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 Contraceptive CHOICE Project

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Background 

  • Title: The Contraceptive CHOICE Project: Reducing Barriers to Long-Acting Reversible Contraception 

  • Publishing Info:

    • Done by a group at the department of Ob/Gyn at Washington St. Louis School of Medicine (first author was a PhD!) 

    • Published in AJOG in 2010 (first 2500 patients) 

    • Follow up was published in Clinical Ob/Gyn 2014 - 9256 women 

  • Who funded this study 

    • Funded by an anonymous foundation + also Midcareer Investigator Award in women’s Health Research, Clinical Translational Science Award, and NCRR 

  • Why was this study done? 

    • About half of the pregnancies that occur in the US are unintended 

    • A lot of pregnancies results from incorrect or inconsistent use of birth control methods 

    • At the time, LARC use was low, <3% of women in the US used a LARC 

    • CHOICE was done to promote use of LARCs in the St. Louis region 

  • Goal: 

    • Objective: provide no-cost contraception to a large number of women in that region 

      • Secondary: reduce unintended pregnancy at the population level 

    • In order to accomplish, had to overcome two barriers: 

      • Financial obstacles 

      • Lack of patient awareness of LARC method safety and efficacy 

Methods 

  • Type of study

    • Prospective cohort study of 10,000 women in St. Louis region

  • Intervention

    • Provided each participant with the contraceptive of her choice at no cost for three years  

  • Subject recruitment

    • Convenience sample - meaning no randomization, etc. Just chose women at specific clinic locations and via general awareness of CHOICE through medical providers 

      • Clinics were university-affiliated clinics, two facilities providing abortion services, community clinics, etc. 

    • Eligibility: 

      • Age 14-45

      • Reside in or seek clinical services at recruitment sites in St. Louis region 

      • Sexually active with male partner in last 6 months or anticipate sexual activity with male partner in next 6 months 

      • No tubal or hysterectomy 

      • Does not desire pregnancy in next year 

      • Not currently using contraceptive method or interested in starting a new reversible contraceptive method 

    • Recruitment and screening was done by person on site or by telephone 

      • Person was trained with scripted intro to LARC methods if LNG-IUD, copper IUD, and subdermal implant

      • Enrollment occurs in 1.5-2 hr in person process

        • Rule out pregnancy

        • Due to staff constraints, not everyone got the same counseling - so at the community sites, patients received routine family planning counseling 

      • Informed consent 

    • LARC method

      • If they wanted a LARC method, then they had insertion by trained professional 

      • Emergency contraception was provided if needed  

    • Follow up: phone follow up at 3, 6, 12, 18, 24, 30, 36 months post enrollment 

      • Given $10 for each completed survey 

      • Also screened for gonorrhea and chlamydia at 12, 24, and 36 month contacts 

      • Huge undertaking to follow people for 3 years! 

      • Collected info on baseline demographics, OB and gyn history, etc. 

Results 

  • Findings for first 2500 women (2010 study) 

    • Population

      • Between August 2007 - December 2008, screened 4107 women, 3522 met eligibility criteria, 2500 enrolled 

      • 74% (1845/2500) of enrollments occurred at university-based recruitment site  

      • Average age: 25 (range 14-45), majority were 25 or younger (only 36.9% >25)  

      • 49% white, 44% black 

      • 42% no insurance, more than half reported difficulty paying for transportation food, housing, or medications 

      • 63.7% single or never married

      • 41% nulliparous, 54% of parous women reported having 2 or more children 

      • 67.1% chose a LARC, and 32.9% chose other methods 

        • Of those that chose LARCs: 46.8% LNG-IUD, 9.3% Copper IUD, 11.0% subdermal implant 

        • LARC users more likely to be recruited at an abnortion clinic (RR 1.2, 95% CI 1.1-1.2), report greater parity, or history of abrotion 

        • Those who reported black or other race, single or never married, one or no lifetime partners were less likely to choose LARC 

  • Findings for all the patients 

    • Demographics were overall pretty similar 

    • At the end of the study:

      • LARC users were more likely than non-LARC users to continue at the 12 and 24 months with method (86% vs. 55% at 12 months, 77% vs 41% at 24 months)  

