Intracervical insemination versus intrauterine insemination with cryopreserved donor sperm in the natural cycle: a randomized controlled trial.

STUDY QUESTION: Is intracervical insemination (ICI) non-inferior to IUI with cryopreserved donor sperm in the natural cycle in terms of live birth? SUMMARY ANSWER: ICI with cryopreserved donor sperm in the natural cycle was inferior to IUI in terms of live birth. WHAT IS KNOWN ALREADY: Both ICI and IUI in the natural cycle are performed as first-line treatments in women who are eligible for donor sperm treatment. High-quality data on the effectiveness of ICI versus IUI with cryopreserved donor sperm in the natural cycle in terms of live birth is lacking. STUDY DESIGN, SIZE, DURATION: We performed an open-label multicentre randomized non-inferiority trial in the Netherlands and Belgium. PARTICIPANTS/MATERIALS, SETTING, METHODS: We randomly allocated women who were eligible for donor sperm treatment with cryopreserved donor semen to six cycles of ICI in the natural cycle or six cycles of IUI in the natural cycle. The primary outcome was conception within 8 months after randomization leading to a live birth. Secondary outcomes were ongoing pregnancy, multiple pregnancy, clinical pregnancy, miscarriage and time to conception leading to live birth. We calculated relative risks (RRs) and risk differences (RDs) with 95% CI. Non-inferiority would be shown if the lower limit of the 95% RD CI was <-12%. MAIN RESULTS AND THE ROLE OF CHANCE: Between June 2014 and February 2019, we included 421 women, of whom 211 women were randomly allocated to ICI and 210 to IUI. Of the 211 women allocated to ICI, 2 women were excluded, 126 women completed treatment according to protocol and 75 women did not complete 6 treatment cycles. Of the 210 women allocated to IUI, 3 women were excluded, 140 women completed treatment according to protocol and 62 women did not complete 6 treatment cycles. Mean female age was 34 years (SD ±4) in both interventions. Conception leading to live birth occurred in 51 women (24%) allocated to ICI and in 81 women (39%) allocated to IUI (RR 0.63, 95% CI: 0.47 to 0.84). This corresponds to an absolute RD of -15%; 95% CI: -24% to -6.9%, suggesting inferiority of ICI. ICI also resulted in a lower live birth rate over time (hazard ratio 0.58, 95% CI: 0.41-0.82). Our per-protocol analysis showed that, within the 8 months treatment horizon, 48 women (38%) had live births after ICI and 79 women (56%) had live births after IUI (RR 0.68, 95% CI: 0.52-0.88; RD -18%, 95% CI: -30% to -6%). LIMITATIONS, REASONS FOR CAUTION: The study was non-blinded owing to the nature of the interventions. We consider it unlikely that this has introduced performance bias, since pregnancy outcomes are objective outcome measures. WIDER IMPLICATIONS OF THE FINDINGS: Since ICI in the natural cycle was inferior to IUI in the natural cycle with cryopreserved donor sperm in terms of live birth rate, IUI is the preferred treatment. STUDY FUNDING/COMPETING INTEREST(S): This trial received funding from the Dutch Organization for Health Research and Development (ZonMw project number 837002407). B.W.J.M. is supported by an NHMRC Investigator grant (GNT1176437), reports consultancy for ObsEva and has received research funding from Guerbet, Ferring and Merck. The other authors do not declare a COI. TRIAL REGISTRATION NUMBER: NTR4462. TRIAL REGISTRATION DATE: 11 March 2014. DATE OF FIRST PATIENT'S ENROLMENT: 03 June 2014.

Intrauterine insemination or intracervical insemination with cryopreserved donor sperm in the natural cycle: a cohort study.

