Maternal inflammatory, lipid and metabolic markers and associations with birth and breastfeeding outcomes.

Background: Conditions in utero influence intrauterine and postnatal infant growth and a few studies indicate that maternal inflammation and insulin resistance might affect birth and breastfeeding outcomes. Furthermore, hormones in human milk (HM) may influence infant appetite-regulation and thereby milk intake, but the associations are less understood. Objective: (1) To investigate associations between maternal inflammatory, lipid and metabolic markers and birth and breastfeeding outcomes, and (2) to assess predictors of maternal inflammatory, lipid and metabolic markers in pregnancy. Methods: Seventy-one mother-infant dyads participating in the Mothers, Infants and Lactation Quality (MILQ) study were included in the present study. Fasting blood samples were collected around 28th gestational week, and HM samples at three time points from 1.0 to 8.5 months, where milk intake was assessed using 24-h test weighing. Maternal plasma inflammatory, lipid and metabolic markers included high-sensitive C-reactive protein (hs-CRP), tumor-necrosis factor-α (TNFα), interferon-γ (IFNγ), Interleukin (IL)-6, IL-8, high-, low-, and very-low-density lipoprotein (HDL, LDL, VLDL), total-cholesterol, triglycerides, leptin, adiponectin, insulin, C-peptide, the homeostasis model assessment of insulin resistance (HOMA-IR) and glucose concentration at t = 120 min following an oral glucose tolerance test. Of these, TNFα, IFNγ, IL-6, IL-8, leptin, adiponectin and insulin were also measured in HM samples. Results: HDL in pregnancy was inversely associated with gestational age (GA) at birth and GA-adjusted birthweight z-score, whereas triglycerides and glucose (t = 120) were positively associated with GA-adjusted birthweight z-score. Higher hs-CRP, VLDL and triglycerides were associated with a higher placental weight. Furthermore, higher HDL, insulin, leptin and HOMA-IR were associated with longer duration of exclusive breastfeeding (EBF). Higher pre-pregnancy BMI was the main predictor of higher levels of hs-CRP, log-TNFα, leptin, insulin, C-peptide, and HOMA-IR. Conclusion: Maternal lipid and metabolic markers influenced birthweight z-score and placental weight as well as duration of EBF. Furthermore, pre-pregnancy BMI and maternal age predicted levels of several inflammatory and metabolic markers during pregnancy. Our findings indicate that maternal lipid and metabolic profiles in pregnancy may influence fetal growth and breastfeeding, possibly explained by overweight and/or higher placental weight. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT03254329.

[Possible vertical transmission, prematuredelivery, neonatal morbidity and death in pregnant women with COVID-19].

COVID-19 increases the risk of preterm delivery in Nordic women requiring intensive care but has not been linked to foetal death. We present two cases of mild COVID-19 in pregnant women admitted due to reduced foetal movements. The babies were delivered preterm due to abnormal cardiotocography values. The first baby developed atypical respiratory distress, and the second baby was stillborn. Placenta and amnion tests from both patients were positive for SARS-CoV-2 variant B.1.617.2. These cases emphasise cautious follow-up of pregnant patients admitted with COVID-19, regardless of severity, as it may affect the foetus.

Medication used in Denmark in the latent phase of labor - Do we know what we are doing?

OBJECTIVE: To describe the various combinations of medication used in Denmark in the latent phase of labor (i.e. for therapeutic rest) and to estimate the frequency of use. METHODS: An informal e-mail survey based on personal information from Danish midwives or staff obstetricians. The main outcome measures were type and dosage of medications used individually or in combination ("cocktail") for therapeutic rest in Danish delivery wards during the latent phase of labor and also the frequency of their use. RESULTS: All twenty-one delivery wards in Denmark participated in the survey. The types and dosages of medication varied substantially. Two delivery wards used prescriptions on morphine with no other medication for therapeutic rest. The remaining 19/21 delivery wards (90%) used a standard "cocktail" with two to four different types of medications; 19/21 wards (90%) used a mild analgesic (paracetamol), 17/21 (81%) used anxiolytics/hypnotics, and 14/21 (64%) wards used a strong analgesic (opioid) in their basic cocktail. Ten delivery wards (48%) combined an opioid, a sedative, and paracetamol in their basic cocktail. Between 7% and 21% of all pregnant women were given a cocktail. CONCLUSION: In a small country, we found considerable national variation in the medication or combinations of medication used in the latent phase of labor, and polypharmacy was standard in the majority of the delivery wards.