      • At 12 months, the IUDs had highest continuation rates (88% for LNG-IUD, 84% for copper iUD), same at 24 months (79% for LNG-IUD and 77% copper) 

  • Some people voiced concern that with increased LARC use, there may be increase in high risk sexual behavior — no evidence to suggest that there was increased sexual risk-taking 

    • 71% reported no change in their number of sexual partners at 6 and 12 months; only 16% report increase, and of those, 80% experienced a change from 0 to 1 partners 

    • Percent of women reporting multiple partners at baseline was significantly reduced at 6 and 12 months (5.2%, 3.5%, 3.3% respectively) 

  • Reduction of unintended pregnancies! 

    • Failure rates for pill, patch, and ring = 4.8%, 7.8%, 9.4% at 1, 2, and 3 years 

    • Failure rate for LARC users remained <1% throughout the 3 year follow up (cumulative was 0.3%, 0.6%, and 0.9% at each year respectively) 

    • Non-LARC users were 22x as likely to experience an unintended pregnancy compared to LARC counterparts 

    • Adolescent users of pill, patch, or ring were twice as likely as older women to experience unintended pregnancies 

Very cool: super decreased rates of pregnancy, birth and abortion among teens! 

National for each: 158/1000, 94/1000, 41/1000

CHOICE: 34/1000, 19.4/1000, 9.7/1000 - Greater than 75% reduction! 

  • Contraception in the overweight and obese populations 

    • BMI was not found to be significant factor associated with increased risk of method failure for pill, patch, or vaginal ring (there were a total of 334 unintended pregnancies, 128 were determined to be contraceptive failure)

    • Weight gain

      • Those who perceived weight gain were more likely to be implant or DMPA users 

      • Objective weight gain on average was 10.3 lbs 

      • Adjusted models only identified black race as having significant association with weight gain in 12 months 

  •  STIs: Prevalence of GC, CT, and trich were higher in the CHOICE cohort than the national average at baseline 

    • 7.9% had one or more 

Conclusions 

  • Huge # of women seeking reversible contraception 

    • When barriers of cost, access, and knowledge are removed, women choose the most effective and least-user dependent methods more often 

      • In general population, LARC use was 3% 

      • In this population, 46% chose LNG IUD, 11.9% chose Copper IUD, and 16.9% chose implant 

    • Continue to use them 

    • Also found they were highly satisfied 

    • Also decrease risk of unintended pregnancies, teen pregnancies 

What do we do now? 

  • Some pretty cool follow up: 

    • Colorado Family Planning Initiative - provides access to long-acting reversible contraception 

    • Teen birth rates cut in half, abortion rates cut in half 

    • Average rate of first birth increased by 1.2 years among all women 

    • Cost avoided: $66.1-69.6 million

  • Per CDC we have definitely increased LARC use now! 

    • 2015-2017: LARC use was up to 10.3% 

    • LARC was highest among women 20-29 (13.1%)

The CHAP Trial

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The CHAP Trial: Chronic Hypertension And Pregnancy

Formal Publication Title: Treatment for Mild Chronic Hypertension during Pregnancy

https://www.nejm.org/doi/full/10.1056/NEJMoa2201295 

Some general background information

  • Who did the study and who published it?

    • The CHAP Consortium - a group of institutions in the USA, with protocol approved by the National Heart, Lung, and Blood Institute (NHLBI). 

    • Recruiting took place across 61 institutions in the USA

  • Where was it published? 

    • The New England Journal of Medicine in May 2022 - hot off the press!

  • Why was the study done? 

    • Recall that after the CHIPS trial (we covered last week!), we still had some outstanding questions:

      • 1) In the wake of CHIPS, there was renewed interest in the concern about antihypertensives and growth restriction. 

      • 2) The CHIPS trial lumped together gHTN and cHTN – CHAP restricted care to true cHTN.

      • 3) While CHIPS showed looser control of HTN didn’t result in major outcomes differences, there were some non-significant differences in rates of severe blood pressures and lab abnormalities.

    • With all of these things taken together, CHAP aimed to more narrowly answer the question of whether tight versus loose control of cHTN would result in fewer adverse pregnancy outcomes. 

