Overweight and obesity as risk factors for cervical cancer and detection of precancers among screened women: A nationwide, population-based cohort study.

OBJECTIVE: Obesity is a known risk factor for many types of cancer. However, there is no clear evidence whether overweight and obesity increases the risk of cervical cancer. We investigated the association between body mass index (BMI) and detection of squamous and glandular cervical cancer and precancer. METHODS: Based on the Medical Birth Registry, we conducted a nationwide cohort study in Denmark of 384,559 women with BMI ≥18.5 kg/m2 (pre-pregnancy BMI reported at the start of the pregnancy) having a cervical cytology screening at age 23-49 years within 5 years following the date of childbirth. The cohort was followed for 10 years from the first cervical cytology screening after the childbirth. We assessed absolute risks of cervical lesions according to BMI with the Aalen-Johansen estimator. We conducted Cox proportional hazards regression analyses to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Analyses were adjusted for age, calendar year, parity, oral contraception use, HPV vaccination, smoking, country of origin, and education. RESULTS: Overweight and obesity were associated with higher rates of cervical cancer (HR = 1.24, 95% CI 1.04-1.49 and HR = 1.14, 95% CI 0.91-1.43, respectively) and lower rates of cervical precancer detection (HR = 0.88, 95% CI 0.84-0.92 and HR = 0.67, 95% CI 0.63-0.71, respectively). CONCLUSIONS: Higher than normal BMI was associated with higher incidence rates of cervical cancer and lower rates of precancer detection, emphasizing the importance of further research in possible mechanisms behind this association.

Requests for vulvoplasty as gender-affirming surgery: a cross-sectional study in Denmark.

BACKGROUND: Vulvoplasty, described as a promising procedure for transgender and gender diverse (TGD) persons who were assigned male at birth and who, for example, do not need a vagina or who have contraindications to vaginoplasty, is a procedure that in accordance with current guidelines is not offered as genital gender-affirming surgery in Denmark. AIM: In this study we sought to quantify the need for offering vulvoplasty in Denmark. MATERIALS AND METHODS: An online questionnaire was developed. The target group included TGD persons who were assigned male at birth and a minimum of 18 years old. Prior to data collection, the questionnaire was tested with stakeholders from the target group and was subsequently distributed exclusively in closed groups and online fora for TGD persons. Data collection took place from September 1 to October 31, 2022. OUTCOMES: Primary outcomes were type of bottom surgery respondents preferred, when vulvoplasty was chosen, the reason(s) for choosing it. RESULTS: A total of 152 responses were included for data analysis, and 134 records were complete responses. Out of 134 respondents, 35 (26.1%) preferred vulvoplasty. The reasons for preferring vulvoplasty were the belief that there is less risk with the procedure (71%), followed by not wanting to dilate (54%), no need for a vagina (48%), and no need for vaginal penetration (40%). Health issues or other reasons were infrequent (5%). Out of 122 respondents who had not had prior bottom surgery, 106 (86.9%) wanted it in the future. CLINICAL IMPLICATIONS: Some TGD individuals in Denmark could benefit from vulvoplasty and would choose it if offered. STRENGTHS AND LIMITATIONS: Strengths of this study were that the questionnaire was thoroughly tested prior to application and that the survey could only be accessed via closed fora and groups for TDG persons. Limitations were that the sample size was small, and that the response rate could not be estimated. CONCLUSION: The results of this study imply that there is an unmet need for vulvoplasty, and bottom surgery in general, in Denmark.

Maternal opioid use during pregnancy and the risk of neonatal opioid withdrawal syndrome in the offspring.

INTRODUCTION: Neonatal opioid withdrawal syndrome (NOWS) is caused by sudden cessation from in utero exposure to opioids. The indications for opioid use during pregnancy are diverse including medication for opioid use disorder and analgesia. The opioid dose typically depends on the indication, with higher doses used for medication for opioid use disorder and lower doses used for analgesia. The aim of this study was to investigate the relationship between maternal opioid dose during pregnancy and the risk of NOWS. MATERIAL AND METHODS: We conducted a historical multicenter cohort study of neonates prenatally exposed to opioids in Eastern Denmark during a six-year period from 2013 to 2018. The data was extracted from reviewing the individual's medical record(s), which were identified through a search of the Danish National Patient Register. Four groups (quartiles) according to maternal opioid dose during the last four weeks prior to delivery were compared. Unadjusted and adjusted logistic regression analyses were conducted to examine the risk of NOWS while controlling for relevant covariates. RESULTS: A total of 130 in utero opioid exposed neonates were included. The majority of the pregnant patients (88%) were treated with opioids for analgesic purposes. Overall, 52% of neonates developed NOWS. The cumulative incidence of NOWS was 21%, 28%, 67% and 91% at maternal average daily dose of morphine milligram equivalent during the last four weeks prior to delivery of 0.7-14 (group I), 14.3-38.6 (group II), 40-90 (group III) and 90.9-1440 (group IV), respectively. Compared to group I the adjusted odds (aOR) of NOWS increased significantly in group III (aOR 10.6 [2.9-39.1]) and group IV (aOR 37.8 [7.6-188.2]) but not in group II (aOR 1.5 [0.4-5.2]). No cases of NOWS were reported at maternal dose less than an average daily dose of five morphine milligram equivalent during the last four weeks prior to delivery. No significant changes in the incidence of NOWS were observed between 2013 and 2018. CONCLUSIONS: The odds of neonatal opioid withdrawal syndrome increased significantly as the maternal average daily dose of morphine milligram equivalent during the last four weeks prior to delivery surpassed 40.

