A 1H NMR comparative study of human adult and fetal hemoglobins

AbstractThe affinities of the individual subunits in human adult and fetal hemoglobins to azide ion have been determined from the combined analysis of NMR and optical titration data. Structural and functional non-equivalence of the constituent subunits, i.e. α and β subunits in human adult hemoglobin and α and γ subunits in human fetal hemoglobin, has been confirmed. The function of the α subunits, which are common to both hemoglobins, is essentially identical in these hemoglobins and, in spite of the substitutions of 39 amino acid residues between β and γ subunits, they exhibit similar azide ion affinities. The present study also demonstrates that the NMR spectral comparison between the two proteins provides signal assignments to the individual subunits in intact tetramer

Lifestyle intervention prior to IVF does not improve embryo utilization rate and cumulative live birth rate in women with obesity:a nested cohort study

STUDY QUESTION: Does lifestyle intervention consisting of an energy-restricted diet, enhancement of physical activity and motivational counseling prior to IVF improve embryo utilization rate (EUR) and cumulative live birth rate (CLBR) in women with obesity? SUMMARY ANSWER: A 6-month lifestyle intervention preceding IVF improved neither EUR nor CLBR in women with obesity in the first IVF treatment cycle where at least one oocyte was retrieved. WHAT IS KNOWN ALREADY: A randomized controlled trial (RCT) evaluating the efficacy of a low caloric liquid formula diet (LCD) preceding IVF in women with obesity was unable to demonstrate an effect of LCD on embryo quality and live birth rate: in this study, only one fresh embryo transfer (ET) or, in case of freeze-all strategy, the first transfer with frozen-thawed embryos was reported. We hypothesized that any effect on embryo quality of a lifestyle intervention in women with obesity undergoing IVF treatment is better revealed by EUR and CLBR after transfer of all fresh and frozen-thawed embryos. STUDY DESIGN, SIZE, DURATION: This is a nested cohort study within an RCT, the LIFEstyle study. The original study examined whether a 6-month lifestyle intervention prior to infertility treatment in women with obesity improved live birth rate, compared to prompt infertility treatment within 24 months after randomization. In the original study between 2009 and 2012, 577 (three women withdrew informed consent) women with obesity and infertility were assigned to a lifestyle intervention followed by infertility treatment (n = 289) or to prompt infertility treatment (n = 285). PARTICIPANTS/MATERIALS, SETTING, METHODS: Only participants from the LIFEstyle study who received IVF treatment were eligible for the current analysis. In total, 137 participants (n = 58 in the intervention group and n = 79 in the control group) started the first cycle. In 25 participants, the first cycle was cancelled prior to oocyte retrieval mostly due to poor response. Sixteen participants started a second or third consecutive cycle. The first cycle with successful oocyte retrieval was used for this analysis, resulting in analysis of 51 participants in the intervention group and 72 participants in the control group. Considering differences in embryo scoring methods and ET day strategy between IVF centers, we used EUR as a proxy for embryo quality. EUR was defined as the proportion of inseminated/injected oocytes per cycle that was transferred or cryopreserved as an embryo. Analysis was performed per cycle and per oocyte/embryo. CLBR was defined as the percentage of participants with at least one live birth from the first fresh and subsequent frozen-thawed ET(s). In addition, we calculated the Z-score for singleton neonatal birthweight and compared these outcomes between the two groups. MAIN RESULTS AND THE ROLE OF CHANCE: The overall mean age was 31.6 years and the mean BMI was 35.4 ± 3.2 kg/m(2) in the intervention group, and 34.9 ± 2.9 kg/m(2) in the control group. The weight change at 6 months was in favor of the intervention group (mean difference in kg vs the control group: −3.14, 95% CI: −5.73 to −0.56). The median (Q25; Q75) number of oocytes retrieved was 4.00 (2.00; 8.00) in the intervention group versus 6.00 (4.00; 9.75) in the control group, and was not significantly different, as was the number of oocytes inseminated/injected (4.00 [2.00; 8.00] vs 6.00 [3.00; 8.75]), normal fertilized embryos (2.00 [0.50; 5.00] vs 3.00 [1.00; 5.00]) and the number of cryopreserved embryos (2.00 [1.25; 4.75] vs 2.00 [1.00; 4.00]). The median (Q25; Q75) EUR was 33.3% (12.5%; 60.0%) in the intervention group and 33.3% (16.7%; 50.0%) in the control group in the per cycle analysis (adjusted B: 2.7%, 95% CI: −8.6% to 14.0%). In the per oocyte/embryo analysis, in total, 280 oocytes were injected or inseminated in the intervention group, 113 were utilized (transferred or cryopreserved, EUR = 40.4%); in the control group, EUR was 30.8% (142/461). The lifestyle intervention did not significantly improve EUR (adjusted odds ratio [OR]: 1.36, 95% CI: 0.94–1.98) in the per oocyte/embryo analysis, taking into account the interdependency of the oocytes per participant. CLBR was not significantly different between the intervention group and the control group after adjusting for type of infertility (male factor and unexplained) and smoking (27.5% vs 22.2%, adjusted OR: 1.03, 95% CI: 0.43–2.47). Singleton neonatal birthweight and Z-score were not significantly different between the two groups. LIMITATIONS, REASONS FOR CAUTION: This study is a nested cohort study within an RCT, and no power calculation was performed. The randomization was not stratified for indicated treatment, and although we corrected our analyses for baseline differences, there may be residual confounding. The limited absolute weight loss and the short duration of the lifestyle intervention might be insufficient to affect EUR and CLBR. WIDER IMPLICATIONS OF THE FINDINGS: Our data do not support the hypothesis of a beneficial short-term effect of lifestyle intervention on EUR and CLBR after IVF in women with obesity, although more studies are needed as there may be a potential clinically relevant effect on EUR. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by a grant from ZonMw, the Dutch Organization for Health Research and Development (50-50110-96-518). A.H. has received an unrestricted educational grant from Ferring pharmaceuticals BV, The Netherlands. B.W.J.M. is supported by an NHMRC Investigator grant (GNT1176437). B.W.J.M. reports consultancy for Guerbet, has been a member of the ObsEva advisory board and holds Stock options for ObsEva. B.W.J.M. has received research funding from Guerbet, Ferring and Merck. F.J.M.B. reports personal fees from membership of the external advisory board for Merck Serono and a research support grant from Merck Serono, outside the submitted work. TRIAL REGISTRATION NUMBER: The LIFEstyle RCT was registered at the Dutch trial registry (NTR 1530). https://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1530

