Drinking water nitrate and risk of pregnancy loss: a nationwide cohort study.

BACKGROUND: Nitrate contamination is seen in drinking water worldwide. Nitrate may pass the placental barrier. Despite suggestive evidence of fetal harm, the potential association between nitrate exposure from drinking water and pregnancy loss remains to be studied. We aimed to investigate if nitrate in drinking water was associated with the risk of pregnancy loss. METHODS: We conducted a nationwide cohort study of 100,410 pregnancies (enrolled around gestational week 11) in the Danish National Birth Cohort (DNBC) during 1996-2002. Spontaneous pregnancy losses before gestational week 22 were ascertained from the Danish National Patient Registry and DNBC pregnancy interviews. Using the national drinking water quality-monitoring database Jupiter, we estimated the individual and time-specific nitrate exposure by linking geocoded maternal residential addresses with water supply areas. The nitrate exposure was analyzed in spline models using a log-transformed continuous level or classified into five categories. We used Cox proportional hazards models to estimate associations between nitrate and pregnancy loss and used gestational age (days) as the time scale, adjusting for demographic, health, and lifestyle variables. RESULTS: No consistent associations were found when investigating the exposure as a categorical variable and null findings were also found in trimester specific analyses. In the spline model using the continuous exposure variable, a modestly increased hazard of pregnancy loss was observed for the first trimester at nitrate exposures between 1 and 10 mg/L, with the highest. adjusted hazard ratio at 5 mg/L of nitrate of 1.16 (95% CI: 1.01, 1.34). This trend was attenuated in the higher exposure ranges. CONCLUSION: No association was seen between drinking water nitrate and the risk of pregnancy loss when investigating the exposure as a categorical variable. When we modelled the exposure as a continuous variable, a dose-dependent association was found between drinking water nitrate exposure in the first trimester and the risk of pregnancy loss. Very early pregnancy losses were not considered in this study, and whether survival bias influenced the results should be further explored.

Endometrial preparation methods prior to frozen embryo transfer: A retrospective cohort study comparing true natural cycle, modified natural cycle and artificial cycle.

PURPOSE: The aim of this study was to compare the outcomes of three endometrial preparation methods prior to frozen embryo transfer (FET): Natural cycle (NC), modified natural cycle (mNC), and programmed/artificial cycle (AC) protocols. Primary outcomes investigated were clinical pregnancy rate (CPR) and live birth rate (LBR). METHODS: A retrospective study on 2080 FET cycles including patients ≤ 35 years with a BMI ≤ 30 who underwent FET with a single autologous blastocyst stage embryo at Aarhus University Hospital or Horsens Regional Hospital in the period 2013-2019. Only blastocysts frozen by vitrification were included. No luteal phase support (LPS) was used in natural cycles. RESULTS: In NC, mNC and AC, CPRs were 34.9%, 40.6% and 32.0%, while LBRs were 32.3%, 36.3% and 26.6%, respectively. There were no significant differences in main outcomes when comparing AC with NC [LBR: OR = 0.9 (0.6; 1.2), p = 0.4]. Compared to NC, mNC-FET displayed significantly higher positive hCG, implantation rate, CPR and LBR [LBR: OR = 1.4 (1.0; 1.9), p = 0.03]. An analysis with mNC as reference group demonstrated significantly better outcomes in the mNC group compared to AC [LBR: OR 0.6 (0.5; 0.8), p = < 0.01]. CONCLUSION: The present study overall demonstrated better outcomes including LBR with mNC protocol as compared to NC and AC protocol, while comparison of AC and NC showed both protocols to be equally effective. A programmed cycle may be necessary for women with anovulatory cycles; however, normo-ovulating women may be offered a natural cycle protocol. TRIAL REGISTRATION NUMBER: 3-3013-3047/1 and 31-1522-44. Date of registration: June 24, 2019 and April 23, 2020.

Monochorionic twins after single blastocyst transfer: retrospective cohort and blinded time lapse annotation analysis.

