 1 January 1973 to 31 December 2018. Methods. We linked data on maternal cancer, obstetrical, and neonatal outcomes. Exposure was defined as pregnancies exposed to maternal cancer (n = 1,068). The control group comprised pregnancies without cancer. The groups were compared using logistic regression analysis and adjusted for potential confounders. Main outcome Measures. The primary outcome was the iatrogenic termination of the pregnancy (induced abortions/labor induction or elective caesarean section). Secondary outcomes were adverse neonatal outcomes. Results. More women with cancer in pregnancy, as compared to the control group, experienced first-trimester induced abortion; adjusted odds ratio (aOR) 3.7 (95% CI 2.8─4.7), second-trimester abortion; aOR 9.0 (6.4─12.6), iatrogenic preterm delivery; aOR 10.9 (8.1─14.7), and iatrogenic delivery below 32 gestational weeks; aOR 16.5 (8.5─32.2). Neonates born to mothers with cancer in pregnancy had a higher risk of respiratory distress syndrome; aOR 1.5 (1.2─2.0), but not of low birth weight; aOR 0.6 (0.4─0.8), admission to neonatal intensive care unit more than seven days; aOR 1.4 (1.1─1.9), neonatal infection; aOR 0.9 (0.5─1.5) nor neonatal mortality; aOR1.3 (0.6─2.6). Conclusion. Cancer in pregnancy implies an increased risk of iatrogenic termination of pregnancy and iatrogenic premature birth. Neonates born to mothers with cancer in pregnancy had no increased risk of severe adverse neonatal outcomes.

BJOG-21-0722 Statistical associations versus causal inference.Øjvind Lidegaard, professor 11Department of Gynaecology, Rigshospitalet, University of Copenhagen, DenmarkMany clinicians are of the opinion that observational studies may provide only “statistical associations”, but not “causal inference”. And further, that only randomized designs ensure causal interpretation. For the same reason, many medical journals have made rules for all observational studies finding significant statistical associations to be presented as just “associations” often emphasizing that a causal inference is not possible.I hereby sign up to the growing group of epidemiologists, who are of the opinion that just well confounder controlled observational studies are the very design most often providing convincing evidence of a causal interference. Prospective cohort studies better than retrospective case-control studies, but even the latter design has given us important knowledge of risk factors of rare clinical outcomes such as thrombotic diseases, a long list of cancers, obstetrical complications, including latest stillbirths.In a new original Swedish study, Heiddis Valgeirsdottir et al. demonstrate in a nationwide historical follow-up study, that women with polycystic ovary syndrome (PCOS) once pregnant have a 50% increased risk of experiencing stillbirth, as compared to women without PCOS (1). Further, that the rate ratio of stillbirth between women with and without PCOS increased by increasing gestational age, peaking at 42 weeks with 4.3 deaths per 1000 ongoing pregnancies in women with PCOS versus 1.0 deaths per 1000 ongoing pregnancies in women without PCOS.Any such association should certainly be controlled for a long list of potential confounders, the most important being maternal age, calendar year, parity, hypertensive disorders, diabetes, and educational length. Adiposity (BMI) was undertaken in an additional adjustment, because this covariate correctly could be considered as both a confounder (adiposity being a risk factor for stillbirth, and PCOS women more often being adipose), but also as a mediator; women with PCOS are more likely to develop adiposity due to their PCOS. The authors chose carefully to present the BMI adjusted results as the main results, thereby if anything underestimating the risk of stillbirths in women with PCOS.This is far from the first contribution from Scandinavian National Health Registers, identifying and quantifying risk factors for different diseases. We should always be aware that some unknown or unmeasured potential confounders not being controlled for, could reduce (or enhance) the results, and that other research groups should confirm the Swedish findings. A causal inference was made more likely with a suggested biomedical mechanism by which PCOS could confer such a risk. But already with this new carefully provided observational evidence, we should reasonably consider pregnant women with PCOS not to go too far beyond term, to prevent stillbirths in this group, which according to the study results accounts about 5% of all stillbirths. A pragmatic first recommendation could be induction of women with PCOS at 41 gestational weeks.Valgeirsdottir H et al. BJOG 2021; 128: xxx-xxx.