Abstract
A dearth of evidence exists on embryos derived from oocytes without two pronuclei (2PN) or ‘normal fertilization’, i.e. embryos arising from non-pronuclear oocytes (0PN), mono-pronuclear oocytes (1PN) and tri-pronuclear oocytes (3PN). We searched the published literature on non-2PN oocytes and their clinical outcomes using a two-part collection strategy of relevant articles. A total of 33 articles were deemed eligible for the scoping review. A significant difference exists between potential development of oocytes with an abnormal number of pronuclei and those with 2PN in most studies; the abnormal pronuclei oocytes occur rarely and significant attrition occurs between day 1 and day 6, with corresponding reduction in chromosome integrity and clinical utility. Most recent studies describe outcomes of blastocysts derived from non-2PN oocytes, rather than cleavage stage embryo transfers. Compared with 2PN oocytes, blastocyst rates are lower in 1PN oocytes (68.3 versus 32.2%), with larger 1PN oocytes having better developmental potential compared with their smaller counterparts. Blastocysts from 1PN oocytes seem to have a slightly reduced implantation potential compared with those from 2PN blastocysts (33.3% versus 35.9%), with a reduced ongoing pregnancy rate (27.3% versus 28.1%). Live birth rates were only reported in 13 of the included studies. The comparators varied between studies, with live birth rates provided ranging from 0–66.7%, with two case reports (100%); this is a clear indication of the variability in practices and the significant heterogeneity of studies. A distinct lack of evidence exists on non-2PN oocytes; however, it seems that most abnormally fertilized oocytes that are non-viable will developmentally arrest in culture, and those that are viable can form viable pregnancies. Concerns remain about the outcome of pregnancies arising from the use of abnormally fertilized oocytes. Coupled with appropriate outcome measures, abnormally fertilized oocytes hold the potential to increase the pool of embryos eligible for transfer.
KEYWORDS
Introduction
The drive to improve success rates within IVF has focused on producing top-quality embryos, ranking the available embryos and transferring those with the highest chances of sustained development before transferring others with less developmental potential. We recently discussed the lack of evidence in predicting the success rates of low-grade blastocysts (commonly classed as <3BB). We expressed concern about neglecting these embryos in couples who lack good-quality embryos and noted that, once implantation from this quality of blastocyst is achieved, the course of pregnancy is usually uncomplicated, without an increase in adverse perinatal or pregnancy outcomes (
Hammond et al., 2021
; Kemper et al., 2021
).‘Normal fertilization’ is defined as the presence of two pronuclei and two polar bodies in an oocyte. A dearth of evidence exists on embryos derived from oocytes without such normal fertilization, i.e. embryos arising from non-pronuclear oocytes (0PN), mono-pronuclear oocytes (1PN) and tri-pronuclear oocytes (3PN). This is not a new concept.
Levron et al., 1995
and Sultan et al., 1995
were the first to describe the potential fertilization of 1PN IVF oocytes. Manor et al., 1996
published a paper entitled ‘Undocumented embryos: do not trash them, FISH (fluorescence in-situ hybridization) them’, discussing that undocumented embryos should be analysed, not discarded (Manor et al., 1996
). Data on clinical prognosis of embryos from non-2PN oocytes are generally limited as most clinics do not offer the option to use them. Assessment for fertilization can be seen as a diagnostic test, with both false positives and false negatives, particularly with a predominately static snapshot observation where true fertilization status may not be fully revealed (Alpha Scientists in Reproductive Medicine, ESHRE Special Interest Group of Embyology 2011
). Even with improved visualization of pronuclei with the assistance of time-lapse videography, the prognosis of such ‘abnormally’ fertilized embryos is still poorly understood. As with low-grade blastocysts, embryos from non-2PN oocytes may be the only options available for some patients; therefore, clinicians should be able to accurately advise patients about the relative chances of viability of embryos from non-2PN oocytes.In this scoping review, we examine the available published research on outcomes for embryos from non-2PN oocytes, and highlight the need for dedicated studies examining these important clinical questions.
