Original Investigation | Diabetes and Endocrinology

Glycemic Control Trajectories and Risk of Perinatal Complications

Among Individuals With Gestational Diabetes
Rana F. Chehab, PhD; Assiamira Ferrara, MD, PhD; Mara B. Greenberg, MD; Amanda L. Ngo, MPH; Juanran Feng, MS; Yeyi Zhu, PhD

Abstract Key Points

Question Among individuals with
IMPORTANCE Glycemic control is the cornerstone of gestational diabetes management. Glycemic
gestational diabetes, are distinct
control trajectories account for differences in longitudinal patterns throughout pregnancy; however,
glycemic control trajectories from
studies on glycemic control trajectories are scarce.
gestational diabetes diagnosis to
delivery associated with differential risk
OBJECTIVE To examine whether glycemic control trajectories from gestational diabetes diagnosis
of perinatal complications?
to delivery were associated with differential risk of perinatal complications.
Findings In this cohort study of 26 774
DESIGN, SETTING, AND PARTICIPANTS This population-based cohort study included individuals individuals with gestational diabetes, 4
with gestational diabetes with longitudinal electronic health record data from preconception to glycemic control trajectories (stably
delivery who received prenatal care at Kaiser Permanente Northern California (KPNC) and were optimal, rapidly improving to optimal,
enrolled in KPNC’s telemedicine-based gestational diabetes care program between January 2007 slowly improving to near-optimal, and
and December 2017. Data analysis was conducted from September 2021 to January 2022. slowly improving to suboptimal) were
identified. A gradient of increasing risk
EXPOSURES Glycemic control trajectories were derived using latent class modeling based on the of cesarean delivery, shoulder dystocia,
American Diabetes Association’s recommended self-monitoring of blood glucose measurements. large-for-gestational-age, and neonatal
Optimal glycemic control was defined as at least 80% of all measurements meeting the targets at intensive care unit admission was
KPNC clinical settings. observed across stably optimal to slowly
improving to suboptimal glycemic
MAIN OUTCOMES AND MEASURES Multivariable Poisson regression models were used to control trajectories.
estimate the associations of glycemic control trajectories with cesarean delivery, preterm birth,
Meaning These findings suggest that
shoulder dystocia, large- and small-for-gestational-age, and neonatal intensive care unit admission
gestational diabetes interventions
and stay of 7 days or longer.
should help individuals achieve glycemic
control early after diagnosis and
RESULTS Among a total of 26 774 individuals (mean [SD] age, 32.9 [5.0] years; 11 196 Asian or Pacific
throughout pregnancy to decrease the
Islander individuals [41.8%], 1083 Black individuals [4.0%], 7500 Hispanic individuals [28.0%], and
risk of perinatal complications.
6049 White individuals [22.6%]), 4 glycemic control trajectories were identified: stably optimal
(10 528 individuals [39.3%]), rapidly improving to optimal (9151 individuals [34.2%]), slowly
improving to near-optimal (4161 individuals [15.5%]), and slowly improving to suboptimal (2934 + Supplemental content
individuals [11.0%]). In multivariable models with the rapidly improving to optimal trajectory group Author affiliations and article information are
as the reference group, glycemic control trajectories were associated with perinatal complications listed at the end of this article.

with a gradient across stably optimal to slowly improving to suboptimal. For individuals in the stably
optimal trajectory group, there were lower risks of cesarean delivery (adjusted relative risk [aRR],
0.93 [95% CI, 0.89-0.96]), shoulder dystocia (aRR, 0.75 [95% CI, 0.61-0.92]), large-for-gestational
age (aRR, 0.74 [95% CI, 0.69-0.80]), and neonatal intensive care unit admission (aRR, 0.90 [95% CI,
0.83-0.97]), while for patients in the slowly improving to suboptimal glycemic control trajectory
group, risks were higher for cesarean delivery (aRR, 1.18 [95% CI, 1.12-1.24]; (P for trend < .001),
shoulder dystocia (aRR, 1.41 [95% CI, 1.12-1.78]; P for trend < .001), large-for-gestational-age (aRR,
1.42 [95% CI, 1.31-1.53]; P for trend < .001), and neonatal intensive care unit admission (aRR, 1.33
[95% CI, 1.20-1.47]; P for trend < .001). The risk of small-for-gestational-age was higher in patients in

(continued)

Open Access. This is an open access article distributed under the terms of the CC-BY License.

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 JAMA Network Open | Diabetes and Endocrinology Glycemic Control Trajectories and Risk of Perinatal Complications in Gestational Diabetes

Abstract (continued)

the stably optimal group (aRR, 1.10 [95% CI, 1.02-1.20]) and lower in the slowly improving to
suboptimal group (aRR, 0.63 [95% CI, 0.53-0.75]).

CONCLUSIONS AND RELEVANCE These findings suggest that slowly improving to near-optimal
and slowly improving to suboptimal glycemic control trajectories were associated with increased risk
of perinatal complications. Future interventions should help individuals achieve glycemic control
early after gestational diabetes diagnosis and throughout pregnancy to decrease the risk of perinatal
complications.

JAMA Network Open. 2022;5(9):e2233955. doi:10.1001/jamanetworkopen.2022.33955

Introduction
Gestational diabetes, one of the most common pregnancy complications,1 affects around 8% of
pregnancies each year in the US.2 Gestational diabetes is associated with a higher risk of adverse
perinatal outcomes, including hypertensive disorders of pregnancy, cesarean delivery, macrosomia,
shoulder dystocia, neonatal hypoglycemia, and increased long-term risk of diabetes and
cardiovascular disease.3 Randomized clinical trials of treatment of gestational diabetes using medical
nutrition therapy and insulin therapy reduced the rate of perinatal complications,4,5 suggesting that
glycemic control may improve perinatal outcomes.
The essential role of glycemic control in gestational diabetes management has been widely
acknowledged, with the American Diabetes Association (ADA) recommending the use of self-
monitoring of blood glucose as the primary measure of glycemic control during pregnancy.6
However, large-scale, population-based data on glycemic control profiles based on serial self-
monitoring of blood glucose measurements and their associations with perinatal complications
among individuals with gestational diabetes are sparse.7 Furthermore, conventional dichotomization
of glycemic control status (ie, optimal vs suboptimal) does not capture the progressive changes of
glycemic control during pregnancy. Thus, studies of glycemic control trajectories, which account for
differences in glycemic control patterns throughout pregnancy and profile the time-specific glycemic
control status and its longitudinal trends following gestational diabetes diagnosis to delivery, are
warranted.
To better inform gestational diabetes management, we conducted a population-based study of
26 774 individuals with gestational diabetes in an integrated health care system providing universal
supplemental gestational diabetes care via a telemedicine program. We profiled distinct glycemic
control trajectories after gestational diabetes diagnosis through delivery and examined whether the
trajectories were differentially associated with the risk of perinatal complications. We also assessed
whether individual-level multidomain factors were associated with the glycemic control trajectories
to inform preventive and intervention strategies.