Safety considerations for transplanting cryopreserved ovarian tissue to restore fertility in female patients who have recovered from Ewing's sarcoma.

Ewing's sarcoma (EWS) is a highly malignant cancer in children, adolescents and young adults. The chemotherapy required to treat female EWS patients may cause primary ovarian insufficiency and infertility as a side effect. Cryopreservation of ovarian tissue before the start of chemotherapy can potentially preserve fertility. When the patient has been cured and primary ovarian insufficiency has developed, transplantation of frozen/thawed ovarian tissue can restore ovarian function. The tissue is usually collected before chemotherapy is initiated, and malignant cells may contaminate the stored ovarian tissue, potentially causing recrudescence of the original cancer after transplantation. The risk of EWS metastasizing to the ovary is probably low but has not been studied in great detail. This review describes the available evidence on the risk of malignant cell contamination in the ovaries of EWS patients and presents a new case of malignant cells in an ovarian biopsy from a girl with EWS.

Ovarian volume throughout life: a validated normative model.

The measurement of ovarian volume has been shown to be a useful indirect indicator of the ovarian reserve in women of reproductive age, in the diagnosis and management of a number of disorders of puberty and adult reproductive function, and is under investigation as a screening tool for ovarian cancer. To date there is no normative model of ovarian volume throughout life. By searching the published literature for ovarian volume in healthy females, and using our own data from multiple sources (combined n=59,994) we have generated and robustly validated the first model of ovarian volume from conception to 82 years of age. This model shows that 69% of the variation in ovarian volume is due to age alone. We have shown that in the average case ovarian volume rises from 0.7 mL (95% CI 0.4-1.1 mL) at 2 years of age to a peak of 7.7 mL (95% CI 6.5-9.2 mL) at 20 years of age with a subsequent decline to about 2.8 mL (95% CI 2.7-2.9 mL) at the menopause and smaller volumes thereafter. Our model allows us to generate normal values and ranges for ovarian volume throughout life. This is the first validated normative model of ovarian volume from conception to old age; it will be of use in the diagnosis and management of a number of diverse gynaecological and reproductive conditions in females from birth to menopause and beyond.

Risk of transferring malignant cells with transplanted frozen-thawed ovarian tissue.

Ovarian tissue cryopreservation and transplantation is a real option to preserve and restore fertility in young cancer patients. However, there is a concern regarding the possible presence of malignant cells in the ovarian tissue, which could lead to recurrence of the primary disease after reimplantation. A review of the existing literature was done to evaluate the risk of transplanting malignant cells in case of the main malignant indications for ovarian tissue cryopreservation. For ovarian tissue from patients with hematologic malignancies, it is of paramount importance to identify minimal residual disease before ovarian tissue transplantation. Indeed, these pathologies, reviewed here in detail, are considered to be most at risk of ovarian metastasis.

Ovarian tissue cryopreserved for fertility preservation from patients with Ewing or other sarcomas appear to have no tumour cell contamination.

AIM: The chemotherapy required to treat patients with sarcoma may as a side-effect induce infertility in girls and young women. If these patients have ovarian cortical tissue cryopreserved prior to chemotherapy, they may, if necessary, have the tissue transplanted and restore their fertility. The aim of this study was to evaluate the risk of residual cancer cells in the ovarian cortex intended for transplantation. PATIENTS AND METHODS: Ovarian tissue stored for fertility preservation from 16 surviving patients diagnosed with sarcoma (nine with Ewing sarcomas, four with osteosarcomas, two with synovial sarcomas and one with chondrosarcoma) was evaluated for the presence of malignant cells by histology and by transplantation to immunodeficient mice for 20 weeks. A fraction of the tissue from patients with Ewing sarcoma was also evaluated for the presence of the molecular marker EWS-FLI1 by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The transplant itself and selected murine organs were analysed for the presence of malignant cells by histology. RESULTS: All the mice accommodated the human tissue for 20 weeks of transplantation period with none of the mice developing any sign of cancer. In no instance were any cancer cells detected by histology or RT-qPCR. CONCLUSION: Ovarian tissue from patients with sarcoma appears to be without metastatic malignant cells in numbers that allow detection. Although the actual pieces of ovarian tissue used for transplantation remain unchecked, the current data indicate that the procedure is safe at least in patients that survive the sarcoma disease.

The safety of transplanting cryopreserved ovarian tissue in cancer patients: a review of the literature.