Materials and methods
We searched the published literature on non-2PN oocytes and their clinical outcomes using a two-part collection strategy of relevant articles. Two different PubMed searches were conducted. As some results were only included in one of the searches, both were included. The first search was conducted using the following terms: (((blastocyst) AND ((‘abnormal pronuclear’ OR ‘abnormal fertilisation’ OR ‘abnormal fertilization’ OR ‘monopronucl*’ OR ‘micropronucl*’ OR ‘nonpronuclear’)) OR (‘1PN’ OR ‘3PN’ OR ‘0PN’))) AND (‘ploidy’ OR ‘aneuploid’ OR ‘euploid’). The second search used: (blastocyst[Title]) AND ((((((abnor*[Title]) OR (pronuc*[Title])) OR (fertil*[Title])) OR ((multi* nuc*) OR (monopron*) OR (nonpronuc*))) OR ((1PN) OR (3PN) OR (0PN))) OR ((*ploid*[Title]))), and was limited to 1990-present, human species, full-text and English language. Finally, we used personal knowledge of the topic to collate a list of articles, some of which overlapped with the formal search strategy.
Results
The first search yielded 18 results, of which eight were deemed to be applicable to the study question. The second search identified 122 results, of which 11 results were included; five of these overlapped with the first search. Expert input added a further 19 articles.
A total of 33 articles were deemed eligible for the scoping review (
Balakier et al., 1993
; Levron et al., 1995
; Palermo et al., 1995
; Sultan et al., 1995
; Staessen and Steirteghem, 1997
; Gras and Trounson, 1999
; Petignat et al., 2001
; Dasig et al., 2004
; Otsu et al., 2004
; Noyes et al., 2008
; Liao et al., 2009
; Reichman et al., 2010
; Wang et al., 2012
; Mateo et al., 2013
, Mateo et al., 2020
; Itoi et al., 2015
; Li et al., 2015
; Li et al., 2016
; Li et al., 2020
; Li et al., 2021
; Liu et al., 2016
; Yin et al., 2016
; Bradley et al., 2017
; Capalbo et al., 2017
; - Capalbo A
- Treff N
- Cimadomo D
- Tao X
- Ferrero S
- Vaiarelli A
- Colamaria S
- Maggiulli R
- Orlando G
- Scarica C
- Scott R
- Ulbadi FM
- Rienzi L.
Abnormally fertilized oocytes can result in healthy live births: improved genetic technologies for preimplantation genetic testing can be used to rescue viable embryos in in vitro fertilization cycles.
Fertil. Steril. 2017; 108 (e3): 1007-1015
Dai et al., 2017
; Araki et al., 2018
; Destouni et al., 2018
; Kai et al., 2018
; Xie et al., 2018
; Fabozzi et al., 2019
; Si et al., 2019
; Tan et al., 2019
; Paz et al., 2020
). No randomized controlled trials were identified The included studies feature 13 retrospective studies, eight experimental/point-in-time analyses, seven prospective studies, four case reports and one case-control trial.Despite the relative lack of evidence on the outcomes of non-2PN oocytes, some key findings can be obtained from published research. More recent studies describe outcomes of blastocysts derived from non-2PN oocytes, rather than cleavage stage embryo transfers. This is largely a function of the increase in the practice of blastocyst culture as well as a trend to keeping all oocytes, regardless of fertilization status, in culture with minimal interruption up to day 5 and beyond.
