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 

The CHIPS Trial

The CHIPS Trial: The Control of Hypertension In Pregnancy Study

Formal Publication Title: Less-Tight versus Tight Control of Hypertension in Pregnancy

https://www.nejm.org/doi/full/10.1056/nejmoa1404595

Some general background information

• Who did the study and who published it?

  • An open, multicenter, international, randomized controlled trial. 

    • Coordinating center: University of British Columbia (go Canada again!)

  • Where was it published? The New England Journal of Medicine in 2015 

• Why was the study done? 

  • Hypertension is common – at the time of this publication, it was estimated to affect 10% of pregnancies, with 1% being cHTN, 5-6% being gHTN, and 2-3% being preeclampsia.

  • Treatment of blood pressure at specific thresholds had not really been well defined.

    • On one hand – using antihypertensives liberally and early might help prevent maternal / fetal complications related to uncontrolled HTN.

    • On the other hand – antihypertensives might have their own consequences, as shown in other smaller studies (i.e., FGR).

• What was the research question?

  • To compare tight versus less-tight control of non-proteinuric, non-severe hypertension in pregnancy

Methods

• Who participated and when?

  • Subjects were recruited from March 2009 to August 2012 - 95 sites in 16 countries enrolled at least one patient.

  • Eligibility: 

    • Had non-severe, non-proteinuric preexisting hypertension or gestational hypertension

      • That’s right – they treated gHTN too! More on that later

      • Preexisting HTN defined as diagnosis pre-20 wks, gestational HTN defined as diagnosis after 20wks

    • A DBP of 90-105 if not receiving therapy, or 85-105 if already on treatment

      • BP were obtained at least 4 hours apart or at two consecutive outpatient visits, with the second measurement taken within 1 week prior to randomization.

      • Both BPs needed to be elevated to be included.

    • Live singleton fetus between 14w0d and 33w6d

  • Exclusion criteria

    • SBP of 160 or higher (but could be included later if they were treated and met all other eligibility criteria)

    • Proteinuria > 0.3mg/day on 24h, or a P:C >0.263, or a dipstic of 2+ or more

    • Used an ACE-I at or after 14 weeks

    • Had a contraindication to either trial group because of preexisting disease

      • Examples provided included pregestational diabetes or renal disease 

    • Multiple gestations, anomalies, or plans for TOP

    • Previous participation in the trial 

• How was the study done?

  • Randomized in blocks of 2 or 4 patients using a telephone line and pager system

  • 1:1 ratio of less-tight control (defined as target DBP 100 or lower) versus tight control (target DBP 85 or lower)

    • Control of BP was expected to the target level until delivery, with a goal of between-group difference of DBP of 5mmHg (goal based on a pilot trial of the protocol).

  • Recommendation for labetalol as drug of first choice.

    • ACE-I, ARBs, renin inhibitors, and atenolol were not permitted prior to delivery.

    • No drugs were provided by the study – this was left to physician discretion. 

  • BP at subsequent prenatal visits were obtained 3x per visit. The average of the 2nd and 3rd DBPs obtained were considered to be the DBP for the visit and used for med targeting.

    • Participants also kept a diary to record this info as well as medications and co-interventions (i.e., ultrasound, clinic visit info)

  • Adherence to protocol based on a “clinically reasonable standard” was assessed within 4 weeks of randomization.

    • This isn’t totally elaborated on, but did follow to some degree blood pressure measurements in the patient’s diary and the interventions listed.

    • Thereafter, patients were seen on a schedule dictated by their doctor/midwife. 

  • A standardized questionnaire was then given to patients at 6 weeks postpartum to identify post discharge complications.

• What outcomes were they looking for?

  • Primary outcome

    • Composite of pregnancy loss (miscarriage, ectopic, termination, stillbirth, or neonatal death) or high-level neonatal care (“greater than normal” newborn care) for more than48 hours until 28 days of life or discharge home, whichever was later.

  •  Secondary outcome

    • Maternal outcomes and complications up to six weeks postpartum, including:

      • Stroke, death, eclampsia, blindness, uncontrolled HTN, use of inotropic agents, pulmonary edema, respiratory failure, myocardial ischemia/infarction, hepatic dysfunction, hepatic hematoma or rupture, renal failure, and transfusion. 

  • Outcomes were adjudicated by a committee who were not aware of group assignments and not involved in patient’s care.

