Sildenafil citrate therapy for severe early‐onset intrauterine growth restriction
Abstract
Please cite this paper as: von Dadelszen P, Dwinnell S, Magee LA, Carleton BC, Gruslin A, Lee B, Lim KI, Liston RM, Miller SP, Rurak D, Sherlock RL, Skoll MA, Wareing MM, Baker PN, for the Research into Advanced Fetal Diagnosis and Therapy (RAFT) Group. Sildenafil citrate therapy for severe early‐onset intrauterine growth restriction. BJOG 2011;118:624–628.
Currently, there is no effective therapy for severe early‐onset intrauterine growth restriction (IUGR). Sildenafil citrate vasodilates the myometrial arteries isolated from women with IUGR‐complicated pregnancies. Women were offered Sildenafil (25 mg three times daily until delivery) if their pregnancy was complicated by early‐onset IUGR [abdominal circumference (AC) < 5th percentile] and either the gestational age was <25+0 weeks or an estimate of the fetal weight was <600 g (excluding known fetal anomaly/syndrome and/or planned termination). Sildenafil treatment was associated with increased fetal AC growth [odds ratio, 12.9; 95% confidence interval (CI), 1.3, 126; compared with institutional Sildenafil‐naive early‐onset IUGR controls]. Randomised controlled trial data are required to determine whether Sildenafil improves perinatal outcomes for early‐onset IUGR‐complicated pregnancies.
Introduction
Complicating approximately 0.2% of pregnancies, severe early‐onset intrauterine growth restriction (IUGR) increases the risk of perinatal morbidity and mortality, particularly as a result of iatrogenic premature delivery.1 Survival rates for severely growth‐restricted fetuses very remote from term (<28 weeks of gestation) are dismal.1, 2 Following supportive data from rat and guinea pig models of IUGR, Wareing et al.3 determined that ex vivo myometrial small artery function was aberrant in IUGR (increased contraction/reduced vasodilatation; n = 27 normal pregnancies, n = 12 IUGR pregnancies). Furthermore, incubation with Sildenafil citrate reversed the increase in contraction and improved significantly endothelial‐dependent vasodilatation in arteries from pregnancies complicated by IUGR.3 They postulated that Sildenafil citrate may offer a potential therapeutic strategy to improve uteroplacental blood flow in IUGR pregnancies.
For this case–control comparison, the hypothesis was that Sildenafil citrate therapy would increase the likelihood of increased growth velocity [measured by abdominal circumference (AC) (ultrasound)] for fetuses of pregnancies complicated by severe early‐onset IUGR. In this article, we report the use of Sildenafil citrate as an innovative therapy in the management of severe early‐onset IUGR, and compare the outcomes of Sildenafil‐treated pregnancies with similar pregnancies that remained Sildenafil‐naive.
Methods
Within the British Columbian Provincial Health Services Authority, patients facing a dire prognosis are offered innovative therapy through a formal information sharing and consenting process. From 2004 to 2009, we offered Sildenafil citrate (25 mg per os three times daily until delivery) as innovative therapy to 10 women with severe early‐onset IUGR (‘Sildenafil‐treated’). For analytical purposes, Sildenafil‐treated outcomes were compared with a series of 17 women who fulfilled the treatment criteria but either declined or were not offered Sildenafil (‘Sildenafil‐naive’). This evaluation of outcomes for Sildenafil‐treated and naive women received the approval of the University of British Columbia Children’s and Women’s Research Ethics Board (certificate numbers H09‐03393 and H09‐02319, respectively).
Women were offered Sildenafil if their pregnancy was complicated by severe early‐onset IUGR (ultrasound estimation of the fetal AC of <5th percentile4) with an estimated probability of ‘intact’ survival of <50%,5 excluding known aneuploidy, anomaly, syndrome or congenital infection, or if there was a plan to terminate the pregnancy.
