Impact of male factor infertility on offspring health and development

Long-term health and developmental outcomes in children conceived with intracytoplasmic sperm injection

2019 Study Abstract

Monitoring the safety of intracytoplasmic sperm injection (ICSI) has been impeded by uncertainties regarding the extent to which offspring health is influenced by paternal characteristics linked to male infertility or the processes that ICSI treatment entails.

Few studies examining long-term health and developmental outcomes in children conceived with ICSI have considered the influence of paternal infertility adequately.

In the available literature, large population-based studies suggest underlying male factors, and the severity of male factor infertility, increase the risk of mental retardation and autism in offspring, as does the ICSI procedure itself, but these findings have not been replicated consistently.

Robust evidence of the influence of male factors on other health outcomes is lacking, with many studies limited by sample size.

Nevertheless, emerging evidence suggests children conceived with ICSI have increased adiposity, particularly girls.

Further, young men conceived with ICSI may have impaired spermatogenesis; the mechanisms underlying this remain unclear, with inconclusive evidence of inheritance of Y chromosome microdeletions.

The current inconsistent and often sparse literature concerning the long-term health of children conceived with ICSI, and the specific influence of male infertility factors, underscore the need for concerted monitoring of children conceived with this technique across the lifespan.

With the rapid expansion of use of ICSI for non-male factors, sufficiently large studies that compare outcomes between groups conceived with this technique for male factors versus non-male factors will provide critical evidence to elucidate the intergenerational impact of male infertility.

Reference. Image credit fertilitysmarts.

Medically assisted reproduction and birth outcomes

A within-family analysis using Finnish population registers

Large registry study finds lighter birth weight and higher prematurity rates observed after IVF largely attributable to factors other than treatment.


Children born after medically assisted reproduction are at higher risk of adverse birth outcomes than are children conceived naturally. We aimed to establish the extent to which this excess risk should be attributed to harmful effects of treatment or to pre-existing parental characteristics that confound the association.

We used data from Finnish administrative registers covering a 20% random sample of households with at least one child aged 0–14 years at the end of 2000 (n=65 723). We analysed birthweight, gestational age, risk of low birthweight, and risk of preterm birth among children conceived both by medically assisted reproduction and naturally. First, we estimated differences in birth outcomes by mode of conception in the general population, using standard multivariate methods that controlled for observed factors (eg, multiple birth, birth order, and parental sociodemographic characteristics). Second, we used a sibling-comparison approach that has not been used before in medically assisted reproduction research. We compared children conceived by medically assisted reproduction with siblings conceived naturally and, thus, controlled for all observed and unobserved factors shared by siblings.

Between 1995 and 2000, 2776 (4%) children in our sample were conceived by medically assisted reproduction; 1245 children were included in the sibling comparison. Children conceived by medically assisted reproduction had worse outcomes than did those conceived naturally, for all outcomes, even after adjustments for observed child and parental characteristics—eg, difference in birthweight of −60 g (95% CI −86 to −34) and 2·15 percentage point (95% CI 1·07 to 3·24) increased risk of preterm delivery. In the sibling comparison, the gap in birth outcomes was attenuated, such that the relation between medically assisted reproduction and adverse birth outcomes was statistically and substantively weak for all outcomes—eg, difference in birthweight of −31 g (95% CI −85 to 22) and 1·56 percentage point (95% CI −1·26 to 4·38) increased risk of preterm delivery.

Children conceived by medically assisted reproduction face an elevated risk of adverse birth outcomes. However, our results indicate that this increased risk is largely attributable to factors other than the medically assisted reproduction treatment itself.

The impact of assisted reproductive technology on the offspring

Association of birth defects with the mode of assisted reproductive technology in a Chinese data-linkage cohort

2018 Study Abstract

To evaluate the impact of assisted reproductive technology (ART) on the offspring of Chinese population.

Retrospective, data-linkage cohort.

Not applicable.

Live births resulting from ART or natural conception.


Main Outcome Measure(s)
Birth defects coded according to ICD-10.

Births after ART were more likely to be female and multiple births, especially after intracytoplasmic sperm injection (ICSI). ART was associated with a significantly increased risk of birth defects, especially, among singleton births, a significantly increased risk in fresh-embryo cycles after in vitro fertilization (IVF) and frozen-embryo cycles after ICSI. Associations between ART and multiple defects, between ART and gastrointestinal malformation, genital organs malformation, and musculoskeletal malformation among singleton births, and between ART and cardiac septa malformation among multiple births were observed.