  • What was the research question?

    • Will a blood pressure goal of <140/90 (versus 160/105) result in a lower incidence of adverse maternal and perinatal outcomes in patients with chronic hypertension in pregnancy? 

      • → essentially the same question, but more narrowly targeted, than CHIPS. 

Methods

  • Who participated and when?

    • Recruited 

    • Eligibility: 

      • Pregnant patients with known or new cHTN and singleton pregnancy prior to 23 weeks (33w6d in CHIPS)

        • New cHTN was diagnosed based on criteria of BP 140/90 on 2 occasions at least 4 hours apart prior to 20 weeks gestation without prior diagnosis.

        • Pre-existing cHTN was defined by documented elevations in BP and previous/current antihypertensive therapy, including lifestyle modifications alone. 

      • Pregnancy dating needed to be confirmed according to ACOG criteria with ultrasound performed before randomization. 

    • Exclusion criteria:

      • Severe HTN or BP requiring more than one antihypertensive treatment;

      • Secondary cause of hypertension (i.e., renal artery stenosis);

      • Multiple gestation;

      • “Pre-specified high risk illnesses or complications that may warrant treatment at a lower BP level” - severe cardiac or renal dz as examples

      • OB conditions that increased fetal risk;

      • Contraindications to first-line antihypertensive drugs used in pregnancy

  • How was the study done?

    • BP was measured with an automated cuff (same across sites) to screening/enrollment and to guide medication adjustments, with research staff performing measurements by a specified protocol.

    • Randomized to:

      • Tight control group: goal BP < 140/90

      • Less tight group: goal BP <160/105

        • Therapy, if ongoing, was stopped in the less tight group unless severe BP developed.

        • If a severe BP was seen, the target for acute treatment was <140/90.

    • Web-based variable block randomization program.

    • Treatment was supplied as 1st line with nifedipine XL or labetalol and prescribed by trial investigators

      • Amlodipine and methyldopa were also considered if preferred by patient

      • Meds were prescribed to maximal recommended dose that was not associated with poor side effects before iniiating a second medication

      • Control group received medications in a similar fashion only if severe HTN developed.

      • Pill counts were performed to assess adherence.

  • What outcomes were they looking for?

    • Primary outcome

      • A composite of:

        • Preeclampsia with severe features occurring up to 2 weeks after birth;

        • Medically-indicated preterm birth before 35 weeks because of maternal/fetal illness (i.e., not for PPROM/PTL)

        • Placental abruption

        • Fetal/neonatal death

          • ACOG criteria were used to define preeclampsia with severe features; however, a BP of 160/100 or greater in absence of signs and symptoms of preeclampsia/proteinuria/lab abnormalities was not considered sufficient to diagnose PEC with SF.

      • The primary outcome was assessed in five pre-specified subgroups as well:

        • cHTN treatment status at baseline:

          • New diagnosis of cHTN

          • Diagnosed and receiving meds

          • Diagnosed and not receiving meds

        • Race/ethnicity

        • Diabetes status

        • Gestational age at enrollment (<14 weeks or > 14 weeks)

        • BMI (<30, 30-40, and >40).

    • A primary safety outcome was also prespecified: poor fetal growth

      • Defined as birth weight less than 10%ile for gestational age and infant sex

      • Also assessed at <5%ile.

    • Secondary outcomes were numerous:

      • Maternal death and various serious complications

      • Exposure to severe hypertension

      • Cesarean delivery

      • Any preterm birth and any serious neonatal complications/NICU stay

  • Patients were followed to 6 weeks postpartum

  • A blinded outcome adjudication committee reviewed all patient charts suspected of having primary or secondary outcomes to assess and confirm

  • 2404 patients was the intended sample size (1202 per group) to detect a reduction of 25% in the primary composite outcome, at a baseline incidence as low as 10%.

    • The discussion in the methods of how this sample size was agreed upon was very interesting and worth a look through for any of our statistics friends out there! – initially wanted to have 4700 patients but after IRB review settled upon this smaller size.

Results

  • Who did they recruit? 

    • 29,772 patients underwent screening, and 2419 subsequently underwent randomization; the final sample size for analysis was 2408, with 1208 in the active treatment arm (tighter control) and 1200 in the control arm (loose control).