  • Additional outcomes analyzed included fetal growth and newborn complications, and incidence of severe hypertension (> 160/110) in the mother

• Some statistics interestingness:

  • This trial had some interesting analyses that we don’t frequently see in RCTs:

    • There were multiple levels of comparisons planned, and for this reason, the alpha level for significance (i.e., p value to look for) was 0.046.

    • Similarly, for secondary outcome, p<0.01 was needed, and for the additional subsequent outcomes, p<0.001 was needed.

      • We would love to have you super statistics-minded brains email us about why these adjustments are made – it has to do with the number of comparisons made and the two interim analyses that were performed to assure safety during the trial.

Results

• Who did they recruit? 

  • 1030 eligible women were recruited - 519 for less-tight, and 511 for tight control

    • Ultimately, one site needed to be excluded due to concerns about data integrity – so 497 patients were assigned to less-tight, and 490 to tight control.

    • Six patients were lost to follow up or withdrew so no data was available

    • 24 patients discontinued BP treatment prior to delivery, but their data was included as part of an intention-to-treat analysis

    • 10 patients (five in each group) had incomplete data after they were lost to follow up for the postpartum survey. 

    • 21 patients were found to have been ineligible after data analysis.

  • “Clinically reasonable adherence” to assigned treatment protocol was slightly worse in the less-tight group (76.6%) versus the tight group (82%).

  • Baseline characteristics were overall very similar:

    • Similar BMI, nulliparity, gestational age at randomization, gestational DM rate, smoking rate.

    • 25% in each group had gestational hypertension, whereas 75% had chronic HTN

      • 16% in the less-tight and 12% in the tight group had a severe-range BP at some point prior to enrollment (only statistical difference at p=0.049)

      • About 57% in each group were on antihypertensive meds at enrollment

  • Blood pressure was higher in the less-tight control group by average of 5.8 mmHg systolic, and 4.6 mmHg diastolic.

    • SBP: 138.8 vs 133.1 mmHg, p<0.001

    • DBP: 89.9 vs 85.3 mmHg, p<0.001

  • Antihypertensive meds were taken by fewer patients in the less-tight control group after randomization (73.4% vs 92.6%) and this continued after delivery (65.5% vs 78.3%). 

  • Labetalol was most commonly used agent (68.9% vs 68.8% between groups)

    • Four protocol violations for use of atenolol prior to delivery.

• Outcomes

  • Primary: neonatal composite – no difference. 

    • No significant differences with respect to other perinatal outcomes for newborns, including SGA <10% or <3%, or rates of respiratory complications.

• Secondary outcomes

• Maternal outcomes – no difference overall but rare serious events.

  • No maternal deaths.

  • In less severe events:

    • Frequency of severe hypertension was higher in the less-tight control group than tight control group (40.6% vs 27.5%, p<0.01)

    • Higher rates of abnormal labs consistent with severe preeclampsia in less-tight group (more frequent rates of thrombocytopenia, liver enzyme elevations) – however, these did not meet prespecified limit for statistical significance (0.001 for these other outcomes)

Conclusions and What We Do Now

• The authors conclude from this study that: 

  • Infant: “tight versus less tight control of maternal hypertension resulted in no significant difference in risk of adverse perinatal outcomes”

  • Maternal: “Less-tight control did not significantly increase risk of overall serious maternal complications.” 

    • While there was a more significant rate of severe hypertension and markers of severe preeclampsia, they didn’t meet the study’s threshold for significance (admittedly very challenging at p<0.001).

• CHIPS is interesting in that it has dictated how we treat hypertension and allowed for “less-tight control” as the dominant paradigm in US practice:

  • In most places, treatment of hypertension prior to more significant values consistent with severe BP is not performed.

  • Gestational hypertension is not typically treated unless severe-range pressures result

    • And nowadays, that’s classified as severe preeclampsia!

• It is interesting to think about this and the challenges with preeclampsia management – maybe we would prevent some severe preeclampsia with more aggressive treatment?

  • Those numbers are so small though, it’s hard to know.

  • But severe BP control in preeclampsia we know is very important to prevent stroke, seizures, and other complications…

• CHIPS did provide some reassuring data in that tighter and less-tight control paradigms didn’t seem to adversely affect birth weight.

• Given some of the limitations of CHIPS and some of these open questions, the CHAP trial was performed to better evaluate the strategy for treatment of specifically mild chronic hypertension in pregnancy. 