Vitamin D3 among neonates born after in vitro fertilization compared with neonates from the general population.

INTRODUCTION: Sufficient levels of vitamin D have been associated with higher chances for both clinical pregnancy and live birth among women undergoing assisted reproductive techniques, whereas low levels of maternal vitamin D have been associated with preeclampsia and late miscarriage. In Denmark, subgroups at risk for low vitamin D levels, including neonates and toddlers, are recommended to use supplementation. The aim was to study the level of vitamin D3 among neonates born after in vitro fertilization compared with neonates from the general population. MATERIAL AND METHODS: In this cohort study a random sample of 1326 neonates representing the general population and 1200 neonates conceived by in vitro fertilization born in Denmark from 1995 to 2002 were identified from registries covering the whole Danish population. Information on use of assisted reproduction was collected from the Danish In Vitro Fertilization register, ICD-10 code: DZ358F. 25-Hydroxyvitamin D was measured from dried blood spots routinely collected by heel prick 48-72 h after birth and corrected according to the hematocrit fraction for capillary blood of neonates. Linear regression analysis was performed, both crude and adjusted, for predefined putative confounders, identified through directed acyclic graphs. RESULTS: Vitamin D3 analysis could be performed from a total of 1105 neonates from the general population and 1072 neonates conceived by in vitro fertilization that were subsequently included in the study. The median vitamin D3 was 24.0 nmol/L (interquartile range [IQR] 14.1-39.3) and 33.0 nmol/L (IQR 21.3-48.8) among neonates from the general population and neonates conceived by in vitro fertilization, respectively. The adjusted mean difference between neonates from the general population and those conceived by in vitro fertilization was 6.1 nmol/L (95% confidence interval 4.1-8.1). CONCLUSIONS: In this study, children born after in vitro fertilization have a higher vitamin D3 than a random sample of neonates in Denmark.

Preterm birth and subsequent intelligence and academic performance in youth: A cohort study.

INTRODUCTION: Worldwide, more children than before survive preterm birth. Preterm birth can affect long-term cognitive outcomes. The aim of our study was to investigate the association between preterm birth and academic performance and intelligence in youth. MATERIAL AND METHODS: This cohort study included all liveborn children in Denmark from 1978 to 2000. We used uni- and multivariable logistic and linear regressions to analyze associations between gestational age and school graduation, grade point average (GPA), attending conscription, and male intelligence scores at conscription. We adjusted for a priori defined potential confounders. RESULTS: The study included 1 450 681 children and found an association between preterm birth and lower academic performance, with children born extremely preterm having the lowest odds of graduating from lower- and upper secondary education (LSE and USE) and appearing before the conscription board (odds ratios of 0.45 [0.38-0.54], 0.52 [0.46-0.59], and 0.47 [0.39-0.56] for LSE, USE, and conscription, respectively, compared to the term group). Statistically significant differences were observed in LSE for total GPA and core subject GPA with higher GPAs in the term group, which were considered clinically relevant for mathematics with a 0.71 higher grade point for the term compared to the extremely preterm. Conversely, USE differences were less evident, and in linear regression models we found that preterm birth was associated with higher GPAs in the adjusted analyses; however, this was not statistically significant. We demonstrated statistically significant differences in intelligence scores at conscription with lower scores in the three preterm groups (-5.13, -2.73, and - 0.76, respectively) compared to the term group. CONCLUSIONS: Low gestational age at birth was associated with not graduating from LSE and USE, achieving lower GPAs in LSE, not attending conscription, and lower intelligence scores in young adulthood. The findings remained significant after adjusting for potential confounders.

Utilization of healthcare prior to endometriosis diagnosis: a Danish case-control study.

