Abstract
Background:
Racial and socioeconomic disparities in preterm birth (PTB) and small for gestational age (SGA) birth are growing in the United States, increasing the burden of morbidity and mortality particularly for Black women and birthing persons as well as their infants. Group prenatal care (GPNC) is one of the only interventions to show potential to reduce the disparity, but the mechanism is unclear.
Objectives:
The goal of this project was to identify whether GPNC was associated with a reduction in systemic inflammation during pregnancy, and lower prevalence of inflammatory lesions in the placenta at delivery, in comparison to individual prenatal care (IPNC).
Study Design:
The Psychosocial Intervention and Inflammation in Centering Study (PIINC) was a prospective cohort study that exclusively enrolled participants from a large randomized controlled trial of GPNC (the Cradle study, R01HD082311, ClinicalTrials.gov: NCT02640638) that was performed at a single site in Greenville, SC from 2016–2020. Cradle randomized patients to either GPNC or IPNC and collected survey data during the 2nd and 3rd trimesters. The PIINC cohort additionally provided serum samples at these two survey time points and permitted collection of placental biopsies for inflammatory and histologic analysis, respectively. We examined associations between GPNC treatment and a composite of z-scored serum inflammatory biomarkers (CRP, IL-6, IL-1ra, IL-10, and TNF-α) in both the 2nd and 3rd trimesters, as well as with the prevalence of placental maternal acute and chronic inflammatory lesions. Analyses were conducted using the Intent to Treat (ITT) principle, and results were also examined by attendance of visits in the assigned treatment group (modified Intent to Treat or mITT, and Median or More number of visits M+) and were stratified by race and ethnicity.
Results:
1256/1375 (92%) of Cradle participants who were approached enrolled in PIINC, which included 54% of the total Cradle participants. The PIINC cohort did not differ from the Cradle cohort by demographic or clinical characteristics. Among the 1256 PIINC participants, 1133 (89.6%) had placental data available for analysis. 549/1133 were assigned to GPNC and 584/1133 were assigned to IPNC. In the ITT and mITT cohorts, participation in GPNC was associated with a higher serum inflammatory score, but was not associated with increased prevalence of placental inflammatory lesions. In stratified analyses, GPNC was associated with higher 2nd trimester inflammatory biomarker composite (mITT: B=1.17, p=0.02 and M+: B=1.24, p=0.05) among Hispanic/Latine participants.
Conclusions:
Unexpectedly, GPNC was associated with higher maternal serum inflammation during pregnancy, especially for Hispanic/Latine participants.
Keywords: group prenatal care, systemic inflammation, placental inflammation, biomarkers, placental inflammatory lesions, placental histology
Introduction
Racial and socioeconomic disparities in preterm birth (PTB) and small for gestational age (SGA) birth are growing in the United States, increasing the burden of morbidity and mortality particularly for Black women and birthing persons as well as their infants 1–3. Few interventions have shown promise in reducing these disparities, with the exception of group prenatal care (GPNC) 4–9. GPNC is an innovative model of prenatal care delivery that, unlike traditional individual prenatal care (IPNC), centers pregancy care around group learning. In GPNC, groups of up to 12 pregnant patients at approximately the same gestational age meet together for a series of 10 prenatal care visits. Physical evaluation by a medical care provider occurs within the group space, and patients actively participate in care by measuring their own weight and blood pressure and participating in regular sessions of facilitated prenatal education. Pregnant individuals are empowered through peer support to participate, learn, make informed decisions, self-manage their care activities and thereby reduce their psychosocial and behavioral pregnancy risks 9–13. Two randomized clinical trials and several retrospective cohort studies have demonstrated that participation in GPNC was associated with decreased rates of SGA and PTB for patients at greater risk of adverse outcomes, including Black individuals 4,7–9 and adolescents 7,14. However, the recent Cradle RCT of GPNC showed no difference in the overall rates of preterm birth or low birthweight between group and individual prenatal care. Cradle did demonstrate that lower rates of preterm birth and low birthweight for Black participants were observed with increased participation in group prenatal care, suggesting a need for further studies15.
It is hypothesized that GPNC works in part by reducing the physiologic stress response during pregnancy, which has been widely found to predict risk for adverse birth outcomes 16–19 and contribute to the perinatal disparities gap 20. However, the physiologic impact of GPNC on pregnancy has not been tested in previous trials. Substantial evidence points to excessive inflammation as a likely mediator of the relationship between stress and adverse pregnancy outcomes 19,21–24. Higher concentrations of inflammatory biomarkers in maternal circulation during pregnancy, as well as in the placenta at the time of delivery, have been associated with PTB 25,26, SGA 27–29, and complications for the birth parent and the infant 30. While GPNC has been found to reduce perceived stress and increase social support 11 9, GPNC’s ability to reduce inflammatory activity has not been evaluated.
The goal of this project was to identify whether GPNC was associated with a reduction in systemic inflammatory biomarkers during pregnancy, and lower prevalence of inflammatory lesions in the placenta at delivery, in comparison to IPNC.