Tubal flushing with oil-based or water-based contrast at hysterosalpingography for infertility:long-term reproductive outcomes of a randomized trial

Objective: To determine the impact of oil -based versus water -based contrast on pregnancy and live birth rates <5 years after hysterosalpingography (HSG) in infertile women. Design: A 5 -year follow-up study of a multicenter randomized trial. Setting: Hospitals. Patient(s): Infertile women with an ovulatory cycle, 18 - 39 years of age, and having a low risk of tubal pathology. Intervention(s): Use of oil -based versus water -based contrast during HSG. Main Outcome Measure(s): Ongoing pregnancy, live births, time to ongoing pregnancy, second ongoing pregnancy. Result(s): A total of 1,119 women were randomly assigned to HSG with oil -based contrast (n = 557) or water -based contrast (n = 562). After 5 years, 444 of 555 women in the oil group (80.0%) and 419 of 559 women in the water group (75.0%) had an ongoing pregnancy (relative risk [RR] 1.07; 95% con fi dence interval [CI] 1.00 - 1.14), and 415 of 555 women in the oil group (74.8%) and 376 of 559 women in the water group (67.3%) had live births (RR 1.11; 95% CI 1.03 - 1.20). In the oil group, 228 pregnancies (41.1%) were conceived naturally versus 194 (34.7%) pregnancies in the water group (RR 1.18; 95% CI 1.02 - 1.38). The time to ongoing pregnancy was signi fi cantly shorter in the oil group versus the water group (10.0 vs. 13.7 months; hazard ratio, 1.25; 95% CI 1.09 - 1.43). No difference was found in the occurrence of a second ongoing pregnancy. Conclusion(s): During a 5 -year time frame, ongoing pregnancy and live birth rates are higher after tubal fl ushing with oil -based contrast during HSG compared with water -based contrast. More pregnancies are naturally conceived and time to ongoing pregnancy is shorter after HSG with oil -based contrast. Clinical Trial Registration Number: Netherlands Trial Register (NTR) 3270 and NTR6577(www.trialregister.nl). (Fertil Steril (R) 2020;114:155-62. (C) 2020 by American Society for Reproductive Medicine.