STUDY QUESTION: Do women with endometriosis have higher utilization of primary and secondary healthcare prior to diagnosis compared to women without endometriosis? SUMMARY ANSWER: Women with a hospital-based diagnosis of endometriosis had an overall higher utilization of both primary and secondary healthcare in all 10 years prior to diagnosis. WHAT IS KNOWN ALREADY: Endometriosis is associated with a diagnostic delay, but only a few studies have investigated the potential consequences of this delay with regard to the utilization of healthcare. To the best of our knowledge, no study has investigated it in a period corresponding to the estimated diagnostic delay. STUDY DESIGN, SIZE, DURATION: This national Danish registry-based case-control study included 129 696 women. Cases were women with a first-time hospital-based diagnosis of endometriosis between 1 January 2000 and 31 December 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified 21 616 cases using density sampling. Each case was matched on age at the date of diagnosis (index date) to five women without diagnosed endometriosis (n = 108 080). The utilization of healthcare was assessed for the 10 years before the index. MAIN RESULTS AND THE ROLE OF CHANCE: Cases had significantly higher use of healthcare in all 10 years preceding the index. The mean number of yearly contacts with the GP was 9.99 for cases and 7.85 for controls, with an adjusted incidence rate ratio of 1.28 (1.27; 1.29). For hospital contacts, the association increased slightly in the first 9 years and was most profound in the last year preceding index when the adjusted incidence rate ratio was 2.26 (95% CI 2.28; 2.31). LIMITATIONS, REASONS FOR CAUTION: We were not able to include women with an endometriosis diagnosis from the general practitioner or private gynaecologist. Therefore, our results are only applicable to hospital-based diagnoses of endometriosis. We do not have information on the specific reasons for contacting the healthcare providers and we can therefore only speculate that the higher utilization of healthcare among cases was related to endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: This study is in agreement with the other known studies on the subject. Future studies should include specific reasons for contacting the healthcare system and thereby identify any specific contact patterns for women with endometriosis. With this knowledge, healthcare professionals could be better at relating certain healthcare seeking behaviour to endometriosis earlier and thereby reduce the time from onset of symptoms to diagnosis. STUDY FUNDING/COMPETING INTEREST(S): This study is supported by grants from the project 'Finding Endometriosis using Machine Learning' (FEMaLe/101017562), which has received funding from The European Union's Horizon 2020 research and innovation program and Helsefonden (21-B-0141). K.Z. report grants from Bayer AG, Roche Inc. and Volition, royalties from Oxford-Bayer scientific collaboration in gynaecological therapies, non-financial collaboration with the World Endometriosis Society and World Endometriosis Research Foundation and is a Wellbeing of Women research advisory committee member. All this is outside the submitted work. The other authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Endometriosis patients benefit from high serum progesterone in hormone replacement therapy-frozen embryo transfer cycles: a cohort study.

RESEARCH QUESTION: What is the optimal serum progesterone cut-off level in patients with endometriosis undergoing hormone replacement therapy frozen embryo transfer (HRT-FET) with intensive progesterone luteal phase support? DESIGN: A cohort study, including 262 HRT-FET cycles in 179 patients all diagnosed with endometriosis either by laparoscopy or by ultrasound in patients with visible endometriomas. Pre-treatment consisted of 42 days of oral contraceptive pills and 5 days' wash-out, followed by 6 mg oral oestrogen daily. Exogenous progesterone supplementation with vaginal progesterone gel 90 mg/12h commenced when the endometrium was 7 mm or thicker. From the fourth day of vaginal progesterone supplementation, patients also received intramuscular progesterone 50 mg daily. Blastocyst transfer was scheduled for the sixth day of progesterone supplementation. RESULTS: The overall positive HCG, live birth (LBR) and total pregnancy loss rates were 60%, 39% and 34%, respectively. The optimal progesterone cut-off level was 118 nmol/l (37.1 ng/ml) defined as the maximum of the Youden index. The unadjusted LBR was significantly higher in patients with progesterone measuring 118 nmol/l or above compared with patients with progesterone measuring less than 118 nmol/l (51% [44/86] versus 34% [59/176], P = 0.01), whereas the adjusted odds ratio for a live birth was 2.1 (95% CI 1.2 to 3.7) after adjusting for age, body mass index, blastocyst score, blastocyst age, quality and number of blastocysts transferred. CONCLUSIONS: Serum progesterone levels above 118 nmol/l (37.1ng/ml) resulted in significantly higher LBR compared with lower serum progesterone levels, suggesting that a threshold for optimal serum progesterone exists.

Birthweight and gestational age in the Faroe Islands: A comparison between birthweight and gestational age in the Faroe Islands and other Nordic countries.