Evidence on the incidence of useable blastocysts from non-2PN oocytes is limited, particularly for presumed 0PN oocytes. Although most clinics report 2PN rates of 65–80% per mature oocyte, the incidence of 1PN oocytes is 1–8% and 3PN oocytes is 1–7% (
Papale et al., 2012
; ESHRE Special Interest Group of Embryology, Alpha Scientists in Reproductive Medicine 2017
; Li et al., 2020
). A recent study of 6466 oocytes reported that 11.2% and 14.8% of 0PN and 1PN embryos formed good-quality blastocysts, with blastulation rates higher after IVF compared with intracytoplasmic sperm injection (ICSI) (Chen et al., 2020
).Compared with 2PN oocytes, blastocyst rates are lower in 1PN oocytes (68.3% versus 32.2%, n = 557 versus n = 47, P < 0.01; ‘good quality’ blastocysts 38.5% versus 17%, P < 0.01) (
Araki et al., 2018
). Compared with smaller counterparts, 1PN oocytes with a larger pronucleus have developmental potential (56.1% for an area of pronucleus ≥710 μm versus 17.9% ≤509 μm) (Araki et al., 2018
). The use of either conventional IVF or ICSI affects the number of blastocysts formed from 1PN oocytes (conventional IVF 2PN 55.7% versus 1PN 21.4%; ICSI 2PN 46.4% versus 1PN 10.7%) and the implantation rate (conventional IVF 2PN 39.0% versus 1PN 33.3%; ICSI 2PN 46.7% versus 1PN 0%) (Itoi et al., 2015
). Data on developmental potential of presumed 0PN oocytes is not as robust as most studies, and only provide blastocyst transfer results or genetic analyses.Blastocysts from 1PN oocytes seem to have a marginally reduced implantation potential compared with those from 2PN blastocysts after conventional IVF (33.3% versus 39%), with a reduced ongoing pregnancy rate (adequate for 1PN blastocysts from IVF but not from ICSI) (
Itoi et al., 2015
). Presumed 0PN oocytes have a similar or reduced implantation potential compared with those from 2PN blastocysts (Itoi et al., 2015
); evidence for relative developmental potential of presumed 0PN compared with 1PN blastocysts is lacking.Live birth rates were only reported in 13 of the included studies (Table 1) (
Gras and Trounson, 1999
; Dasig et al., 2004
; Reichman et al., 2010
; Itoi et al., 2015
; Liu et al., 2016
; Bradley et al., 2017
; Capalbo et al., 2017
; - Capalbo A
- Treff N
- Cimadomo D
- Tao X
- Ferrero S
- Vaiarelli A
- Colamaria S
- Maggiulli R
- Orlando G
- Scarica C
- Scott R
- Ulbadi FM
- Rienzi L.
Abnormally fertilized oocytes can result in healthy live births: improved genetic technologies for preimplantation genetic testing can be used to rescue viable embryos in in vitro fertilization cycles.
Fertil. Steril. 2017; 108 (e3): 1007-1015
Destouni et al., 2018
; Xie et al., 2018
; Si et al., 2019
; Li et al., 2020
; Li et al., 2021
; Paz et al., 2020
). The comparators varied between studies, with rates provided ranging from 0–66.7%, with two case reports. This is a clear indication of the variability in practices and the significant heterogeneity of studies.TABLE 1LIVE BIRTH RATES
| Article | Investigation | Live birth rate % (n) |
|---|---|---|
Gras and Trounson, 1999 | 1PN | 100 (1/1) |
Dasig et al., 2004 | 1PN | 100 (1/1) |
Reichman et al., 2010 | 1PN 3PN | 1.3 (1/78) 0 (0/9) |
Itoi et al., 2015 | 1PN IVF 1PN ICSI | 27.3 (9/33) 0 (0/4) |
Liu et al., 2016 | 0PN | 4.6 (13/285) |
Bradley et al., 2017 | 1PN | 30.8 (8/26) |
Capalbo et al., 2017
Abnormally fertilized oocytes can result in healthy live births: improved genetic technologies for preimplantation genetic testing can be used to rescue viable embryos in in vitro fertilization cycles. Fertil. Steril. 2017; 108 (e3): 1007-1015 | 1PN | 0.4 (3/719) |
Destouni et al., 2018 | 0PN | 23.1 (3/13) |
Xie et al., 2018 | 1PN | 66.7 (2/3) |
Si et al., 2019 | 1PN | 14.0 (26/186) |
Li et al., 2020 | 1PN, IVF, fresh 1PN, ICSI, fresh 1PN, IVF, frozen 1PN, ICSI, frozen | 8.0 (9/113) 0 (0/70) 32.1 (63/196) 15.3 (9/59) |
Li et al., 2021 | 0PN 1PN | 35.6 (155/435) 27.4 (77/281) |
Paz et al., 2020 | 0PN | 48.1 (13/27) |
ICSI, intracytoplasmic sperm injection; OPN, embryos arising from non-pronuclear oocytes;1PN, embryos arising from mono-pronuclear oocytes; 3PN, embryos arising from tri-pronuclear oocytes.
Limitations of current research
Naturally, embryos from 2PN zygotes are deemed ideal and are used preferentially; as such, significant evidence is available on outcomes.
Despite the limited evidence available for the outcomes of blastocysts from abnormally fertilized embryos, a small proportion of blastocysts from presumed 0PN and 1PN oocytes can form viable pregnancies, as most of the abnormally fertilized oocytes will naturally become non-viable and developmentally arrest in culture.