Materials and Methods
Participants, Design and Setting
The Psychosocial Intervention and Inflammation in Centering Study (PIINC) enrolled participants from a large randomized controlled trial of GPNC (the Cradle study, R01HD082311, ClinicalTrials.gov: NCT02640638) that was performed at a single site in Greenville, SC starting on February 24, 2016 31. The PIINC study (1R01HD092446–01A1, ClinicalTrials.gov: NCT04097548) was initiated on August 8, 2018 after approval by the NorthShore University HealthSystem Institutional Review Board (EH17–256). To qualify for the Cradle parent study, individuals had to be between 14– 45 years of age, carry a singleton pregnancy, initiate prenatal care before 20 6/7 weeks’ gestational age, be comfortable reading and speaking English or Spanish, and be less than 24 0/7 weeks at the time of study enrollment. Prospective participants were excluded if they had medical or pregnancy complications that would preclude prenatal care delivery by a nurse practitioner. Examples include pregestational diabetes, chronic hypertension on medications, any disease requiring chronic immunosuppression (such as solid organ transplant) and severe obesity with body mass index >50 kg/m2. Patients anticipating a planned preterm delivery for reasons such as a history of myomectomy or classical uterine incision were excluded, as well as those with a plan for history indicated cerclage. Finally, patients with medical, social or behavioral conditions that would preclude group participation such as active tuberculosis, current incarceration, or severe uncontrolled psychiatric illness, were also excluded. Patients could only participate in the study with one pregnancy to maintain independence. Cradle participants were enrolled at their first prenatal care appointment or during their dating ultrasound appointment and randomly assigned in a 1:1 allocation to GPNC or IPNC, stratified by self-reported maternal race and ethnicity using REDCap (Research Electronic Data Capture) 32 electronic data capture tools. In addition to the treatments described below, Cradle participants completed demographic and stress surveys at the time of enrollment, as well as during the third trimester. Detailed delivery data were collected via abstraction of the Electronic Medical Record after delivery.
Recruitment for PIINC occurred at a subsequent prenatal visit. Given that PIINC recruitment began after Cradle was underway, we recruited participants at 2 time points. Most of the sample was recruited before 24 and 0/7 weeks’ gestation and provided two blood draws, one at enrollment between 20–25 weeks’ gestation (second trimester) and the second >32 weeks’ gestation but prior to the onset of labor (third trimester). Cradle participants who were >24 weeks’ gestation at the start of the PIINC trial were consented for only the third trimester blood draw. All PIINC participants consented to collection of placental biopsies at the time of delivery.
Interventions
The IPNC arm received prenatal care following the schedule of visits recommended by the American College of Obstetricians and Gynecologists 33,34.
The GPNC arm received CenteringPregnancy curriculum (Centering Healthcare Institute, Boston MA) 35 36. In GPNC, Groups of 8-12 pregnant patients due to deliver in the same month are scheduled for ten 2-hour sessions, which include a brief physical assessment and group discussion. GPNC participants typically have individual prenatal care visits in addition to the 10 scheduled GPNC sessions as needed.
Procedures
At each of the two study visits, a single sample of maternal blood was collected via antecubital venipuncture into 10-mL serum-separating Vacutainer tubes (BD Biosciences, Mississuaga, ON). Tubes were spun within 30 to 120 minutes following the blood draw at 1200 RCF for 10 minutes, as per manufacturer’s instructions. Serum was harvested and stored at −30C until the end of the study. At that point, five biomarkers of low-grade inflammation associated with PTB and SGA were measured in batch, with technicians blind to patient data. The biomarkers were C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), interleukin10 (IL-10), and tumor necrosis factor-α (TNF-α). All were measured in triplicate using immunoassay on an automated microfluidic platform (Simple Plex, Protein Simple) 37. The lower limit of detection for CRP was 1.24 pg/ml, and for the cytokines ranged from 0.08 pg/mL (IL-8) to 0.28 pg/mL (TNF-α). Across runs, the average intra-assay coefficients of variation for triplicate samples were 2.4% (CRP), 2.6% (IL-6), 2.1% (IL-1ra), 4.5% (IL-10), and 1.7% (TNF-α). The inter-assay coefficients of variation were 6.0% (CRP), 3.0% (IL-6), 3.2% (IL-1ra), 4.5% (IL-10), and 1.3% (TNF-α).
To reduce the chance of false discovery, and leverage the relationships among the biomarkers (in a principal components analysis, a single factor solution emerged that explained 45% of common variance 38), we used a parsimonious approach to modeling the serum inflammatory measures - a composite score for each trimester 39,40. First, to reduce the significant right skew, each inflammatory biomarker was log-transformed, and then standardized (z-score). Then, a composite score at each time point was calculated as sum of standardized values. A composite score greater than 3 standard deviations above the mean was treated as an outlier and excluded from the analysis.
At the time of delivery, large biopsies (2in x 2in x 2in) were collected from 4 distinct regions of the placental parenchyma through the maternal side. Additionally, a 2×7in roll of membranes were collected. All specimens were collected and fixed in formalin within 30 minutes of delivery. The formalin fixed placental tissue, membranes, and parenchymal sections were processed into slides for analysis by a perinatal pathologist (LME). Hematoxylin and eosin-stained, 5 μm thick sections of the membranes, basal plate, and villous parenchyma were examined for chronic and acute inflammation, using methods and criteria detailed in our group’s earlier papers and consistent with Amsterdam consensus criteria19,41 42. Chronic inflammatory lesions, characterized by the presence of lymphocytes, histiocytes or plasma cells in placental tissues, included chronic chorioamnionitis, chronic marginating choriodeciduitis, chronic villitis, chronic basal villitis, chronic deciduitis with plasma cells, chronic decidual perivasculitis, chronic intervillositis and eosinophilic/T-cell vasculitis. Acute inflammatory lesions were characterized by neutrophilic infiltration in maternal compartments (acute subchorionitis, chorionitis, and chorioamnionitis).
Study Outcomes
Our primary outcomes were (1) the level of maternal circulating inflammatory biomarkers in both the second and third trimesters, and (2) the presence of inflammatory lesions in the placenta at the time of delivery.
