Within-trial cost-effectiveness of lifestyle intervention using a 3-tier shared care approach for pregnancy outcomes in Chinese women with gestational diabetes.

This study assessed within-trial cost-effectiveness of a shared care program (SC, n = 339) for pregnancy outcomes compared to usual care (UC, n = 361), as implemented in a randomized trial of Chinese women with gestational diabetes (GDM). SC consisted of an individualized dietary advice and physical activity counseling program. The UC was a one-time group education program. The effectiveness was measured by number needed to treat (NNT) to prevent one macrosomia/large for gestational age (LGA) infant. The cost-effectiveness was measured by incremental cost-effectiveness ratio in terms of cost (2012 Chinese Yuan/US dollar) per case of macrosomia and LGA prevented. The study took both a health care system and a societal perspective. This study found that the NNT was 16/14 for macrosomia/LGA. The incremental cost for treating a pregnant woman was ¥1,877 ($298) from a health care system perspective and ¥2,056 ($327) from a societal perspective. The cost of preventing a case of macrosomia/LGA from the two corresponding perspectives were ¥30,032/¥26,278 ($4,775/$4,178) and ¥32,896/¥28,784 ($5,230/$4,577), respectively. Considering the potential severe adverse health and economic consequences of a macrosomia/LGA infant, our findings suggest that implementing this lifestyle intervention for women with GDM is an efficient use of health care resources.

Introduction

Gestational diabetes mellitus (GDM), defined as diagnosis of hyperglycemia of any degree during pregnancy, is associated with adverse pregnancy outcomes including macrosomia [1], preterm birth [1, 2], shoulder dystocia, birth trauma and neonatal morbidities [American journal of obstetrics and gynecology. 1988 ">3-5]. GDM also predisposes offspring born to women who had GDM during the index pregnancy to higher risk of childhood obesity [6], and the mothers themselves to higher risk of developing diabetes during their lifetime [7, 8].

Lifestyle intervention is effective in improving pregnancy outcomes among women with GDM [9, 10]. The Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) reported that intensive lifestyle intervention reduced the rate of serious perinatal complications, defined as death, shoulder dystocia, bone fracture, and nerve palsy, macrosomia and preeclampsia among women with GDM [9]. GDM in this study was defined by the World Health Organization’s criteria (fasting plasma glucose levels ≥7.8 mmol/l, or 2-hour plasma glucose levels between 7.8 mmol/l and 11.1 mmol/l) [11], based on a 75-gram 2-hour oral glucose tolerance test (OGTT). Another multicenter randomized trial reported that intensive lifestyle intervention reduced the rates of macrosomia [10], shoulder dystocia and pregnancy-induced hypertension (PIH) [10] in women with mild GDM, defined by the Fourth International Workshop-Conference on GDM’s criteria (a fasting glucose level < 5.3 mmol/l and one glucose measurement that exceeds the following thresholds: 1-hour, 10.0 mmol/l; 2-hour, 8.6 mmol/l; and 3-hour, 7.8 mmol/l) [12], based on a 100-gram 3-hour OGTT.

We conducted a randomized trial of Chinese women with GDM using the International Association of Diabetes and Pregnancy Study Group’s (IADPSG) criteria (fasting plasma glucose levels ≥5.1 mmol/l, or 1-hour plasma glucose levels ≥10.0 mmol/l, or 2-hour plasma glucose levels ≥8.5 mmol/l, based on a 75-gram 2-hour OGTT) [13]. The primary objective of the study was to test if lifestyle intervention delivered in the 3-tier prenatal care system (SC), as compared with usual antenatal care (UC), could improve pregnancy outcomes among Chinese women with GDM. The secondary objective was to assess the cost-effectiveness of the lifestyle intervention program if the program was effective. We previously reported that the lifestyle intervention program reduced the risk of macrosomia and large for gestational age (LGA) [14]. Here we report the results of the cost-effectiveness of the intervention as implemented in the trial.