Methods
This cohort study was approved by the KPNC institutional review board, which waived the
requirement for informed consent from study individuals given the use of only electronic health
record (EHR) data and the large sample size, which made it not possible to obtain authorization from
each individual included in the study. The study followed the Strengthening the Reporting of
Observational Studies in Epidemiology (STROBE) reporting guideline.

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 JAMA Network Open | Diabetes and Endocrinology Glycemic Control Trajectories and Risk of Perinatal Complications in Gestational Diabetes

Study Design
This is a longitudinal cohort study of individuals with gestational diabetes who received prenatal care
between January 1, 2007, and December 31, 2017, at Kaiser Permanente Northern California (KPNC),
an integrated health care delivery system serving 4.5 million members who are highly representative
of the underlying population.8,9 Pregnant individuals at KPNC are universally screened (96%) for
gestational diabetes at 24 to 28 weeks of gestation.10 Gestational diabetes is diagnosed via a 2-step
approach (a 50-g, 1-hour glucose challenge test [GCT] followed by a diagnostic 100-g, 3-hour oral
glucose tolerance test [OGTT]) according to the Carpenter and Coustan criteria, as recommended by
the American College of Obstetricians and Gynecologists11 or according to the recommendations by
the International Association of Diabetes and Pregnancy Study Groups and ADA.6,12 Individuals with
diabetes prior to pregnancy were identified through the KPNC diabetes registry and excluded.13
Since 2007, individuals with gestational diabetes have been universally offered enrollment to a
nurse-based management program providing supplemental care via telemedicine by the KPNC
Regional Perinatal Service Center (RPSC).6 This program offers telephone counseling 7 days a week
on diet, physical activity therapy, and glucose monitoring using a glucometer.

Glycemic Control Assessment

We used self-monitoring of blood glucose measurements to assess glycemic control as
recommended by the ADA.6 Individuals enrolled in the RPSC program are instructed to record self-
monitored of blood glucose measurements 4 times per day: fasting before breakfast and 1 hour after
breakfast, lunch, and dinner. The measurements are then reported to the nurses or dietitians during
weekly counseling calls and recorded in the Patient Reported Capillary Glucose Clinical Database.
Optimal glycemic control was defined based on RPSC clinical practice as at least 80% of all self-
monitoring of blood glucose measurements meeting the ADA targets: less than 95 mg/dL for fasting
and less than 140 mg/dL for 1-hour postprandial glucose (to convert to millimoles per liter, multiply
by 0.0555).14 If optimal glycemic control is not achieved over a 2-week period, the gestational
diabetes treatment plan is intensified.

Perinatal Complications
Data on the following perinatal complications were collected from the EHR: cesarean delivery,
preterm birth (<37 weeks of gestation), shoulder dystocia, admission to neonatal intensive care
(NICU), NICU stay of 7 days or longer, stillbirth, and sex- and gestational age–specific birthweight
categories based on a 2017 US reference population (small-for-gestational age [SGA], <10th
percentile; appropriate-for-GA, 10th-90th percentile; and large-for-GA [LGA], >90th percentile]).15

Individual-Level Multidomain Factors

Data on individual-level factors across 3 domains were obtained from the EHR: sociodemographic,
clinical, and lifestyle factors; indicators of gestational diabetes severity; and indicators of gestational
diabetes management adherence. Sociodemographic factors included age at delivery, race and
ethnicity, Medicaid or Medicare insurance during pregnancy, and neighborhood poverty level
(quartiles) derived using an individual’s probability of falling below the poverty threshold levels based
on the percentage below the poverty level in their neighborhood census block group using
individual’s address as recorded in the EHR.16 Race and ethnicity were self-reported and categorized
as Hispanic, non-Hispanic Asian or Pacific Islander, non-Hispanic Black, non-Hispanic White, and
other. The other race and ethnicity category included American Indian or Alaskan Native individuals
and those who identified as multiracial or with missing race and ethnicity, which were combined
owing to small sample size. Race and ethnicity were included because of known associations with
perinatal outcomes. Clinical and lifestyle factors included multiparity, prepregnancy body mass index
(BMI; calculated as prepregnancy weight [measured closest to the last menstrual period within 12
weeks prior] in kilograms divided by height in meters squared [measured within 12 months before
pregnancy]), smoking and alcohol use during pregnancy, and gestational weight gain (calculated

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 JAMA Network Open | Diabetes and Endocrinology Glycemic Control Trajectories and Risk of Perinatal Complications in Gestational Diabetes

using weight at last menstrual period and weight at delivery) compared with Institute of Medicine
recommendations.17
Indicators of gestational diabetes severity included higher OGTT glucose levels (ie, ⱖ2 of the
fasting, 1-hour, 2-hour, and 3-hour glucose levels during OGTT >1 SD above the respective population
mean), early gestational diabetes diagnosis (ie, before 24 weeks of gestation), and gestational
diabetes treatment modality. Indicators of gestational diabetes management adherence included
engagement in the RPSC program (ie, completing ⱖ1 call biweekly with RPSC nurses between the
RPSC program enrollment and delivery) and daily frequency of self-monitoring of blood glucose
measurements.