RESEARCH QUESTION: Is it possible to identify monochorionic twin pregnancies before blastocyst transfer based on maternal or embryo characteristics registered by time lapse? DESIGN: A retrospective cohort study including women who received fertility treatment (n = 6501) between 2010 and 2019 at two fertility clinics in central Denmark. The treatment resulted in 2239 pregnancies after single embryo transfer (SET) and, of those, 43 (1.92%) were monochorionic twins. Baseline characteristics, information on assisted reproductive technology and ultrasonic findings at gestational week 8 were collected on all women. Furthermore, a blinded time lapse annotation analysis was conducted by two independent laboratory technicians on a total of 85 embryos. A total of 22 embryos leading to monochorionic pregnancies were matched with 63 embryos leading to singleton pregnancies. RESULTS: A monochorionic twin rate of 1.92% was found. No significant difference was found in maternal age, the use of intracytoplasmic sperm injection compared with IVF, indication for treatment or other maternal characteristics. In the blinded annotation analysis, inner cell mass grade A was associated with an increased risk of twinning (P = 0.04) in fresh embryos. The s3 division timing was found to be significantly shorter in fresh twin compared with singleton embryos (P = 0.006). No other time lapse parameters were found to be characteristic of twin embryos. CONCLUSION: To the best of our knowledge, this is the first blinded annotation study to identify aspects in time lapse resulting in monochorionic twins after SET. Whether inner cell mass grade A and s3 reflect a biological background for monochorionic twinning merits further investigation.

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.

Female cigarette smoking and successful fertility treatment: A Danish cohort study.

INTRODUCTION: Despite smoking being a well-established risk factor for adverse pregnancy and neonatal outcomes, a substantial proportion of women of reproductive age smoke. Previously, meta-analyses have indicated a significantly negative impact of female smoking on outcomes of assisted reproduction, yet most of the included studies have several, essential methodological limitations. We aimed to investigate whether female cigarette smoking may affect the chance of achieving a clinical pregnancy and live birth among women and couples receiving medically assisted reproduction treatment. MATERIAL AND METHODS: A cohort study with longitudinally and repeatedly collected exposure information from 1 January 2010 to 31 August 2015, including data on 1708 women and potential partners initiating either intrauterine insemination, in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) or frozen embryo transfer treatment cycles at the public Fertility Clinic, Aarhus University Hospital, Denmark. Smoking was assessed from self-reported questionnaires completed before treatment. Outcomes were a clinical pregnancy and a live birth. Information on these was obtained from the Danish national health registries, allowing complete follow-up. To evaluate associations between female occasional/daily cigarette smoking and successful medically assisted reproduction treatments, a modified Poisson regression with robust standard errors was used. RESULTS: Female occasional/daily cigarette smoking was not associated with the chance of achieving a clinical pregnancy or a live birth in all intrauterine insemination or IVF/ICSI treatment cycles. When compared with nonsmokers, the adjusted relative risk for obtaining a live birth for those reporting smoking was 1.22 (0.70-2.12) among women initiating 1456 intrauterine insemination treatment cycles. Among women initiating 2788 IVF/ICSI treatment cycles, those reporting occasional/daily smoking had a relative risk for obtaining a live birth of 1.15 (0.82-1.60) when compared with nonsmokers. CONCLUSIONS: Occasionally/daily cigarette smoking women had similar chance of achieving a clinical pregnancy or a live birth as the nonsmokers when receiving medically assisted reproduction treatments. However, tobacco use before and during pregnancy remains a major cause of reduced fertility as well as maternal, fetal, and infant morbidity and mortality, and should strongly be discouraged.

Improving the maturation rate of human oocytes collected ex vivo during the cryopreservation of ovarian tissue.