Materials and methods

Brief description of the trial

Details of the trial including background, methods, study outcomes and research settings were described elsewhere [14]. Briefly, between December 2010 and October 2012, 19,847 pregnant women who were between 24 and 28 weeks of gestation underwent a 50-gram 1-hour glucose challenge test (GCT) at primary hospitals within the 3-tier’s health care network in the six central urban districts of Tianjin, China. The 3-tier network prenatal care system consists of more than 300 primary hospitals throughout the city (first level), 16 district-level Women and Children’s Health Centers (WCHC), more than 50 secondary obstetric hospitals (second level), 1 city-level WCHC (TWCHC) and 7 tertiary obstetric hospitals (third level). Structured prenatal care was delivered within the network. First, all pregnant women in the city were registered at a primary hospital and received their routine prenatal care until the 32nd gestational week. Then they were referred to one of the secondary or tertiary obstetric hospitals for the remainder of their prenatal care. If women experienced pregnancy complications, they were referred to third-level treatment facilities.

The GCT test identified 2921 women with plasma glucose (PG) values of ≥7.8 mmol/L. A following 75-gram OGTT test was performed in these women and 1,440 of them were diagnosed with GDM using the IADPSG’s criteria [14]. Of the 1440 women with GDM, the 948 who agreed to participate in the study and did not meet any of the exclusion criteria were randomly assigned to either the shared care (SC) group (n = 474) or the usual care (UC) group (n = 474). However, the intervention effect on 242 participants might have been contaminated due to (1) unavailability of separate spaces for the intervention and control groups at the central intervention site due to building renovation; and (2) the staff at this study site did not follow data collection procedures as specified in the study protocol (i.e., the same staff members collected data for both study groups due to insufficient manpower). Therefore, we excluded those 242 participants from the main analysis [14]. In addition, six study participants who chose to deliver their infants at hospitals outside Tianjin were excluded. Thus, 700 study participants were included in the final analysis: 339 from the SC and 361 from the UC. A simple randomization procedure without replacement (i.e., by the time sequence of visits to the clinic and a list of priori computer-generated random assignment status by X.Y.) was used to perform the random assignment by the intervention team members [14]. The study flow diagram (S1 Fig) shows the details. Major demographic and clinical information of the study participants are listed in S1 Table. There were no significant differences between the two groups for the baseline clinical and biochemical characteristics. A more detailed description of the study participants can be found in our previous study [14]. The RCT was registered at Clinicaltrials.gov (NCT01565564). Ethics approval of the original study was granted by the Human Subjects Committee of the Tianjin Women’s and Children’s Health Center, and all participants provided written informed consent.

Women in the UC group were offered one hospital-based group diabetes education session lasting for 30–40 minutes with a focus on diet and physical activity. In addition to UC, the SC group was offered structured intensive lifestyle intervention, including (1) one group general diabetes/GDM counseling and education materials at enrollment, (2) two detailed individualized consultations from trained doctors and laboratory testing at the time of the 30th and 34th gestational weeks, (3) three health education sessions with trained nurses at the time of the 27th, 29th and 33th gestational weeks, and (4) regular self-monitoring of blood glucose (SMBG) [14]. The dietary advice and physical activity counseling included recommendations on a tailored diet and a minimum 30 minutes daily of light/moderate physical activity such as walking. The diet recommendation was based on pre-pregnancy body mass index (BMI), i.e., 35 kcal per day for one kilogram of body weight (35 kcal/day/kg) for women with BMI at <18.5 kg/m2; 30–35 kcal/day/kg for women with BMI at 18.5–23.9 kg/m2; 25–30 kcal/day/kg for women with BMI at 24.0–27.9 kg/m2; 25 kcal/day/kg for women with BMI at 28.0 kg/m2 and more. In addition, the SC group was offered a free glucose meter with a memory function and free tests trips. The SC participants were also asked to monitor blood glucose (SMBG) 4 times a day for the initial two weeks and then daily at different time points (alternating between pre-breakfast and 2 hours after each of the three meals) until the end of pregnancy. Glycemic control goals were set at ≥3.5-≤5.1 mmol/l for fasting capillary blood glucose and ≤7.0 mmol/l for 2-hour postprandial capillary blood glucose up to the 36th gestational week and ≤8.0 mmol/l from the 36th week onwards. If blood glucose values exceeded the target values two times or more during a 2-week interval or the 2-hour postprandial capillary blood glucose exceeded 9.0 mmol/l once during a 1-week period, insulin therapy would be recommended by the intervention team and started by a senior obstetrician. The obstetric care was the same for both study groups.

