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Fertility research publications

Our group, led by Professor Macklon and Professor Cheong our centre is at the leading edge of fertility research. Below are some of our publications:

Biological clock and reproduction

Sadek K, Macklon N, Bruce K, Cagampang F, Cheong Y (2011). Hypothesis: Role for the circadian Clock system and sleep in the pathogenesis of adhesions and chronic pelvic pain?  Medical Hypotheses;76(3): 543-546

K.H. Sadek, F.R. Cagampang,  K.D. Bruce, N. Macklon, Y. Cheong (2011). Expression of housekeeping genes in endometrial tissues from healthy women and those with Polycystic Ovarian Syndrome. Hum Reprod (in print).

Shreeve, N, Cagampang, F, Sadek, K, Tolhurst, M, Houldey, A, Hill, C M, Brook, N, Macklon , N, Cheong, YC (2013) Poor sleep in PCOS; is melatonin the culprit? Human Reproduction, 28, (5), 1348-1353.(doi:10.1093/humrep/det013). (PMID:23438443).

Biological rhythm and fertility

Professor Ying Cheong and her team are working on how the biological rhythm for day and night and the monthly cycle influences reproduction. This work examines the role of clock genes (genes that regulate time within the body) in the regulation of fertility and pregnancy and how the disruption of this body clock/rhythm can have detrimental impact on reproductive health.

Poor sleep in PCOS; is melatonin the culprit? - Shreeve, N., Cagampang, F., Sadek, K., Tolhurst, M., Houldey, A., Hill, C. M., Brook, N., Macklon , N. and Cheong, Y.
Published:2013

Publication:
Human Reproduction Volume: 28, (5)Page Range:1348-1353doi:10.1093/humrep/det013 PMID:23438443
Influence of shift work on early reproductive outcomes: a systematic review and meta-analysis - Stocker, L.J., Macklon, N.S., Bewley, S.J. and Cheong, Y.
Published:2014

Publication:
Obstetrics & Gynecology Volume: 124, (1)Page Range: 99-110doi: 10.1097/AOG.0000000000000321 PMID:24901274
Variation in stability of housekeeping genes in health and adhesion-related mesothelium - Sadek, Khaled, Cagampang, F.R., Bruce, K.D., Macklon , N. and Cheong, Ying
Published:2012

Publication:
Fertility and Sterilitydoi:10.1016/j.fertnstert.2012.06.033 PMID:22795637
Variation in stability of housekeeping genes in endometrium of healthy and polycystic ovarian syndrome women - Sadek, K. H. , Cagampang, F. R., Bruce, K. D., Shreeve, N., Macklon, N.S. and Cheong, Ying
Published:2012

Publication:
Human Reproduction Volume:27, (1)Page Range:251-256doi:10.1093/humrep/der363 PMID:22052386

Complementary Medicine

Acupuncture and herbal medicine in IVF: a review of the evidence for clinical practice. 
Cheong YC, Nardo LG, Rutherford T, Ledger W. 
Hum Fertil 2010;13(1):3-12.

Acupuncture and assisted conception. 
Cheong YC, Hung Yu Ng E, Ledger WL.
Cochrane Database of Systematic Reviews 2008; Issue 1: Art. No.: CD006920. DOI: 10.1002/14651858.CD006920.

Acupuncture in the treatment of infertility. 
Cheong Y, Mikhail MA. 
MIMS Women’s Health 2010;5(3):42-43.

Cheong YC, Dix S, Ng EHY, Ledger WL, Farquhar C (2013) Acupuncture and assisted conception. The Cochrane Library, 1-76. (doi:10.1002/14651858.CD006920.pub3).

Cheong Y (2013). Alternative therapies for chronic pelvic pain In Chronic pelvic pain. Edited by Ledger, Schlaff & Vancaillie, Cambridge University Press, Cambridge, UK.

In addition to publishing more than 100 scientific papers, Professor Macklon has produced two books: IVF in the Medically Complicated Patient, which won an award from the BMA, and The Textbook of Periconceptional Medicine, which is the first book in this new field. He Dr Cheong, and Mr Brook regularly contribute expert chapters to international books in the field. You can keep up to date with our scientific publications by searching under our names on the ‘PubMed’ website at: https://www.ncbi.nlm.nih.gov/pubmed

Endometrial receptivity

How can we measure how receptive the lining of the womb is to receiving an embryo? This is an important question, since we know that the chance of success from treatment is partly dependent on the receptivity of the endometrium (the cells lining the inside of the womb). Professor Macklon’s group have pioneered the development of a new and safe way of removing a tiny amount of fluid from the womb and analysing this in different ways. We have discovered a molecular profile which indicates that the womb is receptive, and used this approach to study how the hormone treatment you receive during IVF might affect endometrial receptivity.