STUDY QUESTION: Does intrauterine insemination in the natural cycle lead to better pregnancy rates than intracervical insemination (ICI) in the natural cycle in women undergoing artificial insemination with cryopreserved donor sperm. SUMMARY ANSWER: In a large cohort of women undergoing artificial insemination with cryopreserved donor sperm, there was no substantial beneficial effect of IUI in the natural cycle over ICI in the natural cycle. WHAT IS KNOWN ALREADY: At present, there are no studies comparing IUI in the natural cycle versus ICI in the natural cycle in women undergoing artificial insemination with cryopreserved donor sperm. STUDY DESIGN, SIZE, DURATION: We performed a retrospective cohort study among all eight sperm banks in the Netherlands. We included all women who underwent artificial insemination with cryopreserved donor sperm in the natural cycle between January 2009 and December 2010. We compared time to ongoing pregnancy in the first six cycles of IUI and ICI, after which controlled ovarian stimulation was commenced. Ongoing pregnancy rates (OPRs) over time were compared using life tables. A Cox proportional hazard model was used to compare the chances of reaching an ongoing pregnancy after IUI or ICI adjusted for female age and indication. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included 1843 women; 1163 women underwent 4269 cycles of IUI and 680 women underwent 2345 cycles of ICI with cryopreserved donor sperm. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics were equally distributed (mean age 34.0 years for the IUI group versus 33.8 years for the ICI group), while in the IUI group, there were more lesbian women than in the ICI group (40.6% for IUI compared with 31.8% for ICI). Cumulative OPRs up to six treatment cycles were 40.5% for IUI and 37.9% for ICI. This corresponds with a hazard rate ratio of 1.02 [95% confidence interval (CI) 0.84-1.23] after controlling for female age and indication. Increasing female age was associated with a lower OPR, in both the IUI and ICI groups with a hazard ratio for ongoing pregnancy of 0.94 per year (95% CI 0.93-0.97). LIMITATIONS, REASONS FOR CAUTION: This study is prone to selection bias due to its retrospective nature. As potential confounders such as parity and duration of subfertility were not registered, the effect of these potential confounders could not be evaluated. WIDER IMPLICATIONS OF THE FINDINGS: In women inseminated with cryopreserved donor sperm in the natural cycle, we found no substantial benefit of IUI over ICI. A randomized controlled trial with economic analysis alongside, it is needed to allow a more definitive conclusion on the cost-effectiveness of insemination with cryopreserved donor sperm. STUDY FUNDING/COMPETING INTERESTS: No funding was used and no conflicts of interest are declared.

A neonate with recurrent vomiting and generalized hypotonia diagnosed with a deficiency of dihydropyrimidine dehydrogenase.

Deficiency of dihydropyrimidine dehydrogenase (DPD) is a rare inborn error of pyrimidine metabolism. To date, only about 50 patients are known worldwide. The clinical picture is varied and is not yet fully described. Most patients are diagnosed at the age of 1-3 years. We present a patient diagnosed 8 weeks postpartum. The female patient presented in the first 3 days after birth with agitation, choking, and vomiting. Six weeks later, the patient presented again with vomiting and insufficient weight gain. Metabolic screening of urine showed a strongly increased excretion of uracil and thymine, with no other abnormalities. This suggested a deficiency of DPD which was confirmed by enzyme analysis in peripheral blood mononucleair (PBM) cells (patient: activity <0.01 nmol/mg/h; controls: 9.9 +/- 2.8 nmol/mg/h). The patient was homozygous for the IVS14+1G>A mutation.MRI of the brain showed some cerebral atrophy; myelinization appeared normal. Many patients with DPD-deficiency suffer from convulsions and mental retardation, some show microcephaly, feeding difficulties, autism, and hypertonia. Our patient showed feeding difficulties and in the second half-year she developed slight motor retardation and generalized hypotonia. Further observation of the development of the patient may shed more light on the relationship between clinical symptoms and DPD deficiency. DPD deficiency may present in newborns with vomiting and hypotonia as the main symptoms.

A new Dutch Law regulating provision of identifying information of donors to offspring: background, content and impact.

In 2004 a law was introduced in The Netherlands, which gives offspring conceived by semen or oocyte donation the right to know the identity of the donor. The law also regulates the provision of other information concerning the donor to the offspring, their parents or their general practitioner. With the introduction of this law, a choice has been made in which the wish of offspring prevails above others involved. Donors can no longer claim absolute anonymity; they are anonymous at the time of donation, but if a child aged > or =16 years requests information the donor may now be traced. During 15 years of debate on the abolition of donor anonymity the number of donors decreased by >70% and the number of semen banks by 50%. We describe the debate which led to the law, the characteristics of the law itself and note some of the probable and possible consequences for donor offspring, parents, donors and semen banks.

[The Dutch law on artificial-insemination donor data: content and consequences]. / Wet Donorgegevens Kunstmatige Bevruchting: inhoud en gevolgen.