PURPOSE: The aim of the present study was to improve the in vitro maturation (IVM) procedure using oocytes from surplus ovarian tissue after fertility preservation. METHODS: Twenty-five patients aged 17-37 years were included in the study. Maturation was compared between oocytes collected in HEPES-buffered medium or saline, and we determined whether transport on ice prior to oocyte collection affected maturation. Two different IVM media were used that were supplemented with and without recombinant human midkine. Mature oocytes were assessed for aneuploidy using next-generation sequencing (NGS). RESULTS: On average, 36 immature oocytes were collected from each patient (range 7-90, N = 895). Oocytes recovered from HEPES-buffered medium matured at a higher rate than oocytes recovered from saline (36% vs 26%, p < 0.01). Ovarian transportation on ice prior to the procedure negatively affected maturation compared with non-transported samples (42% vs 27%, p < 0.01). The addition of midkine improved maturation rate (34% vs 27%, p < 0.05). On average, 11 MII oocytes were obtained per patient (range 1-30). NGS of 53 MII oocytes and their first polar bodies indicated that 64% were euploid. CONCLUSIONS: The study demonstrated unexpectedly high number of immature oocytes collected from surplus ovarian tissue without any stimulation. The overall MII rate was one in three, resulting in a total number of MII oocytes that was similar to the number obtained after ovarian stimulation. If these MII oocytes prove suitable for IVF, they will provide a substantial improvement in fertility preservation for patients and advance IVM as an interesting platform for further improvements in assisted reproduction.

Transplantation of frozen-thawed ovarian tissue: an update on worldwide activity published in peer-reviewed papers and on the Danish cohort.

PURPOSE: The purpose of the study is to review all peer-reviewed published reports of women receiving ovarian tissue transplantation (OTT) with frozen/thawed tissue (OTC) with respect to age, diagnosis, transplantation site, fertility outcome, and potential side effects, including data from all women in the Danish program. METHODS: A systematic review of the literature was performed in PubMed combined with results from all patients who had received OTT in Denmark up to December 2017. RESULTS: OTT has been reported from 21 different countries comprising a total of 360 OTT procedures in 318 women. In nine women, malignancy was diagnosed after OTT; none were considered to be directly caused by the OTT. Despite a potential under reporting of cancer recurrence, there is currently no evidence to suggest that OTT causes reseeding of the original cancer. Renewed ovarian endocrine function was reported in 95% of the women. Half of all children born following OTT resulted from natural conception, and newborns were reported to be healthy except for one neonate with a chromosome anomaly with a family disposition. Women who conceived after OTT were significantly younger than those who failed. CONCLUSION: This study found no indications of sufficient numbers of malignant cells present in the ovarian tissue to cause recurrence of cancer after OTT. Further, it is unlikely that OTC affects the well-being of children born. OTC is now an established method of fertility preservation in Denmark with public reimbursement. The current data encourage that women who require gonadotoxic treatment should be offered an individual evaluation considering fertility preservation.

Fertility Treatment and Childhood Epilepsy: A Nationwide Cohort Study.

BACKGROUND: Fertility treatment includes hormonal stimulation of the woman and in vitro manipulation of gametes and embryos that may influence prenatal brain development. We aimed to investigate the association between fertility treatment and childhood epilepsy, including specific types of treatment and indications, as well as subtypes of epilepsy. METHODS: In this nationwide birth cohort study, we included all pregnancies in Denmark resulting in live-born singletons, 1995-2003. Children conceived by fertility treatment and children developing epilepsy (until 2013) were identified from Danish national registers. RESULTS: A total of 565,116 pregnancies were included; 8,071 children (1.4%) developed epilepsy. Children conceived after ovulation induction or intrauterine insemination had a slightly higher risk of childhood epilepsy (hazard ratio [HR]: 1.15; 95% confidence interval [CI]: 1.00, 1.31). The association was more pronounced for the subtypes idiopathic generalized and focal epilepsy. Regarding the specific hormonal treatments, only clomiphene citrate was associated with an increased risk of childhood epilepsy, also in a sibling analysis (HR: 2.07; 95% CI: 1.05, 4.08). In vitro fertilization or intracytoplasmic sperm injection was not associated with an overall increased risk of childhood epilepsy but with idiopathic generalized epilepsy (HR: 1.43; 95% CI: 0.99, 2.05). No clear associations were seen regarding other treatment types or indications. CONCLUSIONS: Children conceived by ovulation induction or intrauterine insemination with clomiphene citrate may be at slightly increased risk of childhood epilepsy. Furthermore, children conceived by in vitro fertilization or intracytoplasmic sperm injection may be at slightly increased risk of idiopathic generalized epilepsy.