Statistical Analysis
Analytic groups
The primary analysis was performed according to the intent-to-treat principle, but two additional analytic samples were planned.
First, the modified intent-to-treat (mITT) sample included participants who attended one or more visits or sessions in their assigned treatment arm.
Second, the Median or More (M+) sample included participants who attended at least the median number of visits in their assigned treatment arm (GPNC and IPNC).29,30,42–45
In each sample (ITT, mITT, M+), descriptive statistics and risk factors for preterm birth of participants were compared between treatment arm using non-parametric Wilcoxon rank sum test for continuous variables and chi-square or Fisher’s exact test for categorical variables.
Inflammatory outcomes and treatment groups
Associations of treatment group with composite inflammatory biomarker scores--both second and third trimesters-- using the ITT, mITT, and M+ subsets were examined using linear regression models and associations with binary inflammatory outcomes (acute inflammation, chronic inflammation) were examined using logistic regressions.
Racial and ethnic differences in inflammatory outcomes by treatment group
Per the registered statistical plan, we examined the interaction effect of treatment group and race and ethnicity (i.e., Black, Hispanic, and White) on cumulative inflammatory biomarker score at both time points using multiple linear regression and on placental inflammation using logistic regression. All regression models were adjusted for maternal age, initial BMI, and smoking 3 months before pregnancy, and because inflammation generally increases across gestation 21,43, models of the inflammatory composite were additionally adjusted for gestational age at the time of the blood draw.
P-value less than 0.05 was considered statistically significant. All analyses were performed using SAS version 9.4 (SAS Institute Inc. Cary, NC).
Results
Characteristics of the full Cradle cohort are reported elsewhere 15. 1256/1375 (92%) of Cradle participants who were approached enrolled in PIINC, 54% of all Cradle participants. The PIINC cohort did not differ from the Cradle cohort by demographic or clinical characteristics. Among the 1256 PIINC participants, 1133 (89.6%) had placental data available for analysis. 549/1133 were assigned to GPNC and the 584/1133 were assigned to IPNC. Detailed baseline characteristics are shown in Table 1 and were balanced between the GPNC and IPNC treatment arms, with the exception of smoking in the 3 months prior to pregnancy, which was more common among participants in IPNC compared to GPNC (42% versus 31%). Overall, 36.3% of participants reported Black race, 22.8% reported Hispanic ethnicity, 39.8% reported White race, and 1.1% reported Other race or ethnicity. The median age was 24.2 (IQR 20.8 – 28.1) years, and 44.0% participants were primiparous. Most participants (96.4%) were Medicaid eligible at delivery. 27.1% of participants had not completed a high school degree, 24.9% were married, and 34.3% of pregnancies were planned. While rates of PTB were low overall, in all 3 analytic groups PTB was more common in the GPNC group compared to the IPNC group. Participants in GPNC attended a median 6 (IQR 1–8) GPNC visits, and participants in IPNC attended median 10 (IQR 8–12) IPNC visits.
Table 1.
Descriptive statistics of the three analytic samples
| Intent-to-Treat (ITT) N=1133 | Modified Intent-to-Treat (mITT) N=1013 | Median or more visits in the assigned group (M+) N=660 | |||||
|---|---|---|---|---|---|---|---|
| Overall | IPNC | GPNC | IPNC | GPNC | IPNC | GPNC | |
| 1133 | 584 | 549 | 576 | 437 | 347 | 313 | |
| Number of assigned visits attended, median (IQR) | 10 (8 – 12) | 6 (1 – 8) | 10 (8 – 12) | 7 (5 – 8) | 11 (10 – 12) | 8 (7 – 9) | |
|
| |||||||
| Demographic Characteristics | |||||||
| Maternal age, median (IQR) | 24.2 (20.8 – 28.1) | 24.1 (20.8 – 28.2) | 24.6 (21 – 28) | 24.1 (20.7 – 28.1) | 24.4 (21 – 28) | 24.2 (20.9 – 28.6) | 24.6 (21.2 – 28.6) |
| Gestational age at entry to prenatal care, weeks, median (IQR) | 8.3 (6.7 – 10.9) | 8.4 (6.9 – 11.2) | 8.3 (6.6 – 10.6) | 8.4 (6.9 – 11.3) | 8.3 (6.7 – 10.3) | 7.9 (6.6 – 9.7) | 8 (6.6 – 10.1) |
| Gestational age at Cradle study enrollment, weeks, median (IQR) | 11 (9 – 14.1) | 11 (9 – 14.4) | 11 (8.9 – 13.9) | 11 (9.1 – 14.5) | 10.9 (8.7 – 13.4) | 10.6 (8.9 – 13) | 10.6 (8.7 – 12.9) |
| Race, % | |||||||
| Black | 411 (36.3) | 214 (36.6) | 197 (35.9) | 210 (36.5) | 158 (36.2) | 101 (29.1) | 113 (36.1) |
