Trends in the incidence of births and multiple births and the factors that determine the probability of multiple birth after IVF treatment.

BACKGROUND: We aimed to review trends in the probability of birth and multiple birth before and after the legal restriction limiting the maximum allowable number of embryos transferred, and to examine factors that determine the probability of multiple birth following IVF treatment. METHODS: We analysed data relating to 7170 IVF and 530 intracytoplasmic sperm injection cycles reaching embryo transfer undertaken by 4417 women at a single tertiary referral assisted conception centre in the UK between 1984 and 1997. Probability of birth, and of proportion of multiple births among those who gave birth, was explored using logistic regression analysis. RESULTS: Between 1984 and 1997 there was a significant increase in probability of birth but no change in the probability of multiple birth. The trend in probability of birth was almost wholly explained by the significant increase in number of embryos created per cycle. Pooling all the data, risk factors for increased chance of birth and multiple birth were: younger age (<35 years), diagnoses other than tubal infertility, fewer than three previous unsuccessful cycles, previous IVF live birth and a large number of embryos created. Given these factors, increasing the number of embryos transferred did not increase the chance of a birth, but did increase the chance of a multiple birth. CONCLUSIONS: The probability of birth has increased and the probability of multiple birth has remained unchanged, despite legislation limiting the number of embryos transferred in the UK. Efforts should be made to reduce the incidence of multiple births by transferring fewer embryos, especially in the presence of good prognostic factors for birth.     

Month of birth is not a risk factor for narcolepsy with cataplexy in the Netherlands

The month of birth has been proposed as a risk factor for narcolepsy, suggesting a harmful influence during early development. Several authors have described an excess of births in March in those developing narcolepsy later. Analysis methods in published studies varied, but no study corrected completely for possible changes in seasonal birth pattern over time in the appropriate population. The present study describes changes in seasonal birth pattern of the entire Dutch population over a 79-year span and compared the monthly birth pattern of Dutch narcoleptics with the population data. Month and year of birth were noted for 307 patients with non-familial narcolepsy with cataplexy, born in the Netherlands between 1923 and 2001. The numbers of live births per month and per year from the entire Dutch population for the same period were used to calculate a virtual data set of expected births per month with exactly the number of cataplexy cases, but with the birth pattern of the Dutch population. Observed and expected numbers per month were compared using the chi-square test. In the 1970s the peak of births shifted from spring to autumn, confirming the need to correct for changing seasonal patterns. There was no significant difference between observed and expected birth numbers per month. An effect of birth month on the occurrence of narcolepsy with cataplexy was not found in a study of 307 cases after adjusting for changing birth patterns in the general population.     

Low negative affect prior to treatment is associated with a decreased chance of live birth from a first IVF cycle

BACKGROUND: Psychological variables, such as anxiety and depression, may have a negative impact on IVF outcomes, but the evidence remains inconclusive. Previous studies have usually measured a single psychological parameter with clinical pregnancy as the outcome. The objective of the current study was to determine whether pretreatment or procedural psychological variables in women undergoing a first IVF cycle affect the chance of achieving a live birth from that cycle. METHODS: Between February 2002 and February 2004, 391 women with an indication for IVF were recruited at two University Medical Centres in The Netherlands. Pretreatment anxiety and depression were measured with the Hospital Anxiety and Depression Scale. The Daily Record Keeping Chart was used to measure negative and positive affect before treatment and daily during ovarian stimulation. Multiple stepwise forward logistic regression analysis was performed with term live birth as the dependent variable. RESULTS: Regression analysis showed that women who expressed less negative affect at baseline were less likely to achieve live birth (P = 0.03). After one IVF cycle, women who received a standard IVF strategy were more likely to reach live birth delivery than those who received a mild IVF strategy (P = 0.002). A male/female indication for IVF was associated with a higher chance of achieving term live birth than a female only indication (P = 0.03). Age, duration of infertility or type of infertility were not independent predictors of live birth. CONCLUSIONS: The relationship between psychological parameters and IVF success rates is more complex than commonly believed. The expression of negative emotions before starting IVF might not be always detrimental for outcomes.     