Statistical Analysis
Glycemic control trajectories were derived using latent class models18 fit using SAS Proc Traj version
202019,20 (SAS Institute). Details on trajectory modeling are presented in the eAppendix and eTable 1
in the Supplement. To examine the associations between glycemic control trajectories, perinatal
complications, and individual-level multidomain factors, we constructed multivariable Poisson
regression models to estimate adjusted relative risks (aRRs) and 95% CIs. Generalized estimating
equations were used to calculate the robust SEs that account for clustering due to multiple index
pregnancies of the same participant during the study period. We constructed sequential
multivariable models adjusting for sociodemographic, clinical, and lifestyle factors (model 1);
additionally, indictors of gestational diabetes severity (model 2); and additionally, gestational
diabetes management adherence indicators (model 3). For the first part of the analysis, the glycemic
control trajectories served as the exposure and the perinatal complications were the outcome of
interest. For the second part, the individual-level multidomain factors were the exposure and the
glycemic control trajectories served as the outcome of interest.
To reduce bias due to missing data (ranging between 0.2% for neighborhood poverty level and
9.6% for alcohol during pregnancy), we used multiple imputation based on all covariates, exposures,
and outcomes of interest to create 10 complete data sets and combined the analyses results on each
complete data set using Rubin rule.21 P values were corrected according to the Benjamini-
Hochberg procedure controlling the false discovery rate. P for trend was calculated using the Poisson
trend test.22 A 2-sided P < .05 was considered significant. All analyses were performed with SAS
version 9.4 (SAS Institute). Data analysis was conducted from September 2021 to January 2022.

Results
Characteristics of the Study Population
Among 30 597 individuals with gestational diabetes who received prenatal care at KPNC in 2007 to
2017, 26 774 individuals (mean [SD] age, 32.9 [5.0] years; 11 196 Asian or Pacific Islander individuals
[41.8%], 1083 Black individuals [4.0%], 7500 Hispanic individuals [28.0%], and 6049 White
individuals [22.6%]) were enrolled in the RPSC program and included in our analysis. A total of 9835
infants (35.1%) born to individuals with gestational diabetes were delivered via cesarean section,
2553 infants (9.5%) were born preterm, 601 infants (2.2%) had shoulder dystocia, 4050 infants
(15.1%) were born LGA, 2588 infants (9.7%) were born SGA, 3127 infants (11.7%) were admitted to
NICU, and 1120 infants (4.2%) had a NICU stay of at least 7 days (Table 1). Stillbirth after gestational
diabetes diagnosis was rare (<0.1%) and not examined as a perinatal complication.
A total of 3823 individuals (12.5%) were excluded for the following reasons: 2099 did not enroll
in the RPSC program, 32 were aged younger than 18 years at the time of delivery, 320 had missing
data on race and ethnicity, and 1372 had nonsingleton gestations (Figure 1). Compared with the
analytical sample of 26 774 individuals, individuals with gestational diabetes who did not enroll in the
RPSC program were more likely to be younger, to be Black or Hispanic, to be multiparous, to have
obesity before pregnancy, and to smoke during pregnancy and less likely to consume alcohol during
pregnancy (eTable 2 in the Supplement).

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 JAMA Network Open | Diabetes and Endocrinology Glycemic Control Trajectories and Risk of Perinatal Complications in Gestational Diabetes

Table 1. Individual-Level Multidomain Factors and Perinatal Complications by Glycemic Control Trajectories
Among Individuals With Gestational Diabetes Who Received Prenatal Care in 2007-2017

No. (%)
Total
Factor T1 (n = 10 528) T2 (n = 9151) T3 (n = 4161) T4 (n = 2934) (N = 26 774)
Age at delivery, y
18-24 585 (5.6) 409 (4.5) 179 (4.3) 140 (4.8) 1313 (4.9)
25-29 2238 (21.3) 1764 (19.3) 743 (17.9) 574 (19.6) 5319 (19.9)
30-34 3959 (37.6) 3440 (37.6) 1543 (37.1) 1060 (36.1) 10 002 (37.4)
35-55 3746 (35.6) 3538 (38.7) 1696 (40.8) 1160 (39.5) 10 140 (37.9)
Race and ethnicity
Asian or Pacific 4667 (44.3) 3755 (41.0) 1710 (41.1) 1064 (36.3) 11 196 (41.8)
Islander
Black 273 (2.6) 382 (4.2) 222 (5.3) 206 (7.0) 1083 (4.0)
Hispanic 2805 (26.6) 2607 (28.5) 1181 (28.4) 907 (30.9) 7500 (28.0)
White 2455 (23.3) 2067 (22.6) 895 (21.5) 632 (21.5) 6049 (22.6)
Othera 328 (3.1) 340 (3.7) 153 (3.7) 125 (4.3) 946 (3.5)
Neighborhood poverty
level quartile
(% below threshold)b
1 (0-4, lowest) 4084 (38.8) 3430 (37.5) 1570 (37.7) 977 (33.3) 10 061 (37.6)
2 (5-9) 2627 (25.0) 2255 (24.6) 1027 (24.7) 764 (26.0) 6673 (24.9)
3 (10-19) 2535 (24.1) 2262 (24.7) 1034 (24.8) 798 (27.2) 6629 (24.8)
4 (≥20, highest) 1257 (11.9) 1186 (13.0) 523 (12.6) 390 (13.3) 3356 (12.5)
Medicaid or Medicare 845 (8.0) 923 (10.1) 413 (9.9) 388 (13.2) 2569 (9.6)
during pregnancy
Multiparity 5898 (56.0) 5327 (58.2) 2573 (61.8) 1940 (66.1) 15 738 (58.8)
Prepregnancy BMI
<18.5 214 (2.0) 101 (1.1) 28 (0.7) 9 (0.3) 352 (1.3)
18.5-24.9 3221 (30.6) 1786 (19.5) 720 (17.3) 360 (12.3) 6087 (22.7)
25.0-29.9 3677 (34.9) 2972 (32.5) 1317 (31.7) 844 (28.8) 8810 (32.9)
≥30.0 3416 (32.4) 4292 (46.9) 2096 (50.4) 1721 (58.7) 11 525 (43.0)
Gestational weight gainc
Below 4101 (42.8) 3092 (36.8) 1255 (32.5) 680 (25.1) 9128 (37.2)
recommendations
As recommended 3099 (32.4) 2535 (30.2) 1249 (32.4) 776 (28.6) 7659 (31.2)
Above 2372 (24.8) 2775 (33.0) 1355 (35.1) 1259 (46.4) 7761 (31.6)
recommendations
Smoking during 183 (1.7) 248 (2.7) 101 (2.4) 140 (4.8) 672 (2.5)
pregnancy
Alcohol during 608 (5.8) 589 (6.4) 303 (7.3) 232 (7.9) 1732 (6.5)
pregnancy
Higher OGTT glucose 733 (7.0) 1234 (13.5) 575 (13.8) 579 (19.7) 3121 (11.7)
levelsd
Early GDM diagnosise 1962 (18.6) 1794 (19.6) 1545 (37.1) 1001 (34.1) 6302 (23.5)
RPSC program 1110 (10.5) 1039 (11.4) 495 (11.9) 364 (12.4) 3008 (11.2)
engagementf
Frequency of SMBG
measurements tertile
(times/d)
1 (≤2) 2805 (26.6) 2602 (28.4) 1420 (34.1) 1304 (44.4) 8131 (30.4)
2 (3) 3914 (37.2) 3430 (37.5) 1598 (38.4) 1031 (35.1) 9973 (37.2)
3 (≥4) 3809 (36.2) 3119 (34.1) 1143 (27.5) 599 (20.4) 8670 (32.4)
GDM treatment
modality
Lifestyle 9408 (89.4) 4584 (50.1) 1563 (37.6) 493 (16.8) 16 048 (59.9)
Oral medications 1081 (10.3) 4193 (45.8) 2209 (53.1) 1713 (58.4) 9196 (34.4)
Insulin therapy 39 (0.4) 374 (4.1) 389 (9.4) 728 (24.8) 1530 (5.7)
Cesarean delivery 3267 (31.0) 3273 (35.8) 1540 (37.0) 1305 (44.5) 9385 (35.1)
Preterm birth 919 (8.7) 860 (9.4) 382 (9.2) 392 (13.4) 2553 (9.5)
Shoulder dystocia 170 (1.6) 209 (2.3) 114 (2.7) 108 (3.7) 601 (2.2)