Obstetric and neonatal outcomes of pregnancies conceived after preimplantation genetic diagnosis: cohort study and meta-analysis.

Preimplantation genetic diagnosis (PGD) may pose risks to pregnancy outcome owing to the invasiveness of the biopsy procedure. This study compares outcome of singleton and twin clinical pregnancies conceived after fresh embryo transfers of PGD (n = 89) and matched intracytoplasmic sperm injection (ICSI) pregnancies (n = 166). The study was carried out in a single university affiliated centre. Because of the paucity of available data, a literature-based meta-analysis of studies comparing neonatal outcome of PGD and ICSI pregnancies was also conducted. In the retrospective cohort study, obstetric and neonatal outcome were available in 67 PGD and 118 ICSI pregnancies. Perinatal outcomes were comparable between PGD and ICSI pregnancies. Meta-analysis revealed similar outcomes, except for higher rate of low birth weight (<2500 g) neonates in ICSI twin pregnancies (RR 0.86, 95% CI 0.74 to 1.0). Mean birth weight, gestational age at birth, pre-term deliveries (<37 weeks) and malformations were all comparable. In this cohort study and subsequent meta-analysis, no association was found between PGD conceived pregnancies and risks of adverse neonatal or obstetrical outcomes compared with ICSI pregnancies. Hence, blastomere biopsy for PGD does not seem to increase the risk for adverse perinatal outcome compared with ICSI pregnancies.

Parental Infertility, Fertility Treatment, and Childhood Epilepsy: A Population-Based Cohort Study.

BACKGROUND: A few studies have indicated an increased risk of epilepsy in children conceived by fertility treatment possibly due to characteristics of the infertile couple rather than the treatment. We therefore aimed to investigate the association between parental infertility, fertility treatment, and epilepsy in the offspring, including the subtypes of epilepsy; idiopathic generalised epilepsy and focal epilepsy. METHODS: This cohort included all pregnancies resulting in liveborn singletons from the Aarhus Birth Cohort, Denmark (1995-2013). Information on time to pregnancy and fertility treatment was obtained from pregnancy questionnaires in early pregnancy. Children developing epilepsy were identified from the Danish National Patient Register and the Danish National Prescription Registry until 2013. Data were analysed using Cox proportional hazards regression adjusted for potential confounders. RESULTS: A total of 60 440 pregnancies were included, and 0.8% of the children developed epilepsy.The primary analyses showed no association between parental infertility or fertility treatment, and the overall risk of childhood epilepsy (hazard rate ratios (HRs); 95% confidence intervals (CIs): 1.08 (0.73, 1.60) and 1.04 (0.71, 1.52)). In secondary analyses, both parental infertility and fertility treatment were associated with an increased risk of idiopathic generalised epilepsy (HRs and 95% CIs: 2.25 (1.10, 4.58) and 2.45 (1.26, 4.75)). No association was seen for focal epilepsy. CONCLUSION: Parental infertility or fertility treatment was not associated with an overall risk of childhood epilepsy. Parental infertility may be associated with an increased risk of idiopathic generalised epilepsy; a subtype of epilepsy believed to be of genetic origin.

A retrospective consecutive case-series study on the effect of systemic treatment, length of admission time, and co-morbidities in 98 bullous pemphigoid patients admitted to a tertiary centre.

Bullous pemphigoid (BP) is a common blistering disease caused by antibodies directed against hemi-desmosomal proteins BPAG1 and BPAG2. The disease is characterised by intense pruritus and blistering of the skin. The systemic treatment with the highest level of evidence for BP is systemic glucocorticoids. However, since the disease often occurs in the elderly patients, and since the most common co-morbidities are diabetes and neurological diseases, glucocorticoid-sparing drugs are often introduced. We retrospectively identified all BP patients admitted to our tertiary clinic over a 7-year period in order to register demography, treatment and co-morbidities. The most common steroid-sparing drugs were azathioprine (87%) and methotrexate (11%). Less than 2% were treated with dapsone, rituximab and cyclosporin A. As expected, we found a relatively high rate of neurological disorders, diabetes, and malignancies, but surprisingly we also found an increased rate of cardiovascular diseases compared to the Danish population in general.