Cumulative pregnancy and live birth rates in women with antiphospholipid antibodies undergoing assisted reproduction.

The aims of this study were to investigate the influence of antiphospholipid antibodies (APA) on cumulative pregnancy and live-birth rates in patients undergoing assisted reproductive treatment. Serum samples from 173 patients were collected prior to initiation treatment cycle and tested by enzyme-linked immunosorbent assay (ELISA) for the presence of immunoglobulin (Ig)G, IgM and IgA against cardiolipin, phosphoserine, phosphoethanolamine, phosphoinositol, phosphatidic acid, and phosphoglycerol. Fifty-six samples from patients who had at least two failed cycles by assisted reproductive treatment were also tested by a bioassay for the presence of lupus anticoagulants. Both cumulative pregnancy and live birth rates were not affected by the presence of any specific or any number of seropositive APA. There was no association between multiple assisted reproductive treatment failures and APA seropositivity. Neither the serum concentration of any of the 18 APA, nor the number of positive APA was correlated with the number of assisted reproductive treatment failed cycles or affected the probability of pregnancy. No patient was found to be positive for lupus anticoagulants. Using life table analyses, which has been recognized as the most appropriate method available to analyse assisted reproductive treatment results, we conclude that there is no relationship between circulating APA and assisted reproductive treatment outcome. APA do not affect the early process of implantation or maintenance of pregnancy among assisted reproductive treatment patients.     

The effect of various infertility treatments on the risk of preterm birth

BACKGROUND: The high incidence of preterm birth (<37 weeks gestation) is a major concern in assisted reproductive technology. The objective of this study was to compare the risk of preterm birth from singleton pregnancies following either low technology treatment (intrauterine insemination and donor insemination) or high technology treatment (IVF, ICSI and gamete intra-Fallopian transfer) with that of naturally conceived pregnancies. METHODS: Three cohorts of pregnancies resulting from either low or high technology treatment or from natural conception were included in the study. A number of potential risk factors were adjusted for. RESULTS: The incidence of very preterm birth (<32 weeks of gestation) was not significantly increased in the low technology treatment group (1.0 versus 1.3% in controls) but was significantly higher in the high technology treatment group (5.2%, P < 0.001). In spontaneous, elective Caesarean section (CS) and induced delivery onset, the risk of preterm birth increased gradually from the controls to the low technology treatment group to the high technology treatment group, while for an emergency CS the risk of preterm birth was very high in both treatment groups. CONCLUSIONS: The overall incidence of preterm birth increased significantly from the controls to the low technology treatment group and to the high technology treatment group. Logistic regression analysis showed that younger and older age, previous perinatal death and emergency CS were associated with an increased risk, while a previous live birth reduced the risk. The length of the infertile period did not seem to affect the risk in any of the treatment groups.     

Improvement of delivery and live birth rates after ICSI in women aged >40 years by ovarian co-stimulation with growth hormone

BACKGROUND: Growth hormone (GH) is required for ovarian follicular development, and its administration during ovarian stimulation improves pregnancy rate in cow and sheep. Data on the use of exogenous GH in human assisted reproduction treatment are inconsistent. This prospective randomized study evaluates the usefulness of GH administration in women of >40 years undergoing ovarian stimulation for assisted reproduction treatment. METHODS: One hundred women of >40 years undergoing assisted reproduction treatment were randomized between a GH treatment group and a placebo group. Assisted reproduction treatment outcomes were evaluated. RESULTS: In patients of the GH treatment group, a similar number of oocytes, embryos and pregnancies was achieved as compared with the placebo group. However, the patients treated with GH suffered fewer pregnancy losses, resulting in higher delivery and live birth rates. These patients also showed higher peak serum estradiol concentration and higher concentrations of GH and estradiol in pre-ovulatory follicular fluid as compared with the placebo group. CONCLUSIONS: Administration of GH during ovarian stimulation alleviates age-related decrease in assisted reproduction treatment efficiency. This effect appears to be mainly due to an improvement of oocyte developmental potential, but GH action on the uterus cannot be excluded.     

