The CLASP Trial

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CLASP: A randomized trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women 

Background: 

  • Who did the study and who published it? 

    • CLASP: Collaborative Low-dose Aspirin Study in Pregnancy Collaborative Group 

      • Coordinating center in Oxford, UK but multiple centers in the UK participated 

      • Published in the Lancet in 1994.

  • Why was the study done? 

    • Preeclampsia is a serious condition that can lead to both maternal and fetal morbidity and mortality 

    • Specifically, it can cause fetal growth restriction and neonatal demise due to prematurity

    • Those that did the study hypothesized that preeclampsia is due to structure and occlusive changes in the spiral arteries that can affect uteroplacental circulation

      • Thought that this contributed to FGR as well 

    • Therefore, if there is some way to prevent preeclampsia, it might also prevent some cases of FGR without preeclampsia 

    • PEC associated with deficient intravascular production of prostacyclin and excessive production of thromboxane → aspirin can modify these pathways, so low-dose aspirin might help by blocking thromboxane 

  • What was the research question?

    • Can use of low-dose aspirin in pregnancy decrease fetal/neonatal morbidity and mortality in those at high risk of developing severe preeclampsia or fetal growth restriction? 

Methods: 

  • Who participated in the study? 

    • Conducted in 213 centers in 16 countries over 5 years (from January 1988 to December 1992) 

    • Inclusion criteria 

      • Between 12-32 weeks of gestation 

      • If there was sufficient risk of preeclampsia or IUGR as deemed by the opinion of the responsible clinician, but no clear indication for or against low-dose aspirin otherwise. Divided into two groups  

        • Prophylactic entry - women with history of PEC or IUGR in previous pregnancy, chronic hypertension, renal disease, or other risk factors (maternal age, family history, multiple pregnancy) 

        • Therapeutic entry - women with signs or symptoms of preeclampsia or IUGR in current pregnancy 

    • Exclusion criteria 

      • Increased risk of bleeding 

      • Asthma 

      • Allergy to aspirin 

      • High likelihood of imminent delivery 

  • How was the study done? 

    • Randomized controlled trial 

    • Staff would call a central 24-hour service at Clinical Trial Service Unit at Oxford —> randomized by computer to get a specific trial treatment pack containing aspirin or placebo tablets 

      • Minimization algorithm was used to limit differences between treatment groups for certain prognostic baseline variables 

    • Treatment was either 60 mg aspirin daily or matching placebo tablet 

      • Sign of the times: currently, we use 81 mg here in the US and the current low dose aspirin in the EU is 150 mg 

    • Follow-up 

      • Single page follow-up form completed after hospital discharge of both mother and baby (or 6 weeks postpartum if either had not been discharged) 

      • Compliance with study treatment 

      • Use of antihypertensives or anticonvulsant drugs (remember this was before magnesium!) 

      • Major events that occurred after randomization (esp. Preeclampsia, fetal loss, maternal or neonatal bleeding) 

      • Birthweight, vital status of baby, and neonatal complications 

  • What outcomes were they looking for? 

    • Main outcomes: 

      • Development of proteinuric pre-eclampsia 

      • Estimated duration of pregnancy 

      • Crude birthweight, birthweight <3rd%ile for sex and gestational age 

      • Stillbirth/neonatal death due to preeclampsia or maternal hypertension or associated with IUGR, or ascribed to maternal or neonatal bleeding 

      • Death of baby at any time attributed to preeclampsia, maternal hypertension, or IUGR 

    • A word on definitions 

      • This was 1994, so the definition of preeclampsia was very different 

      • Defined proteinuric preeclampsia as:  

        • For those with baseline diastolic pressure <90 mmHg, hypertension defined as rise of at least 25 mmHg to 90 mmHg or higher 

        • For those with initial diastolic pressure of 90mmHg or higher, increment of at least 15 mmHg was required 

        • Proteinuria was defined as appearance after randomization of at least 1+ on protein stick-testing during pregnancy w/o UTI evidence 

      • Defined IUGR as: 

        • Birthweight <3rd%ile for sex and estimated gestational maturity 

      • Preterm delivery: before 37 weeks 

    • Other outcomes 

      • Also looked at comparisons regarding parity, prophylactic use according to time of entry (<20 weeks or >20 weeks), and therapeutic use according to time of entry (<28 weeks or > 28 weeks) 

    • Statistics 

      • Wanted to be able to detect a decrease of a quarter in incidence of proteinuric preeclampsia, increase of 100g in mean birthweight, and increase of 1 day of mean duration of gestation 

      • Initially wanted 4000 women, but because this size could not detect differences in rate of stillbirth and neonatal death ascribed to preeclampsia, ultimately decided to include 10,000 women 

Results:

  • Who did they recruit? 

