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 PROLONG Trial (Progesterone for Preterm Birth, Part II)

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Last week, we introduced our major progesterone trial series with a discussion of the Meis trial. We finish up this week talking about the follow up trial: the PROLONG study.

The PROLONG Trial 

Methods

  • Location

    • 93 total centers across 9 countries  

  • Eligibility criteria and exclusion criteria: pretty much the same as the earlier trial 

  • Randomization and treatment 

    • Randomized 2:1 to receive 17OHP weekly, to start between 16-20w6d 

    • Placebo was benzyl benzoate, caster oil, benzyl alcohol 

  • Outcomes 

    • Measured preterm birth <35 weeks 

    • Composite neonatal morbidity and mortality index 

    • Secondary outcomes: 

      • Neonatal death, PTB <32 weeks, PTB <37 weeks and also medical indicated preterm births 

    • Primary safety outcome: fetal/early infant death 

  • Stats 

    • Unlike previous trial, wanted it to have adequate power to identify both the primary efficacy and the primary safety analyses 

    • Therefore, needed 1665 liveborn infants to detect a reduction of 35% in the rate of the composite index 

    • Needed 1707 patients to provide 98% power to detect a reduction of approximately 30% in the rate of PTB <35w0d

Results 

  • Timeline: November 12, 2009 - October 8, 2018 

  • Total of 1740 women were consented and agreed to study 

    • 1130 allocated to 17OHP, 578 allocated to placebo 

    • 390 were randomized in the US, 1317 randomized in non-US 

  • Demographics were similar between groups 

    • 88.8% vs. 87.2% Caucasion in 17OHP vs. placebo groups 

    • Prepregnancy BMI 23 

    • Almost 90% were married, living with partner compared to just about 50% in the other study 

    • Only 7-8% smoked in pregnancy compared 20-22% in other study 

  • So… similar for each arm of this study, but very different demographic compared to the Meis trial.

  • Primary Outcome 

    • Preterm birth prior to 35 weeks: 11.0% in 17OHP vs. 11.5%

      • Spontaneous was 8.4 vs 8.9%, RR 0.93, 95% CI 0.67-1.30

    • Not a primary outcome, but PTB <37 weeks: 23.1% vs 21.9% RR 1.06, 95% CI 0.88-1.28! 

      • So different from 36 vs. 50% in Meis study 

    • Neonatal outcomes: 

      • Unsurprisingly, given no diff in preterm labor, no diff in composite neonatal morbidity and mortality 

  • Secondary Outcome 

    • Preterm birth <32 weeks - also not different 

    • Other things: cerclage, preterm labor eval, tocolysis, corticosteroids, maternal GDM, preeclampsia, chorio, abruption, CS all not different 

    • Neonatal: no difference in anything, including neonatal death, RDS, NEC, IVH, NICU admission, birth weight, TTN, PDA, ROP

Conclusions

  • Study was done in consultation with the FDA as part of approval for use of 17OHP 

  • Unlike the findings in the MFMU trial, this study had much lower event rate of PTB and did not confirm treatment efficacy 

Discussion points

  • While the Meis study was conducted in the USA, the PROLONG study was mostly not, and that was because the findings from the Meis study had changed practice 

  • Most places in the US were already prescribed 17OHP and likey didn’t want to change their practice 

  • Also, the Meis showed a large predominance of black women (60%), while there were very few in the PROLONG study 

  • Finally, there was a huge discrepancy in baseline preterm labor rates between the two studies, with the rates in PROLONG about ½ has much as that of the Meis study 

  • Why castor oil? 

    • Not that it has shown to cause preterm labor, but castor oil can cause contractions, usually due to GI distress when ingested 

  • Consequences of the Studies 

  • Follow up to the study 

    • EPPPIC - Evaluating Progesterone for Preventing Preterm birth International Collaborative - meta-analysis of individual participant data from randomized controlled trials 

      • Published in the Lancet in 2021 

      • Basically: 31 trials were included with individual participant data

        • From these studies, it seems that vaginal progesterone and 17OHP both reduce birth before 34 weeks gestation in high risk singleton pregnancies 

        • Absolute risk reduction is greater for women with short cervices 

        • The data seems a little better for vaginal progesterone in consistently decreasing preterm birth <37 weeks and <34 weeks

        • For 17OHP the data just crosses the line of no effect at <34 weeks 

The Meis Trial (Progesterone for Preterm Birth, Part I)

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One of the hottest controversies in OB in the last several years has been about the role of progesterone for treating preterm birth. We covered these trials very briefly in our episode on preterm birth prevention. Today, let’s dive deeper and start with part I - talking through the Meis Trial.

Next week, we’ll talk in depth about the PROLONG trial and some takeaways for your practice.

Background: 

  • Titles 

    • The Meis Trial - Prevention of Recurrent Preterm Delivery by 17 Alpha-Hydroxyprogesterone Caproate 

    • The PROLONG Trial - 17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A multicenter, International, Randomized Double-Blind Trial 

  • Who wrote the papers and where were they published? 

    • Meis: Dr. Paul Meis!  - Done with the NICHHD as part of the MFMU 

      • Published in the NEJM! Very fancy - published 2003 

    • PROLONG: Done by Dr. Sean Blackwell (was a president of SMFM!) and a bunch of people who are active in SMFM like Dr. Cynthia Gyamfi-Bannerman, Dr. Brenna Hughes, Dr. Judette Louis 

      • Published in American Journal Perinatology in 2020; which is a good journal but… nowhere near the impact factor of NEJM lol 

  • Who funded the studies? 

