Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilisation: cross sectional study

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.e8632 (Published 15 January 2013)
Cite this as: BMJ 2013;346:e8632

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To the Editor of BMJ,

We read with interest the study by Henriksson et al that highlights an increased risk of venous thromboembolism in pregnant women after in vitro fertilization (IVF), particularly during the first trimester (1). While high levels of endogenous estradiol due to ovarian hyperstimulation may result in a hypercoagulable state, such a mechanism does not appear relevant after transfer of thawed embryos. Other factors, including hormone therapy, may therefore be involved in determining thrombotic risk and deserve further discussion.

Women who become pregnant after IVF are often prescribed hormones for several weeks. While progesterone is almost universally given for luteal phase support, estrogens are also commonly used, especially in France. Oral estrogens dose dependently activate blood coagulation and increase the risk of venous thromboembolism (2,3). A hypercoagulable state induced by oral estrogens could therefore explain the increased risk of venous thrombosis found in the study by Henriksson et al. However, such an adverse effect could be avoided to a large extent by using transdermal estrogens that have no effect on haemostasis (4) and may be safer (3,5). It would be of great interest if the authors provided information on hormonal management of pregnant women after IVF, including molecules, dosage and route of administration. If such data are not available in their database, could the authors describe briefly the medical practices in this area in Sweden?

References :

1. Henriksson P, Westerlund E, Wallen H, Brandt L, Hovatta O, Ekbom A. Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilisation: cross sectional study. Bmj;346:e8632.
2. Caine YG, Bauer KA, Barzegar S, ten Cate H, Sacks FM, Walsh BW, et al. Coagulation activation following estrogen administration to postmenopausal women. Thromb Haemost 1992;68(4):392-5.
3. Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. Bmj 2008;336(7655):1227-31.
4. Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol 1997;17(11):3071-8.
5. Scarabin PY, Oger E, Plu-Bureau G. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003;362(9382):428-32.

Competing interests: None declared

Valérie Scarabin-Carré, Medical gynaecologist and PhD student

Professor Pierre-Yves Scarabin

Inserm, Centre for Research in Epidemiology and Population Health, U1018, Hormones and Cardiovascular Disease Team, Univ Paris-Sud, 16 av. Paul Vaillant Couturier 94807 Villejuif Cedex

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12 February 2013

I did not write, as the authors say, that increases in thrombosis in IVF pregnancies “should” be due to progesterone use but “could” be. My paper, “Venous changes with oral contraceptives”, recorded different venous effects due to over 60 dose combinations of seven types of progestins and two types of oestrogens.1 Combinations with a lower progesterone and higher oestrogen balance immediately produced more dilated endometrial venous sinusoids and/or stromal condensation relating to venous complaints than sequential combinations using oestrogen only pills for 15 days. An increased risk of thrombosis is due to changes in blood vessels, blood flow as well as changes in blood constituents.

One lesson of postpartum stilboestrol-induced thrombosis epidemic in the 1950s and 1960s was that untreated pregnancy per se carried a very low risk of thrombosis.2 The risk will have increased now because many women have taken contraceptive progestins for years before becoming pregnant. Some of them develop the Antiphospholipid Syndrome or Systemic Lupus Erythematous and have a lifetime’s increased risk of thrombosis.3,4

Further hormone use is a mistake.

1.Grant ECG. Venous effects of oral contraceptives. BMJ 1969;2:73-7.

2.Grant ECG. Thrombosis and heart attacks with contraceptive and menopausal hormones. J Nutr Environ Med 1998; 8:159-167.

3.Grant ECG. Systemic lupus erythematosus. Lancet. 2001 Aug 18;358(9281):586.

4.Grant ECG. The Hughes (Anti-phospholipid) Syndrome. J Nutr Environ Med 1998; 8:1 59-167

Competing interests: None declared

Ellen CG Grant, Physician and medical gynaecologist

Retired, Kingson-upon-Thames, KT2 7JU, UK

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11 February 2013

PhD student Eli Westerlund, Associate professor Håkan Wallén, Biostatistician Lena Brandt, Professor Outi Hovatta, Professor Anders Ekbom, Professor Peter Henriksson.

To the Editor of BMJ,

We have read the response and suggestion by Ellen CG Grant that the increased risk of venous thromboembolism in women who were pregnant after in vitro fertilization (1) should be due to progesterone. This treatment is almost universally given after oocyte retrieval as “luteal phase support” during the in vitro fertilization procedure.

