Abstract Is conception using in vitro fertilization (IVF) associated with the multiple congenital anomaly pattern referred to as VACTERL? Children conceived through IVF were more than twice as likely to develop VACTERL compared to those naturally conceived (OR 2.57, 95% CI 1.93-3.39). VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities) is a multiple congenital anomaly pattern with a likely multifactorial origin, as few genetic or non-genetic risk factors have been identified. Some studies have suggested a potential link between IVF and VACTERL, yet this relationship has not been thoroughly investigated while accounting for other maternal characteristics. Given the rarity of VACTERL, large datasets with comprehensive information on fertility treatment parameters, maternal characteristics, and birth outcomes are essential to better understand this association. Study design, size, duration
We performed a population-based study of live births in four U.S. states (Massachusetts, New York, North Carolina, and Texas) between 2004 and 2018, linking birth records and birth defect data to IVF cycles reported in the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS). Naturally conceived births were selected as controls at a 10:1 ratio during the same period as the IVF birth. The study included a total of 1,315,867 live births. Participants/materials, setting, All study children were linked to state birth defect registries, with defects classified using British Pediatric Association codes. VACTERL cases were identified by code 759.890 or the presence of at least three associated anomalies. Children with known chromosomal or other genetic syndromes were excluded. Logistic regression was used to assess the association between IVF conception and VACTERL. Covariates included maternal age, race/ethnicity, education, and state. Main We identified 363 cases of VACTERL - 78 conceived through IVF (0.053%) and 285 naturally conceived (0.024%). Of these, 232 cases were identified using the diagnostic code 759.890, while 131 additional cases were identified by at least three of the six VACTERL associated anomalies. The most frequent VACTERL congenital anomalies were cardiac defects (54%), followed by renal anomalies (50%) and anal atresia (32%). In unadjusted analysis, IVF was significantly associated with an increased prevalence of VACTERL (OR 2.27, 95% CI 1.75-2.89). After adjusting for maternal socio-demographics, the association was further strengthened (OR 2.57, 95% CI 1.93-3.39) and supported in sensitivity analyses restricted to 1,226,080 singletons (OR 2.74, 95% CI 1.92-3.83). Evaluation of specific IVF treatment parameters (n = 141,882) revealed the highest prevalence of VACTERL in 58 of 102,099 births from fresh embryos (0.057% vs. 0.050% from thawed embryos), 41 of 69,765 births from ICSI (0.059% vs. 0.052% without ICSI), and 27 of 48,629 births from male infertility (0.056% vs. 0.055% without male infertility). Refining our multivariable model of IVF, we found that use of ICSI without a diagnosis of male infertility had the strongest association with VACTERL of all IVF groups (OR 3.04, 95% CI 1.90-4.65) compared to natural conceptions. Limitations, We were unable to assess familial clustering and terminations in the prevalence of VACTERL. However, our analyses are representative of live births and we accounted for maternal characteristics associated with both birth defect risks and the use of fertility treatment. The use of IVF is associated with VACTERL in offspring, but the absolute risk for VACTERL in IVF-conceived offspring remains low. The mechanisms underlying this association are unclear, but altered DNA methylation patterns have been implicated in both IVF and VACTERL etiology. No
Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, and the International Standard ISO 23162:2021. With these tools, we propose that authors should be instructed to follow these laboratory methods in order to publish studies in peer-reviewed journals, preferable by using a checklist as suggested in an Appendix to this article.