Contemporaneous (2004–2009) Sildenafil‐naive controls were identified within the Diagnostic Ambulatory Program Ultrasound Database at British Columbia Women’s Hospital. Matching criteria were as follows: (i) maternal age (±5 years); (ii) gestational age at eligibility (±14 days); (iii) parity (0, 1, ≥2); and (iv) eligibility to be offered Sildenafil (Table 1).
| Variable | Sildenafil‐naive (n = 17) | Sildenafil‐treated (n = 10) | P (MWu or Fisher’s exact) |
|---|---|---|---|
| Maternal characteristics | |||
| Maternal age at estimated date of delivery (years) | 33 (28, 36.5) | 34 (25, 40.5) | 0.73 |
| Nulliparous, n (%) | 8 (47) | 5 (50) | 1.00 |
| Pregnancy characteristics | |||
| GA at eligibility, days since LMP (median expressed as weeks and days) | 148 (138, 163) (21 weeks + 1 day) | 158 (148, 165) (22 weeks + 4 days) | 0.15 |
| Uterine artery notching at eligibility, n (%) | 10 (59) | 8 (80) | 0.41 |
| AC < 1st percentile at eligibility, n (%) | 10 (59) | 6 (60) | 1.00 |
| AC discrepancy at eligibility (days)* | 18.5 (13, 22.5) | 21 (11.5, 25) | 0.82 |
| Umbilical artery Doppler EDF absent/reversed, n (%) | 4 (24) | 5 (50) | 0.22 |
| Amniotic fluid index <50 mm, n (%) | 2 (12) | 4 (40) | 0.15 |
| Maternal outcomes | |||
| Secondary development of pre‐eclampsia, n (%) | 2/12 (5 × TA) (13) | 5/9 (1 × IUFD) (56) | 0.16 |
| Perinatal outcomes | |||
| Increased AC growth velocity post‐eligibility/on Sildenafil, n (%) | 7 (41) | 9 (90) | 0.02 |
| Eligibility‐to‐delivery interval (days) | 42 (17, 55) | 31.5 (9.5, 81) | 0.87 |
| GA at delivery, days since LMP (median expressed as weeks and days) | 181 (166, 208) (25 weeks + 6 days) | 190 (179, 230) (27 weeks + 1 day) | 0.28 |
| Live birth, n (%) | 6 (35)** | 7 (70)*** | 0.12 |
| Survival to primary hospital discharge, n (%) | 6 (35)** | 5 (50%)*** | 0.69 |
| Intact survival at primary hospital discharge, n (%) | 5 (29) | 5 (50) | 0.42 |
- AC, abdominal circumference; GA, gestational age; IUFD, intrauterine fetal death; LMP, last menstrual period (scan‐confirmed); MWu, Mann–Whitney U‐test; TA, therapeutic abortion.
- *AC discrepancy: GA (by scan‐confirmed GA; in days) – equivalent GA of AC at eligibility (50th percentile; in days).
- **Five stillbirths as a result of late termination; six permissive stillbirths (estimated fetal weight of <500 g).
- ***One stillbirth occurred within 48 hours of starting Sildenafil (reversed end‐diastolic flow on day of prescription), one stillbirth occurred during in utero transfer to USA (neonatal intensive care unit occupancy), one permissive stillbirth (estimated fetal weight of <500 g); one neonatal death caused by extremely low birthweight (birthweight = 345 g; not resuscitated); one neonatal death caused by nosocomial fungaemia at 2 weeks of age.
Other than Sildenafil therapy, management was similar between the two groups, and included increased fetal (umbilical artery and ductus venosus Doppler indices, fetal biometry; amniotic fluid index, deepest vertical amniotic fluid pocket and nonstress tests) and maternal [measurement of blood pressure, proteinuria (dipstick and random protein : creatinine ratio), pulse oximetry, complete blood count, creatinine, uric acid, aspartate transaminase, bilirubin and albumin] surveillance. Fetal surveillance occurred at least as frequently as every 6–8 days for outpatients and at least twice weekly for inpatients. Maternal tests were repeated at least every 14 days in outpatients and every week in inpatients. Women in the Sildenafil‐treated group were also monitored for adverse side‐effects, such as flushing, lightheadedness and visual disturbance.
Decisions about pregnancy termination (either therapeutic abortion or delivery) were made using standard clinical assessments. Antenatal betamethasone for fetal lung maturation was administered routinely once ‘viability’ (in general, ≥24+0 weeks of gestation and estimated fetal weight of ≥500 g) was reached. No mothers in either group received antenatal magnesium for neonatal neuroprotection; the seven women (two naive, five treated) who developed pre‐eclampsia received peripartum magnesium for eclampsia prophylaxis.