    • 83 patients were lost to follow up for the complete study; 38 in the active group and 45 in the control group.

  • Baseline characteristics were similar:

    • cHTN status:

      • 56% in each arm had known cHTN and were receiving medication

      • 22% had known cHTN but were not on medication

      • 22% had newly diagnosed cHTN

    • BMI: both around 37.5

    • DM: 15.8% in each arm

    • 44.7% in each arm on aspirin therapy 

  • Labetalol was most common medication used (61.7%) followed by nifedipine (35.6%), and only 2.7% received other meds.

    • Active treatment group had more patients taking meds (88.9% for active, 24.4% for control).

    • BP also was predictably lower in the active treatment group after randomization:

      • 129.5 mmHg vs 132.6 mmHg (-3.1) systolic

      • 79.1 mmHg vs 81.5 mmHg (-2.3) diastolic

  • Outcomes

    • Primary: composite of severe preeclampsia, abruption, medically-indicated PTB < 35wk, fetal/neo death

      • 30.2% of active treatment group

      • 37.0% of control group

        • aRR 0.82, CI 0.74 - 0.92 – p<0.001

        • Number of patients needed to treat to prevent one primary outcome event: 14.7 (95% CI 9.4 - 33.7)

      • By event:

        • PEC + SF: 23.3% active vs 29.1% control

        • PTB < 35 wks: 12.2% active vs 16.7% control

      • By pre-specified subgroups:

        • The benefit seemed to be present for all pre-specified subgroups, except:

          • Newly diagnosed cHTN (RR 1.00)

          • BMI > 40 (RR 0.98)

  • Primary safety outcome: birth weight < 10%ile

    • 11.2% in active group vs 10.4% in control group

      • aRR 1.04, 95% CI 0.82 - 1.31; p=0.76.  → not statistically different!

    • For <5%ile: 5.1% vs 5.5% – also not different!

      • I.e, more aggressive treatment didn’t seem to impact rates of birth weight <10% or <5% as potentially feared.

  • Secondary outcomes:

    • Maternal: no substantial differences, except:

      • Severe-range HTN in 36.1% of active and 44.2% of control

      • Preeclampsia in 24.4% of active and 31.1% of control (RR 0.79, CI 0.69-0.89)

    • Fetal: no substantial differences, except:

      • PTB before 37 weeks: 27.5% active and 31.4% control (RR 0.87, CI 0.77-0.99)

      • Low birth weight <2500g: 19.2% active and 23.1% control (RR 0.83, CI 0.71-0.97)

  • Interesting as well that aspirin use did not seem to demonstrate a difference in development of any primary or secondary outcome… 

Conclusions and What We Do Now / What Should We Take Away

  • The authors conclude from this paper that having a target BP of 140/90 or lower was associated with better pregnancy outcomes than a target of 160/105, without any significant differences in safety outcomes for neonates.

  • Strengths:

    • A diverse, nationwide cohort with lots of patients

    • Strictly looking at chronic hypertension with early pregnancy enrollment (prior to 23 weeks)

    • Modern definitions of preeclampsia and other hypertensive disorders of pregnancy 

    • Overall results consistent with CHIPS – i.e., ~50% reduction in rates of severe-range BP, no difference in birth weight/growth restriction

  • Weaknesses:

    • High ratio of patients screened : patients enrolled – over 29k were screened for a trial size of ~2400!

      • This probably reflects a lot of vigorous selection which is a strength of this study, and importantly the demographics of those screened versus selected did not significantly differ. 

    • Left out a lot of higher risk patients: cardiac/renal disease patients, secondary hypertension, etc.

      • Additionally, in the prespecified subgroup analyses, the treatment effect was not seen in patients with BMI > 40 or patients with newly diagnosed cHTN – the study was not powered to assess these independently but may need to be seen if other strategies are better in these groups.

    • The definition of cHTN changed! – ACC/AHA in 2017 (mid-recruitment) lowered the target to 130/80. We don’t know if that might be better, or worse, as a target.

    • Only short term follow up – longer term follow up will help inform if there are any benefits ultimately with maternal or neonatal risks.