This study suggests that ART increases the risk of birth defects. Subgroup analyses indicate higher risk for both fresh and frozen embryos, although nonsignificantly for frozen embryos after IVF and for fresh embryos were presented with low power. Larger sample size research is needed to clarify effects from fresh- or frozen-embryo cycles after IVF and ICSI.

Maternal antidepressant use associated with increased risk of miscarriage

Major depression, antidepressant use, and male and female fertility : Cohort study

2018 Study Abstract

To determine if maternal major depression (MD), antidepressant use, or paternal MD are associated with pregnancy outcomes after non-IVF fertility treatments.

Cohort study, DOI:, May 2018.


Participants in two randomized trials: PPCOS II (clomiphene citrate versus letrozole for polycystic ovary syndrome), and AMIGOS (gonadotropins versus clomiphene citrate versus letrozole for unexplained infertility).

Female and male partners completed the Patient Health Questionnaire (PHQ-9). Female medication use was collected. PHQ-9 score ≥10 was used to define currently active MD.

Main Outcome Measure(s)
Primary outcome: live birth. Secondary outcomes: pregnancy, first-trimester miscarriage. Poisson regression models were used to determine relative risks after adjusting for age, race, income, months trying to conceive, smoking, and study (PPCOS II versus AMIGOS).

Data for 1,650 women and 1,608 men were included. Among women not using an antidepressant, the presence of currently active MD was not associated with poorer fertility outcomes (live birth, miscarriage), but rather was associated with a slightly increased likelihood of pregnancy. Maternal antidepressant use (n = 90) was associated with increased risk of miscarriage, and male partners with currently active MD were less likely to achieve conception.

Currently active MD in the female partner does not negatively affect non-IVF treatment outcomes; however, currently active MD in the male partner may lower the likelihood of pregnancy. Maternal antidepressant use is associated with first-trimester pregnancy loss, which may depend upon the type of antidepressant.

IVF success : the importance of characterizing optimal embryo transfer technique

Live birth rate following embryo transfer is significantly influenced by the physician performing the transfer: data from 2707 euploid blastocyst transfers by 11 physicians

Pregnancy and live birth rates obtained after in vitro fertilization (IVF) are highly variable depending on the practitioner who performs the embryo transfer, regardless of the number of transfers performed per practitioner and years of practice, according to a US study presented in 2016 at the American Society for Reproductive Medicine (ASRM) conference in Salt Lake City.

2016 Study Abstract

Multiple prior studies have demonstrated variation in IVF success rates according the provider performing the embryo transfer procedure. However, these studies were limited by lack of control for embryonic aneuploidy and evaluation of cleavage stage transfers only. Thus, our objective was to isolate the contribution of physician variability on the chance of embryo transfer (ET) success in contemporary ART by evaluating euploid blastocyst transfers in a single practice setting.

Retrospective cohort.

Materials and Methods
All euploid blastocyst transfers from 2011 to 2015 were evaluated. The physician performing the ET, maternal age, blastocyst grade, and information regarding fresh versus frozen transfer were recorded. During the study period, 11 physicians were randomly assigned to be “ET physician of the day” in a rotating fashion. To avoid selection bias, all transfers not performed by the assigned “physician of the day” were excluded to assure that the randomness provided by the rotating schedule remained intact. Analysis was performed using chi-squared tests.

There were 2707 euploid ETs performed that met inclusion criteria. The mean number of transfers per physician was 246. There was no difference in maternal age, blastocyst grade, or proportion of fresh vs. frozen transfers among the physicians. The implantation rate (IR), clinical pregnancy rate (CPR), and live birth rate (LBR) differed significantly between worst performing and best performing physicians. When compared to worst performer, an additional live birth could be expected for every 6 ETs performed by the best performer. There was no association between success rates and number of ETs performed by provider during the study period or number of years elapsed since completion of training.

When controlling for embryonic factors by utilizing euploid blastocyst transfers, live birth rate is still strongly influenced by the physician performing the transfer procedure. Given that these data only include ETs in which patients were randomly assigned to a given provider, the impact of the physician factor on success rates is truly isolated. These findings highlight the importance of characterizing optimal ET technique and present an opportunity for improving success rates through remediation of experienced providers and formalized instruction of trainees.