    • 9364 women randomized (4683 in aspirin arm and 4681 in placebo arm) 

      • 74% in prophylaxis for preeclampsia, 12% for prophylaxis of IUGR alone 

      • 11% for treatment of preeclampsia, 3% for treatment of IUGR alone 

    • Some other interesting characteristics: 

      • 62% of women were enrolled at 20 weeks gestation or earlier 

      • 2% had already developed preeclampsia 

      • 28% were primigravidas 

    • Post delivery follow up forms were obtained for 9309 patients (99.4%) 

    • Compliance 

      • Of the 8915 randomized patience where compliance information as gathered, 96% started the medication, 66% continued treatment for 95% of the time, and 88% continued for 80% of the time between randomization and delivery 

  • Outcomes - note, there are a TON of findings in the results section, but for time purposes, here are the main ones 

    • Preeclampsia 

      • 6.7% of women on aspirin had preeclampsia compared to 7.6% of those with placebo 

        • 12% reduction, but not statistically significant 

        • No difference when looking specifically at women who entered for prophylaxis vs. therapeutic reasons 

      • Effect was greater among women who entered for prophylaxis at 20 weeks gestation or earlier (22% reduction) p =0.02) 

      • Interestingly, when looking at those that delivered earlier, there was a progressively greater reduction in preeclampsia with aspirin use 

  • Duration of pregnancy 

    • Average duration of pregnancy was 1 day longer among aspirin allocated patients than placebo allocated women (38.15 vs. 37.99 weeks), p=0.05 

    • Aspirin did reduce likelihood of delivery before 37 weeks 

      • 19.7% vs. 22.2%, p=0.003 

    • Seemed to be in prophylactic group 2 fewer preterm deliveries/100 women allocated to aspirin 

    • In therapeutic group, benefit was about 5 fewer preterm deliveries/100 women allocated to aspirin  

  • Birthweight 

    • Aspirin group had babies that were on average 32 g greater (p=0.05) 

    • Slightly smaller proportion of babies with IUGR, but not statistically significantly different 

    • Interestingly, among women entered for therapeutic reasons, aspirin seemed to have discrepant effects, with increased incidence of IUGR among those entered at 28 weeks or earlier and decreased incidence among those entered later 

  • Stillbirth

    • 129 (2.7%) stillbirths/neonatal deaths in the aspirin group vs. 136 (2.8%) in the placebo group 

    • Not statistically significantly different 

  • Safety 

    • Intraventricular hemorrhage rates were not different in the two groups 

    • No significant differences in fetal or neonatal deaths attributed to hemorrhage 

Impact 

  • Conclusions from this study: 

    • Impact of aspirin on preeclampsia and fetal sequelae were smaller than previously thought 

    • POtentially important effect of aspirin could be discerned on prevention or delay of delivery with early-onset preeclampsia 

  • How do we practice now and why? 

    • So… why are we using aspirin for everything nowadays? 

      • It’s important to realize that this study, while groundbreaking, was almost 30 years ago 

    • Aspirin does have a good mechanism to potentially decrease preeclampsia development, but may need to be used earlier in pregnancy 

      • Hypothesis as stated before is that preeclampsia might be associated wit vascular disturbances and coagulation defects resulting from an imbalance in prostacyclin and TXA2 

    • Until recently, this has not borne out in the data 

    • Another study in 2017 - Aspirin for Evidence-Based Preeclampsia Prevention Trial 

      • Randomized 1776 women and was based on first trimester screening algorithms 

      • Used 150 mg aspirin vs. placebo 

      • Found significant decrease rate of preterm preeclampsia (4.3% vs. 1.6%, OR 0.38, 95% CI 0.2-0.74) 

    • Meta Analysis in 2014 from the USPSTF guideline pooled data from 15 high-quality RCTs, and showed a 24% reduction in preeclampsia (RR0.76, CI 0.62-0.95) with low dose aspirin prophylaxis (60 - 150 mg/day) 

  • So what are the actual recommendations, and what are the lingering questions? 

    • Basically, based on the data from the USPSTF guidelines, in low risk groups (where disease prevalence is 2%), the number needed to treat to prevent preeclampsia is 500

      • Compared to those in a high risk group with disease prevalence of 20%, the number needed to treat is only 50 

      • USPSTF guideline recommends giving low-dose aspirin after 12 weeks of gestation to women with absolute risk of preeclampsia of at least 8% (optimally before 16 weeks) 

      • ACOG has a list of guidelines regarding who meets criteria for aspirin prophylaxis  - can post on website

    • Lingering questions 

      • What is the best dose? 