Use of corticosteroids in early pregnancy is not associated with risk of oral clefts and other congenital malformations in offspring.

Corticosteroids are commonly used to treat inflammatory diseases. There is conflicting evidence regarding the association of corticosteroid use in pregnancy and congenital malformations in offspring. We conducted a prevalence study of 83,043 primiparous women who gave birth to a live-born singleton in northern Denmark, in 1999-2009. Through medical registries, we identified prescriptions for corticosteroids, congenital malformations, and covariates. Furthermore, we summarized the literature on this topic. Overall, 1449 women (1.7%) used inhaled or oral corticosteroids from 30 days before conception throughout the first trimester. Oral cleft in the offspring was recorded for 1 of the users (0.08%) and 145 of the nonusers (0.2%), prevalence odds ratio (OR) 0.47 [95% confidence interval (CI), 0.07-3.34]. The prevalence OR for congenital malformations overall was 1.02 (95% CI, 0.79-1.32). According to published studies, the use of corticosteroids in early pregnancy was associated with congenital malformations overall with relative estimates ranging from 0.8 (95% CI, 0.4-1.7) to 2.1 (95% CI, 0.5-9.6). For oral clefts, the ORs ranged from 0.6 (95% CI, 0.2-1.7) to 5.2 (95% CI, 1.5-17.1). We found no evidence of an association between use of corticosteroids in early pregnancy and risk of congenital malformations in offspring.

Does binge drinking during early pregnancy increase the risk of psychomotor deficits?

BACKGROUND: The potential effects of binge drinking during pregnancy on child motor function have only been assessed in a few, small studies. We aimed to examine the effects of binge alcohol consumption during early pregnancy, including number of binge episodes and timing of binge drinking, on child motor function at age 5. METHODS: We performed a prospective follow-up study of 678 women and their children sampled from the Danish National Birth Cohort based on maternal alcohol consumption during pregnancy. At 5 years of age, the children were tested with the Movement Assessment Battery for Children. Parental education, maternal IQ, prenatal maternal smoking, the child's age at testing, sex of child, and tester were considered core confounders, while the full model also controlled for prenatal maternal average alcohol intake, maternal age and prepregnancy body mass index, parity, home environment, postnatal parental smoking, health status, participation in organized sport, and indicators for hearing and vision impairment. RESULTS: There were no systematic or significant differences in motor function between children of mothers reporting isolated episodes of binge drinking and children of mothers with no binge episodes. No association was observed with respect to the number of binge episodes (maximum of 12) and timing of binge drinking. CONCLUSIONS: In this study, we found no systematic association between isolated episodes of binge drinking during early pregnancy and child motor function at age 5.

Low to moderate alcohol intake during pregnancy and risk of psychomotor deficits.

BACKGROUND: To examine the effects of low to moderate alcohol consumption during pregnancy on child motor function at age 5. METHODS: A prospective follow-up study of 685 women and their children sampled from the Danish National Birth Cohort based on maternal alcohol consumption during pregnancy. At 5 years of age, the children were tested with the "Movement Assessment Battery for Children" (MABC). Parental education, maternal IQ, prenatal maternal smoking, the child's age at testing, and gender of child were considered core confounders, while the full model also controlled for prenatal maternal binge drinking episodes, age, maternal prepregnancy body mass index, parity, home environment, postnatal parental smoking, health status, and indicators for hearing and vision impairment. RESULTS: There were no systematic or significant differences in motor function between children of mothers reporting low to moderate levels of average alcohol consumption during pregnancy and children of mothers who abstained. CONCLUSIONS: In this study, we found no systematic association between low to moderate maternal alcohol intake during pregnancy and child motor function at age 5.

