Erik Ernst

The first woman to give birth to two children following transplantation of frozen/thawed ovarian tissue

Worldwide eight children have been born as a result of transplanting frozen/thawed ovarian tissue. Two of these children were born in Denmark following transport of the ovarian tissue for a period of 5 h prior to cryopreservation. One of these women, who was originally transplanted with six pieces of ovarian cortex, after having experienced a period of menopause has now conceived again following natural conception. She gave birth to a healthy girl on 23 September 2008 and is therefore the first woman in the world to have had two children, from separate pregnancies, born as a result of transplanting frozen/thawed ovarian tissue. This result encourages further development of cryopreservation of ovarian tissue for fertility preservation as a clinical procedure for girls and young women facing gonadotoxic treatment.

Low concentration of circulating antimüllerian hormone is not predictive of reduced fecundability in young healthy women: a prospective cohort study.

OBJECTIVEnTo evaluate whether circulating levels of antimüllerian hormone (AMH) predict fecundability in young healthy women.nnnDESIGNnProspective cohort study.nnnSETTINGnGeneral community.nnnPATIENT(S)nA total of 186 couples who intended to discontinue contraception to become pregnant were followed until pregnancy or for six menstrual cycles.nnnINTERVENTION(S)nNone.nnnMAIN OUTCOME MEASURE(S)nFecundability was evaluated by the monthly probability of conceiving (i.e., fecundability ratio [FR]). In addition, circulating levels of LH, FSH, T, and sex hormone-binding globulin (SHBG) were evaluated in 158 of 186 women.nnnRESULT(S)nFifty-nine percent of couples conceived during the study period. Compared to the reference group of women with medium AMH (AMH quintiles 2-4), fecundability did not differ significantly in women with low AMH (AMH quintile 1) (FR 0.81; 95% confidence interval [CI] 0.44-1.40). In contrast, women with high AMH (AMH quintile 5) had reduced fecundability (FR 0.62; 95% CI 0.39-0.99) after adjustment for covariates (womans age, body mass index [BMI], smoking, diseases affecting fecundability, and oligozoospermia). Irregular menstrual cycles were more prevalent in women with high AMH compared with women with low or medium AMH levels, and they had higher levels of LH (geometric mean: 8.4 vs. 5.3 IU/L) and LH:FSH ratio (2.4 vs. 1.8). After exclusion of women with irregular cycles, women with high AMH still had reduced fecundability (FR 0.48; 95% CI 0.27-0.85) and elevated LH:FSH ratio (2.4 vs. 1.7).nnnCONCLUSION(S)nLow AMH in healthy women in their mid-20s did not predict reduced fecundability. Even after exclusion of women with irregular cycles, the probability of conceiving was reduced in women with high AMH.

Caffeine intake and fecundability : A follow-up study among 430 Danish couples planning their first pregnancy

Fecundability has been defined as the ability to achieve a recognized pregnancy. Several studies on caffeine and fecundability have been conducted but have been inconclusive. This may be explained partly by lack of stratification by smoking. Furthermore, few researchers have tried to separate the effect of caffeine from different sources (coffee, tea, cola, and chocolate). Clearly, the relationship between caffeine and fecundability needs further research, given the high prevalence of caffeine intake among women of childbearing age. We examined the independent and combined effects of smoking and caffeine intake from different sources on the probability of conception. From 1992 to 1995, a total of 430 couples were recruited after a nationwide mailing of a personal letter to 52,255 trade union members who were 20 to 35 years old, lived with a partner, and had no previous reproductive experience. At enrollment and in six cycles of follow-up, both partners filled out a questionnaire on different factors including smoking habits and their intake of coffee, tea, chocolate, cola beverages, and chocolate bars. In all, 1596 cycles and 423 couples were included in the analyses. The cycle-specific association between caffeine intake and fecundability was analyzed in a logistic regression model with the outcome at each cycle (pregnant or not pregnant) in a Cox discrete model calculating the fecundability odds-ratio (FR). Compared to nonsmoking women with caffeine intake less than 300 mg/d, nonsmoking women who consumed 300 to 700 mg/d caffeine had a FR of 0.88 [95% confidence interval (CI) 0.60-1.31], whereas women with a higher caffeine intake had a FR = 0.63 (95% CI 0.25-1.60) after adjusting for female body mass index and alcohol intake, diseases of the female reproductive organs, semen quality, and duration of menstrual cycle. No dose-response relationship was found among smokers. Among males, the same decline in point estimates of the FR was present. Smoking women whose only source of caffeine was coffee (>300 mg/d) had a reduced fecundability odds-ratio (FR = 0.34; 95% CI 0.12-0.98). An interaction between caffeine and smoking is biologically plausible, and the lack of effect among smokers may be due to faster metabolism of caffeine. Our findings suggest that especially nonsmoking women who wish to achieve a pregnancy might benefit from a reduced caffeine intake.