Hyperemesis gravidarum severity, enteral tube feeding and cardiometabolic markers in offspring cord blood

Publisher Copyright: © The Authors 2022.Peer reviewedPublisher PD

Thyroid-stimulating hormone and free thyroxine fail to predict the severity and clinical course of hyperemesis gravidarum : A prospective cohort study

Funding information: This prospective cohort study was supported by a research grant from North West Hospital Group, Alkmaar, the Netherlands (Grant number: 2013T085) and by a research grant from the Amsterdam Reproduction and Development (AR&D) Research Institute, Amsterdam UMC, the Netherlands (Project number: 23346). ACKNOWLEDGMENTS We thank Dr. J.P. Bestwick (employed at Queen Mary University of London, London, UK) and Professor Dr. J.H. Lazarus (employed at Cardiff School of Medicine, Cardiff, UK) for providing TSH medians from their study in the UK. Dr. J.P. Bestwick and Professor Dr. Lazarus have nothing to disclose.Peer reviewedPublisher PD

Reduced oxygen concentration during human IVF culture improves embryo utilization and cumulative pregnancy rates per cycle

STUDY QUESTION: Do different oxygen levels during human IVF embryo culture affect embryo utilization, cumulative IVF success rates per cycle and neonatal birthweight?SUMMARY ANSWER: After 2 days of culture, a lower oxygen level (5%) leads to more good-quality embryos and more embryos that can be cryopreserved, and thereby to a higher cumulative live birth rate per cycle when compared to embryo culture in 20% oxygen, while birthweights are similar.WHAT IS KNOWN ALREADY: Several studies have compared IVF outcome parameters after embryo culture in a more physiological level of 5% oxygen and the atmospheric level of 20%. Although there is consensus that embryo development improves in 5% oxygen, effects on pregnancy and live birth rates are mainly seen in blastocyst, but not cleavage-stage transfers. A major drawback of these studies is that only fresh embryo transfers were included, not taking additional frozen-thawed transfers from these cycles into account. This might have underestimated the effects of oxygen level, especially in cleavage-stage embryo transfers. Furthermore, little is known about the effect of oxygen level during culture on birthweight.STUDY DESIGN, SIZE, DURATION: This is a cohort study in 871 consecutive patients who had an IVF cycle between January 2012 and December 2013, and 5-7 years follow-up to allow transfer of frozen-thawed embryos. Based on daily availability of positions in the incubators, all oocytes and embryos of one cycle were allocated to one of the three incubators with traditional ambient oxygen levels (6% CO2 and 20% O2 in air), or to a fourth incubator that was adjusted to have low oxygen levels of 5% (6% CO2, 5% O2 and 89% N2). Embryos were cultured under 5 or 20% oxygen until Day 2 or 3, when embryos were transferred or cryopreserved, respectively. Clinical and other laboratory procedures were similar in both groups.PARTICIPANTS/MATERIALS, SETTING, METHODS: To compare embryo characteristics and (cumulative) pregnancy outcomes between the two oxygen groups, for each patient only the first cycle in the study period was included in the analysis, resulting in 195 cycles in the 5% group (1627 oocytes) and 676 in the 20% oxygen group (5448 oocytes). Embryo characteristics were analysed per cycle and per embryo and were corrected for maternal age, cycle rank order, fertilization method (IVF or ICSI) and cause of subfertility. Perinatal data from the resulting singletons (n = 124 after fresh and 45 after frozen-thawed embryo transfer) were collected from delivery reports from the hospitals or midwife practices.MAIN RESULTS AND THE ROLE OF CHANCE: In the 5% oxygen group, there