Complete hydatidiform mole and normal live birth: a novel case of confined placental mosaicism: case report

Hydatidiform molar change, characterized by abnormal fetoplacental development and placental villous trophoblast hyperplasia, results from genetically abnormal conception, in which there is an excess of paternally derived genetic material. The majority of pregnancies in which molar change has been reported in association with a live fetus represent dizygotic twin pregnancies in which one fertilization results in a complete hydatidiform mole (CM) and the other a normal co-twin. In such cases, there is usually a clear distinction, both sonographically and pathologically, between the molar and non-molar regions of the placenta. We present a singleton pregnancy, with diffuse placental molar change detected prenatally, which resulted in a chromosomally and phenotypically normal female infant at term. Pathological examination revealed the presence of intermixed populations of morphologically normal chorionic villi and villi with the characteristics of CM. Studies of genetic polymorphisms demonstrated that the CM, normal villi and fetus were all derived from the same sperm; the fetus was diploid and biparental whereas the areas of pathological CM were androgenetic and monospermic. We believe this represents the first well-documented case of apparent confined placental mosaicism involving CM and a coexisting normal fetus, which has presumably arisen following mitotic abnormalities in the early post-fertilization period.     

The relations between musculoskeletal diseases and mobility among old people: are they influenced by socio-economic, psychosocial, and behavioral factors?

The aims of this study were (a) to analyse the association between musculoskeletal diseases and mobility cross-sectionally at age 75 and between musculoskeletal diseases and subsequent onset of tiredness and need of help to mobility from age 75 to 80 and (b) to describe whether these associations are influenced by socioeconomic, psychosocial, and behavioral factors. The data are derived from a cross-sectional study of 75-year-old people (n = 480) and a follow-up study among 111 persons without tiredness at baseline and 243 persons without need of help to mobility at baseline. The key predictor variable was musculoskeletal diseases. The outcome was measured by 2 mobility scales. Persons with both musculoskeletal and other diseases were at larger risk of tiredness and need of help cross-sectionally and of onset of need of help compared to others. In addition, physical activity had strong independent influence on mobility both cross-sectionally and longitudinally. Consequently prevention of mobility disability should focus on persons with musculoskeletal diseases and on sedentary persons.     

Is risk to motor neuron disease influenced by the season of birth?

Months of the birth in 310 cases with motor neuron disease were compared with 244 of their spouses who were used as the controls. Cases were born more often in the spring to summer months and less in the winter months. Birth factors should be carefully evaluated in this disease.     

A randomized double-blind controlled study on the efficacy of laser zona pellucida thinning on live birth rates in cases of advanced female age

BACKGROUND: It is conceivable that defective embryo hatching plays a part in the mechanisms involved in the decrease of embryo implantation rates with advancing age. In an effort to test this hypothesis, we tested the effectiveness of assisted hatching (AH) in women > or =37 years of age. METHODS: We prospectively studied 103 IVF-embryo transfer patients undergoing 103 embryo transfers. All of them were > or =37 years of age and had <3 previous IVF-embryo transfer attempts. Laser-AH of transferred embryos was either performed (AH group, n = 49) or not (control group, n = 54) according to randomized and double-blind methodology. Primary outcome was live birth rate. RESULTS: Population characteristics were comparable in AH and control groups as well as the mean number of embryos transferred (2.7 +/- 0.6 versus 2.7 +/- 0.6) and the prevalence of top quality embryos transferred (65 versus 59%, respectively). We failed to find any statistically significant difference between AH and control groups with regard to implantation (16.1 versus 16.7%, respectively) and live birth rates (22.4 versus 29.6%, respectively). CONCLUSION: The present study indicates that AH does not improve IVF-embryo transfer outcome in women aged > or =37 years.     

