The PROLONG Trial (Progesterone for Preterm Birth, Part II)

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 

  • After Meis, everyone started doing 17OHP 

  • After PROLONG, an FDA advisory committee proposed to take Makena (17OHP) off the market in 2019 (9 to 7 vote) 

    • https://www.nytimes.com/2022/03/25/health/fda-drug-approvals-makena.html ← NY times article about all this 

  • Plan: Oct 17-19 the FDA’s advisory committee will meet to discuss the medicine and hear arguments if it should stay on the market 

• 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)

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 CHAP Trial

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. 

      • Some smaller trials continued to substantiate this association; but a large meta-analysis referenced in the CHAP background found no association between SGA and cHTN treatment.

    • 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)

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• 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

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!

Exercise in Pregnancy

Additional reading for today in ACOG Committee Opinion 804!

What are the definitions of physical activity and exercise? 

• Per ACOG: 

  • Physical activity: bodily movement produced by contractions of skeletal muscles in all stages of life

  • Exercise: physical activity consisting of planned, structured, and repetitive bodily movements done to improve one or more components of physical fitness 

  • Physical activity can maintain and improve cardiorespiratory fitness, reduce the risk of obesity and associated comorbidities, and results in greater longevity 

Is exercise safe in pregnancy?

• Yes!

  •  Not just in pregnancy, but for all individuals, the US Department of Health and Human Services Physical Activity Guidelines for Americans says: 

    • At least 150 min of mod intensity aerobic activity per week

    • Recommended also in pregnancy and postpartum period 

    • Those that engaged in vigorous-intensity aerobic activity or who were physically active before pregnancy can continue those activities 

    • Few maternal conditions that would not allow aerobic exercise 

• What are the downsides of not exercising?

  • Physical inactivity is the 4th leading risk factor for early mortality worldwide 

  • Physical inactivity and weight gain in pregnancy have been recognized as independent risk factors for maternal obesity and pregnancy related complications like GDM  

• What are the benefits of exercising? 

  • Increased likelihood of vaginal delivery! 

  • Low incidence of: excessive weight gain, GDM, gestational hypertensive disorders, preterm birth, c-section, lower birth weight 

• What exercises are safe? 

  • Aerobic: walking, stationary bike, aerobic exercises, dancing, stretching, water aerobics 

  • Anaerobic: resistance training (weights, elastic bands) 

  • Borg rating of perceived exertion: 6 - 20 (6 to 7 is very, very light, and 19-20 is very, very hard) 

    • Recommend moderate intensity, which is about a 13-14 (somewhat hard) 

      • About 20-30 min per day for most days of the week 

    • Also talk test: if you can talk while exerting yourself, likely not over exerting 

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Note: ACOG issued a correction to this table; it should read “First Trimester, Less Than 12 Weeks Gestation.”

What are some modifications we should consider in pregnancy? 

• Changes in pregnancy 

  • Weight gain, difference in weight distribution 

    • About 60% of pregnant patients will experience low back pain 

  • Increase in blood volume, heart rate, stroke volume, cardiac output = normal (recall our very first few episodes on physiologic changes in preg!)

    • Maintaining supine positioning after 20 weeks may lead to decrease venous return → can lead to SOB, dizziness, hypotension, etc 

  • Minute ventilation increases by 50% 

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• Other modifications: 

  • Remember to stay well hydrated, wear loose-fitting clothing, and avoid high heat and humidity (ie. hot yoga) 

  • Exercise by itself isn’t expected to increase body temp to point of concern 

• Fetal response 

  • Studies show some minimal to mod increase in fetal heart rate by 10-30 bpm during maternal exercise 

  • Three meta-analyses show that there is minimal to no difference in birth weight 

  • However, women who continue to exercise vigorously in third trimester are more likely to deliver babies weighing 200-400g less than controls, though no increased risk of FGR 

When to stop exercising 

• Don’t exercise if:

  • Have vaginal bleeding, abdominal pain, regular painful contractions, leaking fluid 

  • Dyspnea before exertion, dizziness, headache, chest pain

  • Muscle weakness affecting balance, calf pain or swelling  

Special considerations 

• Obesity

  • Encourage patients to have healthy lifestyle modification in pregnancy that include physical activities and judicious diets 

  • Can start with low-intensity, short periods of exercise if not exercising already 

  • Then can build up gradually 

• Athletes

  • Vigorous-intensity exercise even in 3rd trimester appears to be safe and healthy for most pregnancies 

  • Further research is needed for exercise intensity exceeding 90% of max heart rate