  • We’ll review this in a future podcast – but as a preview, it seems to favor more tight control! So perhaps a new strategy is already being employed at your institution or is incoming!

The MAGPIE Trial

We’re going to start dedicating a few episodes to landmark trials of obstetrics and gynecology. Have a suggestion for other trials we should review? Let us know!

The MAGPIE Trial

Do Women with pre-eclampsia, and their babies, benefit from magnesium sulfate? The Magpie Trial: a randomized placebo-controlled trial 

MAGPIE = MAGnesium sulfate for Prevention of Eclampsia

Find the trial text available here from The Lancet (2002)

Some general background information 

• Magpie Trial Collaborative Group - huge group that spanned many continents and countries.

• Funded by lots of people, but ultimately coordinated by the Resource Centre for Randomised Trials at the Institute of Health Sciences in Oxford, UK

• Why was the study done? 

  • For many decades, anticonvulsant drugs were used on women with pre-eclampsia with the thought that it could prevent eclamptic seizures. Of these, magnesium sulfate was one of the medications 

  • However, in 1998, a systematic review looked at four trials compared anticonvulsants with no anticonvulsants, and of these, magnesium sulfate was thought to be the most promising choice for eclampsia prevention

  • At the time of the study, while magnesium was starting to be used more and more to prevent seizures in those that had preeclampsia, there were still those that used other medications like diazepam, other benzos, phenytoin, barbiturates, etc. 

• What was the research question? 

  • Do women with pre-eclampsia or their babies (or both) “do better” if they are given magnesium sulfate compared to placebo, regardless of whether treatment is started before or after delivery and irrespective of any previous anticonvulsant therapies

Methods 

• Who participated, and when?

  • Initial pilot trial ran from 2/23-7/14/1998 

  • Actual trial was from 7/15/1998-11/29/2001. 

  • Study was conducted in 33 countries and spanned 6 continents

  • Eligibility:

    • If they had preeclampsia and uncertainty about whether to use magnesium 

    • Had not yet given birth or <24 hr postpartum 

    • BP had to be >140/90 mmHg x2 , with proteinuria 1+ or more 

    • Note: their definition of severe preeclampsia were a little different 

      • Severe: DBP >110 mmHg x2 or SBP > 170 mmHg x2 or proteinuria >3+

        • Or DBP >100, or SBP >150, and proteinuria >2+ and at least two signs or symptoms of imminent eclampsia  

  • Exclusion criteria:

    • Hypersensitivity to magnesium, hepatic coma due to renal failure, or myasthenia gravis 

    • If urine output was <25 mL/hr, then the dose was halved  

• How was the study done? 

  • Patients were randomized and groups were balanced for severity of preeclampsia, gestation at randomization, delivered or not, if given anticonvulsant drugs before trial entry, if multiple pregnancy, and country

  • Randomized to either magnesium or placebo

    • Magnesium: 4 g magnesium loading dose over 10-15 minutes; maintenance was then followed by infusion over 24 hours of 1g/hr

      • If areas of low resource needed to do IM, then it was an initial 4 g IV combined with maintenance of 5 g magnesium IM injected into each buttock (10g total) every 4 hours for 24 hours 

    • Placebo: similar looking pack, but was saline in the same mL amounts 

  • Monitoring:

    • Monitored reflexes - if these were depressed, then mag dose was adjusted to prevent toxicity 

    • Checked reflexes and respirations q30 minutes 

    • If eclamptic seizure: trial had to be stopped; eclamptic rescue pack was given with two packs; so those that had no mag were given 4 g mag total, and those with mag previously were given another 2g  

  • Outcomes of the trial:

    • Primary: eclampsia and death of baby before discharge from hospital (for women who were randomized before delivery)  

    • Secondary: serious maternal morbidity (won’t go through all of them, but essentially resp depression, resp arrest, pneumonia, cardiac arrest, coagulopathy, renal failure, liver failure, pulmonary edema, cerebral hemorrhage), toxicity (ie. need for ca gluconate, stopping or reducing mag), and other side effects of mag sulfate (ie. n/v, flushing, drowsiness, confusion, etc)

      • If women were randomized before delivery: also looked at complications of labor and delivery, neonatal morbidity 

    • Other: LOS, admission to ICU, NICU LOS 

What were the results? 