Luke B et al., 2022·Human reproduction (Oxford, England)·Free full text on PubMed Central
Is there an association between fertility status, method of conception and the risks of birth defects and childhood cancer? The risk of childhood cancer had two independent components: (i) method of conception and (ii) presence, type and number of birth defects. The rarity of the co-occurrence of birth defects, cancer and ART makes studying their association challenging. Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects or cancer but have been limited by small sample size and inadequate statistical power, failure to adjust for or include plurality, differences in definitions and/or methods of ascertainment, lack of information on ART treatment parameters or study periods spanning decades resulting in a substantial historical bias as ART techniques have improved. This was a population-based cohort study linking ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 1 January 2004 to 31 December 2017 that resulted in live births in 2004-2018 in Massachusetts and North Carolina and live births in 2004-2017 in Texas and New York. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Non-ART siblings were identified through the ART mother's information. Children from non-ART births were classified as being born to women who conceived with ovulation induction or IUI (OI/IUI) when there was an indication of infertility treatment on the birth certificate, and the woman did not link to the SART CORS; all others were classified as being naturally conceived. The study population included 165 125 ART children, 31 524 non-ART siblings, 12 451 children born to OI/IUI-treated women and 1 353 440 naturally conceived children. All study children were linked to their respective State birth defect registries to identify major defects diagnosed within the first year of life. We classified children with major defects as either chromosomal (i.e. presence of a chromosomal defect with or without any other major defect) or nonchromosomal (i.e. presence of a major defect but having no chromosomal defect), or all major defects (chromosomal and nonchromosomal), and calculated rates per 1000 children. Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CIs of the risk of birth defects by conception group (OI/IUI, non-ART sibling and ART by oocyte source and embryo state) with naturally conceived children as the reference, adjusted for paternal and maternal ages; maternal race and ethnicity, education, BMI, parity, diabetes, hypertension; and for plurality, infant sex and State and year of birth. All study children were also linked to their respective State cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs of cancer by birth defect status (including presence of a defect, type and number of defects), and conception group. A total of 29 571 singleton children (2.0%) and 3753 twin children (3.5%) had a major birth defect (chromosomal or nonchromosomal). Children conceived with ART from autologous oocytes had increased risks for nonchromosomal defects, including blastogenesis, cardiovascular, gastrointestinal and, for males only, genitourinary defects, with AORs ranging from 1.22 to 1.85; children in the autologous-fresh group also had increased risks for musculoskeletal (AOR 1.28, 95% CI 1.13, 1.45) and orofacial defects (AOR 1.40, 95% CI 1.17, 1.68). Within the donor oocyte group, the children conceived from fresh embryos did not have increased risks in any birth defect category, whereas children conceived from thawed embryos had increased risks for nonchromosomal defects (AOR 1.20, 95% CI 1.03, 1.40) and blastogenesis defects (AOR 1.74, 95% CI 1.14, 2.65). The risk of cancer was increased among ART children in the autologous-fresh group (HR 1.31, 95% CI 1.08, 1.59) and non-ART siblings (1.34, 95% CI 1.02, 1.76). The risk of leukemia was increased among children in the OI/IUI group (HR 2.15, 95% CI 1.04, 4.47) and non-ART siblings (HR 1.63, 95% CI 1.02, 2.61). The risk of central nervous system tumors was increased among ART children in the autologous-fresh group (HR 1.68, 95% CI 1.14, 2.48), donor-fresh group (HR 2.57, 95% CI 1.04, 6.32) and non-ART siblings (HR 1.84, 95% CI 1.12, 3.03). ART children in the autologous-fresh group were also at increased risk for solid tumors (HR 1.39, 95% CI 1.09, 1.77). A total of 127 children had both major birth defects and cancer, of which 53 children (42%) had leukemia. The risk of cancer had two independent components: (i) method of conception (described above) and (ii) presence, type and number of birth defects. The presence of nonchromosomal defects increased the cancer risk, greater for two or more defects versus one defect, for all cancers and each type evaluated. The presence of chromosomal defects was strongly associated wi [truncated]
The summary presented herein represents Part I of the two-part series dedicated to the Diagnosis and Treatment of Infertility in Men: AUA/ASRM Guideline. Part I outlines the appropriate evaluation of the male in an infertile couple. Recommendations proceed from obtaining an appropriate history and physical exam (Appendix I), as well as diagnostic testing, where indicated. The Emergency Care Research Institute Evidence-based Practice Center team searched PubMed®, Embase®, and Medline from January, 2000 through May, 2019. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. (Table 1) This summary is being simultaneously published in Fertility and Sterility and The Journal of Urology. This Guideline provides updated, evidence-based recommendations regarding evaluation of male infertility as well as the association of male infertility with other important health conditions. The detection of male infertility increases the risk of subsequent development of health problems for men. In addition, specific medical conditions are associated with some causes for male infertility. Evaluation and treatment recommendations are summarized in the associated algorithm. (Figure 1) The presence of male infertility is crucial to the health of patients and its effects must be considered for the welfare of society. This document will undergo updating as the knowledge regarding current treatments and future treatment options continues to expand.