In 2004, a law was introduced in the Netherlands that gives children conceived by artificial insemination with donor semen (AID), oocytes or embryos the right to learn the identity of the donor when they are 16. The permanently anonymous semen donor will now be replaced by donors that are anonymous at the time of insemination, but traceable later. During the period preceding and immediately following the enactment of the law, the number of semen donors and semen banks dropped drastically and there was a change in the type of donor. The law, furthermore, creates several new moral and psychological dilemmas for both parents and AID-offspring. For parents, for example: should I tell my child that he was conceived by AID, knowing that he may become acquainted with the donor, with all the consequences that may entail? And for AID-offspring, if they have been told that they were conceived by AID: do I really wish to meet the donor? It must still be shown whether AID-offspring will feel a need for contact with the donor, and whether such contact is satisfying.

[Cryopreservation of semen of adolescents and young adult men with cancer]. / Invriezen van sperma bij pubers en jonge volwassen mannen met kanker.

The importance of cryopreserving semen for young male cancer patients is illustrated in three case descriptions. A 28-year-old man with chronic myeloid leukaemia that resulted in azoospermia, later fathered a child with his semen that had been stored prior to chemotherapy. In an 18-year-old adolescent with non-Hodgkin lymphoma the possibility to store cryopreserved semen was only raised after chemotherapy had been started and had caused azoospermia. This caused the patient serious regret. A 14-year-old boy with acute lymphatic leukaemia had his semen stored despite initial hesitations due to his young age. The cancer hardly ever affects the semen quality to the extent that cryopreservation of the semen becomes impossible. The aim should be to obtain several ejaculates prior to the cancer therapy and to store multiple portions, so that later a number of fertilisation attempts are possible. The primary attending physician is initially responsible for raising the possibility of semen cryopreservation. Ideally, however, all health professionals involved should be aware of this aspect. There is a need for multidisciplinary protocols for oncology centres and sperm banks, so that the timely informing of patients is guaranteed, responsibilities are recorded--with appropriate procedures to prevent unnecessary delay--and procedures that concur with legal requirements and financial constraints are established.

[Hydrops fetalis as an indication for a systematic investigation into the presence of lysosomal storage diseases]. / Hydrops foetalis als indicatie voor systematisch onderzoek naar lysosomale stapelingsziekten.

As a result of the decreased incidence of immunological hydrops fetalis and increased insight, the role of inborn errors of metabolism (IEM) as a cause of hydrops fetalis has acquired increased significance. This growing awareness of the manifestation of IEM in pregnancy has revealed that some 20 of these disorders may cause hydrops fetalis, accounting for a few percent of all cases. These IEM are, for the most part, lysosomal storage diseases. We recommend that standard metabolites and enzymes reflecting lysosomal storage diseases be measured in the amniotic fluid and the amniocytes already withdrawn for karyotyping. The value of the diagnosis of lysosomal storage diseases lies in the opportunity for risk evaluation, genetic counselling and targeted prenatal diagnostics in case of subsequent pregnancies. Obtaining insight into the possible therapestic interventions during the pregnancy in which the hydrops is observed is not a goal of this protocol since the necessary investigations are too time-consuming.

[Spreading of hereditary diseases through donor sperm: no reason for reducing the number of offspring per donor in the Netherlands]. / Verspreiding van erfelijke ziekten door donorsperma: geen reden voor verlaging van het aantal nakomelingen per donor in Nederland.

In the Netherlands, a limit of 25 offspring per sperm donor has been applied for many years. This figure was based on the assumption that children from sperm donors are not at greater risk of having consanguineous relationships than a random individual of the Dutch population. After the report in 2002 that a donor, whose sperm was used to father 18 children by artificial insemination, had developed a serious hereditary brain disease, the question of whether the limit of 25 should be reduced was raised. From a population genetics point of view, reducing the number of children per donor will only result in greater genetic diversity being transmitted to the offspring of sperm donors. Moreover, the number of children from sperm donors is a negligibly small proportion of the general population (0.5% of the total number of newly-borns). Since no knowledge of other offspring from one particular donor is available to individuals making use of donor insemination, only optimally guaranteed safety (both genetic and microbial) is important to these people and their offspring, given that the risk of inbreeding is acceptably low. Finally, the interests of the donor can be properly safeguarded through individual agreements. Therefore, to conclude, there are no reasons to reduce the limit of 25 offspring per sperm donor.