| Hispanic | 258 (22.8) | 129 (22.1) | 129 (23.5) | 128 (22.2) | 107 (24.5) | 85 (24.5) | 84 (26.8) |
| White | 451 (39.8) | 234 (40.1) | 217 (39.5) | 231 (40.1) | 167 (38.2) | 155 (44.7) | 111 (35.5) |
| Other | 13 (1.1) | 7 (1.2) | 6 (1.1) | 7 (1.2) | 5 (1.1) | 6 (1.7) | 5 (1.6) |
| Language, English % | 1024 (90.4) | 531 (90.9) | 493 (89.8) | 524 (91) | 390 (89.2) | 312 (89.9) | 276 (88.2) |
| Education, High school or above % | 789 (72.9) | 402 (71.9) | 387 (73.9) | 397 (72.1) | 305 (73.3) | 234 (70.3) | 234 (78.3) |
| Employment, Employed full or part-time % | 581 (54.6) | 297 (54.2) | 284 (54.9) | 293 (54.2) | 234 (56.9) | 185 (56.9) | 174 (59.4) |
| Annual household income, % | |||||||
| <$10,000 | 221 (28.7) | 116 (29.1) | 105 (28.3) | 115 (29.3) | 76 (25.8) | 63 (27.3) | 46 (21.6) |
| $10,000-$19,999 | 241 (31.3) | 124 (31.1) | 117 (31.5) | 122 (31) | 97 (32.9) | 73 (31.6) | 70 (32.9) |
| $20,000-$49,000 | 282 (36.6) | 144 (36.1) | 138 (37.2) | 141 (35.9) | 114 (38.6) | 86 (37.2) | 92 (43.2) |
| ≥$50,000 | 26 (3.4) | 15 (3.8) | 11 (3) | 15 (3.8) | 8 (2.7) | 9 (3.9) | 5 (2.3) |
| Marital status, Married % | 259 (24.9) | 134 (24.9) | 125 (24.9) | 133 (24.9) | 105 (25.4) | 90 (27.3) | 86 (28.1) |
| Medicaid eligible, % | 1082 (96.4) | 560 (96.6) | 522 (96.3) | 555 (96.5) | 412 (95.6) | 336 (97.1) | 298 (96.1) |
| Access to health care | |||||||
| Having dental visit within past 2 years, % | 658 (68.5) | 350 (70.7) | 308 (66.2) | 346 (70.9) | 242 (65.4) | 212 (70.7) | 174 (64.4) |
| No insurance any time within past year, % | 540 (49) | 286 (50.4) | 254 (47.7) | 282 (50.4) | 201 (47.6) | 172 (51.2) | 144 (47.7) |
| Pregnancy Intention, % | 373 (34.3) | 186 (33.4) | 187 (35.3) | 183 (33.3) | 151 (35.7) | 126 (38) | 106 (34.9) |
| Parity, Nulliparous, % | 498 (44) | 250 (42.8) | 248 (45.2) | 245 (42.5) | 195 (44.6) | 158 (45.5) | 132 (42.2) |
| Prepregnancy BMI, % | |||||||
| Underweight (<18.5) | 37 (3.3) | 16 (2.7) | 21 (3.8) | 16 (2.8) | 17 (3.9) | 7 (2) | 12 (3.8) |
| Normal (18.5–<25) | 362 (32) | 194 (33.2) | 168 (30.6) | 190 (33) | 140 (32) | 111 (32) | 102 (32.6) |
| Overweight (25-<30) | 292 (25.8) | 151 (25.9) | 141 (25.7) | 150 (26) | 108 (24.7) | 86 (24.8) | 76 (24.3) |
| Obese (30+) | 442 (39) | 223 (38.2) | 219 (39.9) | 220 (38.2) | 172 (39.4) | 143 (41.2) | 123 (39.3) |
| Birth weight percentile, median (IQR) | 40.9 (20.5 – 62.7) | 41.3 (19.4 – 63.3) | 40.7 (21.1 – 61.8) | 41.5 (19.4 – 63.5) | 40.7 (24.2 – 61.9) | 43.7 (21.5 – 63.9) | 42.2 (23.3 – 63.1) |
| SGA (birth weight percentile < 10), % | 138 (12.2) | 73 (12.6) | 65 (11.9) | 73 (12.7) | 50 (11.4) | 36 (10.4) | 37 (11.8) |
| Preterm birth, % | 96 (8.5) | 32 (5.5) | 64 (11.7) | 32 (5.6) | 48 (11.0) | 7 (2) | 25 (8) |
| Risk Factors for Preterm Birth | |||||||
| History of prior LEEP/Cervical survey, % | 11 (1) | 3 (0.5) | 8 (1.5) | 3 (0.5) | 5 (1.1) | 3 (0.9) | 3 (1) |
| Muellerian uterine anomaly, % | 2 (0.2) | 2 (0.3) | 0 (0) | 2 (0.3) | 0 (0) | 1 (0.3) | 0 (0) |
| Pregnancy conceived by ART, % | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |||
| Smoking | |||||||
| Smoking in 3 months before pregnancy, % | 409 (37.1) | 240 (42) | 169 (31.8) | 235 (41.7) | 129 (30.5) | 138 (40.5) | 84 (27.8) |
| Smoking during pregnancy, % | 212 (19.2) | 119 (20.8) | 93 (17.4) | 115 (20.4) | 70 (16.5) | 70 (20.6) | 43 (14.2) |
| Drinking alcohol during pregnancy, % | 45 (4.1) | 21 (3.7) | 24 (4.5) | 21 (3.7) | 20 (4.7) | 14 (4.1) | 11 (3.6) |
| Previous preterm birth, %† | 110 (17.3) | 65 (19.5) | 45 (15) | 65 (19.6) | 33 (13.6) | 33 (17.5) | 19 (10.5) |
| Previous hypertension, % | 125 (11) | 57 (9.8) | 68 (12.4) | 56 (9.7) | 49 (11.2) | 38 (11) | 30 (9.6) |
| Vaginal infection in pregnancy, % | 402 (35.5) | 200 (34.2) | 202 (36.8) | 196 (34.0) | 158 (36.2) | 115 (33.1) | 110 (35.1) |
| Any vaginal bleeding in pregnancy, % | 88 (7.8) | 48 (8.2) | 40 (7.3) | 47 (8.2) | 35 (8) | 33 (9.5) | 25 (8) |
| Cerclage placed during pregnancy, % | 11 (1) | 6 (1) | 5 (0.9) | 6 (1) | 5 (1.1) | 2 (0.6) | 3 (1) |
| Cervical shortening (≤25 mm), % | 17 (1.7) | 10 (1.9) | 7 (1.4) | 10 (1.9) | 5 (1.2) | 4 (1.3) | 4 (1.4) |
Previous preterm birth percentages utilize multiparous patients only; nulliparous participants are excluded from the analysis
Bolded results indicate p<0.05
Pregnancy serum inflammatory profiles by treatment group
The diagram in Figure 1 displays the specimens that were available for this analysis. Pregnancy inflammatory biomarkers were available on 59.8% of the sample (n=677), with 501 specimens collected in the second trimester, 653 specimens in the third trimester, and 487 at both time points.