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 JAMA Network Open | Diabetes and Endocrinology Glycemic Control Trajectories and Risk of Perinatal Complications in Gestational Diabetes

Table 1. Individual-Level Multidomain Factors and Perinatal Complications by Glycemic Control Trajectories
Among Individuals With Gestational Diabetes Who Received Prenatal Care in 2007-2017 (continued)

No. (%)
Total
Factor T1 (n = 10 528) T2 (n = 9151) T3 (n = 4161) T4 (n = 2934) (N = 26 774)
Birth weight categoriesg
AGA 8177 (77.7) 6792 (74.2) 2992 (71.9) 1957 (66.7) 19918 (74.4)
LGA 1039 (9.9) 1417 (15.5) 775 (18.6) 819 (27.9) 4050 (15.1)
SGA 1230 (11.7) 868 (9.5) 352 (8.5) 138 (4.7) 2588 (9.7)
NICU admission 1025 (9.7) 1057 (11.6) 535 (12.9) 510 (17.4) 3127 (11.7)
NICU stay ≥7 d 412 (3.9) 376 (4.1) 163 (3.9) 169 (5.8) 1120 (4.2)

Abbreviations: AGA, appropriate-for-gestational age; BMI, body mass index (calculated as weight in kilograms divided by
height in meters squared); GDM, gestational diabetes; LGA, large-for-gestational age; NICU, neonatal intensive care unit;
OGTT, oral glucose tolerance test; RPSC, Regional Perinatal Service Center; SMBG, self-monitoring of blood glucose; SGA,
small-for-gestational age; T1, stably optimal trajectory; T2, rapidly improving to optimal trajectory; T3, slowly improving
to near-optimal trajectory; and T4, slowly improving to suboptimal trajectory.
a
Other race and ethnicity includes American Indian or Alaskan Native, multiracial, and missing race and ethnicity.
b
Defined as percentage of households in neighborhood below the poverty level, divided into quartiles.
c
Gestational weight gain between last menstrual period and delivery compared with Institute of Medicine
recommendations.17
d
Higher OGTT glucose levels were defined as at least 2 of the fasting, 1-hour, 2-hour, and 3-hour glucose levels during the
100-g, 3-hour oral glucose tolerance test more than 1 SD above the respective population mean.
e
Early GDM diagnosis was defined as diagnosis of GDM before 24 weeks of gestation.
f
RPSC program engagement was defined as at least 1 call biweekly between enrollment into the RPSC management of
glycemic control program and delivery.
g
Birthweight categories were derived using sex- and gestational age–specific percentiles calculated using a 2017 US
reference population.

Figure 1. Study Participant Flowchart

30 597 Individuals with GDM received prenatal

care at KPNC between 2007-2017

2099 Individuals did not enroll in the RPSC program

28 498 Individuals enrolled in the RPSC program

1724 Individuals excluded

32 Aged <18 y at time of delivery
320 Missing data on race and ethnicity
1372 Multiple gestation
GDM, gestational diabetes; KPNC, Kaiser Permanente
Northern California; RPSC, Regional Perinatal
26 774 Individuals included in the analysis
Service Center.

Glycemic Control Trajectories

Individuals with gestational diabetes had a mean (SD) of 239.6 (160.6) self-monitored blood glucose
measurements over 11.8 (6.6) weeks (eTable 3 in the Supplement). We identified 4 distinct glycemic
control trajectories (Figure 2; eFigure in the Supplement). Trajectory 1 (T1) represented the stably
optimal glycemic control trajectory with the largest proportion of individuals in our study (10 528
individuals [39.3%]), which started with a 1.0 probability of optimal glycemic control at gestational
diabetes diagnosis and maintained that until delivery. T2 represented the rapidly improving to
optimal glycemic control trajectory (9151 individuals [34.9%]), which started with less than 0.2
probability of achieving optimal glycemic control, reached optimal control by 8 weeks after diagnosis
and maintained it except for a slight decrease during the last 2 weeks before delivery. T3 represented
the slowly improving to near-optimal glycemic control trajectory (4161 individuals [15.5%]), which

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 JAMA Network Open | Diabetes and Endocrinology Glycemic Control Trajectories and Risk of Perinatal Complications in Gestational Diabetes

started with 0.3 probability of achieving optimal glycemic control and improved to more than 0.8
probability of achieving optimal glycemic control. Finally, T4 represented the slowly improving to
suboptimal glycemic control trajectory (2934 individuals [11.0%]), which had a slowly improving
glycemic control trajectory similar to T3 but started at a lower probability (<0.1) of achieving optimal
glycemic control and improved to a probability of approximately 0.4. In sum, more than 90% of
study individuals had improvements in their glycemic control across pregnancy, with almost 75% of
them (in T1 and T2) reaching optimal control by 8 weeks after diagnosis.