Cost-effectiveness analysis

We measured the cost-effectiveness of this lifestyle intervention using incremental cost-effectiveness ratio (ICER), which was calculated as the incremental cost divided by incremental effectiveness. The incremental cost is the net cost between the SC and UC, and the incremental effectiveness was the net effectiveness between the two study groups. The study took two perspectives: a health system perspective, which considered the direct medical cost only; and a societal perspective, which considered direct medical cost, direct non-medical cost and indirect cost. As we performed a within-trial analysis, our analytical time horizon was from randomization to postnatal hospital discharge of the mother and baby. Analyses were performed on an intention to treat basis. All costs were reported in Chinese yuan (CNY, ¥) (1 CNY = 0.159 US dollars, 31 December 2012).

Effectiveness of the intervention

We measured the effectiveness of the intervention using the number needed to treat (NNT) for two health outcomes: macrosomia and LGA. Macrosomia was defined as birth weight ≥4,000 gram. LGA was defined by birth weight above the gender- and gestational age- specific 90th percentile using the Tianjin local references. NNT was calculated as the inverse of the absolute risk reduction of macrosomia/LGA.

Direct medical costs

Direct medical costs included the intervention costs and the routine surveillance, obstetric and neonatal complications attributable to GDM. The costs associated with various glucose tests to identify women with GDM were the same for both the SC and UC groups. These tests included a GCT at primary hospitals, an OGTT between the 24th and 28th gestational weeks. The cost associated with the initial hospital-based group diabetes education session upon diagnosis of GDM was also the same for both groups. Additional costs for the SC group included (1) one group general diabetes/GDM counseling and education materials at enrollment, (2) two detailed individualized consultations from trained doctors and laboratory testing at the time of the 30th and 34th gestational weeks, (3) three health education sessions with trained nurses at the time of the 27th, 29th and 33th gestational weeks, and (4) SMBG. All women in the SC group were offered a free glucose meter with a memory function and free test strips. Similar to the SC women, additional costs for the UC group included costs associated with a simple diabetes/GDM consultation and laboratory testing at the 34th gestational. The specific cost items included are listed in Table 1. Itemized cost information for each study participant was recorded during the trial period.

Table 1

Intervention costs of a lifestyle intervention program for women with gestational diabetes in China, per study participant, by study arm.

Intervention phase	Shared care (n = 339, CNY, ¥)	Usual care (n = 361 CNY, ¥,)	Incremental cost (CNY, ¥,)	Data Sources
Screening and diagnosis: 24-28th gestational week
GCT	15	15	0	MI
OGTT	120	120	0	MI
Plasma insulin	100	100	0	IDF
Hospital-based education session upon diagnosis of GDM	24	24	0	MI
Enrollment and first intervention
Group counseling	50	0	50	IDF
Education materials	10	0	10	IDF
Individual consultations: 30th and 34th gestational week
Antenatal visit to Obstetricians	22	9	13	IDF
Laboratory testing during 30th gestational week	19	0	19	IDF
Laboratory testing during 34th gestational week	126	98	28	IDF
Nutrition analysis and diet consultation	73	0	73	IDF
Individual consultation	73	12	61	IDF
Health education session: 27th, 29th and 33rd gestational week	120	0	120	IDF
Regular self-monitoring of blood glucose:
Glucose meters	380	0	380	IDF
Glucose test strips	200	0	200	IDF
Insulin therapy in pregnancy	12	3	9	IDF
Total	1,344	381	963	MI or IDF

All costs were reported in Chinese yuan (CNY, ¥) (1 CNY: 0.159 USD, 31 December 2012).