Figure 1: CONSORT diagram for PIINC Study.
The serum inflammatory composite scores are shown in Table 2. The median of the inflammatory composite (summed z scores of log-transformed CRP, IL10, IL1ra, IL6, and TNFa) for the overall sample was −0.2 (−2.3,2.1) during the second trimester, and −0.3 (−2.2,1.8) in the third trimester. In unadjusted analyses, GPNC was associated with significantly higher composite inflammatory scores during the third trimester in the mITT, but not the ITT or M+ groups. When examining each of the inflammatory measures separately, we identified that IL10 was consistently higher among the GPNC group compared to the IPNC group during the third trimester in the ITT and mITT subsets (for ITT and mITT: GPNC: 0.7 (0.5,0.9) versus IPNC: 0.6 (0.4,0.8)). There were no differences in placental histology between the treatment groups in any of the 3 analytic subsets in unadjusted analyses.
Table 2.
Maternal serum inflammatory biomarkers in three analytic samples (unadjusted)
| Intent-to-Treat (ITT) N = 1133 | Modified Intent-to-Treat (mITT) N = 1013 | Median oi iiioie visits in me assigned group (M+) N = 660 | |||||
|---|---|---|---|---|---|---|---|
| Overall | IPNC | GPNC | IPNC | GPNC | IPNC (10 or above) | GPNC (6 or above) | |
| 1133 | 584 | 549 | 576 | 437 | 347 | 313 | |
| median (IQR) | median (IQR) | median (IQR) | median (IQR) | median (IQR) | median (IQR) | median (IQR) | |
| Timepoint 1, n | 501 | 243 | 258 | 237 | 189 | 147 | 128 |
| Composite Inflammatory score | −0.2 (−2.3 – 2.1) | 0.0 (−2.4 – 2.1) | −0.6 (−2.3 – 2.1) | −0.1 (−2.4 – 2.1) | −0.5 (−2.2 – 2) | 0.0 (−2.4 – 2.1) | −0.2 (−2.1 – 1.7) |
| N | 505 | 244 | 261 | 238 | 190 | 148 | 129 |
| log CRP (mg/L) | 2.4 (1.6 – 3.2) | 2.4 (1.7 – 3.2) | 2.4 (1.6 – 3.2) | 2.4 (1.7 – 3.2) | 2.5 (1.6 – 3.2) | 2.2 (1.7 – 3.1) | 2.5 (1.7 – 3.2) |
| log IL-10 (pg/mL) | 0.6 (0.4 – 0.9) | 0.6 (0.4 – 0.8) | 0.6 (0.4 – 0.9) | 0.6 (0.4 – 0.8) | 0.6 (0.4 – 0.9) | 0.6 (0.3 – 0.9) | 0.6 (0.4 – 0.9) |
| log IL-1ra(pg/mL) | 6.1 (5.9 – 6.4) | 6.1 (5.9 – 6.4) | 6.1 (5.9 – 6.5) | 6.1 (5.9 – 6.4) | 6.1 (5.9 – 6.4) | 6.2 (5.8 – 6.4) | 6.1 (5.8 – 6.4) |
| log IL-6 (pg/mL) | 0.7 (0.3 – 1.1) | 0.7 (0.3 – 1.1) | 0.7 (0.3 – 1.1) | 0.7 (0.3 – 1.1) | 0.7 (0.3 – 1.1) | 0.7 (0.2 – 1.1) | 0.7 (0.3 – 1.1) |
| log TNFα (pg/mL) | 2.2 (2.1 – 2.4) | 2.2 (2.1 – 2.4) | 2.2 (2.1 – 2.3) | 2.2 (2.1 – 2.4) | 2.2 (2.1 – 2.3) | 2.2 (2.1 – 2.4) | 2.2 (2.1 – 2.3) |
|
| |||||||
| Timepoint 2, n | 653 | 331 | 322 | 327 | 249 | 203 | 175 |
| −0.3 | −0.5 | −0.1 | −0.5 | 0.0 | |||
| Composite Inflammatory score | (−2.2 – 1.8) | (−2.3 – 1.5) | (−2.1 – 2.1) | (−2.3 – 1.5) | (−1.9 – 1.9) | −0.3 (−2.1 – 1.7) | −0.1 (−2.2 – 2.2) |
| N | 659 | 334 | 325 | 330 | 250 | 205 | 176 |
| log CRP (mg/L) | 2.2 (1.4 – 2.9) | 2.2 (1.4 – 2.8) | 2.3 (1.5 – 2.9) | 2.2 (1.4 – 2.8) | 2.2 (1.5 – 2.9) | 2.2 (1.5 – 2.8) | 2.2 (1.5 – 2.9) |
| log IL-10 (pg/mL) | 0.7 (0.4 – 0.9) | 0.6 (0.4 – 0.8) | 0.7 (0.5 – 0.9) | 0.6 (0.4 – 0.8) | 0.7 (0.5 – 0.9) | 0.7 (0.4 – 0.8) | 0.7 (0.5 – 0.9) |
| log IL-1ra(pg/mL) | 6.2 (5.9 – 6.5) | 6.1 (5.9 – 6.4) | 6.2 (5.9 – 6.5) | 6.1 (5.9 – 6.4) | 6.2 (6 – 6.5) | 6.2 (6 – 6.5) | 6.2 (6 – 6.5) |