Glycemic Control Trajectories Associated With Perinatal Complications

Figure 3 shows the aRRs of the associations between glycemic control trajectories and perinatal
complications. We used T2 as the reference trajectory since it represented a subgroup of individuals
with gestational diabetes showing the greatest improvement in glycemic control and thus reflected
the largest benefit associated with the RPSC program. Overall, the point estimates of the associations
with perinatal complications remained similar, with slight attenuation after sequential adjustment
for sociodemographic, clinical, and lifestyle factors (model 1); indicators of gestational diabetes
severity (model 2); and gestational diabetes management adherence (model 3) (eTable 4 in the
Supplement).
In the fully adjusted model 3, we observed a gradient of associations across glycemic control
trajectories (from T1 to T4) with the following perinatal complications: cesarean delivery, shoulder
dystocia, LGA, SGA, and NICU admission (Figure 3). Specifically, the risk of cesarean delivery
increased across T1 to T4, with T1 showing a lower risk (aRR, 0.93 [95% CI, 0.89-0.96]) and T4
showing a higher risk (aRR, 1.18 [95% CI, 1.12-1.24]) compared with T2 (P for trend < .001). Similarly,
the risk of shoulder dystocia and NICU admission increased across T1 to T4, with T1 showing a lower
risk (shoulder dystocia: aRR, 0.75 [95% CI, 0.61-0.92]; NICU admission: aRR, 0.90 [95% CI,
0.83-0.97]) and T4 showing a higher risk (shoulder dystocia: aRR, 1.41 [95% CI, 1.12-1.78]; P for trend
<.001; NICU admission: aRR, 1.33 [95% CI, 1.20-1.47]; P for trend <.001). The risk of LGA increased
across trajectories (T1: aRR, 0.74 [95% CI, 0.69-0.80]; T3: aRR, 1.11 [95% CI, 1.02-1.20]; T4: aRR, 1.42
[95% CI, 1.31-1.53]; P for trend < .001) compared with T2, whereas the risk of SGA decreased, with
T1 showing a higher risk (aRR, 1.10 [95% CI, 1.02-1.20]) and T4 showing a lower risk (aRR, 0.63 [95%
CI, 0.53-0.75]; P for trend < .001).
The risk of preterm birth and a NICU stay of 7 days or longer did not show a significant trend
across T1 to T4. Compared with T2, the risk of preterm birth was lower in T3 (aRR, 0.86 [95% CI,

Figure 2. Glycemic Control Trajectories Between Gestational Diabetes Diagnosis and Delivery

1.0
T1
Probability of achieving optimal glycemic control

T2
T3
0.8

Trajectories T1-T4 were derived using serial self-

0.6 monitored blood glucose measurements between
gestational diabetes diagnosis and delivery. Optimal
glycemic control was defined as at least 80% of all self-
0.4 monitored blood glucose measurements meeting the
T4
targets recommended by the American Diabetes
Association guidelines and implemented at Kaiser
0.2 Permanente Northern California. T1 indicates stably
optimal (10 528 individuals [39.3%]); T2, rapidly
improving to optimal (9151 individuals [34.2%]); T3,
slowly improving to near-optimal (4161 individuals
0
0 5 10 15 20 25 30 [15.5%]); and T4, slowly improving to suboptimal
Time from GDM diagnosis, gestational wk (2934 individuals [11.0%]).

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 JAMA Network Open | Diabetes and Endocrinology Glycemic Control Trajectories and Risk of Perinatal Complications in Gestational Diabetes

0.77-0.97]) and higher in T4 (aRR, 1.19 [95% CI, 1.06-1.33]; P for trend = .10) and the risk of a NICU
stay of 7 days or longer was lower in T3 (aRR, 0.79 [95% CI, 0.66-0.95]; P for trend = .47).
We conducted several sensitivity analyses to ensure the robustness of our findings. First, we
examined the associations by preterm birth subtype. The positive association of T4 vs T2 with
medically indicated preterm birth was more pronounced compared with spontaneous preterm birth
(eTable 4 in the Supplement). Second, we examined the associations using T1 as the reference
trajectory; similar patterns were observed to those using T2 as the reference trajectory (eTable 5 in
the Supplement). Third, we adjusted for gestational weight gain in the multivariate models, although
it is potentially on the causal pathway between glycemic control and perinatal complications
(eTable 6 in the Supplement). Fourth, we excluded individuals diagnosed with gestational diabetes
before 24 weeks of gestation (eTable 7 in the Supplement). The results of sensitivity analyses were
similar to those of the main analysis.

Individual-Level Multidomain Factors Associated With Glycemic Control Trajectories

The point estimates of the multidomain factors remained similar, with attenuation after sequential
adjustment for the multidomain factors in models 1, 2, and 3 (eTable 8 in the Supplement). In the fully
adjusted model 3, individuals in T1 were less likely to be older or to be Black or other race or ethnicity,

Figure 3. Associations of Glycemic Control Trajectories With Perinatal Complications