En médecine, la longue temporalité est cliniquement et scientifiquement très difficile à prouver

Enthousiasme à court et long terme

Publié par Luc Perino, médecin généraliste, humeur du 28/03/2018

Les plus grands succès de la médecine se sont établis dans le court-terme. La chirurgie de guerre a stoppé la gangrène et les hémorragies. Les césariennes ont sauvé des millions de femmes et de nouveau-nés. L’héparine a empêché la mort immédiate par embolie. La vitamine C a guéri le scorbut en quelques jours. Les antibiotiques ont rayé de la carte en quelques mois les morts par syphilis, pneumonie, choléra, méningite ou septicémie. L’insuline a empêché les diabétiques de type 1 de mourir avant l’âge de 20 ans. Les neuroleptiques ont calmé les délires en quelques minutes. La morphine a neutralisé les agonies terminales. Dans cette liste incomplète des triomphes du XX° siècle, la seule exception concerne les vaccins qui ont donné l’audace du long-terme.

Alors, la médecine, forte de tous ces incontestables succès, a osé aborder plus résolument le long-terme. Elle a opté pour les maladies tumorales, neurodégénératives ou cardio-vasculaires, celles qui nous tuent inévitablement un jour.

Mais, en médecine, la longue temporalité est cliniquement et scientifiquement ingrate, car la preuve y est très difficile. Comment prouver, (hors les règles immuables d’hygiène de vie), que ce que nous faisons aujourd’hui sera bénéfique dans 20, 30 ou 40 ans ? Pour ces maladies multifactorielles de la sénescence, la méthode consiste à mettre en lumière un facteur et à en montrer la variation par action médicale. Ce réductionnisme scientifique est peu satisfaisant, mais l’opinion publique, éblouie par les succès médicaux passés, ne voit pas la forêt de facteurs qui se cache derrière le facteur unique ainsi mis en lumière. En évinçant la science, cet enthousiasme populaire ouvre la porte aux excès.

Dans le même temps, les objectifs à court-terme de la médecine ont changé de nature. La pilule répond à une exigence immédiate, mais elle laisse les femmes atteindre dangereusement l’âge de l’infécondité. Les césariennes et déclenchements d’accouchement atteignent un nombre qui outrepasse les nécessités de court-terme et induisent de multiples pathologies à long terme pour la mère et l’enfant. La réussite d’une FIV est un succès immédiat qui néglige les pathologies qui en découlent. Les succès à court-terme sur les très grandes prématurités sont pourvoyeurs de pathologies à long terme. La pharmacologie préventive apparaît souvent plus nuisible qu’utile à long terme, sans compter ses risques à court-terme. Le dépistage généralisé fait difficilement la preuve de son efficacité à long terme, tout en induisant une morbidité vécue à court terme. La liste est longue de ces nouvelles actions médicales où la preuve à court-terme, souvent illusoire, perturbe l’analyse des preuves à long terme.

Nous pouvons encore espérer que la médecine améliore un peu notre quantité-qualité de vie, mais pour la sérénité que la preuve exige, il faudrait pouvoir contenir l’enthousiasme naïf des patients pour le long terme et l’obsession structurelle des médecins pour le court-terme.

En Savoir Plus

Can in vitro fertilisation increase the risk for preeclampsia ?

Embryo cryopreservation and preeclampsia risk

Pre-eclampsia is a disorder of pregnancy that increases the risk of poor outcomes for both the mother and the baby.

2017 Study Abstract

To determine whether assisted reproductive technology (ART) cycles involving cryopreserved-warmed embryos are associated with the development of preeclampsia.

Retrospective cohort study.

IVF clinics and hospitals.

A total of 15,937 births from ART: 9,417 singleton and 6,520 twin.

We used linked ART surveillance, birth certificate, and maternal hospitalization discharge data, considering resident singleton and twin births from autologous or donor eggs from 2005–2010.

Main Outcome Measure(s)
We compared the frequency of preeclampsia diagnosis for cryopreserved-warmed versus fresh ET and used multivariable logistic regression to adjust for confounders.

Among pregnancies conceived with autologous eggs resulting in singletons, preeclampsia was greater after cryopreserved-warmed versus fresh ET (7.51% vs. 4.29%, adjusted odds ratio = 2.17 [95% CI 1.67–2.82]). Preeclampsia without and with severe features, preeclampsia with preterm delivery, and chronic hypertension with superimposed preeclampsia were more frequent after cryopreserved-warmed versus fresh ET (3.99% vs. 2.55%; 2.95% vs. 1.41%; 2.76 vs. 1.48%; and 0.95% vs. 0.43%, respectively). Among pregnancies from autologous eggs resulting in twins, the frequency of preeclampsia with severe features (9.26% vs. 5.70%) and preeclampsia with preterm delivery (14.81% vs. 11.74%) was higher after cryopreserved versus fresh transfers. Among donor egg pregnancies, rates of preeclampsia did not differ significantly between cryopreserved-warmed and fresh ET (10.78% vs. 12.13% for singletons and 28.0% vs. 25.15% for twins).