BACKGROUND: Transplantation of frozen/thawed ovarian tissue from patients with a malignant condition is associated with a risk of re-introduction of the disease as the tissue usually is removed before anti-cancer therapy and may thus contain malignant cells. We review studies investigating the presence of malignant cells in cryopreserved ovarian tissue from patients with malignant disease and based on the strength of the evidence, recommendations for transplantations are proposed. MATERIALS AND METHODS: A systematic review of the literature. All peer reviewed studies evaluating the presence of malignant cells in cryopreserved human ovarian tissue were included. Data were searched in Pubmed and Embase with no language restrictions. RESULTS: The majority of the reviewed papers were casuistic reports and few of the included papers were specifically designed to search for malignant cells. Ovarian tissue from 422 patients has been subject to testing for malignant cells by imaging, histology, immunohistochemistry, molecular biology, animal- or clinical transplantation. In 31 (7 %) of the cases the applied test raised suspicion of malignant cell infiltration. No transplantation-related relapse of cancer has been reported after 33 transplantations of frozen/thawed ovarian cortex. CONCLUSION: The quality and strength of the evidence is generally low and prospective studies are needed. The risk of re-introducing a malignant condition when transplanting ovarian tissue depends on the particular disease. Based on the available data, the risk was estimated: Leukaemia: HIGH. Gastrointestinal cancers: MODERATE. Breast cancer, sarcomas of the bone and connective tissue, gynaecological cancers, Hodgkin's and Non-Hodgkin's Lymphoma: LOW.

Cryopreservation of ovarian tissue for fertility preservation in young female oncological patients.

Girls and women suffering from a cancer that requires treatment with gonadotoxic drugs may experience cessation of reproductive function as a side effect due to obliteration of the ovarian pool of follicles. Techniques are now available for fertility preservation, such as cryopreservation of mature oocytes, embryos or ovarian cortical tissue. Whereas collection of mature oocytes and embryos requires at least a 2-week period, ovarian tissue may on short notice be frozen prior to treatment and can be transplanted back into women with ovarian failure. Transplanted frozen/thawed tissue supports survival and growth of follicles, giving rise to menstrual cycles and hormone production for several years. Worldwide, the procedure has resulted in the birth of 15 healthy children. Many cancer patients including girls and young women want fertility preservation, and the techniques are now being further developed and implemented in several centers.

Cryopreserved ovarian cortex from patients with leukemia in complete remission contains no apparent viable malignant cells.

Some women suffering from leukemia require bone marrow transplantation to be cured. Bone marrow transplantation is associated with a high risk of sterility, and some patients are offered fertility preservation by cryopreservation of the ovarian cortex. Transplantation of the ovarian cortex to women cured of leukemia who became menopausal is currently not performed because of the risk of introducing the disease. In this study, individual pieces of ovarian cortex intended for reimplantation from 25 patients with leukemia were transplanted to each of 25 nude mice for 20 weeks. The ovarian cortex was examined before and after transplantation by histology and immunohistochemistry, and RT-quantitative PCR (in the 7 patients with a known marker). Seventeen patients had the ovarian cortex retrieved when they were in complete remission. Before transplantation, 4 of 7 pieces (2 from patients in complete remission) of ovarian cortex had a positive RT-quantitative PCR. After transplantation, none of the mice revealed any sign of disease, neither in the pieces of ovarian cortex transplanted nor in any of the murine organs evaluated. Thus, the ovaries from patients in complete remission do not appear to contain viable malignant cells contrasting ovarian tissue retrieved before treatment.

Evaluation of the ovarian reserve in women transplanted with frozen and thawed ovarian cortical tissue.

OBJECTIVE: To investigate ovarian reserve and ovarian function in women transplanted with frozen/thawed ovarian tissue. DESIGN: Retrospective cohort study. SETTING: University hospital. PATIENT(S): 18 women transplanted with their own frozen/thawed ovarian tissue. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Levels of antimüllerian hormone (AMH), duration of function of the transplanted ovarian tissue, outcome of assisted reproduction. RESULT(S): Of the 18 women who received transplanted ovarian tissue, levels of AMH were measured in 12 women; AMH never exceed a concentration of 1 ng/mL, and in several cases they were below the detection limit of the assay in combination with regular menstrual cycles. Two women with AMH below the detection limit conceived spontaneously. The duration of function of the transplants was between 9 months and 7 years and still functioning. Twelve women received assisted reproduction therapy; in 72 cycles, 65 oocytes were retrieved. The pregnancy rate and live-birth rate per cycle were 6.9% (5 of 72) and 2.8% (2 of 72), respectively. CONCLUSION(S): The relatively poor outcome of assisted reproduction in women transplanted with frozen/thawed ovarian tissue may reflect reduced follicular selection rather than defective or aged oocytes. In normal women, reduced follicular selection with age may be part of explaining the decline in female fecundity with increasing age.