The primary outcome for this analysis was the proportion of women in each group for whom fetal AC growth velocity increased post‐eligibility. Fetal growth velocity was defined as the average daily increase in ultrasound‐estimated AC.4 The measurements of AC were performed by standardised ultrasound technique4 and repeated at least four times per scan, with the average AC reported in an effort to reduce inter‐observer variability. The sonographers were not blind to Sildenafil use, and there were seven different sonographers who performed the assessment of AC in the study population.
AC (in millimetres) measured at study eligibility was compared with the most recent measurement of AC at least 12 days previously. The ratio of the observed to expected AC growth in millimetres (ΔAC) was used to estimate the growth velocity. Thus, if the interval between scans was 18 days, and the actual AC increased by the equivalent of 9 days (in millimetres), the average daily growth was deemed to be 0.5. Fetal growth velocity was measured during two epochs. The first was prior to eligibility; determined by the increase in AC since the previous ultrasound. The second epoch was the 12–16 days immediately post‐eligibility. When a baseline AC measurement was not available, AC was assumed to have been on the 50th percentile at 56 days (8 weeks) since the last menstrual period. This will have biased the results towards increased pre‐eligibility growth velocity (as, in most of these pregnancies, decreased fetal growth was first noted after 12 weeks of gestation).
Secondary outcomes for this study were live birth, neonatal survival to hospital discharge, intact survival [i.e. survival to hospital discharge without evidence of severe central nervous system (CNS) injury, grade 3 or 4 intraventricular haemorrhage or cystic periventricular leucomalacia by routine clinical ultrasound], combined non‐CNS severe morbidity (i.e. one or more of bronchopulmonary dysplasia requiring supplemental oxygen on hospital discharge, grade 3 or above retinopathy of prematurity, or necrotising enterocolitis resulting in either short‐bowel syndrome or failure to thrive) and adverse maternal side‐effects of medication.
Fetuses and infants were followed until 28 days of life or primary hospital discharge, whichever was later. Women were followed until primary hospital discharge.
Continuous variables were compared using the two‐sided Mann–Whitney U‐test and dichotomous variables using Fisher’s exact test and relative risks [95% confidence interval (CI)], employing GraphPad Prism software (San Diego, CA, USA). Statistical significance was set at P < 0.05 and/or an odds ratio (95% CI) that did not include unity.
Results
We have summarised the baseline characteristics for both Sildenafil‐naive and Sildenafil‐treated groups in Table 1. All 17 women who met the matching criteria and had sufficient ultrasound data were included in the analyses. The women who received Sildenafil treatment tended to have poorer indices of fetal wellbeing at baseline in terms of umbilical artery Doppler velocimetry and amniotic fluid indices.
Other than one stillbirth within 48 hours of commencing Sildenafil treatment, Sildenafil treatment was associated with increased post‐eligibility fetal AC growth velocity [9/10 (treated) versus 7/17 (naive); odds ratio, 12.9 (95% CI, 1.3, 126)] (Table 1). Both survival to, and intact survival at, hospital discharge tended to be more frequent in the fetuses/neonates exposed to Sildenafil in utero, but we were underpowered to identify or to exclude a significant difference in these outcomes. There were no adverse maternal side‐effects of medication reported in the treated group.
We also examined post‐eligibility fetal growth velocity using individual pregnancies as their own controls compared with pre‐eligibility growth velocity. Sildenafil therapy was associated with a significant increase in fetal growth velocity, expressed as equivalent daily AC growth [pre‐eligibility median, 0.59 (interquartile range, 0.37, 0.79); post‐eligibility median, 0.94 (0.78, 1.39); Wilcoxon P = 0.0039; n = 9), but remaining Sildenafil‐naive was not [pre‐eligibility median, 0.71 (0.48, 0.85); post‐eligibility median, 0.58 (0.38, 0.77); Wilcoxon P = 0.2513; n = 17].