One of the important limitations of current research relates to the timing of the fertilization check. As recommended by the European Society of Human Reproduction and Embryology (ESHRE) (
ESHRE Guideline Group on Good Practice in IVF Labs et al., 2016
), ‘all inseminated or injected oocytes should be examined for the presence of pronuclei and polar bodies at 16–18 hours post insemination’. It is notable that among conference presentations and in formal trials, some centres still examine fertilization at up to 20 h after insemination (Yin et al., 2016
). It is theoretically possible, and the rates thereof are currently unknown, that the brief appearance of one or both pronuclei may be missed by static observation; time-lapse imaging would conclusively show these oocytes as being potentially 2PN. In a study with over 50,000 embryos, as many as 13% had faded pronuclei by 20 h after insemination, representing 3000 2PN that would have been missed without time-lapse monitoring; indeed, up to 300 blastocysts that resulted in live births would have been categorized as unfertilized (Barrie et al., 2021
). With ICSI, more 2PN zygotes will be missed when analysed over 18 h after insemination. This is supported by time-lapse studies showing different timings of pronuclear fading between zygotes created via IVF and ICSI. Relative to insemination, ICSI-originated zygotes were shown to have pronuclear fading 1.4 h earlier than their IVF counterparts (Cruz et al., 2013
), a difference that is made inconsequential for time-lapse algorithms by using pronuclear fading as a reference starting point rather than insemination (Liu et al., 2015
; Liu et al., 2016
). This indicates a significant ‘delay’ in sperm entry in IVF, which requires additional steps to ICSI, including interactions between spermatozoa and cumulus cells as well as zona pellucida; spermatozoa injected via ICSI would have skipped these procedures, potentially leading to the observed earlier pronuclear fading; therefore, this 1.4 h advancement in oocyte activation in ICSI cycles results in an important shift in pronuclear fading in relation to fertilization assessment. No guideline has proposed earlier assessment for ICSI cycles to minimize the risk of missing pronuclei when using static observations. Even with time-lapse imaging, the full developmental footage of pronuclei in zygotes created via IVF is difficult to capture because oocytes are generally co-incubated with spermatozoa overnight before fertilization check. As such, observation of initial pronuclear formation a few hours after sperm entry is not possible owing to the layers of cumulus cells surrounding the oocytes (Mio and Maeda, 2008
). Short insemination protocols, whereby cumulus cells are removed 2–3 h after insemination, combined with time-lapse imaging, offers a better chance to observe pronuclei after IVF (Ménézo and Barak, 2000
; Kattera and Chen, 2003
).Recent publications have also called into question the ‘sacrosanct’ nature of the fertilization check (
Doody, 2020
), noting the significant time taken and the additional complexity. According to Doody, 2020
, among other indications, there are two reasons to identify abnormally fertilized eggs: they will either not produce viable embryos or will result in high-risk pregnancies (Doody, 2020
). The study by Li et al., 2021
, included in our dataset, detected reasonable implantation and live birth rates. They conclude that rather than discarding zygotes after the fertilization check, culture should continue to the blastocyst stage, at which point development can be reassessed. The findings of this review indicate that blastocysts that lack documented fertilization have developmental potential and should be considered for use.A recent report following embryos in time-lapse incubators suggests viable blastocysts from presumed 0PN oocytes are simply 2PN that faded early, rather than blastocysts that never formed visible pronuclei (
Kobayashi et al., 2021
). Although non-time-lapse, single point observations yielded 8% blastocysts from presumed 0PN oocytes, no blastocysts were obtained from oocytes in which pronuclei were not observed throughout the first 20 h of culture monitored by time-lapse. Although this study was small, it is likely that time-lapse imaging in either ICSI or IVF cycles with short insemination would detect pronuclear formation and fading. Although time-lapse imaging is not universally used and analysed, it is important that studies investigating non-2PN oocytes ensure appropriate timing of the fertilization check at 16–18 h after insemination.Another limitation of particular importance to clinicians and patients is the lack of evidence surrounding the pregnancy and perinatal outcomes arising from successful implantation of non-2PN oocytes.