A definite answer to this question should necessitate a direct comparison of women with and without progesterone. This might be possible in the future, since the role of progesterone as luteal phase support has been disputed (2, 3). However, concerning oestrogen and venous thromboembolism, there are a number of studies showing an increased risk afforded by this hormone(4-6). Concerning hormone therapies an increased risk of venous thromboembolism have been observed for “estrogen only” therapy as well as combined estrogen and gestagen treatment(7, 8). The risk of venous thromboembolism does not seem to differ between those therapies.

References

1. Henriksson P, Westerlund E, Wallen H, Brandt L, Hovatta O, Ekbom A. Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilisation: cross sectional study. Bmj. 2013;346:e8632. Epub 2013/01/17.
2. Liu XR, Mu HQ, Shi Q, Xiao XQ, Qi HB. The optimal duration of progesterone supplementation in pregnant women after IVF/ICSI: a meta-analysis. Reproductive biology and endocrinology : RB&E. 2012;10:107. Epub 2012/12/15.
3. Griesinger G. Editorial commentary: is it time to abandon progesterone supplementation of early pregnancy after IVF? Hum Reprod. 2011;26(5):1017-9. Epub 2011/02/08.
4. Stadel BV. Oral contraceptives and cardiovascular disease (second of two parts). N Engl J Med. 1981;305(12):672-7. Epub 1981/09/17.
5. Grady D, Wenger NK, Herrington D, Khan S, Furberg C, Hunninghake D, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med. 2000;132(9):689-96. Epub 2000/04/29.
6. Henriksson P, Edhag O. Orchidectomy versus oestrogen for prostatic cancer: cardiovascular effects. Br Med J (Clin Res Ed). 1986;293(6544):413-5. Epub 1986/08/16.
7. Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet. 1996;348(9033):977-80. Epub 1996/10/12.
8. Marjoribanks J, Farquhar C, Roberts H, Lethaby A. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2012;7:CD004143. Epub 2012/07/13.

Competing interests: None declared

Peter Henriksson, Professor

Elli Westerlund, Lena Brandt, Håkan Wallén, Outi Hovatta, Anders Ekbom

Karolinska Institutet, Dept of Cardiovascolar Medicine, Danderyd Hospital, Stockholm

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PhD student Eli Westerlund, Associate professor Håkan Wallén, Biostatistician Lena Brandt, Professor Outi Hovatta, Professor Anders Ekbom, Professor Peter Henriksson.

To the Editor of BMJ,

We have with great interest read the response by Roach REJ, Rosendaal FR and Helmerhorst FM on our article, which reported an increased risk of venous thromboembolism in women who were pregnant after in vitro fertilisation(1).

First, they raise the important question whether there could be “confounding by indication”. Both treatment of malignant diseases and rheumatoid arthritis per se could reduce fertility, and are known to increase the risk of venous thromboembolism(2-5). Unfortunately, the Medical Birth Register does not include any data on the existence of malignant disease or rheumatoid arthritis. This is also true regarding reduced fertility and if it is due to a male or a female factor. This means that our database does not allow us to address these questions.

Secondly, Roach and co-authors give a suggestion on how to test the hypothesis whether the increase in endogenous estradiol production induced by the controlled ovarian hyperstimulation could be the cause of the increased risk of venous thromboembolism, by e g perturbation in haemostasis leading to a hypercoagulable state(6-8). IVF cycles using previously frozen embryos eliminate the need for ovarian hyperstimulation and thus avoid the increase in endogenous estrogen production. Thus, if increased endogenous estradiol production should indeed explain the increased risk of venous thromboembolism found in this study, one would expect to see a lower risk of thromboembolism in women who became pregnant after transfer of thawed embryos, compared to pregnancy after controlled ovarian hyperstimulation. Unfortunately, also on this point there are no data in the Medical Birth Register allowing us to study this important question.

To conclude we do completely agree that the raised questions are important but the registers that were available do not allow us to address these questions.

References

1. Henriksson P, Westerlund E, Wallen H, Brandt L, Hovatta O, Ekbom A. Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilisation: cross sectional study. Bmj. 2013;346:e8632. Epub 2013/01/17.
2. Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. Jama. 2005;293(6):715-22. Epub 2005/02/11.
3. Lee SJ, Schover LR, Partridge AH, Patrizio P, Wallace WH, Hagerty K, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006;24(18):2917-31. Epub 2006/05/03.
4. Clowse ME, Chakravarty E, Costenbader KH, Chambers C, Michaud K. Effects of infertility, pregnancy loss, and patient concerns on family size of women with rheumatoid arthritis and systemic lupus erythematosus. Arthritis care & research. 2012;64(5):668-74. Epub 2012/02/22.
5. Holmqvist ME, Neovius M, Eriksson J, Mantel A, Wallberg-Jonsson S, Jacobsson LT, et al. Risk of venous thromboembolism in patients with rheumatoid arthritis and association with disease duration and hospitalization. Jama. 2012;308(13):1350-6. Epub 2012/10/04.
6. Westerlund E, Henriksson P, Wallen H, Hovatta O, Wallberg KR, Antovic A. Detection of a procoagulable state during controlled ovarian hyperstimulation for in vitro fertilization with global assays of haemostasis. Thromb Res. 2012;130(4):649-53. Epub 2011/12/14.
7. Curvers J, Nap AW, Thomassen MC, Nienhuis SJ, Hamulyak K, Evers JL, et al. Effect of in vitro fertilization treatment and subsequent pregnancy on the protein C pathway. British journal of haematology. 2001;115(2):400-7. Epub 2001/11/13.
8. Westerlund E, Antovic A, Hovatta O, Eberg KP, Blomback M, Wallen H, et al. Changes in von Willebrand factor and ADAMTS13 during IVF. Blood Coagul Fibrinolysis. 2011;22(2):127-31. Epub 2010/12/31.