Proinflammatory cytokine polymorphisms and the risk of preterm birth and low birthweight in a Japanese population

Pregnancy and parturition involve a complex and poorly understoodmolecular and biological interplay between mother and fetus.Inflammatory cytokines have been reported to be associated withfetal growth and parturition. The aim of this study was to examinewhether common proinflammatory cytokine polymorphisms are associatedwith preterm birth (PTB), low birthweight or intrauterine growthrestriction in a Japanese population. We assessed a consecutiveseries of 414 women who had singleton deliveries in Sapporo,Japan between 2001 and 2005. Genotyping of IL1A –889C/T,+4845G/T (A114S), IL1B –511C/T, –31C/T, IL2 –384T/Gand IL6 –634C/G polymorphisms was determined by an allelicdiscrimination assay. The risk of PTB significantly increasedin women carrying the IL1A –889T allele (CC genotype [reference];CT genotype, odds ratios (OR): 2.5; 95% confidence intervals(95% CI): 1.4–4.8; CT+TT genotypes [dominant genotypemodel], OR: 2.5, 95% CI: 1.3–4.6). Similarly, the riskof PTB significantly increased in women carrying the IL1A +4845Tallele (GG genotype [reference]; GT genotype, OR: 2.4, 95% CI:1.3–4.4; GT+TT genotypes [dominant genotype model], OR:2.3, 95% CI: 1.2–4.2). The frequency of the IL1A TT haplotypein mothers with PTB was significantly higher than in motherswho had a term birth (P < 0.001), whereas the frequency ofthe IL1A CG haplotype in mothers who had a PTB was significantlylower (P < 0.001). Our findings suggest that the polymorphismsand haplotypes in the IL1A gene are associated with PTB in Japanesewomen.     

Psychological factors in the aetiology of infertility: a prospective cohort study

The objectives were to identify and measure psychological factorscharacterizing the period following the cessation of contraceptionand to assess these psychological factors as predictors of thecouples' fertility. A cohort of 63 couples with initially undeterminedfertility status was prospectively studied, first shortly afterthe cessation of contraception, then 13 months later. The ChildProject Questionnaire was constructed to assess psychologicalvariations following the cessation of contraception. An InterspouseDifference Score was constructed to measure the difference betweenthe spouses' responses. Three male and three female factorswere derived from the questionnaire. The Interspouse DifferenceScore was significantly greater in infertile than in fertilecouples. Two psychological factor scores were significantlyhigher in fertile subjects: the wives' level of positive expectationsrelated to motherhood, and the husbands' quality of integrationbetween the wish for a child and sexual relationships. Withinthe group of fertile couples, time to pregnancy was predictedby the husbands' above-cited factor and by the wives' frequencyof thoughts and concerns related to the desired child. The resultssupport the conclusion that in both women and men, psychologicalfactors specifically related to the project of conceiving achild are significant predictors of the couple's fertility status.     

The role of genetic factors in age at natural menopause

BACKGROUND: Environmental factors explain only a small part of the age variance at which menopause commences. The variation in natural menopause is a trait predominantly determined by interaction of multiple genes, whose identity and causative genetic variation remains to be determined. Menopause is a retrospective marker for the reproductive capacity of preceding years, since subfertility and infertility precede menopause at distinct time-intervals. In the present study we have investigated the contribution of genetic factors to menopausal age. METHODS: Data were collected from a random population sample of singleton and twin sisters participating in a prospective breast cancer screening project, who had subsequently experienced natural menopause. Heritability of menopausal age was estimated with analysis of variance, Mx modelling and Gibbs sampling. RESULTS: All produced almost identical heritability estimates of 0.85-0.87 for singleton sisters, suggesting a strong genetic contribution to menopausal age. Twin data were used to distinguish additive genetic from common environmental effects; a heritability of 0.71-0.72 was determined, which does not deviate significantly from the estimate for singleton sisters. CONCLUSIONS: According to our findings, a woman with a family history of early menopause risks early menopause and consequently early reproductive failure herself.     

