Analysis of in vitro fertilization data with multiple outcomes using discrete time‐to‐event analysis

In vitro fertilization (IVF) is an increasingly common method of assisted reproductive technology. Because of the careful observation and follow‐up required as part of the procedure, IVF studies provide an ideal opportunity to identify and assess clinical and demographic factors along with environmental exposures that may impact successful reproduction. A major challenge in analyzing data from IVF studies is handling the complexity and multiplicity of outcome, resulting from both multiple opportunities for pregnancy loss within a single IVF cycle in addition to multiple IVF cycles. To date, most evaluations of IVF studies do not make use of full data because of its complex structure. In this paper, we develop statistical methodology for analysis of IVF data with multiple cycles and possibly multiple failure types observed for each individual. We develop a general analysis framework based on a generalized linear modeling formulation that allows implementation of various types of models including shared frailty models, failure‐specific frailty models, and transitional models, using standard software. We apply our methodology to data from an IVF study conducted at the Brigham and Women's Hospital, Massachusetts. We also summarize the performance of our proposed methods on the basis of a simulation study. Copyright © 2013 John Wiley & Sons, Ltd.     

In vitro fertilization, a practical option after failed artificial insemination with donor semen

The progress of 80 couples who failed to conceive by donor insemination was followed through in vitro fertilization cycles using donor sperm. The outcome was better than that for couples undergoing IVF for tubal disease and significantly better than their chance with further cycles of donor insemination.     

Risk factors associated with very low birth weight in a low-income population

This study aimed to identify risk factors associated with very low birth weight in a general hospital in Caxias do Sul, Rio Grande do Sul State, Brazil. This was a case-control study of 200 newborns with birth weight from 500 to 1,499 g (cases) and 400 with birth weight from 3,000 to 3,999 g (controls). Infants were from singleton pregnancies, and their mother had received prenatal care at public health services. The dependent variable was birth weight, and independent variables included socioeconomic status, schooling, and gestational and birth status. Univariate and multivariate analyses were performed with a 5% level of significance. Mortality in very low birth weight newborns was 32.5%. The limits of viability were 600 g for birth weight and 26 weeks for gestational age. Variables related to very low birth weight were: maternal age > 35 years (p = 0.01), lack of prenatal care (p < 0.0001), illness during the index pregnancy (p = 0.03), maternal hypertension (p = 0.007), hospitalization during pregnancy (p < 0.0001), and prior history of low birth weight (p < 0.0001). Many premature births were due to avertable factors.     

Fertilin beta peptides inhibit sperm binding to zona-free eggs in a homologous baboon in vitro fertilization system.

This study developed a baboon in vitro fertilization system that can be used in testing defined gamete antigens for fertility effects. A laparoscopic procedure that proved very valuable in retrieving eggs from female baboons for in vitro studies was developed. On average, 30 +/- 5 (SD) eggs were harvested per female baboon per cycle. Micromolar quantities of hexapeptides or a 28 aa residue peptide, all corresponding to fertilin beta disintegrin domain, competitively inhibited the binding of zona-free baboon eggs by baboon sperm in vitro. This study demonstrated that fertilin beta has a required role in baboon fertilization.     

中国妇女体外受精-胚胎移植累计活产率分析

目的基于大样本量的体外受精-胚胎移植(IVF-ET)累计活产率的计算,探讨多周期IVF-ET的治疗方案选择。方法选取2009年1月1日至2015年12月31日所有在北京大学第三医院生殖医学中心首次进行IVF-ET治疗的56 499对夫妇,中心常规使用的治疗方案以刺激方案为主,根据患者的不同情况,对部分患者选择自然周期取卵或微刺激方案进行治疗。根据治疗用药的不同,分为GnRH激动剂方案和GnRH拮抗剂方案。假设随访至最后一个周期末活产者的最终结局为无活产和与继续治疗者相同,计算累计活产率的保守估计值和乐观估计值,分析累计活产与促排卵方案的关系。结果研究共包括106740周期。计算得到累计活产率的保守估计值和乐观估计值分别为52.2%和90.7%,并且随着女方年龄的增高而降低。应用Logistic回归分析,排除影响活产的因素,得到第二(P0.001)和第三(P=0.001)新鲜周期选择GnRH激动剂方案的累计活产率会显著地高于GnRH拮抗剂方案。结论年龄是影响IVF-ET治疗结果的重要因素。为了达到更好的治疗效果,在患者第二和第三次促排卵治疗中,可根据患者的情况,优先选择激动剂方案。     

