Supplementary Appendix

This appendix has been provided by the authors to give readers additional information about their work.

Supplement to: Coomarasamy A, Williams H, Truchanowicz E, et al. A randomized trial of progesterone in

women with recurrent miscarriages. N Engl J Med 2015;373:2141-8. DOI: 10.1056/NEJMoa1504927
1 A RANDOMIZED TRIAL OF

2 PROGESTERONE IN WOME N WITH

3 RECURRENT MISCARRIAGES

4
5 Contents

Authors ............................................................................................................................................................ 3

Appendices ...................................................................................................................................................... 6

Supplementary Table S1 Adverse Events ....................................................................................................... 6

Supplementary Table S2 Subgroup Analyses of Primary Endpoint ................................................................ 7

Supplementary Table S3 Exploratory Analyses .............................................................................................. 8

References ..................................................................................................................................................... 10

2
 7 Authors

8 Arri Coomarasamy, School of Clinical and Experimental Medicine, College of Medical and Dental

9 Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom [corresponding

10 author: a.coomarasamy@bham.ac.uk].

11 Helen Williams, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences,

12 University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.

13 Ewa Truchanowicz, School of Clinical and Experimental Medicine, College of Medical and Dental

14 Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.

15 Paul T Seed, Division of Women’s Health, Women’s Health Academic Centre, King’s College London and

16 King’s Health Partners, St Thomas’ Hospital, London SE1 7EH, United Kingdom.

17 Rachel Small, Heart of England NHS Foundation Trust, Birmingham Heartlands Hospital, Bordesley Green

18 East, Birmingham B9 5SS, United Kingdom.

19 Siobhan Quenby, Biomedical Research Unit in Reproductive Health, University of Warwick, Warwick

20 CV4 7AL, United Kingdom.

21 Pratima Gupta, Heart of England NHS Foundation Trust, Birmingham Heartlands Hospital, Bordesley

22 Green East, Birmingham B9 5SS, United Kingdom.

23 Feroza Dawood, Liverpool Women’s Hospital, Liverpool Women’s NHS Foundation Trust, Crown Street,

24 Liverpool L8 7SS, United Kingdom.

25 Yvonne E Koot, Department of Reproductive Medicine, University Medical Centre Utrecht, Utrecht, the

26 Netherlands.

27 Ruth Bender Atik, The Miscarriage Association, 17 Wentworth Terrace, Wakefield WF1 3QW, United

28 Kingdom.

29 Kitty W M Bloemenkamp, Department of Obstetrics, Leiden University Medical Centre, Albiniusdreef 2,

30 2333 ZA Leiden, the Netherlands.

31 Rebecca Brady, Women's Health Research Centre, Imperial College at St Mary’s Hospital Campus, Mint

32 Wing, South Wharf Road, London W2 1NY, United Kingdom.

3
33 Annette Briley, Maternal and Fetal Research Unit, Academic Division of Women’s Health, King’s Health

34 Partners, St Thomas’ Hospital, London SE1 7EH, United Kingdom.

35 Rebecca Cavallaro, Women's Health Research Centre, Imperial College at St Mary’s Hospital Campus,

36 Mint Wing, South Wharf Road, London W2 1NY, United Kingdom.

37 Ying C Cheong, University of Southampton Faculty of Medicine, Princess Anne Hospital, Southampton

38 University Hospital NHS Trust, Southampton SO16 5YA, United Kingdom.

39 Justin J Chu, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences,

40 University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.

41 Abey Eapen, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences,

42 University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.

43 Ayman Ewies, Sandwell and West Birmingham Hospitals NHS Teaching Trust, Dudley Road, Birmingham

44 B18 7QH, United Kingdom.

45 Annemieke Hoek, Department of Reproductive Medicine and Gynaecology, University Medical Center

46 Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands.

47 Eugenie M Kaaijk, Department of Obstetrics and Gynaecology, Onze Lieve Vrouwe Gasthuis, Amsterdam,

48 the Netherlands.

49 Carolien A Koks, Department of Obstetrics and Gynecology, Maxima Medical Centre Veldhoven, De Run

50 4600, 5504 DB Veldhoven, the Netherlands.