Discussion
To our knowledge, this is the first study to assess the potential benefit of Sildenafil therapy targeted to improve perinatal outcomes in pregnancies complicated by severe early‐onset IUGR. Sildenafil treatment was associated with improved fetal growth velocity, as assessed by serial AC measurement by ultrasound, compared with women who remained Sildenafil‐naive. In addition, Sildenafil therapy was associated with a trend towards improvement in both perinatal survival and intact survival, but we were underpowered to assess these outcomes. It is also reassuring that there were no adverse maternal side‐effects from Sildenafil therapy in the study group.
Therefore, Sildenafil may represent a novel intervention for these pregnancies. Currently, women and families faced with the diagnosis of severe early‐onset IUGR have two standard‐of‐care options: expectant management with maternal lifestyle modification and maternofetal surveillance or pregnancy termination. Neither is attractive. Currently, there are no specific evidence‐based therapies for severe early‐onset IUGR. Nonspecific interventions include primarily the lifestyle modifications of reduced work, stopping work, stopping aerobic exercise, rest at home and hospital admission for rest and surveillance. Although these widely accepted interventions are not based on evidence from randomised controlled trials, they are used in the belief that rest will reduce the steal by the glutei and quadriceps from the uteroplacental circulation. Preliminary evidence supports further investigation of calcium channel blockers, but not l‐arginine, to improve fetal growth.6, 7
We chose the outcome of interval AC growth, rather than the more common percentiles for gestational age, to maximise sensitivity. AC percentiles were commonly <1st percentile for gestational age throughout the clinical course of both naive and exposed fetuses in our study population, even though there was an apparent relative improvement in fetal growth velocity in the Sildenafil‐exposed cohort. An AC measured as <1st percentile will remain <1st percentile whether there has been appropriate interval growth or no interval growth whatsoever. However, the clinical implications differ substantially between the two growth patterns. Consequently, we believe that this is the most clinically relevant manner of presenting results in intervention studies of pregnancies complicated by severe IUGR. The caveat, of course, is that this outcome measure may be limited by inter‐observer variability in AC measurement. Inter‐observer variability was not formally assessed in this study among the seven sonographers performing measurements for women in the study population. However, our institutional standards for the repetition of AC measurements and the reporting of only concordant measurements approved by the reporting sonologist probably minimise this variability, and any errors are likely to have been randomly distributed between the exposed and naive cases.
Our findings concur with the observed effect of Sildenafil on isolated resistance arteries from women with IUGR.3 This ex vivo effect was more marked for IUGR arteries than for those from women with pre‐eclampsia, and may help to explain why there was greater apparent benefit in women with pregnancies complicated by IUGR than observed when women were randomised to receive Sildenafil as disease‐modifying therapy in pre‐eclampsia.8
In Manchester, UK, we observed that arteries from women whose pregnancies were complicated by pre‐eclampsia were similarly constricted, but, although resistant to Sildenafil, relaxed in the presence of the phosphodiesterase‐5 inhibitor, UK‐343664. Given the similar primary defect observed in women with IUGR and women with pre‐eclampsia, we performed a small randomised controlled trial to determine whether or not Sildenafil might prolong pregnancy in women with pre‐eclampsia.8 Thirty‐five women with pre‐eclampsia at gestational ages 24–34 weeks were randomly assigned to Sildenafil citrate (n = 17) or placebo (n = 18). Medication was increased every 3 days from 20 mg three times daily to 40 mg and then 80 mg three times daily. There was no difference in time from randomisation to delivery in the two treatment groups. Sildenafil, in the escalating dose regimen 20–80 mg three times daily, was well tolerated.8
The early stillbirth (<48 hours after commencing Sildenafil) within this cohort occurred in the only fetus with reversed umbilical arterial end diastolic flow (REDF) prior to Sildenafil treatment. As Sildenafil may have altered fetal blood distribution to accelerate fetal death, we anticipate that the presence of pre‐randomisation REDF will be an exclusion criterion for the planned pilot trial of Sildenafil for severe early‐onset IUGR.