| log IL-6 (pg/mL) | 1 (0.7 – 1.4) | 1 (0.7 – 1.3) | 1 (0.7 – 1.4) | 1 (0.7 – 1.3) | 1 (0.7 – 1.4) | 1 (0.7 – 1.3) | 1 (0.7 – 1.4) |
| log TNFα (pg/mL) | 2.3 (2.2 – 2.5) | 2.3 (2.2 – 2.4) | 2.3 (2.2 – 2.5) | 2.3 (2.2 – 2.4) | 2.3 (2.2 – 2.5) | 2.3 (2.2 – 2.4) | 2.3 (2.2 – 2.5) |
Table 3 shows the regression results for treatment group and pregnancy composite inflammatory scores. In analyses adjusted for age, BMI, smoking before pregnancy, and the gestational age at the time of the blood draw, the composite inflammatory score during the third trimester was significantly higher among GPNC participants compared to IPNC participants in both the ITT (β=0.44 (0.03, 0.84)) and mITT groups (β=0.45 (0.01, 0.89)). There was no significant association between treatment group and the composite inflammatory score in the second trimester.
Table 3.
Primary regression models for composite IS by treatment group
| Intent-to-Treat (ITT) | Modified Intent-to-Treat (mITT) | Median or more visits in the assigned group (M+) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| GPNC vs IPNC | Unj. Estimate (95% CI) | p | Adj. Estimate (95% CI) | P | Unj. Estimate (95% CI) | p | Adj. Estimate (95% CI) | p | Unj. Estimate (95% CI) | p | Adj. Estimate (95% CI) | p |
| Composite IS second trimester | −0.05 (−0.60 – 0.50) | 0.87 | 0.04 (−0.53 – 0.61) | 0.89 | −0.10 (−0.69 – 0.50) | 0.75 | −0.08 (−0.69 – 0.53) | 0.80 | −0.09 (−0.80 – 0.61) | 0.79 | −0.12 (−0.85 – 0.61) | 0.75 |
| Composite IS third trimester | 0.49 (0.03 – 0.95) | 0.04 | 0.44 (0.03 – 0.84) | 0.04 | 0.51 (0.02 – 1.00) | 0.04 | 0.45 (0.01 – 0.89) | 0.04 | 0.16 (−0.45 – 0.77) | 0.61 | 0.11 (−0.51 – 0.74) | 0.72 |
controlled for age, BMI, smoking before pregnancy, GA at blood draw Bolded results indicate p<0.05
Placental inflammation by treatment group
Inflammatory lesions were present in placentas of 73.8% (n=836) of participants, and were not significantly more common among participants assigned to IPNC 71.9% (n=420) nor GPNC 75.8% (n=416) in the ITT, mITT, or the M+ analytic groups. The prevalence of different lesion types did not differ between the treatment groups in either unadjusted analyses (Table 4) or in regression analyses adjusted for age, first BMI in pregnancy, and smoking status (Table 5).
Table 4.
Distribution of placental inflammatory lesions by treatment group
| Intent-to-Treat (ITT) N=1133 | Modified Intent-to-Treat (mITT) N=1013 | Median or more visits in the assigned group (M+) N = 660 | |||||
|---|---|---|---|---|---|---|---|
| Overall | IPNC | GPNC | IPNC | GPNC | IPNC (10 or above) | GPNC (6 or above) | |
| 1133 | 584 | 549 | 576 | 437 | 347 | 313 | |
| Maternal Acute or Chronic Inflammatory Lesions | 836 (73.8) | 420 (71.9) | 416 (75.8) | 412 (71.5) | 332 (76) | 242 (69.7) | 236 (75.4) |
| Maternal Acute Inflammatory Lesion(s) | 525 (46.3) | 263 (45) | 262 (47.7) | 257 (44.6) | 201 (46) | 154 (44.4) | 138 (44.1) |
| Chronic inflammatory Lesion(s) | 563 (49.7) | 284 (48.6) | 279 (50.8) | 281 (48.8) | 217 (49.7) | 163 (47) | 161 (51.4) |
Adjusted for age, BMI, smoking before pregnancy, GA at blood draw
Bolded results indicate p<0.05
Table 5.