Migration of polymorphonuclear leucocytes is influenced by dendritic cells

Dendritic cells (DCs) are the most potent antigen-presenting cells and populate many tissues where they may participate in inflammatory reactions. The infiltration of polymorphonuclear leucocytes (PMNLs) into tissues is a prominent feature of inflammation. The mechanisms of PMNL recruitment depend on chemotactic factors and adhesion molecules expressed on endothelial cells. The aim of the present study was to determine whether DCs participate in the early recruitment of PMNLs. Dendritic cells derived from peripheral blood monocytes were used for this study. PMNLs incubated with culture supernatant (CS) from untreated or from tumour necrosis factor-alpha (TNF-alpha)-treated (1 hr, 100 U/ml, 37 degrees ) monocyte-derived DCs (moDCs) had increased surface expression of both CD11b and CD18. Moreover, both untreated and TNF-alpha-treated moDCs induced PMNL chemotaxis. By blocking CXCL8, CXCL5, CXCL7 and Pan GRO (CXCL1, CXCL2, CXCL3), we observed that CXCL8/interleukin-8 might be the chemokine that induced the PMNL chemotactic activity in the CS of untreated and TNF-alpha-treated moDC. Furthermore, we investigated the regulation of CXCL8 production in moDCs by adhesion molecule engagement. Our data demonstrated that CD31, CD18, CD29 and CD49d participated in the adhesion of immature moDCs to endothelium. Moreover, engagement of domains 1-3 of CD31, but not of CD29 or CD18, decreased the production of CXCL8 by immature but not mature moDCs (which display lower CD31 levels than immature moDCs). Overall, these results suggest that DCs not only trigger a specific immune response, but also the innate immune response by recruiting PMNLs. Furthermore, our results also suggest that CXCL8 production by immature DCs might be regulated by signalling through CD31 during their migration through the vascular endothelium.     

Comparison of different treatment strategies in IVF with cumulative live birth over a given period of time as the primary end-point: methodological considerations on a randomized controlled non-inferiority trial

BACKGROUND: We discuss methodological considerations related to a study in IVF, which compares the effectiveness, health economics and patient discomfort of two treatment strategies that differ in both ovarian stimulation and embryo transfer policies. METHODS: This was a randomized controlled clinical trial in two large Dutch IVF centres. The tested treatment strategies are: mild ovarian stimulation [including gonadotrophin-releasing hormone (GnRH) antagonist co-treatment] together with the transfer of one embryo, versus conventional stimulation (with GnRH agonist long protocol co-treatment) and the transfer of two embryos. Outcome measures are: (i) pregnancies resulting in term live birth; (ii) total costs per term live birth; and (iii) patient stress/discomfort per started IVF treatment, over a 12 month period. Power considerations for this study were an overall cumulative live birth rate of 45% for the conventional treatment strategy, with non-inferiority of the mild treatment strategy defined as a live birth rate no more than 12.5% lower compared with the conventional study arm. For a power of 80% and alpha of 0.05, 400 subjects are required. RESULTS: As planned, from February 2002 until February 2004, 410 patients were enrolled. CONCLUSIONS: This effectiveness study applies an integrated medical, health economics and psychological approach with term live birth over a given period of time after starting IVF as the end-point. Complete and timely patient enrolment vindicates many of the design decisions.     

Risks of preterm delivery and association with maternal age, birth order, and fetal gender.

The risk of preterm delivery in a recent sample (1990-1994) of Italian liveborns was examined, taking into account child birth order, and maternal age and education in addition to the fetal gender. Univariate analyses showed that a higher risk was associated with male than female babies, with first- than second-born children, with older mothers, and with less educated mothers. The relative weights of the factors examined were evaluated through logistic regression analyses and the highest and the lowest risks were found to be associated with advanced maternal age and male fetal gender respectively. Our findings therefore suggest that biological factors associated more with advanced maternal age than with the male gender of the fetus may influence premature onset of labour.     