Perinatal aRR P for

complications (95% CI) trend
Cesarean delivery
T1 0.93 (0.89-0.96)a
T2 1 [Reference]
<.001
T3 1.01 (0.96-1.06)
T4 1.18 (1.12-1.24)a
Preterm birth
T1 0.98 (0.90-1.07)
T2 1 [Reference]
.10
T3 0.86 (0.77-0.97)a
T4 1.19 (1.06-1.33)a
Shoulder dystocia
T1 0.75 (0.61-0.92)a
T2 1 [Reference] Data are presented as adjusted relative risk (95%
<.001
T3 1.11 (0.88-1.40) confidence interval) calculated using Poisson
T4 1.41 (1.12-1.78)a regression models with robust SEs. P-for-trend was
LGA vs AGAb calculated using the Poisson trend test. Model
T1 0.74 (0.69-0.80)a adjusted for age at delivery, race and ethnicity,
T2 1 [Reference] neighborhood poverty level, Medicare or Medicaid
<.001
T3 1.11 (1.02-1.20)a during pregnancy, multiparity, prepregnancy body
T4 1.42 (1.31-1.53)a mass index, smoking and alcohol during pregnancy,
SGA vs AGAb higher oral glucose tolerance test levels, early
T1 1.10 (1.02-1.20)a gestational diabetes diagnosis, RPSC program
T2 1 [Reference] engagement, and frequency of self-monitoring of
<.001
T3 0.94 (0.83-1.05) blood glucose measurements. aRR indicates adjusted
T4 0.63 (0.53-0.75)a relative risk; AGA, appropriate-for-gestational age;
NICU admission LGA, large-for-gestational age; NICU, neonatal
T1 0.90 (0.83-0.97)a intensive care unit; SGA, small-for-gestational age; T1,
T2 1 [Reference] stably optimal (10 528 individuals [39.3%]); T2, rapidly
<.001
T3 1.01 (0.92-1.12) improving to optimal (9151 individuals [34.2%]); T3,
T4 1.33 (1.20-1.47)a slowly improving to near-optimal (4161 individuals
NICU stay ≥7 d [15.5%]); and T4, slowly improving to suboptimal
T1 1.03 (0.90-1.19) (2934 individuals [11.0%]).
T2 1 [Reference] a
.47 False discovery rate–corrected P < .05.
T3 0.79 (0.66-0.95)a
b
T4 1.08 (0.90-1.30) AGA, LGA, and SGA birthweight categories were
derived using sex and gestational age-specific
0.5 1 2 percentiles calculated using a 2017 US reference
aRR (95% CI) population.

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whereas individuals in T3 or T4 were more likely to be Black compared with individuals in T2

(Table 2). Individuals in T1 were less likely to have Medicaid or Medicare during pregnancy, while
those in T4 were more likely to be in the second or third quartile of neighborhood poverty level and
multiparous. Compared with individuals in T2, those in T1 were less likely to have overweight or
obesity before pregnancy and to smoke during pregnancy, whereas those in T4 were less likely to
have underweight and more likely to have overweight or obesity before pregnancy and to smoke
during pregnancy. Individuals in T3 and T4, compared with those in T2, were more likely to consume
alcohol during pregnancy (Table 2).
As for indicators of gestational diabetes severity and management adherence, individuals in T1
were less likely while individuals in T4 were more likely to have higher glucose levels during the
diagnostic OGTT, compared with T2. Individuals in T3 or T4 were more likely to have early gestational
diabetes diagnosis before 24 weeks of gestation and less likely to engage in at least 1 call biweekly
with RPSC nurses and conduct self-monitoring of blood glucose measurements at least 3 times a day.

Discussion
In a population-based, racially and ethnically diverse cohort study of 26 774 individuals with
gestational diabetes, we identified 4 glycemic control trajectories between diagnosis and delivery:
T1, stably optimal; T2, rapidly improving to optimal; T3, slowly improving to near-optimal; and T4,
slowly improving to suboptimal, which were associated with perinatal complications with a gradient.
Specifically, the risks of cesarean delivery, shoulder dystocia, LGA, and NICU admission were lower
in T1 and higher in T4 compared with T2, with SGA risk following an opposite pattern. Taken together,
our findings highlight the importance of achieving glycemic control early after gestational diabetes
diagnosis and throughout pregnancy to decrease the risk of perinatal complications.
Trajectory analysis using latent class modeling is an innovative semiparametric statistical
method to identify distinct patterns over time using longitudinal data.18 Prior studies on glycemic
control trajectories among nonpregnant individuals used data on glycated hemoglobin (HbA1c)
during transition to adolescence,23 between adolescence and adulthood24 or during adulthood.25
However, during pregnancy, the ADA recommends that self-monitoring of blood glucose, not HbA1c,
should be used as the primary measure of glycemic control due to the physiological increase in red
blood cell turnover leading to lower HbA1c levels.6 Further, HbA1c represents an integrated measure
of glucose, not fully capturing postprandial hyperglycemia,26,27 which is an important
pathophysiologic aspect of gestational diabetes.28 HbA1c is a measure of glycemic control during the
previous 8 to 12 weeks29 and thus is limited in its ability to examine hyperglycemia in a timely manner
for gestational diabetes, which is usually diagnosed at 24 to 28 weeks of gestation, leaving only 12
to 16 weeks from diagnosis to delivery.
We identified a gradient of increasing risk of perinatal complications overall across T1 to T4
glycemic control trajectories. In previous interventions aiming to improve gestational diabetes
outcomes through lifestyle modification or medications,4,5,30-34 some but not all interventions
reported decreased risk of perinatal complications.30,31,33 Importantly, few studies reported
attainment of glycemic control and, to our knowledge, none examined the direct association of
glycemic control via self-monitoring of blood glucose with the risk of perinatal complications. In this
regard, our findings contribute to the literature by illustrating the direct associations of glycemic
control trajectories with the risk of perinatal complications. Individuals in T1 and T2 were more likely
to conduct self-monitoring of blood glucose measurements; thus, the accuracy of classification in
these 2 trajectories may be higher than in T3 and T4. However, the possible misclassification errors in
T3 and T4 may have attenuated the true associations between the glycemic control trajectories and
perinatal complications, resulting in underestimated effect sizes. Of note, we observed a decreasing
trend of SGA risk across T1 to T4; therefore, more efforts are needed to improve glycemic control
while mitigating the risk of SGA.