Among ART pregnancies conceived using autologous eggs resulting in live births, those involving transfer of cryopreserved-warmed embryos, as compared with fresh ETs, had increased risk for preeclampsia with severe features and preeclampsia with preterm delivery.


IVF treatment : a healthy singleton delivery is best achieved by SET

Single-embryo transfer point – it is the way forward

In vitro fertilization (IVF) treatment in the United States is complicated by a high rate of multiple-gestation pregnancies. In 2014, the Society for Assisted Reproductive Technology reported that 23% of women <38 years of age with a pregnancy from their IVF treatment had a twin-gestation pregnancy. Although this is an improvement over past years, it remains an unacceptably high rate of twins, considering the medical risks and financial burdens associated with such pregnancies.

In this issue of Fertility and Sterility, Mersereau et al. have added strong support to the conclusion that single-embryo transfer (SET) is highly effective at reducing multiple-gestation birth rates: a 47% decrease with the use of SET compared with double-embryo transfer (DET). Furthermore, using data from their study and others, Mersereau’s team has led a revision of American Society for Reproductive Medicine committee opinion guidelines to unambiguously call for SET for women under the age of 38 years with a favorable prognosis for pregnancy. With the increasing weight of evidence and explicit professional guidelines, why is DET still so common in the United States?

In their article, Mersereau et al. report a comprehensive analysis of 10 years of national SET data, finding a 10%–15% reduction in live birth rate (LBR) with the use of SET. This reduction is not attractive to either physicians or patients, for whom IVF pregnancy rates matter a great deal. Indeed, we have shown that, despite education about the risks of twins after DET, most patients would still choose this option over SET, even with as little as a 10% drop in the LBR.

Yet we think that the 10%–15% difference in LBR may be an overestimate of the negative effect of SET on LBR, considering trends in current clinical IVF care. As reported, blastocyst transfers are becoming increasingly common, and SET live birth rates are higher with blastocysts than with cleavage-stage embryo. In fact, the LBR differences between DET and SET were still reduced, but only in the 6%–8% range, when looking at fresh blastocyst transfers in a first or second cycle. Even this may be an overestimate of the true difference between DET and SET, because higher pregnancy rates are seen when the single transferred embryo comes from a larger cohort of available embryos.

Thus, it is likely a false comparison to judge the success of SET with one or more embryos cryopreserved (at least two embryos in the cohort) against DET with one or more embryos cryopreserved (at least 3 embryos in the cohort). In a recent analysis of national IVF outcomes data, we strictly controlled for the size of the available cohort and found very similar pregnancy rates in younger good-prognosis patients undergoing elective SET versus DET on day 5–6.

We think that this trend of increasing blastocyst transfers combined with improvements in embryo selection techniques (such as preimplantation genetic screening) will result in further increases in SET pregnancy rates and allow clinics to more confidently offer SET with little to no impact on their clinic-specific pregnancy outcome. Despite continuing technical advances, however, it is likely that small but potentially significant LBR differences will persist between SET and DET if as a field we continue to report and emphasize pregnancy rates per transfer instead of cumulative pregnancy rates per fresh IVF cycle. As mentioned in Mersereau et al.’s paper, predictive models suggest that cumulative LBRs with the use of sequential SET are equal or superior to DET.

Further studies confirming this prediction will help to convince physicians, patients, and insurance providers of the benefits and feasibility of SET, even if this strategy requires additional transfers and a slightly longer time to pregnancy. A healthy singleton delivery should be the goal of all IVF cycles, and this is best achieved by SET.

Do we need to choose between improved sperm selection or efficacy ?

The latest attempt to improve the sperm’s path

Our goal in the in vitro fertilization laboratory is to maximize the ratio between the number of oocytes retrieved and the production of highly viable embryos. We receive the raw material from our patients (oocytes and sperm cells) and, with our knowledge and the available technologies; we try to improve our success rates day by day. One of our endpoints should be the objective application of validated, repeatable, and non-biased therapies and technologies. Few options remain available for oocytes as all the oocytes will be treated to achieve fertilization. In the case of sperm, millions of cells are available to us, but only a few of them will be used. Is there room to improve the sperm’s path? We must move away from the classical methods of sperm selection (swim up or gradients) and pursue any kind of technology that may take into consideration their molecular characteristics, which are related to successful fertilization, embryo development, and live birth.”…

…continue reading What else can we do? The latest attempt to improve the sperm’s path on Fertility and Sterility, Volume 108, Issue 3, Pages 444–445, September 2017.