• 10,141 women were randomized at 175 hospitals in 33 countries

  • 47% in Africa, 27% in the Americas, 15% in Asia, 10% in Europe 

  • Data was available for 10136 women, follow-up was available for 10,110 

• Baseline characteristics (ie. age, primiparity, systolic BP at entry, severe preeclampsia, other problems of preeclampsia, gestational age at entry) were not different at entry 

• Outcomes

  • Primary outcomes

    • Significantly fewer eclamptic convulsions among women with mag sulfate then those in placebo (reduction by about 58%) 

      • (0.8% vs. 1.9% - small numbers 40 vs 96), RR 0.42

      • This effect was seen in patients who had severe preeclampsia and those without severe preeclampsia (RR for both is 0.42) 

    •  No difference in baby death for those randomized before birth 

  • Maternal mortality - also lower among women allocated to mag sulfate (0.2% vs. 0.4%), Relative risk reduction of 45% 

  • Secondary outcomes

    • No clear difference in any measure of maternal morbidity or in composite measures of serious morbidity  

      • There WAS significantly increase in side effects of mag sulfate in mag group( ie. flushing, n/v, muscle weakness, headache, hypotension, dizziness, etc) 

    • No difference in neonatal morbidity 

What was the impact of all this? 

• This was a huge landmark study in Ob/Gyn because of how many people it included across many countries, in both resource rich and resource poor settings 

• Their data was very good: high compliance, high completion of the study 

• Clearly demonstrated that mag sulfate decrease the risk of eclampsia from preeclampsia

• No increased ill effects on babies 

• Also provided a regimen (4g then 1g/hr) as well as timing (24 hours) 

What about now? 

At our institution, we only treat preeclampsia with severe features with magnesium.

But in this study, they included all patients with preeclamptics. Why the change? 

• When looking at the MAGPIE trial, specifically at the women enrolled from high-resource settings in the Western world, the reduction rate of eclamptic seizures was not statistically significant 

  • RR 0.67, 95% CI 0.19-2.37 

• A quarter of women reported adverse effects with magnesium sulfate, primarily hot flashes, and rate of CS was increased by 5% when mag was used 

• Two small randomized trials that allocated women with preeclampsia without severe features to either placebo or mag → no cases of eclampsia among women allocated to placebo and no significant difference in proportion of women that progressed to severe preeclampsia (but small size limits this) 

• Finally, rate of seizures in preeclampsia with severe features w/ mag is 4x higher than those without severe features (4/200 vs 1/100) 

• Also, with calculations of previous data, it appears that 129 women need to be treated to prevent 1 case of eclampsia, but in those with symptoms (ie. headache, blurred vision, etc), NNT is 36 

• What does the practice bulletin say?

  • Evidence less clear about preeclampsia w/o SF and mag 

  • Can be individualized by institution or by physician  

What about dosing? 

• MAGPIE

  • Dosing is 4g loading followed by 1g/hr 

  • But at different institutions, we have seen 6g loading, 2g/hr or 4g loading, 2g/hr 

  • What’s right??  

• The case for more vs. less magnesium

  • There is sparse data about the therapeutic range, which is usually 4.8-9.6 mg/dL or 4-8 mEq/L, but accurate mg concentration clinically effective in prevention of eclampsia has not been established 

  • Higher infusion rates increase potential for toxicity, and infusion rates >2g/hr have been associated with increased perinatal mortality in systematic review of randomized trials 

  • Lower starting bolus may increase time to therapeutic dosing 

  • Then.. there’s the BEAM trial…

    • Mg for cerebral palsy prophylaxis for babies from 24-31 weeks gestation  - regimen was 6g bolus followed by 2g/hr 

    • So many institutions will try and get two birds with one stone (6g bolus, 2g/hr for both CP prophylaxis and seizure prophylaxis if <32 weeks) 

  • … As well as the ACTOMgSO4 trial 

    • Doen in Australia and New Zealand for mag for fetal neuroprotection

    • Their dose was 4g bolus and 2g/hr 

  • Institution dependent, but we have seen a lot of combinations of both! 