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Table 2. Associations of Individual-Level Multidomain Factors With Each Glycemic Control Trajectory

Adjusted relative risk (95% CI)a

Factor T1 T3 T4
Age at delivery, y
18-24 1 [Reference] 1 [Reference] 1 [Reference]
25-29 0.92 (0.87-0.98)b 0.96 (0.84-1.10) 1.03 (0.88-1.21)
30-34 0.87 (0.82-0.92)b 0.97 (0.85-1.11) 1.00 (0.86-1.17)
35-55 0.82 (0.78-0.87)b 0.97 (0.85-1.10) 1.02 (0.87-1.20)
Race and ethnicity
Asian/Pacific Islander 0.97 (0.94-1.01) 1.00 (0.94-1.07) 1.01 (0.93-1.10)
Black 0.84 (0.76-0.92)b 1.17 (1.04-1.31)b 1.24 (1.08-1.41)b
Hispanic 0.98 (0.94-1.02) 0.98 (0.91-1.05) 1.00 (0.91-1.09)
White 1 [Reference] 1 [Reference] 1 [Reference]
Otherc 0.88 (0.81-0.96)b 0.99 (0.86-1.13) 1.10 (0.93-1.29)
Neighborhood poverty level, % below
thresholdc
1 (0-4, lowest) 1 [Reference] 1 [Reference] 1 [Reference]
2 (5-9) 1.00 (0.97-1.03) 1.00 (0.93-1.06) 1.11 (1.02-1.20)b
3 (10-19) 1.00 (0.96-1.03) 0.99 (0.92-1.05) 1.10 (1.02-1.20)b
4 (≥20, highest) 0.99 (0.95-1.04) 0.94 (0.87-1.02) 1.00 (0.90-1.11)
Medicare/Medicaid during pregnancy
No 1 [Reference] 1 [Reference] 1 [Reference] Abbreviations: BMI, body mass index (calculated as
Yes 0.91 (0.86-0.96)b 0.93 (0.85-1.01) 1.07 (0.97-1.17) weight in kilograms divided by height in meters
squared); GDM, gestational diabetes; OGTT, oral
Multiparity
glucose tolerance test; RPSC, Regional Perinatal
No 1 [Reference] 1 [Reference] 1 [Reference] Service Center; SMBG, self-monitoring of blood
Yes 1.02 (0.99-1.05) 1.01 (0.96-1.07) 1.12 (1.05-1.20)b glucose; T1, stably optimal trajectory; T3, slowly
Pre-pregnancy BMI d improving to near-optimal trajectory; and T4, slowly
improving to suboptimal trajectory.
<18.5 1.06 (0.98-1.14) 0.77 (0.55-1.08) 0.48 (0.25-0.92)b
a
Data are calculated using Poisson regression models
18.5-24.9 1 [Reference] 1 [Reference] 1 [Reference]
with robust SEs, with the rapidly-improving-to-
25.0-29.9 0.86 (0.83-0.89)b 1.03 (0.95-1.11) 1.22 (1.10-1.37)b optimal glycemic control trajectory as the reference
b
≥30.0 0.69 (0.67-0.72) 1.00 (0.93-1.08) 1.41 (1.27-1.57)b group for the given trajectory outcome. The model
was adjusted for age at delivery, race and ethnicity,
Smoking during pregnancy
neighborhood poverty level, Medicare or Medicaid
No 1 [Reference] 1 [Reference] 1 [Reference]
during pregnancy, nulliparity, pre-pregnancy body
Yes 0.84 (0.75-0.93)b 0.86 (0.73-1.01) 1.27 (1.11-1.46)b mass index, smoking and alcohol during pregnancy,
Alcohol during pregnancy higher OGTT glucose levels, early GDM diagnosis,
RPSC program engagement, and frequency of SMBG
No 1 [Reference] 1 [Reference] 1 [Reference]
measurements.
Yes 0.97 (0.91-1.02) 1.14 (1.04-1.25)b 1.14 (1.02-1.28)b b
False discover rate–corrected P < .05.
Higher OGTT glucose levelse c
Other race and ethnicity includes American Indian or
No 1 [Reference] 1 [Reference] 1 [Reference] Alaskan Native, multiracial, and missing race and
Yes 0.69 (0.65-0.73)b 1.02 (0.95-1.09) 1.32 (1.22-1.42)b ethnicity.
d
Early GDM diagnosis f Defined as the percentage of households in
neighborhood below the poverty level, divided into
No 1 [Reference] 1 [Reference] 1 [Reference]
quartiles.
Yes 1.04 (1.00-1.07) 1.85 (1.75-1.95)b 1.72 (1.61-1.83)b e
Higher OGTT glucose levels were defined as at least
RPSC program engagementg 2 of the fasting, 1-hour, 2-hour, and 3-hour glucose
No 1 [Reference] 1 [Reference] 1 [Reference] levels during the 100-g, 3-hour oral glucose tolerance
Yes 1.02 (0.97-1.06) 0.82 (0.76-0.90) b
0.68 (0.62-0.76)b test more than 1 SD above the respective
population mean.
Frequency of SMBG measurements
f
tertile (times/d) Early GDM diagnosis was defined as diagnosis of
1 (≤2) 1 [Reference] 1 [Reference] 1 [Reference] GDM before 24 weeks of gestation.
g
2 (3) 1.00 (0.96-1.03) 0.86 (0.81-0.92)b 0.69 (0.64-0.74)b RPSC program engagement was defined as at least 1
b b
call biweekly between enrollment into the RPSC
3 (≥4) 1.02 (0.99-1.06) 0.68 (0.63-0.72) 0.46 (0.42-0.50)
GDM supplemental care program and delivery.

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Several individual-level multidomain factors were associated with distinct glycemic control
trajectories. Compared with individuals in T2, individuals in T3 and T4 were more likely to be Black,
consume alcohol during pregnancy, and have gestational diabetes diagnosis before 24 weeks of
gestation and less likely to adhere to gestational diabetes management (ie, engaging in ⱖ1 counseling
call with RPSC nurses biweekly and conducting self-monitoring of blood glucose ⱖ3 times/d).
Findings from this study provide a better understanding of the subgroups of individuals with
gestational diabetes following distinct glycemic control trajectories and their individual-level
characteristics. This may allow for risk stratification of gestational diabetes–complicated pregnancies
and inform future multicomponent interventions to achieve glycemic control early after gestational
diabetes diagnosis and throughout pregnancy to decrease the risk of perinatal complications.
Specifically, our findings can support efforts targeting modifiable risk factors, such as management
of overweight and obesity among individuals of child-bearing age and engagement in self-monitoring
of blood glucose among individuals with gestational diabetes.