Healthcare Use in the Five Years Before a First Infertility Diagnosis: A Danish Register-Based Case-Control Study in the CROSS-TRACKS Cohort.

Purpose: Infertility may affect somatic and mental health later in life. Nevertheless, health status before diagnosed infertility is sparsely studied in women. We aimed to describe healthcare use in primary and secondary care before a first infertility diagnosis and compare use between cases and controls. Materials and Methods: The case-control study was based on register data and used incidence density sampling. From the CROSS-TRACKS Cohort, we included women residing in the Horsens area in Denmark in 2012-2018 (n = 54,175). Eligible women were aged 18-40 years, nulliparous, and living in heterosexual relationships. Cases were women with a first infertility diagnosis in the Danish National Patient Registry (index date). Five controls were matched on age, birth year, and calendar time. Through linkage to Danish national health registries, we identified general practitioner (GP) attendance, paraclinical examinations, hospital contacts, diagnoses, and redeemed prescriptions. Healthcare use from one year to five years before index date was compared with conditional logistic regression. Results: We identified 711 cases and 3555 controls. At one year before index date, cases consulted their GP (odds ratio (OR) = 5.2, 95% confidence interval (CI): 3.2, 8.3) and visited hospital (OR = 1.2, 95% CI: 1.0, 1.4) and redeemed prescriptions (OR = 2.3 95% CI: 1.9, 2.7) more often compared to controls. Cases more often had blood and hemoglobin tests performed, redeemed more drugs related to genitourinary and hormonal diseases, and were more often diagnosed with endocrine and genitourinary diseases in the year before a first infertility diagnosis compared to controls. Cases and controls had comparable healthcare use from five years to one year before a first infertility diagnosis. Conclusion: Cases and controls had similar healthcare use from five years to one year before a first infertility diagnosis. However, cases had a higher healthcare use in the year preceding a first infertility diagnosis compared to controls.

Nitrate in Drinking Water and Time to Pregnancy or Medically Assisted Reproduction in Women and Men: A Nationwide Cohort Study in the Danish National Birth Cohort.

Purpose: No studies have investigated if drinking water nitrate affects human fecundity. Experimental studies point at detrimental effects on fetal development and on female and male reproduction. This cohort study aimed to explore if female and male preconception and long-term exposure to nitrate in drinking water was associated with fecundability measured as time to pregnancy (TTP) or use of medically assisted reproduction (MAR) treatment. Methods: The study population consisted of pregnant women recruited in their first trimester in 1996-2002 to the Danish National Birth Cohort. Preconception drinking-water nitrate exposure was estimated for the pregnant women (89,109 pregnancies), and long-term drinking water nitrate exposure was estimated from adolescence to conception for the pregnant women (77,474 pregnancies) and their male partners (62,000 pregnancies) by linkage to the national drinking water quality-monitoring database Jupiter. Difference in risk of TTP >12 months or use of MAR treatment between five exposure categories and log-transformed continuous models of preconception and long-term nitrate in drinking water were estimated. Binominal regression models for risk ratios (RR) were adjusted for age, occupation, education, population density, and lifestyle factors. Results: Nitrate in drinking water (median preconception exposure: 1.9 mg/L; median long-term exposure: 3.3 mg/L) was not associated with TTP >12 months or use of MAR treatment, neither in the categorical nor in the continuous models. Conclusion: We found no association between preconception or long-term exposure to drinking water nitrate and fecundability.

Prenatal alcohol exposure - a systematic review of the effects on child motor function.

OBJECTIVE: To systematically review the available evidence on the effects of prenatal alcohol exposure on motor function in humans. DESIGN: Systematic review. POPULATION: Pregnant women and their offspring. METHODS: The search strategy included Medline, Embase, The Cochrane Library and Scopus. The authors read titles and abstracts, and the articles that met the predefined criteria for inclusion were obtained and the full text read. The articles were assessed for quality using the Newcastle-Ottawa Quality Assessment Scale. MAIN OUTCOME MEASURES: Motor function measured on standardized or validated tests. RESULTS: The search resulted in 311 titles and abstracts, of which 39 were found relevant for inclusion. The findings of this review suggest a negative effect when the maternal consumption exceeded a certain level. Of all studies reporting a maternal intake of more than four drinks/day, only one study showed no effect on motor function, and of all studies reporting intake levels of less than 10 drinks/week, only one study showed deficit on the children's motor function. CONCLUSIONS: While it appears consistent that high daily alcohol intake is associated with deficits in gross and fine motor function, and low weekly intake is not associated with such deficits, the issue of binge drinking is unsettled.