Risk of spontaneous preterm birth is associated with common proinflammatory cytokine polymorphisms

BACKGROUND: Preliminary data suggest that common genetic variation in immune response genes can contribute to the risk for spontaneous preterm birth and possibly small-for-gestational age (SGA). METHODS: We investigated the relationship of polymorphisms in 6 cytokine genes associated with inflammation-interleukin (IL)1alpha, IL1beta, IL2, IL6, tumor necrosis factor (TNF), and lymphotoxin alpha (LTA)-with spontaneous preterm and SGA birth in a nested case-control study drawn from a prospective pregnancy cohort. Women were recruited between 24 and 29 weeks' gestation at the Wake County and University of North Carolina, Chapel Hill obstetric clinics between February 1996 and June 2000. We inferred haplotypes using the EM algorithm and the Bayesian method, PHASE. We then compared haplotype frequency distributions and implemented semi-Bayesian hierarchical logistic regression analyses to obtain odds ratio (OR) estimates and 95% confidence intervals (CIs) for each polymorphism. RESULTS: Two haplotypes spanning the TNF/LTA genes were associated with increased risk for spontaneous preterm birth in white subjects (for the AGG haplotype, OR = 1.5 [95% CI=0.8-2.6]; for the GAC haplotype, 1.6 [0.9-2.9]). Additionally, carriers of the GAG haplotype were found to have decreased risk of spontaneous preterm birth (0.6; 0.3-1.0). The TNF(-488)A and LTA(IVS1-82)C variants, constituents of the AGG and GAC haplotypes respectively, were also strongly associated with increased risk of spontaneous preterm birth. CONCLUSIONS: Our results suggest that common genetic variants in proinflammatory cytokine genes could influence the risk for spontaneous preterm birth. Selected TNF/LTA haplotypes were associated with spontaneous preterm birth in both African-American and white subjects. Our data do not support an inflammatory etiology for SGA.     

Risk factors associated with nosocomial bacteremia in low birth weight neonates. Grady Memorial Hospital, Atlanta

BACKGROUND: Nosocomial bloodstream infections occur frequently in Neonatal Intensive Care Units and are associated with recognized and unrecognized risk factors. Little has been published regarding risk factors for bloodstream infections in low birth weight neonates. OBJECTIVE: To investigate risk factors for bloodstream infection in neonates < 1,500 g admitted at a Neonatal Intensive Care Unit. METHODS: A prospective study was undertaken in low birth weight neonates (< 1,500g) during a 22 months period. Bivariant, and logistic regresion (stepwise procedure) analysis was used to determine the significance association of bloodstream infection and perinatal and nosocomial risk factors. RESULTS: A total of 72 patiens with nosocomial bacteriemia and 147 non bacteriemic patients were studied. Independent risk factors associated with bloodstream infection were birth weight, persistence of umbilical catheter > 7 days and persistence of peripheral arterial catheter > 1 day. CONCLUSIONS: The uses of umbilical catheter > 7 days, peripheral arterial catheter > 1 day and birth weight < 1,500 g were significant determinants of nosocomial bloodstream infection risk. Because of the importance of invasive procedures as a source of nosocomial bloodstream infections, the lines duration needs to be reviewed with the aim of reducing the incidence of blood stream infection.     

Economic implications of in vitro fertilization using willingness to pay

Introduction

Fertility levels are determined by social, religious, and cultural factors on one hand, and by financial considerations that affect the demand for children as well as the supply of children on the other. Using theoretical and empirical models we examine the private and social benefit of children, and the private and social welfare differences that are generated by technological innovation in fertility technology.

Subjects and methods

A theoretical model measures the marginal private and social benefit when the children’s potential output depends on the natural potential fertility combined with medical fertility technology. It is followed by an empirical model that focuses on the evaluation of the general public’s, and in vitro fertilization patients’ “willingness to pay” for fertility treatments. The economic evaluation method is based on willingness to pay, which is derived from answers to hypothetical questions.