Chen et al., 2020
examined 6466 embryos that underwent extended culture to day 5 or day 6, derived from 0PN or 1PN oocytes, and low-quality day-3 embryos; blastulation occurred in 17.3%, with good-quality blastocyst formation present in 9.5% (Chen et al., 2020
). Of the 243 resulting cycles using blastocysts arising from non-2PN embryos, clinical pregnancies occurred in 44.9% (Chen et al., 2020
). Limited evidence has shown that the use of these oocytes may result in live births (Liu et al., 2016
), but it is currently unknown whether these pregnancies are more likely to be complicated antenatally or perinatally.Of particular concern is the possibility that abnormally fertilized oocytes may result in molar pregnancies (
Petignat et al., 2001
). We found only one case report of a molar pregnancy from a 1PN in a thorough review of incidence and genetics of 1PN oocytes (Rosenbusch, 2014
). In contrast, most published studies on 1PN oocytes do not report findings of this adverse outcome. Genetic studies have determined that most 1PN blastocysts are diploid, although haploid and uniparental disomy are possible (Bradley et al., 2017
; Kai et al., 2018
). Therefore, further research is needed to determine the relative risk of abnormal pregnancies to allow proper counselling on risks.The evidence is so scant that few national or international guidelines exist on the use of these abnormally fertilized embryos. The ESHRE's Revised Guidelines in 2016 note that ‘embryos derived from ≥3PN oocytes should never be transferred or cryopreserved’ (
ESHRE Guideline Group on Good Practice in IVF Labs et al., 2016
). They go on to state that ‘even if no transferable embryos derived from 2PN oocytes are available, the use of embryos derived from 1PN oocytes or oocytes showing no PN is not recommended’ (ESHRE Guideline Group on Good Practice in IVF Labs et al., 2016
), a guideline that merits review.Finally, in this scoping review, several methodological difficulties were encountered. As can be seen from the article collection process, over 50% of the included studies were not found via the two PubMed searches. The authors struggled to identify terms that would capture most of the studies included in a single search; this unfortunately makes a formal systematic review difficult to conduct. Additionally, the heterogenicity of study designs, investigations and outcomes hinders efforts at conducting a meta-analysis. Finally, the lack of standardized terminology in this area complicates efforts further.
Future directions
This review highlights the need for future research to accurately assess and resolve some of the key issues surrounding blastocysts arising from oocytes with no evidence of or atypical fertilization. The use of time-lapse imaging may allow for significantly enhanced understanding of embryo development, and of the effect of the timing of pronuclear development and disappearance on development. Transfer of blastocysts derived from 0PN or 1PN oocytes can result in normal live births (
Fu et al., 2020
). Some further research examples include more extensive assessment of the effect of variations in pronuclei size (Otsuki et al., 2019
) as well as the effect of micro nuclei associated with two normal pronuclei (Capalbo et al., 2017
).- Capalbo A
- Treff N
- Cimadomo D
- Tao X
- Ferrero S
- Vaiarelli A
- Colamaria S
- Maggiulli R
- Orlando G
- Scarica C
- Scott R
- Ulbadi FM
- Rienzi L.
Abnormally fertilized oocytes can result in healthy live births: improved genetic technologies for preimplantation genetic testing can be used to rescue viable embryos in in vitro fertilization cycles.