INTRODUCTION: This study aimed to examine Faroese infants' birthweight and gestational age in 2010-2019 and compare these findings with other Nordic countries. Risk factors for high birthweight among Faroese infants were also investigated in this study. MATERIAL AND METHODS: All singleton liveborn infants registered in the Faroese Birth Registry in 2010-2019 were included in the study (n = 6121). A comparison was made with data on birthweight and gestational age from Denmark, Iceland, Norway, and Sweden. RESULTS: The mean birthweight increased significantly from 3652 g (95% confidence interval [CI]: 3505-3699 g) in 2010 to 3745 g (95% CI: 3700-3790 g) in 2019, a mean increase in birthweight of 93 g (95% CI: 28-158 g) (p < 0.05). The birthweight increased 186 g (95% CI: 179-193 g) for each gestational week and 11 g (95% CI: 7-15 g) for each year. Changes in gestational age explained 31% of the change in birthweight. The proportion of infants weighing 4500 g or more increased significantly from 6.1% in 2010 to 9.6% in 2019 (p < 0.05). The risk of giving birth to an infant weighing 4000 g or more was consistently associated with previously giving birth (OR 1.98 (95% CI: 1.71-2.30)) and gestational age (OR 1.28 (95% CI: 1.23-1.33) per week increase in gestational age). Infants born in gestational weeks 40 and 42 in 2019 had a higher birthweight z-score than infants born in gestational weeks 40 and 42 in 2010. Compared to other Nordic countries, Faroese infants' mean birthweight was high, the Faroe Islands had a higher number of infants born with a weight of 4000 g or more and a higher proportion of infants born in gestational week 41 or later (31.5%). CONCLUSIONS: Our results showed that the mean birthweight and the proportion of infants with high birthweight significantly increased during 2010-2019 in the Faroe Islands. The mean birthweight, the proportion of infants with high birthweight and the gestational age at birth for Faroese infants was higher than all other Nordic countries. The reasons for this require further investigation.

Maternal alcohol consumption and the risk of miscarriage in the first and second trimesters: A systematic review and dose-response meta-analysis.

INTRODUCTION: According to a precautionary principle, it is recommended that pregnant women and women trying to conceive abstain from alcohol consumption. In this dose-response meta-analysis, we aimed to examine the association between alcohol consumption and binge drinking and the risk of miscarriage in the first and second trimesters. MATERIAL AND METHODS: The literature search was conducted in MEDLINE, Embase and the Cochrane Library in May 2022, without any language, geographic or time limitations. Cohort or case-control studies reporting dose-specific effects adjusting for maternal age and using separate risk assessments for first- and second-trimester miscarriages were included. Study quality was assessed using the Newcastle-Ottawa Scale. This study is registered with PROSPERO, registration number CRD42020221070. RESULTS: A total of 2124 articles were identified. Five articles met the inclusion criteria. Adjusted data from 153 619 women were included in the first-trimester analysis and data from 458 154 women in the second-trimester analysis. In the first and second trimesters, the risk of miscarriage increased by 7% (odds ratio [OR] 1.07, 95% confidence interval [CI] 0.96-1.20) and 3% (OR 1.03, 95% CI 0.99-1.08) for each additional drink per week, respectively, but not to a statistically significant degree. One article regarding binge drinking and the risk of miscarriage was found, which revealed no association between the variables in either the first or second trimester (OR 0.84 [95% CI 0.62-1.14] and OR 1.04 [95% CI 0.78-1.38]). CONCLUSIONS: This meta-analysis revealed no dose-dependent association between miscarriage risk and alcohol consumption, but further focused research is recommended. The research gap regarding miscarriage and binge drinking needs further investigation.

Women with obesity participate less in cervical cancer screening and are more likely to have unsatisfactory smears: Results from a nationwide Danish cohort study.

Some studies found an association between obesity and increased cervical cancer risk, but potential mechanisms are unknown. In this nationwide register-based cohort study, we investigated the association between overweight/obesity and cervical cancer screening participation and risk of unsatisfactory smears. The study population was identified in the Danish Medical Birth Registry. We included 342,526 women aged 23-49 years with pre-pregnancy body mass index (BMI) registered during 2004-2013. Screening participation and unsatisfactory smears during up to four years after child birth were identified in a nationwide pathology register. We used absolute risk regression to estimate the relative absolute risk (RAR) with 95% confidence intervals (CIs) of screening participation according to BMI, adjusted for age, calendar year, sociodemographic characteristics, parity and previous high-grade cervical intraepithelial neoplasia. Among those who were screened (n = 295,482), we used log-binomial regression to investigate the relative risk (RR) of an unsatisfactory smear according to BMI, adjusted for age, year, parity, oral contraceptive use and pathology department. A lower proportion of obese women (79.3%) than women of normal weight (85.8%) were screened, and obese women had lower adjusted probability of being screened than women of normal weight (RARadjusted = 0.94, 95% CI, 0.93-0.95). A higher proportion of obese women (2.4%) than women of normal weight (1.7%) had an unsatisfactory smear, and this association remained after adjustments (RRadjusted = 1.28, 95% CI, 1.19-1.38). In conclusion, women with obesity were less likely to participate in cervical cancer screening and more likely to have an unsatisfactory smear than women of normal weight.