Results

Based on questionnaires distributed between in vitro fertilization actual patients and the general public, the empirical model’s findings are that the average willingness to pay amongst patients is $5,482, whereas for the general public it is $4,398. Both the general public as well the actual patients are willing to pay more than the actual average cost of an in vitro fertilization treatment, which is $3,257.

Conclusion

We find that when considering the appropriate allocation of limited resources, subsidizing fertilization should receive high priority since the net benefits for both patients and society are high.     

Stage-specific toxicity of cypermethrin to medaka (Oryzias latipes) eggs and embryos using a refined methodology for an in vitro fertilization bioassay

Using original artificial fertilization methods with medaka (Oryzias latipes), the effects of exposure to cypermethrin on gametes, fertilization, and embryonic development were investigated. The relative sensitivity was studied with 96-hour duration, 24-hour renewal exposures to six nominal concentrations of cypermethrin ranging from 3.1 100.0 microg cypermethrin/L. Tests were initiated at different developmental stages: unfertilized egg (stage 0), late morula (stage 9), eminence of swim bladder (stage 29), and maximum flexion of the atrioventricular region (stage 34). Cypermethrin did not affect the fertilization process. Predominant sublethal effects in embryos included transient visceral edemas intimately associated to the gall bladder with subsequent pericardial edemas. Other sublethal effects were observed in surviving larvae and included spastic movements with or without ability to respond to stimulus (>/=6.3 microg cypermethrin/L), spinal curvatures, and delayed or absence of swim bladder inflation (>/=12.5 microg cypermethrin/L). The exposure of the gametes (stage 0) or animals during earlier embryonic development (stages 9 or 29) was not a critical window for cypermethrin exposure. Although the incidence of edemas in embryos occurred mainly during exposure of these early developmental stages, embryo and larva lethality and the incidence of transient sublethal effects in hatchlings showed that the later exposure window (stage 34) was the most sensitive. The stage 34 group involved advanced organogenetic stages in which the chorion partially degraded before hatching. Our studies reinforced the idea that a combination of morphologic and functional impairment evaluation is a more sensitive response to developmental toxicants than morphologic defects alone.     

Low birth weight in Spain associated with sociodemographic factors.

STUDY OBJECTIVE--To describe the effect of different social and demographic characteristics on low birth weight (LBW) (less than 2500 g) in Spain, in both preterm (less than 37 weeks' gestation) and term infants (between 37 and 42 weeks' gestation). DESIGN--The study used data obtained from the Spanish birth registry. SETTING--The study was based on those live born infants registered in 1988 from provinces where the birthweight details were completed in at least 99.5% of the birth registration records. PARTICIPANTS--A total of 1332 preterm LBW infants, 1292 term LBW infants, and 38,967 controls were included in the study. MEASUREMENTS AND MAIN RESULTS--The odds ratio (OR) calculated by logistic regression was used as the measure of association between LBW and the sociodemographic variables. The highest ORs of preterm LBW were found in mothers younger than 20 years (1.32; 95% CI 0.98, 1.77) and older than 34 years (1.28; 95% CI 1.04, 1.59), in unmarried mothers (1.68; 95% CI 1.36, 2.07), and in fathers with manual occupations (1.26; 95% CI 1.08, 1.46). In term, live born infants the highest ORs were found in adolescent mothers (1.63; 95% CI 1.25, 2.14), in first born live born infants (1.38; 95% CI 1.09, 1.74) or the fourth born or more (1.28; 95% CI 0.91, 1.80), in unmarried mothers (1.55; 95% CI 1.27, 1.90), in housewives (1.13; 95% CI 0.99, 1.29), and in fathers with manual occupations (1.21; 95% CI 1.04, 1.42). CONCLUSIONS--The results have allowed documentation of the risk of preterm and term LBW in various age and social groups in Spain.     