Fertil. Steril. 2017; 108 (e3): 1007-1015
In addition to new information, time-lapse imaging allows for more timely and accurate fertilization checks to aid in detecting those ‘missed’ pronuclear bodies that present in between static assessment checks. It also allows improved categorization of pronuclear development; for example, pronuclear oocytes that present with unequal sized nuclei, nuclei displaced to the periphery of the cell, or nuclei that fail to join by 16–18 h, have been characterized to have lower developmental potential (
Sadowy et al., 1998
; Scott, 2003
). Polarization of nucleolus precursor bodies predicts implantation as well as embryo morphology assessed on day 3 (Nagy et al., 2003
). In addition, time-lapse monitoring enables differentiation between sperm- and oocyte-originated pronucleus by its proximity to the second polar body, with different morphokinetic and morphometric features reported between the two pronuclei (Orevich et al., 2022
). A more recent study has proposed the use of migration speed of precursor bodies within the male (sperm-originated) pronucleus as a novel predictor of live birth (Inoue et al., 2021
). Furthermore, studies show that existing markers are better assessed by time-lapse imaging, including the cytoplasmic wave (Payne et al., 1997
) and the kinetics of pronuclear chromatin polarisation (Coticchio et al., 2017
).Consensus on the fate of oocytes within 3PN (that they are definitively abnormal) is being challenged by genetic analyses that enable further assessment of these typically discarded embryos. One study reported a diploidy rate of 23% among 30 3PN oocytes after fluorescence in-situ hybridization (
Grau et al., 2015
). The authors hypothesized potential autocorrection mechanisms, such as direct cleavage into three even daughter cells provided that maternal haplotype duplication is absent. It's important to note that further studies are required to confirm whether diploid embryos from 3PN zygotes contain uniform biparental composition. In contrast to typical 3PN, where all nuclei are of similar size, oocytes with two normal sized and one small pronucleus (2.1 or 2+1 PN), or a micronucleus, are also observed. Capalbo et al., 2017
used next-generation sequencing to demonstrate that 12 out of 14 (86%) blastocysts from 2.1 pronuclear oocytes were in fact diploid (- Capalbo A
- Treff N
- Cimadomo D
- Tao X
- Ferrero S
- Vaiarelli A
- Colamaria S
- Maggiulli R
- Orlando G
- Scarica C
- Scott R
- Ulbadi FM
- Rienzi L.
Abnormally fertilized oocytes can result in healthy live births: improved genetic technologies for preimplantation genetic testing can be used to rescue viable embryos in in vitro fertilization cycles.
Fertil. Steril. 2017; 108 (e3): 1007-1015
Capalbo et al., 2017
). The mechanism or significance of a micronucleus coupled with two normal pronuclei is unknown; this small dataset indicates blastocysts derived from these oocytes are mostly normal and merit consideration for transfer. Of note, as next-generation sequencing alone does not exclude uniparental disomy, future genetic studies should apply next-generation sequencing with karyomapping functionality. Nonetheless, these findings highlight that guidelines stating that only zygotes with two pronuclei are diploid are imperfect and merit further attention. The examples provided show that fertilization check is prone to false negatives; however, false positives also occur, as shown by the 0.5% rate of triploidy in blastocyst biopsied for preimplantation genetic testing for aneuploidy (- Capalbo A
- Treff N
- Cimadomo D
- Tao X
- Ferrero S
- Vaiarelli A
- Colamaria S
- Maggiulli R
- Orlando G
- Scarica C
- Scott R
- Ulbadi FM
- Rienzi L.
Abnormally fertilized oocytes can result in healthy live births: improved genetic technologies for preimplantation genetic testing can be used to rescue viable embryos in in vitro fertilization cycles.
Fertil. Steril. 2017; 108 (e3): 1007-1015
Marin et al., 2017
). The addition of artificial intelligence algorithms may also enable improved accuracy of fertilization status, with the caveat that any assessor (human or computer) must be able to appropriately visualize the developing embryonic components. For example, the rapid advancement of computer vision offers further insight into automation of pronuclear detection, with the potential for more accurate measurement of any new parameters (Fukunaga et al., 2020
). With the increasing computing power, deep learning algorithms may be developed to facilitate identification of unknown features at the pronuclear stage, by using enormous amounts of high-resolution imaging data (Riegler et al., 2021
).Authors’ roles
JMK, YL, MA, DEM and BWJM conceived of the study. JMK completed the data collection and wrote the first manuscript. All authors interpreted the data, edited the manuscript, provided responses to the reviewers/editors, and agreed upon the final version.
Data availability
No data was used for the research described in the article.
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Biography
James M Kemper is a Registrar at Monash Women's, Monash Health, and an Affiliate Researcher with the Department of Obstetrics and Gynaecology, Monash University. His publications have focused on embryo quality, preimplantation testing and research quality.
Key message
Live births have been reported from embryos obtained from non-two pronuclei oocytes. For some women, use of these oocytes may improve their options and outcomes. Further studies are required to better understand the origin and potential of these embryos so clinicians may adapt their practice and patients can be properly advised.
Article info
Publication history
Published online: February 21, 2023
Accepted:
February 10,
2023
Received in revised form:
February 7,
2023
Received:
December 20,
2022
Declaration: DE Morbeck reports consultancy for Cook Medical, CooperSurgical and Fujifilm Irvine Scientific. BWJ Mol is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for ObsEva, Merck Merck KGaA and Guerbet.Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