Working with Dr Cheong, he is now looking at the nutritional importance of this fluid from the developing embryo, and how diet and other lifestyle factors such as smoking might affect the fluid which envelopes the embryos as it prepared to implant.

Our work has also led to the discovery of some of the genes which affect successful implantation, and we are now working on new ways of monitoring the inside of the womb. If we can identify why some women find it difficult to fall pregnant despite IVF treatment, we can design new treatments to help them.

Here are some recent publications from our group on this topic.

Ovarian stimulation for in vitro fertilization alters the intrauterine cytokine, chemokine, and growth factor milieu encountered by the embryo.
Boomsma CM, Kavelaars A, Eijkemans MJ, Fauser BC, Heijnen CJ, Macklon NS.
Fertil Steril. . [Epub ahead of print]

Endometrial secretion analysis identifies a cytokine profile predictive of pregnancy in IVF.
Boomsma CM, Kavelaars A, Eijkemans MJ, Lentjes EG, Fauser BC, Heijnen CJ, Macklon NS.
Hum Reprod. 2009 Jun;24(6):1427-35

Cheong Y, Boomsma C, Heijnen C, Macklon N. (2013) Uterine secretomics: a window on the maternal-embryo interface.

Fertility and Sterility, 99, (4), 1093-1099.(doi:10.1016/j.fertnstert.2013.01.144). (PMID:23433513).

The expression of neuronal markers in the endometrium of women with and without endometriosis.
Newman T and Bailey J, Stocker L, Woo YL, Macklon NS, Cheong YC (2013). Hum Reprod (ahead epub).

Implantation

How does the embryo signal to the womb to let it implant? Professor Macklon’s group in Utrecht, the Netherlands, has been using new techniques to understand this important question. We have found that when an embryo is of good quality, it sends out very few signals, and the womb lets it implant. We were the first to show recently that the womb responds to the presence of an unhealthy embryo by becoming less receptive to it. This novel work is changing the way we think about distressing conditions such as recurrent miscarriage.

Here are some of our publications in this area:

What can the clinician do to improve implantation?
Boomsma CM, Macklon NS.
Reprod Biomed Online. 2007;14 Spec No 1:27-37

Natural selection of human embryos: decidualizing endometrial stromal cells serve as sensors of embryo quality upon implantation.
Teklenburg G, Salker M, Molokhia M, Lavery S, Trew G, Aojanepong T, Mardon HJ, Lokugamage AU, Rai R, Landles C, Roelen BA, Quenby S, Kuijk EW, Kavelaars A, Heijnen CJ, Regan L, Brosens JJ, Macklon NS.
PLoS One. 2010 Apr 21;5(4):e10258.

Natural selection of human embryos: impaired decidualization of endometrium disables embryo-maternal interactions and causes recurrent pregnancy loss.
Salker M, Teklenburg G, Molokhia M, Lavery S, Trew G, Aojanepong T, Mardon HJ, Lokugamage AU, Rai R, Landles C, Roelen BA, Quenby S, Kuijk EW, Kavelaars A, Heijnen CJ, Regan L, Macklon NS, Brosens JJ.

Review: in vitro models for the study of early human embryo-endometrium interactions.
Teklenburg G, Macklon NS.
Reprod Sci. 2009 Sep;16(9):811-8. Epub 2009 Apr 24

Improving the success of fertility surgery

Adhesions and endometriosis: challenges in subfertility management : (An expert opinion of the ANGEL-The ANti-Adhesions in Gynaecology Expert PaneL-group); Arch Gynecol Obstet. 2016 Feb 19.
De Wilde RL,Alvarez J, Brölmann H, Campo R, Cheong Y, Lundorff P, Pawelczyk L, Roman H, di Spiezio Sardo A, Wallwiener M.

The impact of endometrioma on IVF/ICSI outcomes: a systematic review and meta-analysis. Human Reproduction Update, 1-17. (doi:10.1093/humupd/dmv035).
Hamdan, M., Dunselman, G., Li, T.C. and Cheong, Y. (2015)

Furness S, Yap C, Farquhar C, Cheong YC (2011). Pre and post operative medical therapy for endometriosis surgery. Cochrane Database of Systematic Reviews Issue 3. Art. No.: CD003678. DOI: 10.1002/14651858.CD003678.pub2.

Cheong Y, Metwally M, Sadek K, Watson A, Li TC (2011).  Adhesion reduction agents in gynaecological procedures: can NHS afford it? An economic cost efficiency analysis.  Journal of Obstetrics and Gynaecology. 31: 631-635.

Y Cheong, M Metwally, K Sadek, N Shreeve, C Farquhar.  Ovarian Surgery for Polycystic Ovarian Syndrome: Cochrane Reviews Meta-analysis Protocol 2011 (in print)

To close or not to close: a systematic review of peritoneal closure and adhesion formation after caesarean section.
Premkumar G, Metwally M, Li TC, Cheong YC.
Eur J Obstet Gynecol 2009;147(1):3-8.