体外受精-胚胎移植中卵巢反应不良患者妊娠成功率的相关因素分析

目的探讨体外受精-胚胎移植中卵巢反应不良患者妊娠成功率的影响因素。方法回顾性分析IVF-ET/IVF-ICSI治疗的1 376个临床卵巢反应不良周期的妊娠情况进行分析,采用回顾性病例对照研究的方法,对妊娠组与非妊娠组的相关因素进行分析。结果两组年龄、不孕年限、不孕原因、是否有手术史,周期数、基础性激素水平、促排卵方案、Gn种类、hCG日激素水平、获卵数、成熟卵子数、hCG日内膜厚度及形态、受精率、可移植胚胎数、优质胚胎数等因素比较,差异有统计学意义。用药方案、女方年龄、可利用胚胎、优质胚胎进入多重线性回归模型。结论影响卵巢反应不良妊娠结局最重要的因素是年龄,对于年龄小于35岁的反应不良患者,可获取卵子数目的减少并不等同于卵子质量的下降,在获得可供移植的胚胎后仍可获得不错的妊娠率。各种超排卵方案中,长方案仍然是妊娠率较高的一种方法,对于具备一定程度卵巢储备的患者,仍然不要放弃传统长方案(包括长效长方案和短效长方案)的使用。     

体外受精-胚胎移植及其衍生技术出生情况的研究

目的:探讨体外受精-胚胎移植及其衍生技术的出生情况。方法:回顾性分析151个生产周期,对剖宫产比率、畸形比率、男女出生比率、早产率、新生儿出生体重等进行分析研究。结果:剖宫产率75.50%,出生畸形率1.55%,与国内报道相比,差异无统计学意义(P>0.05);男女出生比率1.13∶1,早产率10.60%;出生婴儿单胎出生体重(3 303.97±502.08)g,多胎出生体重(2 542.77±352.70)g,两组差异有统计学意义。IVF组、ICSI组、IVF/ICSI组和FET组各组间无统计学差异。结论:为了减少多胎妊娠,实现单胚胎移植是我们今后工作的重要目标之一。     

Social and ethical aspects of in vitro fertilization.

In vitro fertilization (IVF) stands out as one of the contemporary period's most extraordinary technologies, and its social and ethical consequences among the most far reaching. Despite its uncertain effectiveness and medical consequences, IVF has contributed significantly to the medicalization of infertility and the increasingly imperative character of reproductive technology. New developments in IVF, particularly oocyte donation, have created new definitions of treatable infertility and new social needs for IVF; when the technology does not result in pregnancy or healthy babies, these developments have created profound new disappointments. IVF and the commodification of the extracorporeal embryo have also confused the social meaning and legal definition of parenthood. Ultimately the relationship between prospective parents, infertility specialists, and the embryos that they create is a highly ambiguous one. This ambiguity is likely to be a long-term characteristic of efforts to develop, use, and assess assisted reproductive technologies.     

极低体重儿营养相关性胆汁淤积危险因素分析

目的 探讨极低出生体重儿胃肠外营养相关性胆汁淤积症的危险因素.方法 以2013年1月至2015年1月入住盐城市妇幼保健院重症监护病房,使用胃肠外营养(PN)时间＞2周的极低出生体重儿223例为研究对象.将发生胃肠外营养相关性胆汁淤积症(PNAC)的54例为观察组,其余169例为对照组,比较两组患儿在出生情况、胃肠外营养相关因素以及住院期间相关并发症情况.结果 通过多因素Logistic回归分析结果提示出生体重越低、禁食时间越长、开始喂养时间越迟、胃肠外营养持续时间越长,以及合并窒息、颅内出血、败血症等并发症均为PNAC发生的相关危险因素(x2值分别为4.259、5.423、10.227、27.371、3.862、4.110、6.001,均P＜0.05).结论 极低出生体重儿在胃肠外营养过程中,为减少PNAC的发生,应关注如下危险因素出生体重低、禁食时间长、开始喂养时间迟、PN持续时间长,以及合并窒息、颅内出血、败血症等并发症.     

Antimicrobial therapy associated with preterm birth

The effect of 51 antimicrobial drugs was evaluated for the reduction of preterm birth. STUDY DESIGN: Newborn infants without birth defects were selected from the population-based large data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996, for the study. Medically recorded gestational age and the proportion of preterm birth were the primary outcomes of the study and newborn infants born to mothers with or without a given antimicrobial drug were compared. RESULTS: The use of 51 antimicrobial drugs in the mothers of 38 151 newborn infants including at least ten pregnant women was evaluated. Only two: ampicillin and clotrimazole showed an obvious preterm birth preventive effect, mainly after the use during the first trimester of pregnancy. CONCLUSIONS: Our findings suggest that ampicillin and particularly clotrimazole may be effective for the reduction of preterm birth associated with infectious diseases of pregnant women.