Del Giudice F et al., 2020·Fertility and sterility
To investigate the current evidence that correlates impaired male fertility with the risk of developing male-related malignancies. Systematic review and meta-analysis of population-based retrospective cohort studies. Not applicable. PATIENT(S): Men diagnosed with impaired fertility status and subsequently observed to determine incidence risk in developing testicular cancer (TCa) or prostate cancer (PCa). INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Pooled risk ratio (RR) differences among male factor infertility subjects compared with a fertile control population, and meta-regression analysis according to age at baseline, mean follow-up, range of study time, and year of publication. RESULT(S): Six studies met the inclusion criteria and were critically examined. Four studies examined male infertility and TCa (n = 161,634; 174 TCa cases), and four examined infertility in relation to PCa (n = 183,950 men; 377 PCa cases) from 1963 to 2014. The pooled RR was 2.033 (95% confidence interval [CI], 1.66-2.48); heterogeneity: Q = 3.04 (degree of freedom [df] = 3); I2 = 1.55% for TCa and 1.68 (95% CI, 1.17-2.4); Q = 23.3(df = 3); I2 = 87.1% for PCa. CONCLUSION(S): Male infertility was associated with a subsequent risk of both TCa and PCa. Although the clinical significance of these findings remains uncertain, future studies should evaluate the underlying mechanisms to determine whether testis and prostate screening practices should be altered in men with male infertility. CLINICAL PROSPERO 167277.
To assess whether paternal health is associated with maternal peripartum and neonatal outcomes. Retrospective cohort study. University research departments. PATIENT(S): Analytic sample of children born to paired fathers and mothers covering live births within the United States between 2009-2016. INTERVENTION(S): Paternal health status (e.g., metabolic syndrome diagnoses, individual chronic disease diagnoses). MAIN OUTCOME MEASURE(S): Primary outcome of preterm birth (i.e., live birth before 37 weeks), and secondary outcomes of low birth weight, neonatal intensive care unit (NICU) stay, gestational diabetes, preeclampsia, eclampsia, and length of maternal stay. RESULT(S): The IBM Marketscan Research database covers reimbursed health care claims data on inpatient and outpatient encounters who are privately insured through employment-sponsored health insurance. We assessed 785,809 singleton live births, with 6.6% born preterm. The presence of paternal comorbidities was associated with higher odds of preterm birth, low birth weight (LBW), and NICU stay. After adjusting for maternal factors, fathers with most or all components of the metabolic syndrome had 19% higher odds of having a child born preterm (95% CI 1.11-1.28), 23% higher odds of LBW (95% CI 1.01-1.51), and 28% higher odds of NICU stay (95% CI 1.08-1.52). Maternal morbidity (e.g., gestational diabetes or preeclampsia) was also positively associated with preconception paternal health. CONCLUSION(S): Increased preconception paternal comorbidity may be associated with negative infant and maternal outcomes. Although the paternal effect remains modest, these findings highlight the importance of the health of both parents, particularly the mother, on healthy pregnancy.
