STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early-onset fetal growth restriction

K M Groom^{1

2}, L M McCowan^{2

3}, L K Mackay¹, A C Lee⁴, G Gardener⁵, J Unterscheider^{6

7}, R Sekar⁸, J E Dickinson^{9

10}, P Muller¹¹, R A Reid^{12

13}, D Watson¹⁴, A Welsh^{15

16}, J Marlow¹⁷, S P Walker^{7

18}, J Hyett^{19

20}, J Morris²¹, P R Stone³, P N Baker^{1

22}

Affiliations

¹ Liggins Institute, University of Auckland, Auckland, New Zealand.
² National Women's Health, Auckland City Hospital, Auckland, New Zealand.
³ Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand.
⁴ Section of Epidemiology and Biostatistics, University of Auckland, Auckland, New Zealand.
⁵ Mater Centre for Maternal Fetal Medicine, Mater Research Institute, Mater Mother's Hospital, University of Queensland, Brisbane, Qld, Australia.
⁶ Department of Maternal Fetal Medicine, Royal Women's Hospital, Melbourne, Vic, Australia.
⁷ Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Vic, Australia.
⁸ Department of Maternal Fetal Medicine, Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia.
⁹ King Edward Memorial Hospital, Perth, WA, Australia.
¹⁰ Division of Obstetrics and Gynaecology, University of Western Australia, Perth, WA, Australia.
¹¹ Director Maternal Fetal Medicine Service, Women's and Children's Hospital Adelaide, North Adelaide, SA, Australia.
¹² Christchurch Women's Hospital, Christchurch, New Zealand.
¹³ Department of Obstetrics and Gynaecology, University of Otago, Christchurch, New Zealand.
¹⁴ Women's and Children's Service, Townsville Hospital, Townsville, Qld, Australia.
¹⁵ Royal Hospital for Women, Sydney, NSW, Australia.
¹⁶ School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia.
¹⁷ Maternal Fetal Medicine, Wellington Hospital, Wellington, New Zealand.
¹⁸ Mercy Hospital for Women, Melbourne, Vic, Australia.
¹⁹ RPA Women and Babies, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
²⁰ Discipline of Obstetrics, Gynaecology and Neonatology, Faculty of Medicine, University of Sydney, Sydney, NSW, Australia.
²¹ Perinatal Research, Faculty of Medicine and Health, The Kolling Institute, The University of Sydney, Sydney, NSW, Australia.
²² College of Life Sciences, University of Leicester, Leicester, UK.

PMID: 30779295
DOI: 10.1111/1471-0528.15658

Randomized Controlled Trial

STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early-onset fetal growth restriction

K M Groom et al. BJOG. 2019 Jul.

. 2019 Jul;126(8):997-1006.

doi: 10.1111/1471-0528.15658. Epub 2019 Mar 14.

Authors

Affiliations

¹ Liggins Institute, University of Auckland, Auckland, New Zealand.
² National Women's Health, Auckland City Hospital, Auckland, New Zealand.
³ Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand.
⁴ Section of Epidemiology and Biostatistics, University of Auckland, Auckland, New Zealand.
⁵ Mater Centre for Maternal Fetal Medicine, Mater Research Institute, Mater Mother's Hospital, University of Queensland, Brisbane, Qld, Australia.
⁶ Department of Maternal Fetal Medicine, Royal Women's Hospital, Melbourne, Vic, Australia.
⁷ Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Vic, Australia.
⁸ Department of Maternal Fetal Medicine, Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia.
⁹ King Edward Memorial Hospital, Perth, WA, Australia.
¹⁰ Division of Obstetrics and Gynaecology, University of Western Australia, Perth, WA, Australia.
¹¹ Director Maternal Fetal Medicine Service, Women's and Children's Hospital Adelaide, North Adelaide, SA, Australia.
¹² Christchurch Women's Hospital, Christchurch, New Zealand.
¹³ Department of Obstetrics and Gynaecology, University of Otago, Christchurch, New Zealand.
¹⁴ Women's and Children's Service, Townsville Hospital, Townsville, Qld, Australia.
¹⁵ Royal Hospital for Women, Sydney, NSW, Australia.
¹⁶ School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia.
¹⁷ Maternal Fetal Medicine, Wellington Hospital, Wellington, New Zealand.
¹⁸ Mercy Hospital for Women, Melbourne, Vic, Australia.
¹⁹ RPA Women and Babies, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
²⁰ Discipline of Obstetrics, Gynaecology and Neonatology, Faculty of Medicine, University of Sydney, Sydney, NSW, Australia.
²¹ Perinatal Research, Faculty of Medicine and Health, The Kolling Institute, The University of Sydney, Sydney, NSW, Australia.
²² College of Life Sciences, University of Leicester, Leicester, UK.

PMID: 30779295
DOI: 10.1111/1471-0528.15658

Abstract

Objective: To assess the effect of maternal sildenafil therapy on fetal growth in pregnancies with early-onset fetal growth restriction.

Design: A randomised placebo-controlled trial.

Setting: Thirteen maternal-fetal medicine units across New Zealand and Australia.

Population: Women with singleton pregnancies affected by fetal growth restriction at 22⁺⁰ to 29⁺⁶ weeks.

Methods: Women were randomised to oral administration of 25 mg sildenafil citrate or visually matching placebo three times daily until 32⁺⁰ weeks, birth or fetal death (whichever occurred first).

Main outcome measures: The primary outcome was the proportion of pregnancies with an increase in fetal growth velocity. Secondary outcomes included live birth, survival to hospital discharge free of major neonatal morbidity and pre-eclampsia.

Results: Sildenafil did not affect the proportion of pregnancies with an increase in fetal growth velocity; 32/61 (52.5%) sildenafil-treated, 39/57 (68.4%) placebo-treated [adjusted odds ratio (OR) 0.49, 95% CI 0.23-1.05] and had no effect on abdominal circumference Z-scores (P = 0.61). Sildenafil use was associated with a lower mean uterine artery pulsatility index after 48 hours of treatment (1.56 versus 1.81; P = 0.02). The live birth rate was 56/63 (88.9%) for sildenafil-treated and 47/59 (79.7%) for placebo-treated (adjusted OR 2.50, 95% CI 0.80-7.79); survival to hospital discharge free of major neonatal morbidity was 42/63 (66.7%) for sildenafil-treated and 33/59 (55.9%) for placebo-treated (adjusted OR 1.93, 95% CI 0.84-4.45); and new-onset pre-eclampsia was 9/51 (17.7%) for sildenafil-treated and 14/55 (25.5%) for placebo-treated (OR 0.67, 95% CI 0.26-1.75).

Conclusions: Maternal sildenafil use had no effect on fetal growth velocity. Prospectively planned meta-analyses will determine whether sildenafil exerts other effects on maternal and fetal/neonatal wellbeing.

Tweetable abstract: Maternal sildenafil use has no beneficial effect on growth in early-onset FGR, but also no evidence of harm.

Keywords: Fetal growth restriction; intrauterine growth restriction; pre-eclampsia; sildenafil; small for gestational age; uterine artery Doppler.

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Comment in

Sildenafil therapy in early-onset fetal growth restriction: waiting for the individual patient data meta-analysis.
Figueras F. Figueras F. BJOG. 2019 Jul;126(8):1007. doi: 10.1111/1471-0528.15753. Epub 2019 Apr 24. BJOG. 2019. PMID: 30957410 No abstract available.

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STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early-onset fetal growth restriction

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STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early-onset fetal growth restriction

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