Competing interests: None declared

Peter Henriksson, Professor

Elli Westerlund, Lena Brandt, Håkan Wallén, Outi Hovatta, Anders Ekbom

Karolinska Institutet, Dept of Cardiovascolar Medicine, Danderyd Hospital, Stockholm

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The large increases in pulmonary embolism (x7) and venous thromboembolism (x3) in first trimester of pregnancy after in vitro fertilisation (IVF) found by Henriksson and colleagues could be due to progesterone supplements.1

In the 1950s and 1960s there was an epidemic of postpartum thromboembolism (x 18) due to stilboestrol (diethylstilbestrol- DES).2 Although oestrogens have been mostly associated with thrombosis risk, variations in either progestogen or oestrogen doses of combined contraceptive pills alter venous effects.3 Injectable progestin-only contraceptives increase the risk of thrombosis (x 2.67). 4

Progesterone increase in coagulation is progesterone receptor (PR) dependent and requires protein synthesis. Progesterone increases Tissue Factor, coagulation and invasion in breast cancer cell lines.5 There is evidence that progesterone is also carcinogenic in animal studies.6 A case-control study has found an increased risk of breast cancer with prolonged use of progesterone contraceptives in premenopausal women over 40 years of age.7

High doses of progesterone are given for luteal pregnancy support in the majority of IVF cycles worldwide until the 10th to 12th week of gestation although there is little evidence to justify the practice. 8 Premature progesterone rise negatively correlated with live birth rate in IVF cycles with GnRH agonist in an analysis of 2,566 cycles.9 Griesinger asked, “Is it time to abandon supplementation of early pregnancy after IVF?”10 The answer now seems to be “Yes”.

Progesterone trade names include : Crinone, Cyclogest, Endometrin, First Progesterone MC10, First Progesterone MC5, Gestone, Menopause Formula Progesterone, Prochieve, Progest, Progestasert System, Prometrium. There is reputed to be a billion dollar industry marketing progesterone and any connection with potentially fatal thromboembolism is unwelcome news.

Perhaps obstetricians and gynaecologists should learn from history and be wary of giving progesterone.

1 Henriksson P, Westerlund E, Wallén H, Brandt L, Hovatta O, et al. Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilisation: cross sectional study. BMJ 2013; 346:doi:10.1136/bmj.e8632.

2 Daniel DG, Campbell H, Turnbull AC. Puerperal thromboembolism and suppression of lactation. Lancet 1967;2:287-9.

3 Grant ECG. Venous effects of oral contraceptives. BMJ 1969;2:73-7.

4 Mantha S, Karp R, Raghavan V, Terrin N, Bauer KA, Zwicker JI. Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis.BMJ 2012 Aug 7;345:e4944.

5 Henriquez S, Calderon C, Quezada M, Oliva B, Bravo ML, Aranda E, Kato S, Cuello MA, Gutiérrez J, Quest AF, Owen GI. Progesterone utilizes distinct membrane pools of tissue factor to increase coagulation and invasion and these effects are inhibited by TFPI. J Cell Physiol 2011; 226:3278-85.

6 Progesterone CAS no. 57-83-0 Report on Carcinogens, Twelth Edition (2011)National Toxicology Programme, Department of Health and Human Services pp362-3.

7 Fabre A, Fournier A, Mesrine S, Desreux J, Gompel A, Boutron-Ruault MC, Clavel-Chapelon F. 2007. Oral progestagens before menopause and breast cancer risk. Br J Cancer 96(5): 841-844.

8 Liu X-R, Mu H-Q, Shi Q, Xiao X-Q, Qi H-B. The optimal duration of progesterone supplementation in pregnant women after IVF/ICSI: a meta-analysis. Reproductive Biology and Endocrinology 2012, 10:107.