Take away points: 

• Magnesium sulfate can help decrease eclamptic seizures in patients with preeclampsia 

• We have very good date to suggest it can decrease this rate by about 50% 

• However, mag is not a benign drug - 25% have side effects

• You should dose the mag somewhere between 4-6g loading dose and 1-2g/hr, but this is institution dependent 

• It is also institution dependent regarding if preeclampsia without severe features needs mag (in MAGPIE, had same amount of decrease in eclamptic seizures as preeclampsia w/ SF) 

• However, the number of those that get eclamptic seizures overall is low, and even lower in those with preeclampsia w/o SF, so there can be an argument for increased toxicity/side effects with increased NNT for those with PEC w/o SF and therefore forego it 

Thrombocytopenia in Pregnancy

Here’s the RoshReview Question of the Week!

A 23-year-old primigravid woman at 25 weeks gestation presents to the prenatal appointment to follow up on lab results. Her platelet count is noted to be 77,000/μL, decreased from 205,000/μL in the first trimester. She reports no abnormal bruising or bleeding. What is the most likely reason for her thrombocytopenia?

• Autoimmune process

• Consumptive coagulopathy

• Deficient von Willebrand factor-cleaving protease

• Hemodilution

Check your answer and enter the QE Exam Giveaway at the links above!

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Practice Bulletin 207 is our companion reading this week!

Introduction 

• Evaluation of thrombocytopenia in pregnancy can be difficult because there are many things that could cause it - not all of them are related to pregnancy 

• Definition: when platelets are <150,000/microL 

• So what is normal? 

  • Recall in our very first few episodes that pregnancy can lead to increased plasma volume and not necessarily an equal increase in blood components 

  • This can lead to what appears to be some dilutional effects 

  • In the National Health and Nutrition Examination Survey (NHANES), the mean plt count in pregnancy is as follows: 

    • Non pregnant: 273k 

    • 1st trimester: 251k

    • Second trimester 230k

    • Third trimester 225k 

    • Delivery 217 k 

    • Postpartum (7 weeks) 264k  

• Definitely suggests that some decrease in platelet count could be expected in pregnancy

What are the causes of thrombocytopenia in pregnancy?

• Gestational thrombocytopenia - benign and self limited; may even occur in the first trimester, but usually is more common as pregnancy continues; frequency is 5-10% at the time of delivery

  • But remember this is a diagnosis of exclusion! It’s acceptable if there is mild thromboctyopenia, but again, you should look if Plt <100k  

•  Immune Thrombocytopenia (ITP) - 1-3/10,000 pregnancies, but really low plts only affect a small portion of these

  • ITP is more frequent in pregnancy than in the general adult population but may be because of recognition (checking more frequent CBCs in preg) 

  • Autoimmune condition where antiplatelet antibodies interfere with platelet production and causes destruction of circulating platelets

    • Diagnosis based on exclusion of other causes of thrombocytopenia  

• Preeclampsia/HELLP Syndrome

  • Remember that it is very rare <24 weeks, and there are usually other signs and symptoms as well like elevated BP, headache, vision changes, etc. As well as other hematologic abnormalities like anemia due to hemolysis (high LDH), and may have abnormal LFTs 

  • We won’t go too much into preeclampsia since we discuss it elsewhere, but always something to keep in mind 

• Less likely things, but still things to keep in mind 

  • DIC - Disseminated intravascular coagulation

    • There is usually an underlying cause of this such as placental abruption, sepsis, etc 

    • Patients will have bleeding and oozing at IV sites for example 

    • Usually will have low fibrinogen and elevated PT and PTT labs as well  

  • Acute fatty liver of pregnancy 

  • Thrombotic thrombocytopenic purpura (either immune or hereditary)

    • Will usually present with purpura, can have neurological changes, fever, kidney injury, can have elevated BPs and may be confused with PEC 

    • Will have reduced activity of ADMATS13, but this may be a send out lab in most places and will not come back for some time 

    • Will have schistocytes on smear 

  • Lupus 

  • Infection

  • Inherited platelet disorders

So… when should we start to worry?

• When platelets are: 

  • If platelets are between 100k-150k if there are risk factors present (but usually, do not need work up and can be attributed to gestational thrombocytopenia) 

  • At any point <100k (usually this is beyond the lower end of gestational thrombocytopenia)

    • Plts of <100k only occur in 1% of uncomplicated pregnancies 

    • Remember that there is increased risk of spontaneous bleeding if Plt <20k 

    • Some institutions have cut offs for platelets for ability to give neuraxial analgesia - some places are 70-80k, some places are 100k. Please check with your institution and your patients, because this may require treatment or your patient won’t get an epidural! 

