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%)

#MedEd: Transitioning to Residency

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Today we’re joined for a special #MedEd episode by a few guests: Halley Staples, MD, who is a PGY-3 in OB/GYN at WashU in St. Louis; Helen Morgan, MD, who is a clinical professor at U Michigan; and Anita Malone, MD, associate residency program director and assistant professor at U Michigan.

This team in part recently published a narrative experience study of students transitioning into residency in OB/GYN which was fascinating. We talk to them a bit about their experiences and takeaways from their work, as well as their thoughts on the challenging transition time.

Espresso: The Emergency Department Consult

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Why do patients come to the ER with GYN complaints?

  • A whole host of reasons! But some of the most common:

    • Bleeding irregularities – heavy bleeds, mistimed bleeds, unusual bleeding

    • Pain – PID, ovarian cysts, ectopic pregnancy, ovarian torsion, endo, non GYN pain issues

    • Infections – Bartholin’s and other cysts, UTIs, PID

    • Urinary complaints – most often retention or incomplete voiding

    • OB - patients who haven’t established prenatal care, or otherwise sick OB patients (trauma, medical issues) may be first evaluated in the ED

    • Sexual assault and injuries, such as lacerations

Before the Consult: What the EM Clinician Should Do

  • Normal EM things – obtaining your acute history and HPI, vital signs, physical exam, and getting the “sick vs not sick” intuition.

    • Consider pregnancy test and pelvic exam as part of your basics.

      • Pregnancy tests should mostly be protocolized for appropriate patients in EDs, but also frequently missed in the evaluation of reproductive-aged patients.

        • If positive – be sure that your labs include a type-and-screen for Rh status, and likely plan on an ultrasound (especially if the diagnosis of pregnancy is new).

      • Pelvic exams are controversial, and we see the argument:

        • OBs are specialized in performing the exam, and we’re likely to repeat it.

        • However, particularly with bleeding – having a sense of whether the bleeding is light, moderate, or heavy/rapid helps us triage the consult urgency and a differential! 

          • Contraindications to digital pelvic exam –

            • Suspected rupture of membranes at 34 weeks or less (unless laboring);

            • Bleeding in pregnancy without confirmation of placental location.

          • OB residents – this is a long-standing controversial issue and training / advice will differ based on region and one’s own biases.

            • If it hasn’t been done and you can’t go to evaluate immediately, ask kindly for it to be performed and for a call back if the bleeding is concerning. 

        • EMs, consider bouncing back with your OB/GYN colleagues when they do a pelvic exam!

          • Getting to do these exams and then comparing your findings will help you to gain comfort with making calls when you’re in the community on your own!

What constitutes an emergency consult?

  • Sometimes, things can’t wait!

    • If you have clinical suspicion of ovarian torsion or ruptured ectopic pregnancy, those are surgical emergencies and so merit a rapid response from your GYN colleagues.

    • Heavy vaginal bleeding (>1 maxipad per hour) and/or hemodynamically unstable patient – can range from ectopic pregnancies to gynecologic cancers - need an expert in exam present to help triage.

    • Major OB traumas – ideally, this should prompt OB to be present at the time of patient arrival or rapidly.

    • The “sick” OB patient – this should also prompt OB to be present rapidly, especially if the patient is “viable” or the uterus is at/above umbilicus. Considerations for delivery might need to be made.

      • Common reasons for this could be DKA in pregnancy, sepsis in pregnancy or septic abortion, or other decompensated illness.

Framing the ED Consult

  • For our EM colleagues, we love the mnemonic BLUF: bottom line, up front.

    • “This is a consult for possible ectopic and hemodynamic instability” immediately grabs our attention.

    • Follow with that history though so we can help:

      • Gs and Ps – even we mess these up, so just sharing some important pregnancy history can be more helpful (i.e., G3P0020 is less helpful than “two prior ectopics.”)

      • Nature of presenting complaint: as you normally would

      • Vitals / hemodynamic status

      • Laboratory and imaging evaluation done or ongoing

    • In the less-emergent patient, lead off with your BLUF by starting with the specific question or ask:

      • I.e., “This is a consult for a pregnancy of unknown location, and we need your assistance in confirming the findings and coordinating follow up.”

  • For our OB colleagues, help facilitate this conversation:

    • Ask for the BLUF – “before we get to her history, can you tell me what your primary clinical concern or question is? That just helps me to triage more appropriately.” 

    • Recognize you’re not going to always get a history or question on a silver platter.

    • Formulate your differential even if it seems like a slam dunk – and make sure you’re asking the right questions to get there

      • For instance, common misses include pregnancy tests, Rh status.

    • When in doubt, go see the patient faster! You’re the expert here and your expertise is being requested. 

    • Follow up with colleagues after you see the patient, or even better as you are getting ready to see them – particularly at training facilities, your EM resident colleagues may want to go see the patient again with you to get confirmatory findings, pearls of wisdom for their independent practice, and help with counseling.

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.