        • Is it 60? 81? 150? - we don’t know as there hasn’t been a head to head comparison between these doses 

      • What about other things like stillbirth and fetal growth restriction?

        • Insufficient evidence, as few studies have solely looked only at stillbirth or only at FGR  

      • Preterm birth? 

        • Maybe! 

        • There is some good data coming out, so stay tuned 

Fetal Growth Restriction: An Update

Two years ago we did a podcast on fetal growth restriction with Dr. Chris Nau based on ACOG PB 204. Little did we know that soon there would be even more changes to fetal growth restriction management! We offer up today’s podcast as an overview of those changes.

More reading on these changes in the form of SMFM Consult Series #52 and the new ACOG PB #227.

Terminology to Know

  • Estimated fetal weight - is… an estimated fetal weight! In utero 

  • Fetal growth restriction - means “fetal” growth restriction. Again… in utero! 

  • SGA = small for gestational age - refers to the baby when it is born. So:

    • A fetus cannot be SGA, but can be FGR;

    • A baby can be SGA, but not FGR.

Etiologies of FGR 

  • Unchanged… review our prior episode

  • Realize that it can result from multiple maternal, fetal, and placental disorders 

Why do we care? 

  • Fetal growth restriction occurs in up to 10% of pregnancies and is a cause of infant morbidity and mortality around the world 

  • Fetuses <10th%ile at any gestational age have a risk of stillbirth of 1.5%, which is 2x the rate of fetuses with normal growth 

  • Infants with birthweights <10th%ile have increase risk of acidosis at birth, low 5 min Apgar scores, and need for NICU admission, as well as 2-5x rates of perinatal death 

Who is considered fetally growth restricted, and how do we figure that out? 

  • The SMFM Consult Series #52 recommended the definition to be:

    • ultrasonographic EFW < 10%, OR

    • AC <10% for gestational age 

  • You need to do an ultrasound - but prior to that, you probably need to have suspicion. 

    • This can be done with fundal heights at appointments.

    • Make sure you have appropriate dating!

  • US uses population-based fetal growth references (such as Hadlock) in determining fetal weight percentiles:

    • Hadlock was generated from a study of 392 pregnancies in predominantly white, middle-class women at a single institution in TX

    • An NICHD study previously developed racial/ethnic standards for fetal growth 

      • It was found that Hadlock still was better at predicting SGA and composite neonatal morbidity at birth, and had a lower ultrasound-to-birthweight percentile discrepancy than the NICHD growth standard.

    • Hadlock is usually calculated by using BPD, HC, AC, and Femur length 

Classification of fetal growth restriction 

  • Early vs. late fetal growth restriction

    • Again, per SMFM consult series defined as onset <32 weeks (early) or late (at or after 32 weeks) 

    • Early FGR tends to be more severe, tends to follow an established Doppler pattern of fetal deterioration, and can show more severe placental dysfunction than late-onset FGR.

      • Also, early FGR can be associated with genetic abnormalities 

      • Therefore, in early FGR, should get detailed ultrasound.

        • The SMFM consult series also recommends chromosomal microarray analysis if there is also fetal malformation or polyhydramnios is noted. 

  • Severity 

    • EFW <3% has been associated with an increased risk of adverse perinatal outcome irrespective of UA or MCA Dopplers.

Management of Fetal Growth Restrictions 

Remember: The reason we care about fetal growth restriction is its association with stillbirth and perinatal mortality/morbidity. To prevent that, we try and look for signs that the baby/placenta is not doing well. We can do this with umbilical artery dopplers and antenatal testing (ie. BPPs, modified BPPs … see our recent episode!

  • What are umbilical artery dopplers?

    • Assessment of blood flow toward the placenta in the umbilical arteries of the fetus 

    • In systole, the blood is being pumped forward, and in diastole, the blood should still move forward, but may be slower than in systole.

      • We look at the S:D ratios, or the speed of the blood flow toward the placenta in systole compared to diastole 

    • With increasing placental dysfunction comes placental resistance. Therefore, this can start to affect forward flow from the umbilical arteries.

      • In systole, the blood should always flow forward.

      • However, in diastole, without the heart as a pump, that blood flow can slow down. This is where we can begin to see elevated S:D ratios! Generally, elevated is >95%ile.

        • If there is even more resistance, blood flow during diastole stops. This is when you have “absent end diastolic flow” 

        • In very severe cases, the resistance in the placenta is so high that the blood flows backward toward the fetus. This is called “reverse end diastolic flow” 

  • Why do we use them?