Current controversies: Null hypothesis significance testing.

Traditional null hypothesis significance testing (NHST) incorporating the critical level of significance of 0.05 has become the cornerstone of decision-making in health care, and nowhere less so than in obstetric and gynecological research. However, such practice is controversial. In particular, it was never intended for clinical significance to be inferred from statistical significance. The inference of clinical importance based on statistical significance (p < 0.05), and lack of clinical significance otherwise (p ≥ 0.05) represents misunderstanding of the original purpose of NHST. Furthermore, the limitations of NHST-sensitivity to sample size, plus type I and II errors-are frequently ignored. Therefore, decision-making based on NHST has the potential for recurrent false claims about the effectiveness of interventions or importance of exposure to risk factors, or dismissal of important ones. This commentary presents the history behind NHST along with the limitations that modern-day NHST presents, and suggests that a statistics reform regarding NHST be considered.

Risk of complications in the late vs early days of the 42nd week of pregnancy: A nationwide cohort study.

INTRODUCTION: Uncertainty remains about the most appropriate timing of induction of labor in late-term pregnancies. To address this issue, this study aimed to compare the risk of neonatal morbidity and pregnancy- and birth-related complications between gestational age (GA) 41+4 -42+0 and GA 41+0 -41+3  weeks. MATERIAL AND METHODS: This nationwide registry-based cohort study included singleton births without major congenital malformations, with registered GA, and with intended vaginal delivery at GA 41+0 - 42+0  weeks between 2009 and 2018 in Denmark. Logistic regression models were used to estimate the crude risk ratio and adjusted risk ratio (RRA ) of neonatal and obstetric adverse outcomes in births at GA 41+4 - 42+0  weeks compared with GA 41+0 - 41+3  weeks. The results were adjusted for relevant confounders, including induction of labor. RESULTS: A higher incidence of neonatal morbidity and birth complications was observed in births at GA 41+4 -42+0  weeks than in births at GA 41+0 -41+3  weeks. Neonatal morbidities included an increased risk of low Apgar score (Apgar 0-6 after 5 min; RRA 1.17, 95% confidence interval [CI] 1.01-1.34), meconium aspiration (RRA 1.25, 95% CI 1.06-1.48), need for respiratory support (continuous positive airway pressure; RRA 1.09, 95% CI 1.03-1.15), and a composite outcome of need for comprehensive treatment at a neonatal department or neonatal death (RRA 1.65, 95% CI 1.29-2.11). Birth complications included emergency cesarean section (RRA 1.17, 95% CI 1.14-1.21), severe lacerations (RRA 1.11, 95% Cl 1.04-1.17), and increased blood loss after birth (RRA 1.13, 95% CI 1.06-1.21). CONCLUSIONS: Births at GA 41+4 -42+0  weeks were associated with an increased risk of neonatal morbidity and birth complications compared with births at GA 41+0 -41+3  weeks. The results of this study may aid clinicians in deciding when to recommend induction of labor in late-term pregnancies.

Association of Apgar score at 5 minutes with academic performance and intelligence in youth: A cohort study.