were significantly more embryos of good quality (45.8 versus 30.9% in the 20% group, adjusted odds ratio (OR) [95% CI] = 1.9 [1.6-2.4]). This did not result in higher live birth rates per cycle, but after fresh transfers more good-quality spare embryos could be cryopreserved (46.1 versus 29.7%, adjusted OR [95% CI] = 2.0 [1.7-2.5]). After a follow-up period of 5-7 years, in which 82.4% of the cryopreserved embryos from the 5% oxygen group and 85.4% from the 20% oxygen group were thawed, the percentage of patients with at least one live birth resulting from the study cycle was significantly higher in the low oxygen group (adjusted OR [95% CI] = 1.5 [1.01-2.2]). In 124 live born singletons from fresh embryo transfers and in 45 from transfers of cryopreserved embryos, birthweight was similar in both oxygen groups after correction for confounding factors.LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study, and treatment allocation was not randomised. The study was not powered for a predefined birthweight difference. With the number of live births in our study, small differences in birthweight might not have been detected. The selection of embryos to be cryopreserved was based on embryo morphology criteria that might be different in other clinics.WIDER IMPLICATIONS OF THE FINDINGS: Improved embryo utilization by more cryopreservation leading to higher cumulative live birth rates per cycle favours the use of 5% instead of 20% oxygen during human IVF embryo culture. This study also demonstrates that for comparison of different IVF treatment regimens, the cumulative outcome, including transfers of fresh and frozen-thawed embryos, is to be preferred instead of analysis of fresh embryo transfers only.STUDY FUNDING/COMPETING INTEREST(S): No external funding was received for this study. None of the authors has a conflict of interest to declare.</p

Gonadotrophins or clomiphene citrate in couples with unexplained infertility undergoing intrauterine insemination: a cost-effectiveness analysis

Research question: What is the cost-effectiveness of gonadotrophins compared with clomiphene citrate in couples with unexplained subfertility undergoing intrauterine insemination (IUI) with ovarian stimulation under strict cancellation criteria? Design: A cost-effectiveness analysis alongside a randomized controlled trial (RCT). Between July 2013 and March 2016, 738 couples were randomized to gonadotrophins (369) or clomiphene citrate (369) in a multicentre RCT in the Netherlands. The direct medical costs of both strategies were compared. Direct medical costs included costs of medication, cycle monitoring, insemination and, if applicable, pregnancy monitoring. Non-parametric bootstrap resampling was used to investigate the effect of uncertainty in estimates. The cost-effectiveness analysis was performed according to intention-to-treat. The incremental cost-effectiveness ratio (ICER) between gonadotrophins and clomiphene citrate for ongoing pregnancy and live birth was assessed. Results: The mean costs per couple were €1534 for gonadotrophins and €1067 for clomiphene citrate (mean difference of €468; 95% confidence interval [CI] €464–472). As ongoing pregnancy rates were 31% in women allocated to gonadotrophins and 26% in women allocated to clomiphene citrate (relative risk 1.16, 95% CI 0.93–1.47), the ICER was €21,804 (95% CI €11,628–31,980) per additional ongoing pregnancy with gonadotrophins and €17,044 (95% CI €8998–25,090) per additional live birth with gonadotrophins. Conclusions: Gonadotrophins are more expensive compared with clomiphene citrate in couples with unexplained subfertility undergoing IUI with adherence to strict cancellation criteria, without being significantly more effective