9 Huang R, Fang C, Xu S, Yi Y, Liang X. Premature progesterone rise negatively correlated with live birth rate in IVF cycles with GnRH agonist: an analysis of 2,566 cycles. Fertil Steril 2012;98:664-670.

10 Griesinger G. Editorial Commentary: Is it time to abandon progesterone supplementation of early pregnancy after IVF? Hum Reprod 2011; 26: 1017-1019.

Competing interests: None declared

Ellen CG Grant, physician and medical gynaecologist

retired, Kingston-upon-Thames, KT2 7JU, UK

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To the Editor of BMJ,

We read with interest the article by Henriksson et al. that reported on an increased risk of venous thrombosis in women who were pregnant after in vitro fertilisation compared with women with natural pregnancies (1). Although the authors did not speculate on a mechanism for their findings, we propose two suggestions for which an answer may be found in their database.

Firstly, it is possible that the reason why the women underwent IVF is related to the risk of venous thrombosis, i.e. confounding by indication (2). For instance, women with previous treatment for cancer or women with an autoimmune disease are more likely to undergo IVF treatment and also have a higher risk of venous thrombosis than women without these diseases (3-6). It would be interesting to see whether the risk of venous thrombosis differed according to the indication for IVF treatment. Was there a difference in risk between IVF related to male or to female sub fertility, for example?

Secondly, controlled ovarian hyperstimulation leads to an increase in endogenous oestradiol production which has previously been associated with an increase in activated protein C resistance and a hypercoagulable state (7,8). IVF cycles using previously frozen embryos eliminate the need for ovarian hyperstimulation in general (9). Thus, if the increased endogenous oestradiol production can indeed explain the increased risk of venous thrombosis found in this study, one would expect to see a lower thrombosis risk in women who became pregnant after transfer of thawed embryos. Data from a systematic review suggest that among assisted reproductive techniques (ART) such as IVF, controlled ovarian hyperstimulation is largely responsible for another biological effect, namely the worse perinatal outcome after ART than after natural conception. The direct effect of the increased oestradiol concentration on the endometrium may be one of the explanations (9).

References

1. Henriksson P, Westerlund E, Wallén H, Brandt L, Hovatta O, Ekbom A. Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilisation: cross sectional study. BMJ 2013;346:e8632.

2. Rothman KJ. Epidemiology an Introduction. New York: Oxford University Press; 2002.

3. Lee SJ, Schover LR, Partridge AH, Patrizio P, Wallace WH, Hagerty K, et al. American Society of Clinical Oncology. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006;24:2917-31.

4. Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005;293:715-22.

5. Clowse ME, Chakravarty E, Costenbader KH, Chambers C, Michaud K. Effects of infertility, pregnancy loss, and patient concerns on family size of women with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res 2012;64:668-74.

6. Holmqvist ME, Neovius M, Eriksson J, Mantel Ä, Wållberg-Jonsson S, Jacobsson LT, et al. Risk of venous thromboembolism in patients with rheumatoid arthritis and association with disease duration and hospitalization. JAMA 2012;308:1350-6.

7. Westerlund E, Antovic A, Hovatta O, Eberg KP, Blombäck M, Wallén H, et al. Changes in von Willebrand factor and ADAMTS13 during IVF. Blood Coagul Fibrinolysis 2011;22:127-31.

8. Curvers J, Nap AW, Thomassen MC, Nienhuis SJ, Hamulyák K, Evers JL, et al. Effect of in vitro fertilization treatment and subsequent pregnancy on the protein C pathway. Br J Haematol 2001;115:400-7.

9. Keirse MJNC, Helmerhorst FM. Assisted reproductive technology as a risk factor for poor pregnancy outcome. In: Placental bed disorders. Ed: Pijnenborg R, Brosens I, Romero R. Cambridge University Press, UK 2010, chapter 20, pages 207-28.

Competing interests: None declared

Rachel E.J. Roach , PhD Student

Professor Frits R. Rosendaal, Professor Frans M. Helmerhorst

Department of Clinical Epidemiology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands

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In vitro fertilization (IVF) is the hope of an infertile couple for begetting a child. The artificial methods used in creating a viable fetus have been perfected over the years with technical and medical expertise. The couples who undergo the protocol are subjected to very high psychological pressures along with physiological deficits. The metabolic machinery is totally altered in such individuals. Finding abnormal events including thromboembolism in all the trimesters being more prominent in the first trimester of psychologically compromised patients is one event which is of primary concern. But the health concerns of women wanting to beget a child to become a mother remain in the background of her longing to have a baby in her hands.

Competing interests: None declared

dhastagir s sheriff, Professor

Faculty of Medicine, Benghazi University, Benghazi, Libya

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