INTRODUCTION: The Apgar score is routinely given at childbirth worldwide. A low Apgar score at 5 minutes is a strong predictor for neonatal death. Scores below 7 have been associated with higher risks of later neurologic disability. Few studies have assessed the association between Apgar score and school performance and intelligence. The existing literature points towards a possible association between Apgar score and later cognitive function, but the contradictions call for further investigation to fully understand the potential association. This study aimed to examine the possible association between Apgar score at 5 minutes and academic performance and intelligence in youth. MATERIAL AND METHODS: The study is a cohort study. The cohort consists of all Danish liveborn children in 1978-2000 (n = 1 450 681). Data regarding pregnancies, births, parents, school grades, and intelligence of the children were retrieved from different Danish registers. Multiple imputations were performed to avoid discarding data. After exclusion, the final cohort consisted of 1 005 241 children. Associations between Apgar score at 5 minutes and school graduation, grades and attendance, and intelligence scores from conscription were analyzed using univariate and multivariate logistic and linear regressions. RESULTS: No association was found between Apgar score and graduating primary school. Adjusted odds ratio (aOR) of graduating upper secondary education and attending conscription were significantly lower for children with scores below 7 compared with 7-10: graduating upper secondary education: Apgar 0-3: aOR 0.79 (95% CI 0.67-0.93), Apgar 4-6: aOR 0.86 (95% CI 0.81-0.93), attending conscription: Apgar 0-3: aOR 0.73 (95% CI 0.59-0.91), Apgar 4-6: aOR 0.73 (95% CI 0.66-0.80). The Apgar 4-6 group had significantly lower total mean primary school grade average: -0.13 (95% CI -0.21 to -0.054) and lower mean intelligence scores at conscription: -0.57 (95% CI -1.09 to -0.058). All other differences remained insignificant. CONCLUSIONS: Performances when graduating school and attending conscription were overall equal regardless of Apgar score at 5 minutes. Chances of graduating primary school were the same irrespective of the score, but chances of graduating upper secondary education and attending conscription were significantly lower with scores below 7. The results suggest that children with scores below 7 may fail to appear at upper secondary education and conscription, but if they do, they perform equally to anyone else.

Long-term growth in offspring of infertile parents: A 20-year follow-up study.

INTRODUCTION: Long-term growth has been poorly investigated in boys and girls born to parents receiving fertility treatment. This study aimed to investigate the growth of children born following fertility treatment up to adulthood hypothesizing comparable growth in children born to parents receiving fertility treatment or to subfertile parents conceiving spontaneously to that in children spontaneously conceived by fertile parents. MATERIAL AND METHODS: In this historical long-term follow-up study the study population consisted of 4151 singletons born at term in the Aarhus Birth Cohort between 1990 and 1992. Parental lifestyle and sociodemographic characteristics together with multiple measurements of weight and height were collected up to 20 years of age (6.1% of children contributed with at least one measurement for height or weight at age 20 years). The main outcome was difference in z-score for height (m) and weight (kg) between children conceived spontaneously (reference) and children conceived following fertility treatment, children conceived spontaneously by subfertile parents, or unplanned. Results were adjusted for pre-pregnancy maternal and paternal body mass index, maternal educational level, smoking during pregnancy, maternal age, and parity. RESULTS: Singletons conceived following fertility treatment (n = 164; 4.0%) or by subfertile parents (n = 271; 6.5%) had comparable magnitude of weight estimates to children conceived spontaneously (difference in z-score per year 0.0148 [95% CI 0.0026-0.0270] and 0.0069 [95% CI -0.0028 to 0.0165], respectively). Height estimates were also comparable between groups of children conceived following fertility treatment or by subfertile parents (difference in z-score per year 0.0022 [95% CI -0.0075 to 0.0119]) compared with children conceived spontaneously (difference in z-score per year -0.0026 (95% CI -0.0103 to 0.0052). From the beginning of adolescence, we found lower weight for children born to subfertile parents and to parents receiving fertility treatment compared with spontaneously conceived children. CONCLUSIONS: The main finding was equal long-term growth for children born at term by parents who received fertility treatment or parents waiting more than 12 months to conceive compared with spontaneously conceived children.

Cell-based non-invasive prenatal testing for monogenic disorders: confirmation of unaffected fetuses following preimplantation genetic testing.

PURPOSE: Proof of concept of the use of cell-based non-invasive prenatal testing (cbNIPT) as an alternative to chorionic villus sampling (CVS) following preimplantation genetic testing for monogenic disorders (PGT-M). METHOD: PGT-M was performed by combined testing of short tandem repeat (STR) markers and direct mutation detection, followed by transfer of an unaffected embryo. Patients who opted for follow-up of PGT-M by CVS had blood sampled, from which potential fetal extravillous throphoblast cells were isolated. The cell origin and mutational status were determined by combined testing of STR markers and direct mutation detection using the same setup as during PGT. The cbNIPT results with respect to the mutational status were compared to those of genetic testing of the CVS. RESULTS: Eight patients had blood collected between gestational weeks 10 and 13, from which 33 potential fetal cell samples were isolated. Twenty-seven out of 33 isolated cell samples were successfully tested (82%), of which 24 were of fetal origin (89%). This corresponds to a median of 2.5 successfully tested fetal cell samples per case (range 1-6). All fetal cell samples had a genetic profile identical to that of the transferred embryo confirming a pregnancy with an unaffected fetus, in accordance with the CVS results. CONCLUSION: These findings show that although measures are needed to enhance the test success rate and the number of cells identified, cbNIPT is a promising alternative to CVS. TRIAL REGISTRATION NUMBER: N-20180001.