Hysteroscopy and Hysteroscopic Surgery. 
Umranikar S, Umranikar A, Cheong Y. 
Obstetrics, Gynaecology and Reproductive Medicine 2010;20(6):167-173

Ahmad GF, Cheong YC, Metwally ME, Watson AJS (2013). The Use of Adhesion Prevention Agents in Obstetrics and Gynaecology, Scientific Impact Paper 39, RCOG.

Are skin scar characteristics associated with the degree of pelvic adhesions at laparoscopy? 
Stocker LJ, Glazebrook JE, Cheong YC. 
Fertil Steril. 2014 Feb;101(2):501-5. doi: 10.1016/j.fertnstert.2013.10.026. Epub 2013 Nov 26. 
PMID: 
24289993 
[PubMed - in process] 
Related citations

Expression of neuronal markers in the endometrium of women with and those without endometriosis. 
Newman TA, Bailey JL, Stocker LJ, Woo YL, Macklon NS, Cheong YC. 
Hum Reprod. 2013 Sep;28(9):2502-10. doi: 10.1093/humrep/det274. Epub 2013 Jul 2. 
PMID: 
23820422 
[PubMed - in process]

Surgical treatment of fibroids for subfertility.
Metwally M, Cheong YC, Horne AW. 
Cochrane Database Syst Rev. 2012 Nov 14;11:CD003857. doi: 10.1002/14651858.CD003857.pub3. Review. 
PMID: 
23152222 
[PubMed - indexed for MEDLINE] 
Select item 23888428 
Select item 2382042 
Select item 2315222

Mild Stimulation for IVF

At Complete, we use softer, shorter and easier hormone treatments for our patients undergoing IVF or ICSI treatment. Working with Professor Bart Fauser in Rotterdam and Utrecht, Holland, who is now a member of our international advisory board, Professor Macklon carried out a number of pioneering studies over many years to develop a milder hormonal treatment in IVF. These studies showed the benefit to embryos as well as mums to be, and this approach has now been adopted in many clinics across the world.

Here are some of our publications:

The science behind 25 years of ovarian stimulation for in vitro fertilization.
Macklon NS, Stouffer RL, Giudice LC, Fauser BC. 
Endocr Rev. 2006 Apr;27(2):170-207

The impact of ovarian stimulation for IVF on the developing embryo.
Santos MA, Kuijk EW, Macklon NS.
Reproduction. 2010 Jan;139(1):23-34.

Mild ovarian stimulation for IVF.
Verberg MF, Macklon NS, Nargund G, Frydman R, Devroey P, Broekmans FJ, Fauser BC.
Hum Reprod Update. 2009 Jan-Feb;15(1):13-29

Cheong Y, Brook N, Macklon NS. (2011) New concepts in ovarian stimulation. 
In: Human Assisted Reproductive Technology: Future Trends in Laboratory & Clinical Practice. Gardner, David K., Rizk, Botros R.M.B. and Falcone, Tommaso (Eds). Cambridge, GB, Cambridge University Press. pp 54-71. ISBN 978-1-107-00112-1

Miscarriage

First trimester progesterone therapy in women with a history of unexplained recurrent miscarriages: a randomised, double-blind, placebo-controlled, international multi-centre trial and economic evaluation (PROMISE). NEJMN Engl J Med 2015; 373:2141-2148November 26, 2015DOI:10.1056/NEJMoa1504927.
Coomarasamy A, Williams H, T... Cheong YC, Chu J, Eapen A, Essex H, Ewies A, Hoek A, Kaaijk EM, Koks CA, Li TC, MacLean M, Mol BW, Moore J, Parrott S, Ross J, Sharpe L, Stewart J, Trepel D, Vaithilingham N, Farquharson R, Kilby M, Khalaf Y, Regan L, Rai R.

Endometrial Stromal Cells of Women with Recurrent Miscarriage Fail to Discriminate between High- and Low-Quality Human Embryos
Charlotte H. E. Weimar, Annemieke Kavelaars, Jan J. Brosens, Birgit Gellersen, Johanna M. T. de Vreeden-Elbertse, Cobi J. Heijnen, Nick S. Macklon

Periconceptional determinants of health

This research programme focuses on how we can help couples prepare for pregnancy in a way which will optimise their chances of conceiving, and of having a healthy baby. We know that folic acid prevents spina bifida, but our work has shown the importance of folic acid and diet in improving the chance of conceiving from IVF. While working in Holland, Professor Macklon set up the first preconception care clinic in an IVF unit there, and a number of studies to look at how we can use the clinic to help couples conceive. Our ‘Programme for Pregnancy’ is based on this research. There is still much to discover though, so please consider joining us as we continue to find ways of improving fertility treatment outcomes!