Ok, so that’s a lot of causes… how do I go about figuring out what to do? 

• Evaluation of the patient

  • Get a good history and physical - this can sometimes help you determine what it is not

    • If patient is well appearing, with no pain, vaginal bleeding, elevated blood pressure or other complaints, it’s usually not going to be something like AFLP, DIC, TTP, or preeclampsia  

    • Look through the patient’s chart: what were their platelets before? What other medical problems? What about new medications? 

    • Any history of lupus, TTP, liver disease, anemia

    • You have the CBC - did the lab do a smear? Are there abnormalities on the smear, like schistocytes? 

    • Most of the time, if you have someone who is sitting in the clinic and appears well, you may have some time  

• The asymptomatic patient with Plt >100k

  • Usually, plts between 100-150k without other cytopenis or other major clinical findings can be attributed to gestational thrombocytopenia 

  • The other major cause could be ITP, but minor ITP with plt >100k also does not need treatment 

  • Our practice is to check plts monthly to make sure they do not drop below 100k, or below threshold for neuraxial analgesia 

• The asymptomatic patient with Plt <100k 

  • Review the CBC - make sure there are no other cytopenias; ask for a smear 

  • Evaluate for HIV (usually already done in pregnant patients), as this could also lead to thrombocytopenias 

  • Obtain other coagulation panel like PT, PTT, fibrinogen level 

  • Also obtain CMP - evaluate kidney and liver function 

  • If no obvious signs, it is ok to get hematology involved early

  • More likely to be ITP if <100k, and patients can be treated with steroids or even IVIG in refractory cases if needed 

  • This is to make sure that the platelets do not drop further so that they cannot get neuraxial analgesia or so that they don’t drop too low as to cause issues with bleeding 

• What if they are symptomatic and <100k?

  • A lot of this is going to depend on their history and physical again - we are usually pretty good at evaluating for preeclampsia - get their vital signs and do your exam

    • Do they have fever? Purpura? 

  • Labs: CBC, CMP, coag panel, HIV, LDH, urinalysis, bilirubin 

  • If you are suspicious of TTP (ie. fevers, kidney injury, neurological changes) 

    • Make sure to get CT head to rule out bleed 

    • ADAMTS13 

    • Hematology consult 

  • Ok to get MFM and hematology involved early 

Management 

• Treatment for bleeding or severe thrombocytopenia 

  • If Plt are <10k or <20k, there is increased risk of spontaneous bleed 

  • If Plt <20k and severe bleed (ie. intracranial), you should give platelets regardless of the underlying cause of thrombocytopenia (yes, even in ITP if it will get consume)

• Some platelet thresholds to consider in delivery 

  • Vaginal delivery: 20-30k 

  • C/S: 50k 

  • Neuraxial anesthesia: institution based; ours is 80k; most institutions will have a count between 50-80k 

• Other considerations 

  • Operative vaginal deliveries are relatively contraindicated if there is severe maternal thrombocytopenia 

  • This is because there is concern that there could also be fetal thrombocytopenia (ie. immune mediated or hereditary) 

  • However, if you must perform an operative delivery, forceps is favored over vacuum 

  • Remember: Just because someone has ITP does not mean they can’t have an operative delivery 

• Treatment of specific disorders 

  • ITP - steroids or IVIG 

    • Dosing of steroids: prednisone 1mg/kg/day for two weeks followed by gradual taper; may need 2 weeks to see peak effect (usually 1-4 weeks for peak) 

    • IVIG should be given at least 1 week in advance to allow for maximal efficacy and platelet count retesting if trying to raise platelet counts for epidural 

    • If refractory, other methods in pregnancy are not well studied, and you should have a conversation with your MFM and hematology colleagues 

  • TTP - plasma exchange

  • Preeclampsia or DIC due to abruption: delivery! 

• What about fetal testing of platelets?

  • There isn’t really evidence to suggest we should test fetal platelets (ie. either via PUBS or from fetal scalp during labor

  •  We won’t discuss fetal/neonatal thrombocytopenia here, but just some brief reasons to test neonatal platelets: 

    • Maternal ITP 

    • Neonatal thrombocytopenia in previous pregnancy (concern for NAIT, though this is usually not associated with maternal platelet issues) 

    • Congenital anomalies associated with thrombocytopenia 

    • Bleeding or petechia on the infant 

    • Neonatal infections (ie. CMV, rubella) 

Imitators of Pre-Eclampsia

Each of the conditions we’ll discuss today could be an episode all its own, so this will be way too brief to cover these topics in detail! But it’s important to keep a broad diagnostic mind open, especially if you feel the picture doesn’t totally add up. 