Odds Ratios of placental Inflammatory lesions by treatment group
| Intent-to-Treat (ITT) N = 1133 | Modified Intent-to-Treat (mITT) N = 1013 | Median or more visits in the assigned group (M+) N = 660 | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| GPNC vs. IPNC | uOR (95% CI) | p-value | aOR* (95% CI) | p-value | uOR (95% CI) | p-value | aOR* (95% CI) | p-value | uOR (95% CI) | p-value | aOR* (95% CI) | p-value |
| Maternal Acute or Chronic Inflammatory Lesions | 1.22 (0.94 – 1.59) | 0.14 | 1.17 (0.89 – 1.53) | 0.26 | 1.26 (0.95 – 1.67) | 0.11 | 1.22 (0.91 – 1.63) | 0.18 | 1.33 (0.94 – 1.88) | 0.10 | 1.28 (0.90 – 1.82) | 0.18 |
| Maternal Acute Inflammatory Lesion(s) | 1.11 (0.88 – 1.41) | 0.36 | 1.12 (0.88 – 1.42) | 0.36 | 1.06 (0.82 – 1.36) | 0.66 | 1.08 (0.84 – 1.40) | 0.54 | 0.99 (0.73 – 1.34) | 0.94 | 1.03 (0.75 – 1.41) | 0.87 |
| Chronic inflammatory Lesion(s) | 1.09 (0.86 – 1.38) | 0.46 | 1.06 (0.83 – 1.34) | 0.65 | 1.04 (0.81 – 1.33) | 0.78 | 1.00 (0.78 – 1.30) | 0.98 | 1.20 (0.88 – 1.62) | 0.25 | 1.14 (0.83 – 1.56) | 0.42 |
uOR: Unadjusted odds ratio, aOR: adjusted odds ratio
adjusted for age, BMI, and smoking status before pregnancy. Bolded results indicate p<0.05
Interaction effect of treatment group and race/ethnicity with systemic and placental inflammation
Table 6 presents interaction effects of treatment type and race/ethnicity. In both the mITT and M+ subsets, GPNC was associated with higher inflammatory composite scores compared with IPNC, but only for Hispanic/Latine participants. There was no statistically significant treatment-related difference in pregnancy inflammation or placental inflammation for Black or White participants.
Table 6.
Interaction between treatment type (GPNC versus IPNC) and race and ethnicity for serum inflammatory markers and placental inflammation
| Modified Intent-to-Treat (mITT) | Median or more visits in assigned treatment group (M+) | ||||
|---|---|---|---|---|---|
|
| |||||
| Estimate (95% CL) | p-value | Estimate (95% CL) | p-value | ||
|
| |||||
| Composite inflammatory score in 2nd trimester | Black Hispanic/Latine White |
−0.15 (−0.95 – 0.66) 0.06 (−0.94 – 1.06) −0.42 (−1.24 – 0.41) |
0.72 0.91 0.32 |
0.08 (−0.99 – 1.15) 0.26 (−0.89 – 1.41) −0.10 (−1.12 – 0.93) |
0.88 0.66 0.85 |
|
| |||||
| Composite inflammatory score in 3rd trimester | Black Hispanic/Latine White |
0.19 (−0.52 – 0.91) 1.17 (0.31 – 2.03) 0.15 (−0.57 – 0.86) |
0.59 0.01 0.68 |
−0.20 (−1.11 – 0.71) 1.24 (0.24 – 2.24) 0.02 (−0.88 – 0.92) |
0.66 0.02 0.96 |
|
| |||||
| aOR (95% CL) | p-value | aOR (95% CL) | p-value | ||
|
| |||||
|
Maternal Acute or Chronic Inflammatory
Lesions |
Black Hispanic/Latine White |
1.22 (0.75 – 2.00) 1.14 (0.61 – 2.11) 1.35 (0.86 – 2.11) |
0.43 0.68 0.19 |
1.30 (0.70 – 2.41) 1.31 (0.62 – 2.79) 1.35 (0.79 – 2.32) |
0.41 0.49 0.27 |
Adjusted for age, BMI, smoking before pregnancy, GA at blood draw
Bolded results indicate p<0.05
Comment
Principal Findings
GPNC was associated with a higher inflammatory biomarker composite during pregnancy, but not variations in acute or chronic inflammatory lesions in the placenta at delivery. In an interaction analysis, significant associations between GPNC and inflammatory biomarkers were observed among Hispanic/Latine participants, but not other racial/ethnic groups.
Results in the Context of What is Known
Our study is among the first to examine circulating inflammatory biomarkers during pregnancy and placental inflammatory lesions in the context of GPNC. A substantial body of literature has indicated that adverse pregnancy outcomes have a significant inflammatory component 21,23, and that psychosocial stress during pregnancy increases inflammatory profiles and risk for adverse outcomes 44. Two pilots at Prisma prior to the Cradle trial had mixed findings. In the first, we enrolled 20 GPNC participants and 20 IPNC participants with similar demographic and obstetrical profiles and identified that participants in GPNC reported better social support than those in routine prenatal care (p=0.02) and were less likely to manifest acute inflammatory lesions (45% vs. 63%; p= 0.11) 45. The second pilot included 229 participants, 119 in GPNC and 110 in IPNC, and found lower rates of preterm delivery and low birth weight associated with GPNC but did not find significant differences by treatment in serum inflammatory biomarkers IL-1b, TNFa, IL-10, IL-6, and CRP 46. These pilots did not randomize participants to the intervention, which may explain differences with our findings.
Interestingly, we found that the higher inflammatory markers in the GPNC cohort were driven primarily by elevated serum levels in Hispanic/Latine GPNC participants. The majority of the literature exploring racial and ethnic disparities in pregnancy inflammation has focused on Black-white differences 47–49, so our findings represent a relatively novel contribution to this literature that requires further attention in disparities research.
Clinical Implications
GPNC does not appear to reduce systemic or placental inflammatory activity. In contrast to the findings of Cradle, the non-randomized, statewide expansion of group prenatal care in South Carolina from 2013–2017 was associated with a reduction in preterm birth, suggesting there may be factors not considered in this RCT design that impact the utility of GPNC 50. It may be the case individuals who self-select into GPNC reap more therapeutic benefit from the intervention, suggesting that providers and payers increase access to GPNC as one of several pregnancy care options. Ob/Gyn clinicians should be open to exploring new approaches to delivering care, including group visits, virtual visits, and in-home services.