Here are a few publications you may be interested in:

Homocysteine metabolism in the pre-ovulatory follicle during ovarian stimulation.
Boxmeer JC, Steegers-Theunissen RP, Lindemans J, Wildhagen MF, Martini E, Steegers EA, Macklon NS.
Hum Reprod. 2008 Nov;23(11):2570-6

The preconception Mediterranean dietary pattern in couples undergoing in vitro fertilization/intracytoplasmic sperm injection treatment increases the chance of pregnancy.
Vujkovic M, de Vries JH, Lindemans J, Macklon NS, van der Spek PJ, Steegers EA, Steegers-Theunissen RP.
Fertil Steril. 2010 Feb 18

IVF outcomes are associated with biomarkers of the homocysteine pathway in monofollicular fluid.
Boxmeer JC, Macklon NS, Lindemans J, Beckers NG, Eijkemans MJ, Laven JS, Steegers EA, Steegers-Theunissen RP.
Hum Reprod. 2009 May;24(5):1059-66.

Effect of B vitamins and genetics on success of in-vitro fertilisation.
Boxmeer JC, Fauser BC, Macklon NS.
Lancet. 2006 Jul 15;368(9531):200.

Reproductive surgery

Considering what is the best surgery to optimise fertility is often crucial for the success of the assisted conception treatment. Surgery is often a form of treatment but can also be investigative. Professor Ying Cheong and her team has vast experience in reproductive surgery and have conducted vast amount of research to inform best practice for the treatment of fibroids, ovarian cysts, endometriosis with and without pelvic pain and uterine adhesions.

Influence of endometriosis on assisted reproductive technology outcomes - Hamdan, Mukhri, Omar, Siti Z., Dunselman, Gerard and Cheong, Ying
Published:2015

Publication:
Obstetrics and Gynecology Volume: 125, (1)Page Range: 79-88doi: 10.1097/AOG.0000000000000592 PMID:25560108

The impact of endometrioma on IVF/ICSI outcomes: a systematic review and meta-analysis - Hamdan, M., Dunselman, G., Li, T.C. and Cheong, Y.
Published:2015

Publication:
Human Reproduction Update Page Range:1-17doi:10.1093/humupd/dmv035

Adhesions and endometriosis: challenges in subfertility management (An expert opinion of the ANGEL-The ANti-Adhesions in Gynaecology Expert PaneL-group) - de Wilde, R.L., Alvarez, J., Brolmann, H., Campo, R., Cheong, Y., Lundorff, P., Pwelczyk, L., Roman, H., di Spiezio Sardo, A. and Wallwiener, M.
Published:2016

Publication:Archives of Gynecology and Obstetrics Page Range: 1-3doi: 10.1007/s00404-016-4049-2 PMID:26894304

Should women with chronic pelvic pain have adhesiolysis? - Cheong, Y.C., Reading, Isabel, Bailey, Sarah, Sadek, Khaled, Ledger, W. and Li, T.C
Published:2014

Publication:
BMC Women's HealthVolume: 14 Page Range: 36doi: 10.1186/1472-6874-14-36

Are skin scar characteristics associated with the degree of pelvic adhesions at laparoscopy? - Stocker, L.J., Glazebrook, J.E. and Cheong, Y.
Published:2014

Publication:
Fertility and Sterility Volume: 101, (2) Page Range: 501-505doi: 10.1016/j.fertnstert.2013.10.026 PMID:24289993

Stress IVF and Miscarriage

We know that couples find dealing with problems with conceiving very stressful. And IVF itself can be a stressful experience too. Professor Macklon’s group have done a lot of work to try to understand what increases and reduces stress before and during IVF treatment, and what steps can be taken to reduce the anxiety often felt by couples at this time. We are slowly developing new ways of helping women cope with the stress associated with recurrent miscarriage.

Here are some of our recent publications

Why do couples drop-out from IVF treatment? A prospective cohort study.
Verberg MF, Eijkemans MJ, Heijnen EM, Broekmans FJ, de Klerk C, Fauser BC, Macklon NS.
Hum Reprod. 2008 Sep;23(9):2050-5.

Low negative affect prior to treatment is associated with a decreased chance of live birth from a first IVF cycle.
de Klerk C, Hunfeld JA, Heijnen EM, Eijkemans MJ, Fauser BC, Passchier J, Macklon NS.
Hum Reprod. 2008 Jan;23(1):112-6.

Effectiveness of a psychosocial counselling intervention for first-time IVF couples: a randomised controlled trial.
de Klerk C, Hunfeld JA, Duivenvoorden HJ, den Outer MA, Fauser BC, Passchier J, Macklon NS.
Hum Reprod. 2005 May;20(5):1333-8.