    • As a way to assess placental dysfunction 

    • Absent and reverse end diastolic flow are associated with high rates of perinatal mortality. ‘

      • One study shows an odds ratio for fetal death of 3.59 and 7.27 for AEDV and REDV, respectively!

  • What do we do with UAs? 

    • Once fetal growth restriction is diagnosed, UAs should be serially assessed, usually 1-2 weeks depending on your institution 

    • If elevated, they should be assessed more frequently

    • The SMFM series also recommends assessment of dopplers 2-3x/week when UAs become AEDF to assess for REDF 

Management and Delivery Planning

We should mention that this can vary to some degree based on your institution! Generally speaking:

  • If FGR but >/=3rd%ile with normal UA dopplers: 

    • Serial growth scans (every 3-4 weeks) 

    • Weekly or every 2 week UA dopplers 

    • Weekly or 2x/week antenatal testing 

    • Delivery by 39th week 

  • If FGR but <3rd%ile with normal UA dopplers 

    • Same as above, but delivery at 37 weeks 

  • If Elevated S:D ratios (meaning decrease end diastolic flow)

    • Continue weekly dopplers (some institutions will do 2x/week) 

    • Growth scans q2-4 weeks 

    • 2x/week antenatal testing 

    • Delivery at 37 weeks  

  • If absent end diastolic flow 

    • Increase to 2-3x/week dopplers 

    • Discuss corticosteroids for fetal lung maturity 

    • Antenatal testing 2x/week 

    • Consider q2 week growth scans 

    • Deliver at 33-34 weeks (per SMFM). Can consider cesarean delivery. 

  • If reversed end diastolic flow (highest risk for stillbirth) 

    • Inpatient admission 

    • Corticosteroids for FLM 

    • 1-2x/day antenatal testing 

    • Consider q2 week growth scans 

    • Deliver at 30-32 weeks. Can consider cesarean delivery. 

Fetal Growth Restriction

FYI — this podcast has been updated with some new information as of 6/27/2021! Check out the update here.

On today’s episode, we tackle the new ACOG PB 204 on fetal growth restriction. There’s quite a bit to cover, so you’ll see today’s episode is a bit longer. We’ve enlisted the help of Chris Nau, MD, an MFM fellow at Brown, to help us through all the recommendations.

FGR, as Chris explains, results from a process where there is mismatch between fetal demands and placental supply of oxygen and nutrients. Symmetric growth restriction arises earlier, and asymmetric growth restriction arises later, with the differentiating factor being asymmetric growth restriction resulting in a larger head circumference : abdominal circumference ratio. The PB 204 goes into many of the common causes, but the list is long!

ACOG PB 204

ACOG and SMFM state that a sonographic estimated fetal weight less than the 10th percentile is the measurement definition of fetal growth restriction, though as Chris explains, there are a number of limitations to this definition.

Screening is performed using a fundal height at prenatal visits, and if the height is < 2cm discrepant from the gestational age, an ultrasound should be performed. Alternatively ultrasounds can be used primarily, especially with known maternal conditions that might predispose someone to FGR, or if fundal height assessments are difficult.

Once a growth-restricted infant is identified, you should check the due date calculation and make sure it is right! (Check out our previous episode on dating!) Next, re-review the mother’s medical history and pregnancy history, including aneuploidy screening, to date. A level 2 ultrasound may help identify anatomic abnormalities that point to an etiology. And identifying modifiable risk factors, including optimizing medical conditions or smoking cessation, may be worthwhile.

With respect to management, there are variable institutional protocols with respect to monitoring. Umbilical artery velocimetry reduces risk of perinatal death when added to other antenatal testing (i.e., modified BPP). Normal or elevated systolic : diastolic flow ratio does not carry increased risk to the fetus; however absent or reversed end-diastolic flow increases risk for perinatal mortality. Chris reviews our protocol at Brown in the podcast.

Timing of delivery is a tricky one — there is not great evidence, and the newest guidance from PB 204 states that reassuring fetal testing should deliver between 38w0d - 39w6d. If there is FGR plus concerning maternal or fetal findings, delivery should be considered between 32w0d to 37w6d.

When counseling about future pregnancies, there is about a 20% risk of recurrence. At this time, ACOG/SMFM do not recommend baby aspirin for prevention of FGR in the absence of other risk factors for preeclampsia.

Further reading from the OBGProject:
Fetal Growth Restriction: Diagnosis, Evaluation, and Management
Aspirin Treatment - ACOG and USPSTF Recommendations