Assisted reproductive technologies and the risk of stillbirth in singleton pregnancies: a systematic review and meta-analysis.

OBJECTIVE: To identify the risk of stillbirth from in vitro types of assisted reproductive technologies compared with spontaneous conception (SC), limited to singleton births. DESIGN: Systematic literature search and search chaining on online databases: PubMed, Embase, and Scopus. SETTING: Not applicable. PATIENT(S): Singleton pregnancies from in vitro fertilization (IVF) or fertilization by IVF and intracytoplasmic sperm injection (IVF-ICSI). INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Adjusted odds ratio for stillbirth or prevalence of stillbirth in case-control groups of IVF/IVF-ICSI singletons and SCs, respectively, in matched studies. RESULT(S): A total of 19 studies were included, and study quality was mixed. Ten studies qualified for inclusion to the meta-analysis, which revealed a significantly increased risk of stillbirth in IVF/IVF-ICSI compared with that in SC (odds ratio [95% confidence interval]: 1.82 [1.37-2.42]), and there was no evidence of publication bias. CONCLUSION(S): In vitro fertilization and IVF-ICSI treatment increases the risk of stillbirth compared with natural conception. CLINICAL TRIAL REGISTRATION NUMBER: PROSPERO 216768.

[Children born after assisted reproduction].

This review summarises the knowledge of children born after in vitro fertilization (IVF). They have small increased risk of preterm birth, low birthweight and congenital malformations compared with naturally conceived children. High rates of multiples after IVF have been a major explanation, but with increasing use of frozen embryo transfer, single embryo transfer has facilitated a huge decline in rates of IVF multiples. Attention has been drawn to potential metabolic disturbances and cardiovascular disease in IVF offspring. However, IVF children do not seem to have an increased risk of mental or psychiatric disease, and their school performance is similar to naturally conceived children.

Use of cryopreserved ovarian tissue in the Danish fertility preservation cohort.

OBJECTIVE: To evaluate the use of cryopreserved ovarian tissue in the Danish fertility preservation cohort. DESIGN: Retrospective cohort study. SETTING: University hospitals and fertility clinics. PATIENT(S): Ovarian tissue cryopreservation (OTC) was performed for 1,186 Danish girls and women from 1999-2020, of whom 117 subsequently underwent ovarian tissue transplantation (OTT). Subgroup 1 included 759 patients with a follow-up period of >5 years. Out of these, OTT rates were further analyzed for those patients who were alive and aged >24 years in July 2020 (subgroup 2; n = 554). INTERVENTION(S): OTC and OTT. MAIN OUTCOME MEASURE(S): OTT, death, donation of tissue. RESULT(S): In subgroup 1, 14% of the patients had undergone OTT, 18% had died, 9% had donated their tissue for research, and 59% still had their tissue stored. In subgroup 2, 19% had undergone OTT and for most diagnoses the OTT rates ranged from 15% to 22% with benign hematologic diseases having the highest OTT rate (35%). On the basis of the entire cohort, stratified age analysis indicated that women aged ≥30 years at OTC were more likely to return for OTT than women aged 18-29 years at OTC; mean storage times were 3.7 and 3.6 years, respectively. Only 4% of the girls aged <18 years at OTC had undergone OTT. CONCLUSION(S): The OTT rates depended on the diagnosis, age at OTC, and follow-up time. Specific criteria are needed for reporting and comparing OTT rates. Six out of 10 patients still had their cryopreserved tissue stored and longer follow-up is needed, especially for younger girls.