Research Implications
Our findings do not support the hypothesis that inflammation is the main biologic pathway leading to improved pregnancy outcomes seen in prior trials of group prenatal care; however, GPNC may be associated with changes in inflammatory activity for some sub-populations during pregnancy. A deeper investigation of the impact of GPNC engagement with prenatal care on birth outcomes and racial disparities may be warranted. Further, qualitative evaluation of patient experience may reveal alternate biological pathways to be explored in future trials. While studies of inflammatory markers in pregnancy serum have shown a correlation with adverse clinical outcomes 51,52, our findings contribute to the heterogeneity of this body of literature and indicate the difficulty in using serum cytokines to define perinatal clinical risk. It is possible there are other physiologic and psychosocial pathways through which innovative prenatal care models like group prenatal care improve patient outcomes11–13.
Strengths and Limitations
This study has several strengths. The PIINC study was able to capitalize on the randomized study design of Cradle, and due to high enrollment of Cradle participants (92.2%) was able to largely preserve the randomization of the larger group. The patient population recruited into both Cradle and PIINC was ethnically and racially diverse and the majority of participants were of low socioeconomic status, providing the potential to examine how poverty and racism contribute to adverse pregnancy outcomes. Another strength is high retention in the study (98.5%) and high rate of delivery sample collection (90.2%) which provided a largely complete and reliable data set.
There are several limitations to note. The Cradle trial was under-powered to detect differences in clinical outcomes due to lower than expected enrollment rates (43%), lower than expected attendance in the GPNC arm, early termination of the Cradle trial due to the COVID-19 pandemic, and unexpectedly low rates of adverse outcomes in the study sample (PTB rate 9.5% overall, expected 13.4%). It is possible that these potential biases obscured our ability to observe physiologic differences between treatment groups on the pathway to adverse pregnancy outcomes.
Conclusions
Group prenatal care was not associated with significant differences in placental inflammation, and unexpectedly was associated with higher inflammation for Hispanic/Latine patients. That group care may not be the “silver bullet” for improving pregnancy outcomes highlights the urgency of continued innovation in perinatal care delivery, particularly innovations that are patient centered, dismantle systemic racism, and address inequities.
AJOG at a Glance:
A. Why was the study conducted?
To identify whether group prenatal care reduced systemic inflammation or placental inflammation in pregnancy compared to individual prenatal care.
B. What are the key findings?
Participants in group prenatal care were more likely to have elevated inflammation during pregnancy compared to those in individual care, but did not have significantly different rates of placental inflammation. Elevated serum inflammation in the group prenatal care arm was driven primarily by Hispanic/Latine participants, who had higher inflammation than those of other races.
C. What does this study add to what is already known?
Our findings indicate that group prenatal care is not associated with reduced inflammation in pregnancy compared to individual prenatal care.
Financial support:
Research reported in this publication was supported by the United States Department of Health and Human Services through the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development under awards 1 R01 HD092446-01 and R01HD082311. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders did not participation in the study design, data collection, analysis or interpretation, writing the report or in the decision to submit the article for publication.
Footnotes
None of the authors report conflict of interest
ClinicalTrials.gov Identifier: NCT04097548.
Condensation
Tweetable statement: Group prenatal care is not associated with lower inflammation during pregnancy compared to individual prenatal care.
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Contributor Information
Lauren KEENAN-DEVLIN, Department of Obstetrics and Gynecology, NorthShore University HealthSystem, 2650 Ridge Ave, Walgreen Building Suite 1507, Evanston IL 60201.
Gregory E MILLER, Institute for Policy Research & Department of Psychology, Northwestern University.
Linda M ERNST, Department of Pathology and Laboratory Medicine, NorthShore University HealthSystem, Evanston IL 60201/University of Chicago Pritzker School of Medicine.
Alexa FREEDMAN, Department of Obstetrics and Gynecology, NorthShore University HealthSystem, 2650 Ridge Ave, Walgreen Building Suite 1507, Evanston IL 60201.
Britney SMART, Department of Obstetrics and Gynecology, NorthShore University HealthSystem, 2650 Ridge Ave, Walgreen Building Suite 1507, Evanston IL 60201.
Jessica L BRITT, Department of Obstetrics and Gynecology, Prisma Health, 890 West Faris Road, Suite 470, Greenville SC 29605.
Lavisha Singh, Department of Biostatistics, NorthShore University HealthSystem, 1001 University Place, Evanston IL 60201.
Amy H CROCKETT, Division of Maternal Fetal Medicine Department of Obstetrics and Gynecology Prisma Health/University of South Carolina School of Medicine Greenville, 890 West Faris Road, Suite 470, Greenville SC 29605.
Ann BORDERS, Department of Obstetrics and Gynecology, NorthShore University HealthSystem, 2650 Ridge Ave, Walgreen Building Suite 1507, Evanston IL 60201.
Data Sharing:
Deidentified study data will be available publicly on the NICHD/DASH Data and Specimen Hub (https://dash.nichd.nih.gov/) in October 2026, five years after study completion. Prior to that time, researchers with a methodologically sound proposal can direct inquiries to ABorders@northshore.org to gain access to the study protocol, informed consent forms, deidentified data, data dictionaries and the analytic plan. Requestors will need to sign a data access agreement.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Deidentified study data will be available publicly on the NICHD/DASH Data and Specimen Hub (https://dash.nichd.nih.gov/) in October 2026, five years after study completion. Prior to that time, researchers with a methodologically sound proposal can direct inquiries to ABorders@northshore.org to gain access to the study protocol, informed consent forms, deidentified data, data dictionaries and the analytic plan. Requestors will need to sign a data access agreement.