  • Interesting points:

    • NNT of 14.7 to reduce primary outcome is really excellent, especially given the other safety data provided in this trial (short-term).

    • Aspirin use was equal between groups – post hoc analysis demonstrated it did not influence primary outcome measure!

      • This study probably lends some support to the aspirin skeptics out there, but wouldn’t necessarily throw aspirin away based on this trial alone.

  • SMFM CHAP Statement: overall supportive of a target to goal BP of <140/90 based on this trial, mentioning the limitations we just went through. 

The CHIPS Trial

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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 CREST Study

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Here’s the RoshReview Question of the Week!

Which of the following methods of sterilization has the highest relative risk for ectopic pregnancy?

Check your answer and get a special deal on RoshReview at the link above!

Background: 

  • Who did the study? 

    • Study was done by the US Collaborative Review of Sterilization Working Group 

    • CREST was part of the CDC and conducted with the NICHD 

    • Conducted with 10 year follow up and was done at multiple medical centers (Baltimore, MD, Buffalo, NY, Chapel Hill, NC, Honolulu, HI, Houston, TX, Memphis, TN, Sacramento CA, St. Louis, MO, San Francisco, CA) 

  • Where was the study published? 

    • AJOG in 1996 

    • Presented at the Annual Meeting of the American Gynecological and Obstetrical Society in Napa, CA in 1995 

  • Why was the study done?

    • Tubal sterilization is the most prevalent form of contraception among married women and formerly married women in the US 

    • While sterilization was common, there was not widespread data about their efficacy, especially over time 

  • Objective: To assess the effectiveness of various methods of tubal occlusion 

Methods: 

  • Who was included? 

    • Prospective study of women undergoing tubal sterilization at the above mentioned medical centers from 1978 -1986 

    • Ages 15-44 years 

    • Patients were approached before their sterilization procedure 

  • How was it done? 

    • If the patient agreed, information about her history was obtained 

      • Characteristics of the surgical procedure, including complications during the surgery and afterward, were recorded 

      • Contacted at 1 month for brief follow-up 

      • Annual follow-up planned for 5 years for all patients 

      • If they were enrolled early enough, patients also had annual followup for 8-14 years after sterilization 

      • If the patient could not be contacted for the follow up then the last completed interview was used in the analysis 

    • At the follow up, all patients were asked: “Since your tubal sterilization, have you had a positive pregnancy test or been told by a physician that you were pregnant?” 

      • If yes, the interviewer then had a separate form with additional info about the pregnancy 

      • Excluded from further follow up if they became pregnant, had a repeat sterilization, a tubal anastomosis, or hysterectomy 

    • Type of tubal occlusion included: (don’t need to say all of these) 

      • Laparoscopic unipolar coagulation - don’t do these anymore! 

      • Laparoscopic bipolar coagulation - I have never seen this 

      • Laparoscopic silicone rubber band application - I think I did a few of these 

      • Laparoscopic spring clip application - Filshie clips? 

      • Partial salpingectomy (including Pomeroy, other types of partial, and total salpingectomy) 

    • If a pregnancy was identified, they were classified into: 

      • True failure (pregnancy conceived after sterilization) 

      • Luteal phase pregnancy (pregnancies conceived before sterilization but ID’ed after) 

      • Pregnancy resulting from tubal anastomosis or IVF 

      • Or pregnancy of unknown status (didn’t get the information) 

Results 

  • Who: 

    • 10,863 women enrolled → 178 were excluded from analysis

      • Some were due to loss to follow up, refusal to be interviewed at 1 month follow up, or refusal for prolonged follow up 

      • Others excluded because of hysterectomy, repeat tubal ligation, or death  

    • Demographics 

      • Median age: 30 (so pretty young!) 