Lifespan Health · Cycle as a Lifespan Health Marker
Cedars MI et al., 2017·Human reproduction open·Free full text on PubMed Central
Does the fertility status of an individual act as a biomarker for their future health? Data support an association between reproductive health and overall health for men and women. Various chronic conditions, such as diabetes, obesity and cancer, can compromise fertility, but there are limited data for the converse situation, in which fertility status can influence or act as a marker for future health. Data reveal an association between infertility and incident cardiovascular disease and cancer in both men and women. A National Institute of Child Health and Human Development-Centers for Disease Control and Prevention workshop in April 2016 was convened that brought together experts in both somatic diseases and conditions, and reproductive health. Goals of the workshop included obtaining information about the current state of the science linking fertility status and overall health, identifying potential gaps and barriers limiting progress in the field, and outlining the highest priorities to move the field forward. PARTICIPANTS/MATERIALS Approximately 40 experts participated in the workshop. MAIN While the etiology remains uncertain for infertility, there is evidence for an association between male and female infertility and later health. The current body of evidence suggests four main categories for considering biological explanations: genetic factors, hormonal factors, in utero factors, and lifestyle/health factors. These categories would be key to include in future studies to develop a comprehensive and possibly standardized look at fertility status and overall health. Several themes emerged from the group discussion including strategies for maximizing use of existing resources and databases, the need for additional epidemiologic studies and public health surveillance, development of strategies to frame research so results could ultimately influence clinical practice, and the identification of short and long-term goals and the best means to achieve them. LIMITATIONS Further research may not indicate an association between fertility status and overall health. Currently medical care is compartmentalized. Reproductive medicine physicians treat patients for a short period of time before they transition to others for future care. Going forward, it is critical to take an interdisciplinary patient care approach that would involve experts in a broad range of medical specialties in order to more fully understand the complex interrelationships between fertility and overall health. If infertility is confirmed as an early marker of chronic disease then screening practices could be adjusted, as they are for patients with a family history of malignancy. Funding for the workshop was provided by the Fertility and Infertility Branch, National Institute of Child Health and Human Development, National Institutes of Health and the Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control. There are no conflicts of interest to declare. The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention or the National Institutes of Health. Not applicable.
Eisenberg ML, 2015·American journal of epidemiology
Approximately 15% of all couples are unable to conceive after a year and are labeled infertile. In recent years, increasing attention has been given to lifestyle factors that may impact fertility. In the United States, it is estimated that there are more than 17 million current users of marijuana with 4.6 million using marijuana almost daily. Although common, to date, little data exist on the impact of marijuana use on male fertility. In the current issue of the Journal, Gundersen et al. (Am J Epidemiol. 2015;182(6):473-481) provide data examining the relationship between marijuana use and semen quality from young men recruited out of the general Danish population. Men who reported daily marijuana use displayed significant lower sperm concentration and sperm counts compared with nonusers, while testosterone levels were higher. The current report provides important information for patients and providers regarding the negative association of marijuana use on semen quality. Although the benefit of marijuana cessation on recovery is uncertain, further study on the impact of marijuana use on male reproductive health is warranted as more states explore marijuana legalization.
Katz P et al., 2011·Fertility and Sterility·Free full text on PubMed Central
To examine resource use (costs) by women presenting for infertility evaluation and treatment over 18 months, regardless of treatment pursued. Prospective cohort study in which women were followed for 18 months. eight infertility practices. 398 women recruited from infertility practices. Women completed interviews and questionnaires at baseline and after 4, 10, and 18 months of follow-up; medical records were abstracted after 18 months. per-person and per-successful-outcome costs. Treatment groups were defined as highest intensity treatment use. Twenty percent of women did not pursue cycle-based treatment; approximately half pursued IVF. Median per-person costs ranged from $1,182 for medications only to $24,373 and $38,015 for IVF and IVF-donor egg groups, respectively. Estimates of costs of successful outcomes (delivery or ongoing pregnancy by 18 months) were higher ($61,377 for IVF, for example), reflecting treatment success rates. Within the time frame of the study, costs were not significantly different for women whose outcomes were successful and women whose outcomes were not. Although individual patient costs vary, these cost estimates developed from actual patient treatment experiences may provide patients with realistic estimates to consider when initiating infertility treatment.