Strengths and Limitations

This study has several strengths. To our knowledge, this is among the first population-based studies
to profile glycemic control trajectories based on serial self-monitoring of blood glucose
measurements from gestational diabetes diagnosis through delivery. Glycemic control trajectories
uniquely reflect dynamic changes in glycemic control over time, which present valuable information
on both the magnitude and duration of glycemic control exposure compared with a dichotomous
glycemic control status (optimal vs suboptimal). In addition, our study population is racially and
ethnically diverse, improving generalizability of our findings. Furthermore, universal screening for
gestational diabetes and universal referral to the RPSC supplemental care program for individuals
with gestational diabetes minimize misclassification bias and variations in access to health care and
clinical practice, which have been major methodological limitations in the literature.
Our study has some limitations. Although we controlled for an array of covariates, residual
confounding cannot be ruled out. For instance, we did not have data on individuals’ dietary intake or
physical activity during pregnancy. However, diet and physical activity counseling are the major
components of the RPSC supplemental gestational diabetes care program,35 and adjustment for
them may result in over adjustment, given that we have included indicators of gestational diabetes
management adherence in the final model. We excluded individuals who had diabetes prior to
pregnancy but not individuals with prediabetes prior to the index pregnancy because prediabetes
and earlier blood glucose control may be precursors to gestational diabetes per ADA guidelines,6 and
individuals of reproductive age are not universally screened for prediabetes. We used self-
monitoring of blood glucose measurements routinely collected in clinic practice, which were subject
to self-report bias and inherent intraindividual variability that would mostly introduce random errors
rather than systematic bias. However, these data reflect what is currently used in clinical practice to
manage glycemic control; thus, the results are directly applicable to the health care setting.
Furthermore, these variabilities would result in more conservative or underestimated effect sizes of
associations, and the use of serial self-monitoring of blood glucose measurements during pregnancy
to profile glycemic control trajectories would reduce random measurement errors.

Conclusions
This cohort study found that slowly improving glycemic control trajectories following gestational
diabetes diagnosis were associated with increased risk of perinatal complications. Several
sociodemographic, clinical, lifestyle, and gestational diabetes–related multidomain factors were
associated with slowly improving glycemic control trajectories. Future interventions should help
individuals achieve glycemic control early after gestational diabetes diagnosis and throughout
pregnancy to decrease the risk of perinatal complications. Early identification of individuals with
gestational diabetes with the characteristics associated with distinct glycemic control trajectories

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may inform a risk stratification–based model of care for gestational diabetes, serving as a critical step
toward precision medicine. Future studies exploring the long-term outcomes of distinct glycemic
control trajectories as well as barriers and facilitators to achieving optimal glycemic control
trajectories are warranted.

ARTICLE INFORMATION
Accepted for Publication: August 11, 2022.
Published: September 29, 2022. doi:10.1001/jamanetworkopen.2022.33955
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Chehab RF
et al. JAMA Network Open.
Corresponding Author: Yeyi Zhu, PhD, Division of Research, Kaiser Permanente Northern California,
2000 Broadway, Oakland, CA 94612 (yeyi.zhu@kp.org).
Author Affiliations: Division of Research, Kaiser Permanente Northern California, Oakland (Chehab, Ferrara, Ngo,
Feng, Zhu); Department of Obstetrics and Gynecology, Kaiser Permanente Northern California, Oakland
(Greenberg); Regional Perinatal Service Center, Kaiser Permanente Northern California, Santa Clara (Greenberg);
Department of Epidemiology and Biostatistics, University of California, San Francisco (Zhu).
Author Contributions: Drs Chehab and Zhu had full access to all the data in the study and take responsibility for
the integrity of the data and the accuracy of the data analysis.
Concept and design: Chehab, Ferrara, Zhu.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Chehab, Greenberg.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Chehab, Ferrara, Ngo, Feng, Zhu.
Obtained funding: Zhu.
Administrative, technical, or material support: Ferrara, Zhu.
Supervision: Ferrara, Zhu.
Conflict of Interest Disclosures: None reported.
Funding/Support: This work was supported by the National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK; grant No. K01DK120807; Dr Zhu) ; National Heart, Lung, and Blood Institute (grant No.
1R01HL157666; Dr Zhu); NIDDK Health Delivery Systems–Center for Diabetes Translational Research (HDS-CDTR)
Pilot and Feasibility Program (grant No. P30DK092924 Subproject ID No. 8714; Dr Zhu); and NIDDK–HDC-CDTR
(grant No. P30DK092924; Dr Ferrara).
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and
decision to submit the manuscript for publication.

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SUPPLEMENT.
eAppendix. Trajectory Modeling
eFigure. Actual and Estimated Glycemic Control Trajectories Between Gestational Diabetes Diagnosis and Delivery
eTable 1. Trajectory Modeling Fit Criteria
eTable 2. Comparison of Characteristics of Individuals with Gestational Diabetes in the Analytical Sample versus
Those Excluded Due to Missing Data on Self-monitoring of Blood Glucose
eTable 3. Distributions of Self-monitored Blood Glucose Measurements Among Individuals With Gestational
Diabetes Who Received Prenatal Care in 2007-2017 at Kaiser Permanente Northern California
eTable 4. Association of Glycemic Control Trajectories With Perinatal Complications Using the Rapidly Improving
to Optimal GC Trajectory as Reference Group
eTable 5. Association of Glycemic Control Trajectories With Perinatal Complications Using the Stably Optimal GC
Trajectory as Reference Group
eTable 6. Association of Glycemic Control Trajectories With Perinatal Complications Adjusting for Gestational
Weight Gain
eTable 7. Association of Glycemic Control Trajectories With Perinatal Complications Excluding Individuals With
Early Gestational Diabetes Diagnosis Before 24 Weeks Gestation
eTable 8. Associations of Patient-Level Multidomain Factors With Each Glycemic Control Trajectory Compared
With the Rapidly Improving to Optimal Trajectory

JAMA Network Open. 2022;5(9):e2233955. doi:10.1001/jamanetworkopen.2022.33955 (Reprinted) September 29, 2022 14/14

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