Cryopreservation of ovarian tissue for fertility preservation: no evidence of malignant cell contamination in ovarian tissue from patients with breast cancer

Cryopreserved ovarian cortical biopsies from 51 patients with breast cancer were examined by histologic and immunohistochemical analysis and showed no sign of metastases. Autotransplantation of ovarian cortex to patients with low-stage breast cancer disease appears safe, but confirmatory studies are required, including xenotransplantation studies.

Long-term duration of function of ovarian tissue transplants: case reports

These three case reports describe the long-term duration of function of ovarian cortical tissue grafts among patients in a university fertility preservation programme in Europe and in a private practice programme in the USA. One woman underwent sterilizing cancer treatment and had frozen ovarian tissue transplanted, and two women underwent fresh ovarian tissue transplants. The function of ovarian cortical strips has continued for more than 7 years in these three women, with the birth of eight healthy babies following a single graft per patient. In addition to these three cases, transplantation (repeatedly in some cases) of cryopreserved ovarian tissue has restored reproductive function to all other women in the study centres programmes for some years. The sustained longevity of function of the transplanted tissue suggests that it may also be possible to postpone the normal time of menopause or to alleviate its symptoms.

Risk of autism spectrum disorders in children born after assisted conception: a population-based follow-up study

Objectives To assess the risk of autism spectrum disorders (ASD) in children born after assisted conception compared with children born after natural conception. Design Population-based follow-up study. Setting All children born alive in Denmark 1995–2003. Participants 588u2008967 children born in Denmark from January 1995 to December 2003. Assisted conception was defined as in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection and ovulation induction (OI) with or without subsequent insemination. Children exposed to IVF or OI were identified in the IVF Register and in the Danish Drug Prescription Register. Main outcome measures A diagnosis of ASD in the Danish Psychiatric Central Register. Results 33u2008139 (5.6%) of all children born in Denmark in 1995–2003 resulted from assisted conception, 225 of whom (0.68%) had a diagnosis of ASD. Of the 555u2008828 children born in this period after natural conception, 3394 (0.61%) had a diagnosis of ASD. The follow-up time was 4–13u2005years (median 9u2005years). In crude analyses, children born after assisted conception had an increased risk of a diagnosis of ASD: crude hazard rate ratio (HRR) 1.25 (95% CI 1.09 to 1.43). In analyses adjusting for maternal age, educational level, parity, smoking, birth weight and multiplicity, the risk disappeared: adjusted HRR 1.13. (95% CI 0.97 to 1.31). However, subgroup analyses that suggest possible associations in women who received follicle stimulating hormone indicate the need for further study. Discussion This population-based follow-up study found no risk of ASD in children born after assisted conception.

Outcomes of transplantations of cryopreserved ovarian tissue to 41 women in Denmark

STUDY QUESTIONnWhat are the results of transplanting cryopreserved ovarian tissue?nnnSUMMARY ANSWERnThe transplanted ovarian tissue can last up to 10 years, with no relapses following the 53 transplantations, and the chance of a successful pregnancy is currently around one in three for those with a pregnancy-wish.nnnWHAT IS KNOWN ALREADYnCryopreservation of ovarian tissue is now gaining ground as a valid method for fertility preservation. More than 36 children worldwide have now been born following this procedure.nnnSTUDY DESIGN, SIZE, DURATIONnThis is a retrospective cohort study of 41 women who had thawed ovarian tissue transplanted 53 times over a period of 10 years, including 1 patient who was lost to follow-up.nnnPARTICIPANTS/MATERIALS, SETTING, METHODSnThe 41 Danish women, who had in total 53 transplantations, were followed for ovarian function and fertility outcome. Safety was assessed by monitoring relapse in cancer survivors.nnnMAIN RESULTS, AND THE ROLE OF CHANCEnAmong 32 women with a pregnancy-wish, 10 (31%) had a child/children (14 children in total); this included 1 woman with a third trimester on-going pregnancy. In addition, two legal abortions and one second trimester miscarriage occurred. A total of 24 clinical pregnancies were established in the 32 women with a pregnancy-wish. The tissue remained functional for close to 10 years in some cases and lasted only a short period in others. Three relapses occurred but were unlikely to be due to the transplanted tissue.nnnLIMITATIONS, REASONS FOR CAUTIONnSelf-report through questionnaires with only in-one hospital formalised follow-up of transplanted patients could result in unreported miscarriages. The longevity of the tissue may vary by few months compared with those reported because some patients simply could not remember the date when the tissue became non-functional.nnnWIDER IMPLICATIONS OF THE FINDINGSnCryopreservation of ovarian tissue is likely to become integrated into the treatment of young women, with cancer, who run a risk of losing their fertility. The full functional lifespan of grafts is still being evaluated, because many of the transplanted women have continued to maintain ovarian activity. Some of our first cases have had tissue functioning for ∼ 10 years.