Reading: Sibai: Imitators of Severe Pre-Eclampsia (2007)

Previous podcasts: Hypertension and Pregnancy Trio (3/2019)

Diagnosing Pre-Eclampsia:

• Pre-eclampsia is a syndrome - a recognizable complex of symptoms and physical findings that indicate a specific condition, but for which a cause isn’t necessarily understood. 

• We need to think about the symptoms and signs of pre-eclampsia and determine how they overlap with other diseases!

  • What else might tie together: 

    • Hypertension

    • Neurologic changes

    • Pulmonary edema

    • LFT abnormalities and RUQ pain

    • Thrombocytopenia

    • Acute kidney injury

• Some potential examples:

  • Acute hepatitis or cirrhotic liver disease

  • Lupus

  • Meningitis

  • TTP / HUS

  • Drug reactions or overdoses

  • Malignant hypertension (i.e., pheochromocytoma, renal artery stenosis)

  • Heart failure or heart attack

    • You can probably think of more if you try!

• Let’s focus this broad differential on three primary significant culprits today: Acute Fatty Liver of Pregnancy (AFLP); Thrombotic Thrombocytopenic Purpura (TTP) / Hemolytic Uremic Syndrome (HUS); and a Lupus (SLE) Flare

Acute Fatty Liver of Pregnancy

• Exactly what it sounds like -- acute fatty infiltration of the liver, typically in the 3rd trimester, leading to fulminant hepatic failure.

  • Appears to be related to defects in fatty acid metabolism -- 20% of AFLP associated with long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency of the fetus. 

• Incidence: 1 in 7k-20k pregnancies.

• Risk factors:

  • Fetal LCHAD deficiency: fetal homozygosity renders it incapable of processing fatty acids, and mother (typically heterozygous) has decreased function to keep up -- thus the infiltration.

  • Prior history of AFLP

  • Multiple gestation

  • Preeclampsia / HELLP syndrome (so they can even be co-existent!)

  • Male fetal sex

  • Low BMI (<20)

  • Nulliparity

• Typical presentation:

  • 3rd trimester: most common after 30 weeks

  • Often nonspecific symptoms: nausea/vomiting, abdominal pain, malaise, headache, anorexia

  • Frequently with hypertension +/- proteinuria 

    • Reported co-existent HELLP in 20-40% of cases

  • Hypoglycemia is frequent on laboratories - from impaired hepatic gluconeogenesis

    • Additionally can see signs of acute liver failure -- jaundice, ascites, encephalopathy, DIC. 

  • Renal failure upwards of 90% of cases.

• Diagnosis:

  • Typically a clinical diagnosis -- biopsy can be performed to demonstrate fatty infiltration, but rarely performed.

  • Swansea criteria:

    • Ranges pending on reading from 6-9 positive signs. 

      • Most typically need 6 (in my experience)

    • Supposed to be done in patients without HELLP syndrome/preeclampsia, limiting utility.

  • Imaging can be performed, but is also of limited utility in diagnosis

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Swansea Criteria (UpToDate)

• Treatment of AFLP:

• Supportive with critical care expertise! 

• Have ongoing monitoring for:

  • MELD score (Model for End-Stage Liver Disease) - high MELD > 30 associated with increased risk of maternal complications

  • Hypoglycemia: typically need infusion of dextrose-containing fluids

  • Coagulopathy

• Delivery!

  • Labor induction is reasonable if can be reasonable accomplished within 24 hours, and disease not rapidly progressing.

  • Cesarean delivery outright should be considered otherwise.

  • Betamethasone administration for FLM given, but shouldn’t delay delivery.

  • Magnesium as indicated for suspected preeclampsia and/or for CP prophylaxis. 

• Postpartum:

  • Mortality in AFLP is attributable to hemorrhage, liver failure, and kidney injury.

  • AFLP will often resolve within 7-10 days after delivery

  • Hemorrhagic pancreatitis is a potential and fatal complication known to be associated with AFLP - follow lipase

  • Liver transplantation may need to be considered in those with persistent fulminant hepatic failure (though this is rare). 