Preconception exposures to phthalates effect in fathers on reproductive success via embryo quality

Dad’s exposure to phthalates in plastics may affect embryonic development


Are preconception urinary concentrations of phthalates and phthalate alternatives associated with diminished early stage embryo quality in couples undergoing IVF?

Male, but not female, urinary concentrations of select metabolites of phthalates and phthalate alternatives are associated with diminished blastocyst quality.

Although phthalates are endocrine disrupting compounds associated with adverse reproductive health, they are in widespread use across the world. Male and female preconception exposures to select phthalates have been previously associated with adverse reproductive outcomes in both the general population and in those undergoing IVF.

Parental contributions to early embryo development: influences of urinary phthalate and phthalate alternatives among couples undergoing IVF treatment, Oxford Journals, Medicine & Health, Human Reproduction, Advance Access10.1093/humrep/dew301, October 28, 2016.

“Odd ducks Bob, Squish, and Slim. The Boon company seems very proud that their ducks are “BpA-free, Phthalate-free, and PVC-free” I bet they are also Gluten-free, Fat-free, and Sugar-free. So go ahead and eat one!” said Jamie – Image © all rights reserved.

This prospective cohort included 50 subfertile couples undergoing IVF in western Massachusetts.

This study includes the first 50 couples recruited from the Baystate Medical Center’s Fertility Center in Springfield, MA, as part of the Sperm Environmental Epigenetics and Development Study (SEEDS). Relevant data from both partners, including embryo quality at the cleavage (Day 3) and blastocyst (Day 5) stages, were collected by clinic personnel during the normal course of an IVF cycle. A spot urine sample was collected from both male and female partners on the same day as semen sample procurement and oocyte retrieval. Concentrations of 17 urinary metabolite were quantified by liquid chromatography mass spectrometry and normalized via specific gravity. Generalized estimating equations were used to estimate odds ratios (OR) and 95% CI, with urinary phthalates and phthalate alternatives fitted as continuous variables and embryo quality as a binary variable.

The 50 couples contributed 761 oocytes, of which 423 progressed to the cleavage stage, 261 were high-quality cleavage stage embryos, 137 were transferrable quality blastocysts and 47 were high-quality blastocysts. At the cleavage stage, male urinary monoethyl phthalate concentrations were positively associated with high-quality cleavage stage embryos (OR = 1.20, 95% CI 1.01–1.43, P = 0.04); no other significant associations were observed at this stage. At the blastocyst stage, male urinary concentrations of monobenzyl phthalate (OR = 0.55, 95% CI 0.36–0.84, P = 0.01), mono-3-hydroxybutyl phthalate (OR = 0.37, 95% CI 0.18–0.76, P = 0.01), mono-n-butyl phthalate (OR = 0.55, 95% CI 0.42–0.73, P < 0.01) and monomethyl phthalate (OR = 0.39, 95% CI 0.26–0.60, P < 0.01) were inversely associated with high-quality blastocysts. A borderline statistically significant relationship was observed for male concentrations of mono(2-ethylhexyl) phthalate (OR = 0.52, 95% CI 0.27–1.00, P = 0.05) and cyclohexane-1,2-dicarboxylic acid-monocarboxy isooctyl ester (OR = 0.21, 95% CI 0.04–1.03, P = 0.05) at the blastocyst stage. Similar inverse associations were observed between male urinary phthalate metabolite concentrations and likelihood of transferrable quality blastocysts. For female partners, select metabolites were positively associated with odds of high or transferrable blastocyst quality, but the observed associations were not consistent across blastocyst quality measures or between sex-specific and couples-level models. All models were adjusted for age of both partners, urinary metabolite concentrations of female partners and male infertility status, while models of blastocysts were additionally adjusted for embryo quality at cleavage stage.

Our modest sample included only 50 couples contributing one cycle each. In addition, non-differential misclassification of exposure remains a concern given the single-spot urine collection and the short half-life of phthalates.

Our results suggest an inverse association between male preconception concentrations of select phthalate metabolites and blastocyst quality, likely occurring after genomic activation. If corroborated with other studies, such findings will have public health and clinical significance for both the general population and those undergoing IVF.

This work was generously supported by grant K22-ES023085 from the National Institute of Environmental Health Sciences. The authors declare no competing interests.