Alcohol Intake in Early Pregnancy and Risk of Attention-Deficit/Hyperactivity Disorder in Children Up to 19 Years of Age: A Cohort Study.

BACKGROUND: Little is known about maternal alcohol intake in early pregnancy and the risk of attention-deficit/hyperactivity disorder (ADHD) in children beyond 5 years of age. We examined the association between alcohol binge drinking and weekly alcohol intake in early pregnancy and the risk of ADHD in children followed from birth to 19 years of age. METHODS: We included 48,072 children born between 1998 and 2012, whose mothers participated in the Aarhus Birth Cohort. Maternal alcohol intake was obtained from a self-administered questionnaire completed in early pregnancy. ADHD diagnoses were retrieved from the Danish Psychiatric Central Research Register and the Danish National Patient Register. Crude hazard ratio and adjusted hazard ratio (aHR) of ADHD according to alcohol binge drinking or weekly intake of alcohol were calculated using the Cox regression. RESULTS: Compared to children of women with no binge drinking episodes, we observed an aHR for ADHD of 0.91 (95% CI 0.76 to 1.08), 0.73 (95% CI 0.56 to 0.96), and 0.77 (95% CI 0.57 to 1.06) among children of women reporting 1, 2, and 3 or more binge drinking episodes, respectively. Among children of women drinking <1 drink per week, 1 drink per week, 2 drinks per week, and 3 or more drinks per week, we observed an aHR for ADHD of 0.87 (95% CI 0.74 to 1.03), 0.63 (95% CI 0.40 to 0.98), 1.30 (95% CI 0.89 to 1.92), and 0.78 (95% CI 0.38 to 1.59), respectively, when compared to children of women not drinking on a weekly basis. CONCLUSION: We found no evidence that binge drinking or low alcohol intake in early pregnancy was associated with the risk of ADHD in children.

Alcohol Intake in Early Pregnancy and Spontaneous Preterm Birth: A Cohort Study.

BACKGROUND: Limited research has addressed whether maternal alcohol intake in early pregnancy increases the risk of spontaneous preterm birth. In the current study, we examined how alcohol binge drinking and weekly alcohol intake in early pregnancy were associated with spontaneous preterm birth in a contemporary cohort of Danish women. METHODS: We included 15,776 pregnancies of 14,894 women referred to antenatal care at Copenhagen University Hospital, Denmark, between 2012 and 2016. Self-reported alcohol intake in early pregnancy was obtained from a Web-based questionnaire completed prior to the women's first visit at the department. Information on spontaneous preterm birth was extracted from the Danish Medical Birth Register. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) of spontaneous preterm birth according to self-reported alcohol binge drinking and weekly intake of alcohol in early pregnancy were derived from Cox regression. RESULTS: Women reporting 1, 2, and ≥ 3 binge drinking episodes had an aHR for spontaneous preterm birth of 0.88 (95% CI 0.68 to 1.14), 1.34 (95% CI 0.98 to 1.82), and 0.93 (95% CI 0.62 to 1.41), respectively, compared to women with no binge drinking episodes. Women who reported an intake of ≥ 1 drink per week on average had an aHR for spontaneous preterm birth of 1.09 (95% CI 0.63 to 1.89) compared to abstainers. When restricting to nulliparous women or cohabiting women with ≥ 3 years of higher education, this estimate was 1.28 (95% CI 0.69 to 2.40) and 1.20 (95% CI 0.67 to 2.15), respectively. CONCLUSION: We found no evidence that maternal alcohol intake in early pregnancy was associated with a higher risk of spontaneous preterm birth, neither for alcohol binge drinking nor for a low average weekly intake of alcohol.

Sex Differences in Early Cognitive Development After Prenatal Exposure to Opioids.

OBJECTIVE: Prenatal opioid exposure has been linked with impaired cognitive development, with boys potentially at elevated risk. In the present study, we examined cognitive and language development of children prenatally exposed to opioids, with an additional focus on sex differences. METHODS: A sample of 378 children (n = 194 girls and n = 184 boys) aged 1.2-42.8 months was drawn from the Danish Family Outpatient Clinic database. Developmental outcomes were assessed using the Bayley-III cognitive and language scales, and substance exposure was determined with urine screening and/or verbal report. Children exposed to opioids (n = 94) were compared to children with no prenatal substance exposure (n = 38), and children exposed to alcohol (n = 131) or tobacco (n = 115). Group and sex differences were investigated with separate linear mixed models for each Bayley scale, controlling for concurrent cannabis exposure. RESULTS: There were significantly reduced scores in opioid-exposed boys compared to boys with no prenatal substance exposure, but no difference between opioid-exposed and nonexposed girls. Additionally, alcohol-exposed boys had lower cognitive scores than nonexposed boys, and alcohol-exposed girls had lower scores on both scales compared to opioid-exposed girls. There were otherwise no significant differences according to group, sex, or scale. CONCLUSIONS: The present findings indicate poorer cognitive and language development in boys after prenatal opioid exposure. As academic performance is rooted in cognitive functioning, long-term follow-up might be necessary for exposed children.