Tubal flushing with oil-based or water-based contrast at hysterosalpingography for infertility: long-term reproductive outcomes of a randomized trial

OBJECTIVE: To determine the impact of oil-based versus water-based contrast on pregnancy and live birth rates ≤5 years after hysterosalpingography (HSG) in infertile women. DESIGN: A 5-year follow-up study of a multicenter randomized trial. SETTING: Hospitals. PATIENT(S): Infertile women with an ovulatory cycle, 18-39 years of age, and having a low risk of tubal pathology. INTERVENTION(S): Use of oil-based versus water-based contrast during HSG. MAIN OUTCOME MEASURE(S): Ongoing pregnancy, live births, time to ongoing pregnancy, second ongoing pregnancy. RESULT(S): A total of 1,119 women were randomly assigned to HSG with oil-based contrast (n = 557) or water-based contrast (n = 562). After 5 years, 444 of 555 women in the oil group (80.0%) and 419 of 559 women in the water group (75.0%) had an ongoing pregnancy (relative risk [RR] 1.07; 95% confidence interval [CI] 1.00-1.14), and 415 of 555 women in the oil group (74.8%) and 376 of 559 women in the water group (67.3%) had live births (RR 1.11; 95% CI 1.03-1.20). In the oil group, 228 pregnancies (41.1%) were conceived naturally versus 194 (34.7%) pregnancies in the water group (RR 1.18; 95% CI 1.02-1.38). The time to ongoing pregnancy was significantly shorter in the oil group versus the water group (10.0 vs. 13.7 months; hazard ratio, 1.25; 95% CI 1.09-1.43). No difference was found in the occurrence of a second ongoing pregnancy. CONCLUSION(S): During a 5-year time frame, ongoing pregnancy and live birth rates are higher after tubal flushing with oil-based contrast during HSG compared with water-based contrast. More pregnancies are naturally conceived and time to ongoing pregnancy is shorter after HSG with oil-based contrast. CLINICAL TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NTR) 3270 and NTR6577(www.trialregister.nl)

Recurrence, postponing pregnancy, and termination rates after hyperemesis gravidarum: Follow up of the MOTHER study

Introduction: Hyperemesis gravidarum (HG) complicates 1% of pregnancies and has a major impact on maternal quality of life and well-being. We know very little about HG’s long-term impact after an affected pregnancy, including recurrence rates in future pregnancies, which is essential information for women considering subsequent pregnancies. In this study, we aimed to prospectively measure the recurrence rate of HG and the number of postponed and terminated subsequent pregnancies due to HG. We also aimed to evaluate if there were predictive factors that could identify women at increased risk for HG recurrence, and postponing and terminating subsequent pregnancies. Material and methods: We conducted a prospective cohort study. A total of 215 women admitted for HG to public hospitals in the Netherlands were enrolled in the original MOTHER randomized controlled trial and associated observational cohort. Seventy-three women were included in this follow-up study. Data were collected through an online questionnaire. Recurrent HG was defined as vomiting symptoms accompanied by any of the following: multiple medication use, weight loss, admission, tube feeding or if nausea and vomiting symptoms were severe enough to affect life and/or work. Outcome measures were recurrence, postponing, and termination rates due to HG. Univariable logistic regression analysis was used to identify predictive factors associated with HG recurrence, and postponing and terminating subsequent pregnancies. Results: Thirty-five women (48%) became pregnant again of whom 40% had postponed their pregnancy due to HG. HG recurred in 89% of pregnancies. One woman terminated and eight women (23%) considered terminating their pregnancy because of recurrent HG. Twenty-four out of 38 women did not get pregnant again because of HG in the past. Univariable logistic regression analysis identifying possible predictive factors found that having a western background was associated with having weight loss due to recurrent HG in subsequent pregnancies (odds ratio 12.9, 95% CI 1.3–130.5, p = 0.03). Conclusions: High rates of HG recurrence and a high number of postponed pregnancies due to HG were observed. Women can be informed of a high chance of recurrence to enable informed family planning