Weight maintenance through behaviour modification with a cooking course or neurolinguistic programming.

We compared the effect on weight regain of behaviour modification consisting of either a gourmet cooking course or neurolinguistic programming (NLP) therapy. Fifty-six overweight and obese subjects participated. The first step was a 12-week weight loss program. Participants achieving at least 8% weight loss were randomized to five months of either NLP therapy or a course in gourmet cooking. Follow-up occurred after two and three years. Forty-nine participants lost at least 8% of their initial body weight and were randomized to the next step. The NLP group lost an additional 1.8 kg and the cooking group lost 0.2 kg during the five months of weight maintenance (NS). The dropout rate in the cooking group was 4%, compared with 26% in the NLP group (p=0.04). There was no difference in weight maintenance after two and three years of follow-up. In conclusion, weight loss in overweight and obese participants was maintained equally efficiently with a healthy cooking course or NLP therapy, but the dropout rate was lower during the active cooking treatment.

Maternal and perinatal complications by day of gestation after spontaneous labor at 40-42 weeks of gestation.

OBJECTIVE: To evaluate pregnancy outcome after spontaneous labor by day of gestation between 40(+0) and 41(+6) weeks of gestation. DESIGN: Evaluation of prospectively collected labor ward data. SETTING: University Hospital, Denmark. POPULATION: Unselected consecutive cohort of 14 678 spontaneously starting deliveries between 280 and 293 days of gestation during the years 2000-2006. METHODS: Data were registered in a computer program after each delivery by a midwife and the entries further evaluated by a specialist in obstetrics. Complication rates were compared using Fisher's exact test. MAIN OUTCOME MEASURES: Maternal complication rates for each gestation day, including cesarean delivery, maternal blood transfusion, episiotomy, operative vaginal delivery, third and fourth degree perineal lacerations and perinatal morbidity. RESULTS: The cesarean delivery rate increased from 6% on day 280 to 11% on day 293. Cesarean delivery increased from 40 to 41 weeks gestation (7.3 vs. 9.5%, p<0.005), as did maternal transfusion (0.5 vs. 1.2%, p<0.001) and cesarean section on the indication fetal distress (1.5 versus 2.4%, p<0.005), but perineal lacerations did not. Likewise, there was an increase in episiotomy rates (3.0 vs. 3.5%, p=0.08), operative vaginal delivery (5.8 vs. 6.5%, p=0.07) and admission to neonatal intensive care (1.4 versus 2.0%, p=0.009), but no increase in 5 minute Apgar scores <7 or low umbilical artery acid-base values. CONCLUSIONS: Deliveries starting spontaneously in an unselected cohort showed an increase in maternal complications, meconium-stained amniotic fluid and admission to the neonatal intensive care unit.

Legal termination of a pregnancy resulting from transplanted cryopreserved ovarian tissue.

Cryopreservation of ovarian tissue is a promising new technique for fertility preservation in patients facing gonadotoxic treatment. Ovarian tissue is extracted and cryo-stored at low temperature prior to treatment. If the woman becomes menopausal, the tissue can be transplanted and a few months later the woman will start to ovulate and be able to conceive, naturally or with assisted reproduction treatment. Currently, 12 healthy children have been born worldwide as a result of transplanting frozen/thawed ovarian tissue. Of these children 3 are Danish and a number of other Danish women are currently attempting to become pregnant. One of these women conceived naturally and had a normal intrauterine pregnancy following transplantation of cryopreserved ovarian tissue. However, the woman decided to terminate the pregnancy within the legal time frame. This pregnancy imposes cryopreservation of ovarian tissue for fertility preservation as a valid method and illustrates that personal life circumstances may rapidly change.

[Case of severe rhabdomyolosis after protracted overdose of simvastatin]. / Et tilfaelde af svaer rabdomyolyse efter laengerevarende overdosering med simvastatin.

The mechanisms of statin-induced muscle injury are not fully understood, and early recognition of statin myopathy is critical in order to prevent serious sequelae. The case of a 57-year-old woman who had accidentally taken a quadrupled dose of simvastatin over a period of 18 days is presented. The patient was admitted to hospital with severe rhabdomyolysis and treated with forced diuresis. Despite the rhabdomyolysis, the patient's kidney function was not affected, but reduced muscle function was observed which was still not fully regained 6 months later.