      • Most women were non-Hispanic White (52.7%) and had had at least 2 pregnancies 

      • Most common procedure: silicone band (31.2%), followed by bipolar coagulation (21.2%), postpartum partial salpingectomy (15.3%)

        • For us, that is super different! Since I think what i have done the most is postpartum or interval total salpingectomies 

        • Though for a bit, we also did Pomeroys and Parklands  

  • Follow-up 

    • 89.2% were interviewed at 1 year after sterilization, 81% at 3 years, 73% at 5 years, and 57.7% 8-14 years (so some drop off, but that’s expected) 

    • At each follow up interval, younger women (age 18-27) had lower percentage of follow-up than older women 

    • Black, non Hispanic women also had lower rates of follow up compared to white non-Hispanic women 

  • Sterilization failures

    • Out of 10,685 women in the analysis, only 143 were true sterilization failures = 1.3% failure rate  

      • 21 (14.7%) ended in SAB 

      • 26 (18.2%) were TABs 

      • 41 (28.7%) ended in delivery 

      • 47 (32.9%!!!) ended in ectopic pregnancies 

    • Another 34 women not included in analysis had luteal phase pregnancies  

    • 16 were from tubal anastomosis and IVF, and 5 were “unknown” classification

  • Above table: lifetime accumulation of sterilization failure by method from 1-10 years per 1000 procedures and 95% CI (only showing years 1-4 because all the years made the table huge) 

    • We can see that for clip and interval partial salpingectomy, there seems to be a higher rate of lifetime pregnancies 

    • Lowest risk was postpartum partial salpingectomy 

  • Also looked at 10-year cumulative probability of failure is affected by age at tubal sterilization 

    • Probability for failure in women <28 is greater than for women sterilized at ages >34 (makes sense … if you’re younger, you likely have more “fertile” years ahead of you) 

  • After adjustment for age, race, and study site, interval partial salpingectomy, spring-clip application, and bipolar coagulation were more likely than postpartum partial salpingectomy to result in sterilization failure 

  • After adjustment, black women were at higher risk than white women for sterilization failure 

  • There were also interestingly differences between sites! 

So what did this all mean? 

  • Sterilization failure rates 

    • Higher than previously thought! For all comers it was a little over 1% 

    • HIgher failure rates occurred after longer times (ie. more than 1-2 years, which was what other studies had looked at)

      • Failure rates between 5-10 years after procedure ranged from 1.2-8.3/1000 procedures depending on method 

    • Method failure rate also is affected by age, race, and also institution! (meaning how well or properly you do the procedure could affect effectiveness) 

    • Also, risk of ectopic increases with tubal ligation 

  • What was the follow-up or impact of the CREST study? 

    • There was way more data collected than just this, and way more than just this study that was published from the CREST dataset 

    • Some other studies that were interesting: 

      • Risk of regret after tubal sterilization (1985) - 2% regretted after 1 year, 2.7% did so after 2 years 

        • Characteristics of those that had more regret: age <30 (regardless of parity), concurrent C/S

          • After 5 year follow up, risk of regret in those 20-24 was 4.3%, rate for those 30-34 was 2.4% 

          • Where do we get this 20% risk of regret from??? - different study from 1999 - in women <30 years of age 

            • In that same study for women >30, risk of regret was 5.9% 

            • Also, for women <30 the cumulative probability of regret decreased as time since birth of the youngest child increased

            • Risk of regret was actually lowest for women with no previous births!!

      • Unintended laparotomy associated with laparoscopic tubal sterilization: rate was: 51/5021, so about 1%

        • Increased risk: prior abdominal or pelvic surgeries  

      • Characteristics of those that sought tubal reanastomosis

        • 6.2% sought information for reanastomosis 

        • Women who were <30 were more likely to seek out this information 

        • Of those that actually had anastomosis, they were more likely to be white, have lower gravidity, and be younger, and to have experienced changes in marital status

  • How does this change our practice? 

    • We are performing different procedures from the ones that were studied in the CREST procedure

      • Nevertheless, I still quote the findings from this study for patients when they want them: 

        • Risk of failure depends on method

        • Risk overall of failure is low, but can be as high as 1% overall, and even higher depending on age and type of procedure 

        • Risk of conversion to laparotomy from laparoscopy is overall low but increases with more surgeries in the belly 

        • Risk of regret is as high as 20% – I think I may now qualify this only for certain populations! 

      • We shouldn’t NOT perform sterilization procedures, however, just because of risk of regret 

        • Even if someone is nulliparous, young, and not married, if they are well counseled and still desire sterilization, we can perform it