  • LCHAD deficiency testing should be pursued in infants.

    • LCHAD deficiency in newborns can be life-threatening!

Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS)

• Related but different diseases characterized by microangiopathic hemolysis, thrombocytopenia, acute renal failure, neurologic abnormalities, and fever.

• TTP - caused by deficiency in ADAMST13, a protein involved in regulating blood-clotting by cleaving von Willebrand factor from endothelial surfaces, and at the sites of vascular injury.

  • Can be familial or acquired

  • Characterized by marked thrombocytopenia - platelets frequently <20k

• HUS - can be caused by a variety of insults, but commonly Shiga-toxin from certain bacterial organisms as well as with abnormalities in complement system regulation. 

  • Renal failure is the dominating feature of HUS and tends to be particularly severe. 

• Presentation:

  • Also tends to be vague: abdominal pain, nausea/vomiting, headache, vision changes, confusion, fever

  • May also include bleeding: epistaxis, GI bleeding, petechia/purpura, hematuria (particularly in HUS)

  • Can present with or without hypertension

• Diagnosis:

  • Involve your hematology colleagues if there’s suspicion!

  • Early-onset preeclampsia may raise suspicion: 20-26ish week range, but can occur at any point

• Treatment:

  • Plasma exchange: helps to remove large multimers of von Willebrand factor and autoantibodies against ADAMST13. 

  • Steroids - help to calm autoimmune response

  • Splenectomy - helps to avoid sequestration of platelets 

  • Platelet transfusion should be avoided - may contribute to increased microvascular thrombus formation

• Delivery:

  • Not indicated immediately! PLEX and other therapies can be given opportunity to work

  • However, serial / frequent therapy is often indicated to continue pregnancy and prevent relapse

Systemic Lupus Erythematosus / Antiphospholipid Antibody Syndrome

• SLE is an autoimmune disorder with varying symptomatology but can result in significant end-organ damage

  • 30-40% of SLE patients have antiphospholipid antibodies

  • Only 1% of patients will have antiphospholipid antibody syndrome - a disorder that is characterized by microangiopathy affecting multiple organ systems, and with particularly high pregnancy risks

• Diagnosis:

  • Classically SLE diagnosis requires at least 4 / 11 American College of Rheumatology criteria;

  • However, in 2019 the ACR and European League Against Rheumatism came up with a combined criteria based on a points system:

ACR / ELAR Combined Diagnostic Criteria for SLE (2019)

• APLAS diagnostic criteria we’ve previously reviewed in our RPL episode:

• One of two clinical criteria:

  • a) Vascular thrombosis 

  • b) Pregnancy morbidity, defined as:

    • One or more unexplained deaths of morphologically normal fetus after 10 weeks of gestation by ultrasound or direct examination of fetus.

    • One or more premature births of morphologically normal neonate before 34 weeks because eclampsia or severe pre-eclampsia or recognized features of placental insufficiency.

    • Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation with maternal anatomic or hormonal abnormlaities and paternal and maternal chromosomal causes excluded.

• And one of the following laboratory criteria 

  • a) Lupus anticoagulant present in plasma on 2 or more occasions at least 12 weeks apart or 

  • b) Anticardiolipin antibody IgG or IgM isotype in serum or plasma present in medium or high titer on 2 or more occasions at least 12 weeks apart, or  

  • c) Anti-B2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma (in titer >99th%ile), present on two or more occasions at least 12 weeks apart 

• Fortunately, many patients with SLE will come into pregnancy with an established diagnosis.

  • To determine if they’re having a flare to distinguish from preeclampsia, you’ll often use a serum marker for rheumatologic disease, such as:

    • Hypocomplementemia (C3 / C4 levels)

    • Anti ds-DNA antibody levels

• Symptoms are vague, as previously described with the clinical criteria for SLE diagnosis, and have overlap with preeclampsia! 

• Treatment:

  • If known from outset of pregnancy -- these patients should definitely be on aspirin for preeclampsia prevention!

  • Steroids are often used in acute flares - prednisone

  • DMARDs - safe medications for pregnancy can include azathioprine, hydroxychloroquine, and encouraging data exists for immunomodulating antibodies (i.e., adalimumab / Humira)

  • APLAS - low molecular weight heparin for prevention of VTE and pregnancy morbidity

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SIBAI 2009 (ref above)

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SIBAI 2009 (ref above)