51 Tin-Chiu Li, Jessop Wing, Royal Hallamshire Hospital, Glossop Road, Sheffield, South Yorkshire S10 2JF,

52 United Kingdom.

53 Marjory MacLean, Ayrshire Maternity Unit, University Hospital of Crosshouse, Kilmarnock Road,

54 Kilmarnock KA2 0BE, United Kingdom.

55 Ben W Mol, The Robinson Institute, School of Paediatrics and Reproductive Health, University of

56 Adelaide, Adelaide 5000 SA, Australia.

57 Judith Moore, Nottingham University Hospitals NHS Trust, Hucknall Rd, Nottingham NG5 1PB, United

58 Kingdom.

4
59 Jackie A Ross, King’s College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, United

60 Kingdom.

61 Lisa Sharpe, Women’s Health Research Centre, Imperial College at St Mary’s Hospital Campus, Mint

62 Wing, South Wharf Road, London W2 1NY, United Kingdom.

63 Jane Stewart, Newcastle Hospitals NHS Foundation Trust, Royal Victoria Infirmary, Queen Victoria Road,

64 Newcastle upon Tyne, Tyne and Wear NE1 4LP, United Kingdom.

65 Nirmala Vaithilingam, Portsmouth Hospitals NHS Trust, Queen Alexandra Hospital, Cosham, Portsmouth

66 PO6 3LY, United Kingdom.

67 Roy Farquharson, Liverpool Women's Hospital, Liverpool Women’s NHS Foundation Trust, Crown Street,

68 Liverpool L8 7SS, United Kingdom.

69 Mark D Kilby, Centre for Women’s and Children’s Health, School of Clinical and Experimental Medicine,

70 College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT,

71 United Kingdom.

72 Yacoub Khalaf, Assisted Conception Unit, Guy’s and St Thomas’ Foundation Trust, London SE1 9RT,

73 United Kingdom.

74 Mariette Goddijn, Center for Reproductive Medicine, Department of Obstetrics and Gynaecology,

75 Academic Medical Center, Amsterdam, the Netherlands.

76 Lesley Regan, Department of Obstetrics and Gynaecology, Imperial College at St Mary’s Hospital Campus,

77 Mint Wing, South Wharf Road, London W2 1NY, United Kingdom.

78 Rajendra Rai, Department of Obstetrics and Gynaecology, Imperial College at St Mary’s Hospital Campus,

79 Mint Wing, South Wharf Road, London W2 1NY, United Kingdom.

5
80 Appendices

81 Supplementary Table S1 Adverse Events

Progesterone Placebo
Adverse events P value
n (%) n (%)

Number of participants 404 432

Allergy 2 (0.5) 0 (0.0) 0.28

Dermatological 1 (0.2) 3 (0.7) 0.37

Gastro-intestinal 20 (5.0) 14 (3.2) 0.21

Haematological 0 (0.0) 1 (0.2) 0.53

Neurological 7 (1.7) 4 (0.9) 0.31

Urological 3 (0.7) 4 (0.9) 0.77

Miscellaneous 8 (2.0) 4 (0.9) 0.21

Serious Adverse Events * 3 (0.7) 2 (0.5) 0.60

82 * Among these, serious adverse events in the progesterone group comprised one suspected unexpected serious adverse
83 reaction (allergy), one occurrence of neonatal seizures and one diagnosis of hypoxic ischemic encephalopathy,
84 whereas serious adverse events in the placebo group comprised one occurrence of appendicitis and one severe
85 dermatological issue

6
86 Supplementary Table S2 Subgroup Analyses of Primary Endpoint

Relative risk (95%

Progesterone Placebo
Subgroup confidence P value
n/N (%) n/N (%)
interval)
Age
≤35 years * 171/258 (66.3) 191/300 (63.7) 1.04 (0.92 to 1.18) 0.52
>35 years * 91/140 (65.0) 80/128 (62.5) 1.04 (0.87 to 1.25) 0.67
0.98 †

Previous miscarriages
3 148/218 (67.9) 159/236 (67.4) 1.01 (0.89 to 1.14) 0.91
≥4 114/180 (63.3) 112/192 (58.3) 1.09 (0.92 to 1.28) 0.32
0.52 †

Polycystic ovaries
Absent 245/369 (66.4) 252/401 (62.8) 1.06 (0.95 to 1.17) 0.30
Present 17/29 (58.6) 19/27 (70.4) 0.83 (0.56 to 1.23) 0.36
0.25 †

Gestation at treatment start ‡ ¥

<5+0 weeks 120/182 (65.9) 144/212 (67.9) 0.97 (0.84 to 1.12) 0.68
≥5+0 weeks 122/176 (69.3) 113/184 (61.4) 1.13 (0.97 to 1.31) 0.12
0.15 †

Body mass index ¥

Maternal body mass index
223/335 (66.6) 233/365 (63.8) 1.04 (0.94 to 1.16) 0.45
≤30.0kg/m2
Maternal body mass index
39/63 (61.9) 38/63 (60.3) 1.03 (0.78 to 1.36) 0.86
>30.0kg/m2
0.92 †