A very large proportion of young Danish women have polycystic ovaries: is a revision of the Rotterdam criteria needed?

BACKGROUNDnAccording to the Rotterdam 2003 criteria, an ovary is defined as polycystic if 12 or more follicles of 2-9 mm are present, when evaluating the ovary by ultrasonography on Days 3-5 of the menstrual cycle in women not using hormonal contraceptives. The aim of this population-based study was to estimate the prevalence of polycystic ovaries (PCO) in a representative sample of young Danish women according to the Rotterdam criteria.nnnMETHODSnFrom a Danish pregnancy cohort established in 1988-1989, 267 (61%) young adult daughters agreed to participate in a clinical examination and 174 (40%) consented to vaginal ultrasound. Sufficient image quality in at least one ovary was obtained from 154 women. Both users and non-users of hormonal contraceptives were included and the examination was not restricted to a particular time of the menstrual cycle.nnnRESULTSnThe median (range) age was 20.1 (19.5-21.0) years. The median follicle number per ovary was 14 (6-30) and 12 or more follicles were counted in 104 of the 154 women. Thus, the prevalence was estimated to 68% [95% confidence interval (CI): 60-74%]. PCO were present in 80% (95% CI: 65-89%) of non-users (n = 44) of hormonal contraceptives. Of the 104 women with PCO, 41% (95% CI: 32-51%) could be defined as having polycystic ovary syndrome.nnnCONCLUSIONSnA very large proportion of the young women had PCO according to the Rotterdam 2003 criteria. As the number of follicles is higher at a younger age, we believe the Rotterdam criteria should be revised, particularly to avoid misdiagnosis in this age group.

Case report: Stimulation of puberty in a girl with chemo- and radiation therapy induced ovarian failure by transplantation of a small part of her frozen/thawed ovarian tissue

AIM OF THE STUDYnTo induce puberty by transplantation of frozen/thawed ovarian tissue collected prior to gonadotoxic treatment for a cancer.nnnPATIENTS AND METHODSnA 9-year-old girl with Ewing sarcoma had one ovary excised and cryopreserved prior to chemo- and radiotherapy. Functional activity of the remaining ovary was destroyed during treatment. Four and a half years later the girl remained pre-pubertal with postmenopausal levels of FSH. Two of ten pieces of frozen/thawed cortex were transplanted to the remaining ovary in order to stimulate puberty.nnnRESULTSnFour months after the transplantation FSH returned to low levels. During the following year puberty gradually progressed to Tanner stage B4 and P3 and regular menstrual cycles started. However, after 19 months the function of the graft ceased.nnnCONCLUSIONSnWe have shown for the first time in a girl treated for cancer that transplanted ovarian tissue can regain function and secrete estradiol in a sufficient amount to induce puberty. In addition, the majority of her ovarian tissue remains frozen with a possibility to support fertility in adult life.

Menstrual cycle pattern and fertility: a prospective follow-up study of pregnancy and early embryonal loss in 295 couples who were planning their first pregnancy

OBJECTIVEnTo characterize how the menstrual cycle pattern relates to fertility regardless of potential biases caused by inappropriate coital timing during the menstrual cycle or early embryonal loss.nnnDESIGNnProspective follow-up study.nnnSETTINGnHealthy couples recruited throughout Denmark.nnnPATIENT(S)nTwo hundred ninety-five couples who were planning their first pregnancy were followed up from the discontinuation of birth control until a pregnancy was recognized within six menstrual cycles. Early embryonal losses were detected by changes in urinary hCG levels.nnnINTERVENTION(S)nNone.nnnMAIN OUTCOME MEASURE(S)nThe probability of pregnancy occurring within one menstrual cycle (fecundity).nnnRESULT(S)nIn women who had a cycle length that differed by >10 days from the usual cycle length, fecundity was approximately 25% that of women who had no variation (odds ratio 0.25, 95% confidence interval 0.09-0.68). When the combined effect of cycle variation and cycle length was assessed, cycle variation was a persistent strong predictor of fecundity.nnnCONCLUSION(S)nThe mechanisms of the present findings probably are female functional disturbances in ovulation, conception, implantation, or sustained pregnancy, linked with variable menstrual cycle length. Thus, identification of medical and environmental causes of abnormal menstrual cycle patterns may provide clues to the causes of infertility. Moreover, the menstrual cycle pattern also should be taken into consideration in the clinical decision-making process.