[Hypercalcemia due to adult T-cell lymphoma in a man from Surinam]. / Hypercalciëmie door adult T-cellymfoom bij een Surinaamse man.

A 48-year-old male patient from Surinam presented with anorexia, nausea and weight loss. An extreme hypercalcaemia of 5.08 mmol/l was found. Further diagnostic investigations showed that this patient had a HTLV-1 positive adult T-cell leukaemia/lymphoma (ATL/L). This is often associated with multilobularly nucleated lymphocytes, bone destruction and hypercalcaemia. Skin localisations are frequently observed. The combination of cytomorphology, immunophenotyping, HTLV-1 seropositivity and clinical findings points to the diagnosis. The patient was treated with 6 courses of chemotherapy consisting of cyclophosphamide, doxorubicin, teniposide, prednisone, vincristine and bleomycin. Upon inquiry it appeared that he had died elsewhere. Chemotherapy induces a short-lived remission in a minority of ATL/L patients. Antiviral therapy (alpha interferon, zidovudine) might offer new possibilities.

Sensitivity of a hyperosmolar or "low"-osmolar test solution for sugar absorption in recognizing small intestinal mucosal damage in coeliac disease.

Reliability of differential sugar absorption tests is hampered by a lack of standardization of the content and osmolarity of the test solutions. We evaluated the effect of osmolarity of the test solution of the sugar absorption test on the 5 hour urine excretion of orally administered lactulose and mannitol. A group of 28 controls and 14 coeliacs, with villous atrophy grade II to IV, ingested a hyperosmolar sugar absorption test solution and a "low"-osmolar solution, respectively. After an overnight fast, each subject ingested hyperosmolar sugar absorption test solution (2 g mannitol, 5 g lactulose and 40 g sucrose/100 ml (around 1,560 mmol/l)). After two days, this procedure was repeated with low-osmolar solution (2 g mannitol and 5 g lactulose/100 ml (around 375 mmol/l). The influence of the sequence of the tests on the results had previously been excluded. All urine from the 5 h-period following ingestion of the test solution was collected. To calculate the low-osmolar solution ratio, samples were analysed for lactulose and mannitol concentrations by gas chromatography The sensitivity of hyperosmolar SAT solution and low-osmolar solution for the detection of mucosal abnormalities in coeliacs was 64% and 43%, respectively. In conclusion, a hyperosmolar solution discriminates better between normal and damaged mucosa of the small bowel such as villous atrophy due to a relative increase in permeability for lactulose.

Evaluation of the application of carbohydrate deficient transferin in a general hospital; recommendations for use.

We performed a retrospective evaluation of the use of carbohydrate deficient transferrin (CDT) in a general hospital, for diagnosing alcohol abuse. The high specificity for the CDT test and lower sensitivity as reported in the literature were confirmed. Alcohol anamnesis proved rather often to be incomplete. In intensive care medicine, the CDT investigation could be used as a guide to diagnoses and treatment, especially for patients that are difficult to communicate with. For being of use here, results of the CDT determination should be available within a day. CDT proved to be of use also in psychiatric medicine, the test being of help in clarifying the patients acohol addiction.

Coating in vitro of erythrocytes with Tamm Horsfall-protein.

A method is described to coat isolated peripheral blood erythrocytes in vitro with Tamm-Horsfall Protein (THP, uromodulin). Coating of erythrocytes with THP was accomplished by incubation of the cells in the presence of THP, made monomeric by incubation in a high urea concentration. THP-coating of erythrocytes was dependent on the THP-concentration, maximal coating being obtained at a protein concentration > or = 250 mg/ml. The best coating results were obtained if, during the co-incubation of erythrocytes with THP, urea was removed while the sodium chloride concentration was increased up to a physiologic concentration by means of dialysis. This alteration in chemical conditions promotes THP-polymerisation. Erythrocytes coated in this way could be preserved for at least 5 weeks in preserving solution, making them an interesting source of testing and control material. Coating of erythrocytes with THP could also be accomplished under conditions in which THP was preserved in a monomeric form, which suggests that peripheral blood erythrocytes having binding-sites for THP.

Subcutaneous fat necrosis in a neonate, in association with aberrant plasma lipid and lipoprotein values.

A newborn infant with subcutaneous fat necrosis after perinatal hypoxia was found to have several abnormalities of plasma lipids. Further studies are needed to determine whether such abnormalities contribute to the pathophysiology of the skin lesions.