Geographical location ¥
United Kingdom 212/312 (67.9) 207/326 (63.5) 1.07 (0.96 to 1.20) 0.24
Netherlands 50/86 (58.1) 64/102 (62.7) 0.93 (0.73 to 1.17) 0.52
0.27 †
87 * Maternal age at the time of randomization
88 † p interaction
89 ‡ Not including women never commencing treatment, women commencing treatment at unknown gestational age and
90 women commencing treatment later than protocol (total 72, of which 40 in the progesterone group and 32 in the
91 placebo group)
92 ¥ Post hoc analysis

7
93 Supplementary Table S3 Exploratory Analyses

Progesterone Placebo

Relative risk
n/N (%) n/N (%) (95% confidence P value
interval)

Maternal complications *

Pre-eclampsia 7/398 (1.8) 10/428 (2.3) 0.75 (0.29 to 1.96) 0.56

Antepartum hemorrhage 9/398 (2.3) 14/428 (3.3) 0.69 (0.30 to 1.58) 0.38

Preterm prelabor rupture of membranes 11/398 (2.8) 9/428 (2.1) 1.31 (0.55 to 3.14) 0.54

Mode of birth †

Unassisted vaginal 126/262 (48.1) 158/274 (57.7) 0.83 (0.71 to 0.98) 0.03

Instrumental vaginal 44/262 (16.8) 32/274 (11.7) 1.43 (0.94 to 2.19) 0.09

Elective caesarean 41/262 (15.6) 36/274 (13.1) 1.19 (0.79 to 1.80) 0.41

Emergency caesarean 51/262 (19.5) 48/274 (17.5) 1.11 (0.78 to 1.59) 0.56

Neonatal outcomes †

Small for gest. age

45/260 (17.3) 35/274 (12.8) 1.35 (0.90 to 2.04) 0.14
<10th adj. birthweight centile

Very small for gest. age

24/260 (9.2) 18/274 (6.6) 1.41 (0.78 to 2.53) 0.26
<5th adj. birthweight centile
Mean difference
Mean Mean
(95% confidence P value
(std. deviation) (std. deviation)
interval)
n = 260 n = 274 -115.23
Live birthweight (g) 0.05
3,213.65 (707.11) 3,328.87 (635.40) (-229.71 to -0.74)

n = 260 n = 274 -2.50

Adjusted live birthweight centile ‡ 0.33
44.08 (30.58) 46.58 (28.91) (-7.57 to 2.56)
Relative risk
n/N (%) n/N (%) (95% confidence P value
interval)
Arterial cord pH <7.00 2/58 (3.4) 1/54 (1.9) 1.86 (0.17 to 20.0) 0.61

Venous cord pH <7.00 1/55 (1.8) 0/51 (0.0) - -

Apgar score at 1 min. <7 22/257 (8.6) 15/270 (5.6) 1.54 (0.82 to 2.90) 0.18

Apgar score at 5 min. <7 3/257 (1.2) 4/271 (1.5) 0.79 (0.18 to 3.50) 0.76

Early infection 9/260 (3.5) 8/269 (3.0) 1.16 (0.46 to 2.97) 0.75

Necrotizing enterocolitis 0/261 (0.0) 0/270 (0.0) - -

Intraventricular hemorrhage (level 2) 0/261 (0.0) 1/270 (0.4) - -

Pneumothorax 0/261 (0.0) 3/270 (1.1) - -

8
 Neonatal support required †

Surfactant 2/260 (0.8) 3/269 (1.1) 0.69 (0.12 to 4.09) 0.68

Ventilator support 8/260 (3.1) 8/269 (3.0) 1.03 (0.39 to 2.72) 0.94

Discharge on oxygen 0/260 (0.0) 1/269 (0.4) - -

Median days Median days

(interquartile range) (interquartile range)

n=3 n=3
Intermittent positive pressure ventilation - -
2.0 (1.0 to 3.0) 3.0 (1.0 to 30.0)

n=5 n=8
Continuous positive airway pressure - -
2.0 (1.0 to 3.0) 2.5 (1.0 to 4.0)

n=6 n=7
Oxygen - -
3.0 (1.0 to 30.0) 30.0 (1.0 to 80.0)

94 * Endpoint per trial participant with follow-up to primary outcome

95 † Endpoint per neonate born alive after 24 weeks of gestation subject to data availability
96 ‡ Live birthweight centiles adjusted for maternal height, weight (within healthy range of body mass index 18.5kg/m 2
97 to 30.0kg/m2), ethnicity, parity and neonatal gender and gestational age at delivery1
98

9
 99 References

100 1. Gardosi J, Francis A. Customised Weight Centile Calculator. GROW v6.7 UK [2013].

101

10