Identification of Alcohol Risk Drinking Behaviour in Pregnancy Using a Web-Based Questionnaire: Large-Scale Implementation in Antenatal Care.

AIMS: This study aimed to examine the feasibility of a web-based questionnaire when collecting information on alcohol consumption in pregnancy to identify women with risk drinking behaviour, and to describe factors associated with risk drinking behaviour, and the use of specialized care for prenatal risk drinking. METHODS: In 2413 women referred to antenatal care at Odense University Hospital, Denmark, April-October 2018, self-reported alcohol intake was retrieved from a web-based questionnaire. Replies were screened for risk drinking behaviour: current intake of ≥7 drinks/week, ≥3 binge drinking episodes (intake of ≥5 drinks on a single occasion) in pregnancy, binge drinking after recognition of pregnancy and/or a TWEAK-score ≥ 2 points. Women with risk drinking behaviour were called to clarify the need for specialized care. A summary of the interview was obtained from the medical records. RESULTS: Overall, 2168 (90%) completed the questionnaire. Of 2097 women providing information on alcohol intake, 77 (4%) had risk drinking behaviour. Risk drinking was associated with higher alcohol intake prior to pregnancy, spontaneous conception, younger age, nulliparity and higher level of physical activity in pregnancy. Amongst 47 women with risk drinking behaviour reached by phone, five (11%, 95% CI 4-23%) accepted examinations of the child by paediatrician and child psychologist, and <3 (not further specified due to small numbers) were referred to specialized antenatal care. CONCLUSIONS: A web-based questionnaire was feasible when collecting information on alcohol consumption in pregnancy to identify risk drinking behaviour. Women with risk drinking behaviour had a low acceptance of referral to specialized care.

A systematic review on concurrent aneuploidy screening and preimplantation genetic testing for hereditary disorders: What is the prevalence of aneuploidy and is there a clinical effect from aneuploidy screening?

INTRODUCTION: In assisted reproductive technology, aneuploidy is considered a primary cause of failed embryo implantation. This has led to the implementation of preimplantation genetic testing for aneuploidy in some clinics. The prevalence of aneuploidy and the use of aneuploidy screening during preimplantation genetic testing for inherited disorders has not previously been reviewed. Here, we systematically review the literature to investigate the prevalence of aneuploidy in blastocysts derived from patients carrying or affected by an inherited disorder, and whether screening for aneuploidy improves clinical outcomes. MATERIAL AND METHODS: PubMed and Embase were searched for articles describing preimplantation genetic testing for monogenic disorders and/or structural rearrangements in combination with preimplantation genetic testing for aneuploidy. Original articles reporting aneuploidy rates at the blastocyst stage and/or clinical outcomes (positive human chorionic gonadotropin, gestational sacs/implantation rate, fetal heartbeat/clinical pregnancy, ongoing pregnancy, miscarriage, or live birth/delivery rate on a per transfer basis) were included. Case studies were excluded. RESULTS: Of the 26 identified studies, none were randomized controlled trials, three were historical cohort studies with a reference group not receiving aneuploidy screening, and the remaining were case series. In weighted analysis, 34.1% of 7749 blastocysts were aneuploid. Screening for aneuploidy reduced the proportion of embryos suitable for transfer, thereby increasing the risk of experiencing a cycle without transferable embryos. In pooled analysis the percentage of embryos suitable for transfer was reduced from 57.5% to 37.2% following screening for aneuploidy. Among historical cohort studies, one reported significantly improved pregnancy and birth rates but did not control for confounding, one did not report any statistically significant difference between groups, and one properly designed study concluded that preimplantation genetic testing for aneuploidy enhanced the chance of achieving a pregnancy while simultaneously reducing the chance of miscarriage following single embryo transfer. CONCLUSIONS: On average, aneuploidy is detected in 34% of embryos when performing a single blastocyst biopsy derived from patients carrying or affected by an inherited disorder. Accordingly, when screening for aneuploidy, the risk of experiencing a cycle with no transferable embryos increases. Current available data on the clinical effect of preimplantation genetic testing for aneuploidy performed concurrently with preimplantation genetic testing for inherited disorders are sparse, rendering the clinical effect from preimplantation genetic testing for aneuploidy difficult to access.