A limitation of this study is that the cohort of women who chose to undergo therapy with Sildenafil may have differed in some important and systematic manner from the cohort of women who chose to either continue with their pregnancy without treatment or to terminate their pregnancy; we were certainly underpowered to demonstrate this statistically. For example, a greater proportion of fetuses in the Sildenafil‐treated group had umbilical artery Doppler abnormalities and oligohydramnios at eligibility. Although not statistically significant, a greater proportion of treated mothers also developed severe pre‐eclampsia. This increase in pre‐eclampsia in the treated group may be explained by both more severe placental disease at baseline and continued exposure to a poorly functioning placenta, and not a reflection of the Sildenafil therapy itself. These fundamental differences need to be addressed through the rigour of a randomised controlled trial.
This study is further limited by the fact that we did not measure maternal Sildenafil concentrations during therapy to compare the in vivo concentration with the effective concentrations known to dilate maternal uteroplacental vascular endothelium on wire myography.3 In addition, estimations of uterine blood flow were not performed in either cohort of women. However, there were no adverse maternal side‐effects of Sildenafil noted in the treatment group.
The primary risk of Sildenafil treatment is that more babies may survive to face significant, life‐altering, complications of prematurity. Such complications are severe intracranial haemorrhage (and consequent neurodevelopmental delay), hypoxic–ischaemic encephalopathy, severe retinopathy of prematurity, chronic lung disease/bronchopulmonary dysplasia requiring home oxygen therapy, and necrotising enterocolitis resulting in short bowel and failure to thrive.5 This raises moral and ethical concerns, as these complications would alter the life trajectory of, and financial burden for, the affected child and their family. This study design did not permit the analysis of neonatal and long‐term morbidity and mortality, but it is imperative that future studies be designed to address these outcomes.
Conclusions
In summary, we have presented data that suggest that Sildenafil treatment may offer a new opportunity to improve perinatal outcomes for women whose pregnancies are complicated by severe early‐onset IUGR. However, these data are not sufficiently robust to guide decision‐making about the use of Sildenafil citrate in pregnancies complicated by severe early‐onset IUGR. Once a randomised controlled trial has been mounted, we believe that the use of Sildenafil citrate for the indication of severe early‐onset IUGR should only occur within the confines of such a randomised controlled trial. The planned STRIDER (Sildenafil TheRapy In Dismal prognosis Early‐onset intrauterine growth Restriction) Pilot Trial is designed to be the next step in addressing this issue. Should we proceed to a definitive STRIDER Trial, plans will be made to secure funding to maintain contact with the children for neurodevelopmental follow‐up at 5 years of age. Pending the funding of the STRIDER Pilot Trial, we will host a Sildenafil for IUGR Registry through the Motherisk Program, Hospital for Children, Toronto, ON, Canada (http://www.motherisk.org).
Disclosure of interest
None of the authors have a conflict of interest.
Contribution to authorship
PvD, LAM, AG, MMW and PNB developed the hypothesis. SD, BL, KIL and PvD collected the data and performed the analyses. All clinician members of the RAFT team were involved in the care of the women. PvD and SD were primarily responsible for manuscript preparation. All authors contributed to the interpretation of the data and manuscript preparation.
Details of ethics approval
University of British Columbia Children’s and Women’s Research Ethics Board certificate numbers H09‐03393 and H09‐02319.
Funding
PvD, LAM and SPM receive salary support from the Michael Smith Foundation for Health Research. PvD receives additional salary support from the Canadian Institutes for Health Research and the Child and Family Research Institute. SD receives support from the British Columbia Ministry of Health.
Acknowledgements
The other members of the RAFT Group are as follows: Heather Abby, Blair Butler, Leanne Dahlgren, Marie‐France Delisle, Genevieve Eastabrook, Ariadna Fernandez, Alain Gagnon, Zoë Hodgson, Jennifer Hutcheon, Marie‐Hélène Iglesias, KS Joseph, Nancy Kent, Sayrin Lalji, Sarka Lisonkova, Deborah McFadden, Gerald Marquette, Chantal Mayer, Deborah Money, Beth Payne, Tracy Pressey, Denise Pugash, Dorothy Shaw, Francine Tessier, Elizabeth Waterman and Carmen Young. Funding support for individual investigators was received from the Canadian Institutes for Health Research, Michael Smith Foundation for Health Research, the Child and Family Research Institute and the British Columbia Ministry of Health.
Number of times cited: 73
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