孕妇血浆同型半胱氨酸水平与新生儿出生体重的关系

目的探讨孕妇血浆同型半胱氨酸（hcy）水平与新生儿出生体重的关系。方法采用病例对照研究,用高效液相色谱荧光检测法（HPLC-FD）检测60例孕28-34周早产孕妇（病例组）和30例于孕31-34周采血的正常妊娠孕妇（对照组）的血浆同型半胱氨酸水平。用直线相关等统计学方法分析孕妇血浆同型半胱氨酸水平与新生儿出生体重的关系。结果孕妇血浆同型半胱氨酸水平与新生儿出生体重呈负相关关系（早产病例组r=-0.696,P〈0.01;正常对照组r=-0.733,P〈0.01）,早产孕妇血浆同型半胱氨酸水平升高会增加分娩早产小于胎龄儿（SGA）的危险,尤其是早产孕妇血浆同型半胱氨酸水平≥11.0μmol/L时分娩SGA的可能性明显增加（χ^2=8.579,P=0.003）。结论新生儿出生体重受孕妇血浆同型半胱氨酸水平影响,早产孕妇血浆同型半胱氨酸水平升高会显著增加分娩小于胎龄儿的危险。     

Selection of nonmucoid derivatives of mucoid Pseudomonas aeruginosa is strongly influenced by the level of iron in the culture medium.

We investigated the effects of cations on the stability in culture of mucoid strains pf Pseudomonas aeruginosa isolated from patients with cystic fibrosis by studying their effects on the selection of nonmucoid derivatives which arise by spontaneous mutation in cultures of mucoid organisms. Calcium ion concentrations in the range 0.55 to 1.85 mM had no effect on the growth or stability of the mucoid cultures. Higher levels (5.0 mM) inhibited the growth of both mucoid and nonmucoid cells. Likewise, magnesium ion in concentrations of 0.3 to 3.0 mM had no effect. The concentration of iron (either Fe2+ or Fe3+) had a profound effect on the selection of nonmucoid mutants in unshaken cultures of mucoid organisms. In medium containing 0.01 mM iron, nonmucoid mutants rapidly accumulated to a greater than 100-fold-higher frequency than the mucoid forms. Rates of accumulation of nonmucoid derivatives were lower in media containing lower concentrations of iron. The possible role of iron in the selection of nonmucoid cells from a population of mucoid P. aeruginosa is discussed.     

Live birth rates after transfer of equal number of blastocysts or cleavage-stage embryos in IVF. A systematic review and meta-analysis

BACKGROUND: Both cleavage-stage and blastocyst-stage embryo transfer policies have advantages and drawbacks. The number of embryos transferred, however, is a crucial parameter that needs to be considered before attempting any comparison. METHODS: An extensive literature search yielded initially 282 studies from which 8 randomized controlled trials met the inclusion criteria: (i) truly randomized design (ii) policy to transfer equal number of embryos in both the cleavage-stage and the blastocyst-stage groups and (iii) published as full text in a peer-review journal. Primary outcome was the live birth rate and secondary outcomes were clinical pregnancy rate, multiple pregnancy rate, cancellation rate and cryopreservation rate. RESULTS: A total of 1654 patients were reviewed. Live birth rate per randomized patient was significantly higher (n = 6 studies) in patients who had a blastocyst-stage transfer as compared to patients with cleavage-stage embryo transfer [odds ratio (OR): 1.39, 95% confidence interval (CI): 1.10-1.76; P = 0.005]. Clinical pregnancy rate (OR: 1.27, 95% CI: 1.03-1.55; P = 0.02) and cancellation rate per patient randomized (OR: 2.21, 95% CI: 1.47-3.32; P = 0.0001) were significantly higher in patients with a blastocyst-stage embryo transfer as compared to patients in whom a cleavage-stage embryo transfer was performed. The cryopreservation rate was significantly higher in the cleavage-stage group (OR: 0.28, 95% CI: 0.14-0.55; P = 0.0002). CONCLUSIONS: The best available evidence suggests that the probability of live birth after fresh IVF is significantly higher after blastocyst-stage embryo transfer as compared to cleavage-stage embryo transfer when equal number of embryos are transferred in the two groups compared.