    • Meis: NICHD

    • PROLONG: AMAG Pharmaceuticals (those that make Makena) 

  • Why were the studies done? 

    • The initial study (Meis) was done to try and decrease preterm delivery (leading cause of infant mortality and morbidity in the US!). There had been small trials with prophylactic treatment with progestational compounds that had shown promise, but not all of them had positive results 

      • Had been a meta-analysis restricted to 17-OHP that showed a reduction in preterm delivery 

    • The second study was done after the first study was stopped early because it was thought to be unethical to continue recruitment given the robustness of evidence (spoilers, sorry) 

      • The FDA granted conditional approval for 17-OHP for commercial use in 2011 under the provision that another well-conducted randomized controlled trial was done 

      • This was a confirmatory trial for 17-OHP, and the FDA also required a long-term infant follow-up study 

  • Question to answer: Does the use of weekly 17-OHP in pregnancy decrease the risk of preterm birth? 

The MEIS Trial

Methods

  • Done at 19 participating centers, primary USA based 

  • Eligibility criteria

    • History of spontaneous preterm delivery in previous pregnancy between 20w-36w6d 

    • Current pregnancy between 15w0d-20w3d gestation 

    • Ultrasound between 14w0d-20w6d to confirm duration of gestation and to identify any major fetal anomalies 

  • Exclusion criteria 

    • Multifetal gestation

    • Known fetal anomaly 

    • Progesterone or heparin treatment during current pregnancy 

    • Current or planned cerclage 

    • Hypertension requiring medication

    • Seizure disorder 

    • Plan to deliver somewhere other than the 19 participating center 

  • Intervention 

    • Patients that consented were randomized to either IM study drug (17 OHP) or castor oil (omg - need to talk about this after!)

      • Had to be given first dose between 16w0d-20w6d; if they did not return before 20w6d, could not participate

      •  Weekly injections until 36 weeks 

  • Outcomes 

    • Date of delivery, birth weight, neonatal course - to assess for preterm delivery!  

  • Statistics 

    • Power calculation: 

      • Estimated 37% of patients in placebo group would have a preterm delivery 

      • Sample size calculation of 500 women, with 334 in progesterone group and 166 in placebo to find a reduction of 33% in rate of preterm delivery 

    • At second interim analysis, when 463 patients had undergone randomization, outcome data was available for 351 patients

      • The boundary (p=0.015) for test of significance had been crossed for preterm delivery, and enrollment was halted 

Results

  • Timeline: 

    • Started in April 1998, but ultimately stopped in February 1999 because the FDA ordered the company that supplied to the active drug to shut down and mandated a total recall of the company’s drugs because of poor quality control and documentation 

      • 150 patients had been enrolled 

    • The study was then restarted with a new drug company. The 150 women previously with other med were not included in the study data analyses 

    • New Timeline: 

      • September 1999 - February 2002 

  • Patient Demographics 

    • 1039 eligible, 463 eligible women gave their consent  

      • 310 in progesterone group 

      • 153 in placebo group 

    • Patients were similar in mean duration of previous gestational age (that qualified them for the study), mean gestational age at time of randomization, race, marital status, BMI, smoking, education level, etc. 

      • Of note, interestingly, approximately 60% of those in the study identified as non-Hispanic black (compare to PROLONG, which has very different demographics) 

      • Prepregnancy BMI 26 

    • But, women in the placebo group had more previous preterm deliveries (1.6 vs. 1.4, p=0.007) 

    • 91.5% of women were compliant with their injections (meaning they didn’t go more than 10 days without an injection) 

    • 50% reported at least one adverse effect 

      • Most common: 34.2% reported soreness at sight of injection; 14% reported swelling, 11% itching, 6.7% bruising 

      • More women with progesterone had swelling or a lump at injection sight 

  • Primary outcome 

    • Preterm delivery

      • Data was available for 459/463 women

      • Delivery before 37 weeks was reduced, 36.3% for 17-OHP group, 54.9% for placebo group (wtf, that’s super high) RR 0.66, 95% CI 0.54-0.81 

        • Spontaneous PTL was 29.4% vs. 45.1% respectively 

      • Findings were similar for black vs nonblack women 

      • Even more interesting, significant for delivery before 35 and 32 weeks gestation

        • Delivery before 35 weeks: 20.6% vs. 30.7%, RR 0.67, 95% CI 0.48-0.93 

        • Delivery before 32 weeks: 11.4% vs 19.6%, RR 0.58, 95% CI 0.37-0.91

    • Other things were not different: hospital visit for PTL, tocolytic therapy, corticosteroid use, CS, chorio 

  • Secondary outcome 

    • Fetal and neonatal outcomes 

      • No difference in fetal death, antepartum or intrapartum 

      • There was a significant difference in birthweight

        • <2500g was 27.2% vs. 41.1%, RR 0.66 (95% CI 0.51-0.87)  

      • Also difference in supplemental oxygen use (14.9% in 17OHP vs. 23.8% in placebo) 

      • And lastly, difference in IVH (1.3% vs 5.2%) 

    • No difference in neonatal death, TTN, RDS, bronchopulmonary dysplasia, vent support, NEC, retinopathy, etc. 

Conclusions 

  • Authors concluded: treatment with 17OHP weekly from 16-20 weeks to 36 weeks of gestation reduced preterm delivery at 37, 35, and 32 weeks in patients with history of sPTB

    • But … they also did say that there was an overall very high rate of preterm delivery (50% in placebo vs. 36% for 17OHP)

    • Next week, we’ll contrast with PROLONG!

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.