MI, Maternity insurance. IDF, International Diabetes Federation.

Costs for routine surveillance, obstetric and neonatal complications attributable to GDM were collected from the electronic database Pregnant Women Health Records and also from a questionnaire survey at 4–6 weeks after delivery, regardless of the random group assignment. Once women were diagnosed with GDM, they received a hyperglycemia review one week later. Women with GDM were automatically categorized as having a high-risk pregnancy which triggered multidisciplinary clinical management. The management involved clinical review, fetal surveillance and medications if needed at primary hospitals before the 32nd gestational week, and referral to secondary or tertiary hospitals thereafter for continued care until delivery. Both costs of hospitalizations before and during delivery for obstetric and neonatal complications attributable to GDM were included in the analysis. Obstetric complications included poor metabolic control, pre-eclampsia, fetal macrosomia or fetal growth retardation, labor-induction and caesarean delivery. Neonatal complications included hypoglycemia, respiratory distress and other complications, and admission to the neonatal nursery (S2 Table).

Direct non-medical costs and indirect costs

The cost items included in this category were: the travel expenses and time costs related to the use of health services; food costs associated with dietary changes; time lost due to morbidity and outpatient treatments; and overhead charges such as rental, utilities and maintenance costs for the office space. These costs were obtained via a questionnaire at 4–6 weeks after delivery, as listed in Table 2.

Table 2

Direct non-medical and indirect costs associated with a lifestyle intervention program for women with gestational diabetes in China, per study participant, by study arm.

	Shared care (n = 339, CNY, ¥)	Usual care (n = 361 CNY, ¥,)	Incremental cost (CNY, ¥,)	Sources
Travel to follow-up visits	305	283	22	IP
Costs of lower glycemic index snacks	1,095	924	171	IP
Time lost due to outpatient services	1,219	1,130	89	IP
Time lost due to morbidity	425	598	-173	IP
Overhead charges	140	70	70	IDF
Total	3,184	3,005	179	IP or IDF

All costs were reported in Chinese yuan (CNY, ¥) (1 CNY: 0.159 USD, 31 December 2012).

IP, Individual payment. IDF, International Diabetes Federation.

Sensitivity analysis

The first sensitivity analysis was to examine how cost-effectiveness of the intervention would change by excluding data for the 242 women (130 in SC and 112 in UC) for whom the intervention effect could be contaminated as described earlier. The second was to examine how the result would change if the cost of implementing the intervention was higher in different settings by doubling intervention cost.

Results

SC significantly reduced the rates of macrosomia [SC group vs. UC group: 11.2% (38/339) vs. 17.5% (63/361), p = 0.019] and LGA [SC group vs. UC group: 13.0% (44/339) vs. 19.9% (72/361), p = 0.013] in comparison to UC. The NNT for the intervention was 16 to prevent one macrosomia, and 14 to prevent one LGA.

The estimated cost of various cost components per study participant by study group are described in Tables 1–3 and S2 Table, including intervention cost in Table 1, the non-medical and indirect costs in Table 2, the total cost in Table 3, and costs associated with routine surveillance, obstetric and neonatal complications in S2 Table. The direct medical costs per study participant in the SC and UC groups were ¥10,892 and ¥9,015, respectively, which included intervention costs (¥1,344 and ¥381) and costs of routine surveillance, obstetric and neonatal complications attributable to GDM (¥9,549 and ¥8,634). The direct non-medical and indirect costs per subject were ¥3,187 and ¥3,005 in the SC and UC groups, respectively.

Table 3

Total costs of a lifestyle intervention program for women with gestational diabetes in China, per study participant, by study arm.

	Shared care (n = 339, CNY, ¥)	Usual care (n = 361 CNY, ¥,)	Incremental cost (CNY, ¥,)
Direct medical costs per subject
Intervention costs	1,344	381	963
Routine surveillance, obstetric and neonatal complications attributable to GDM	9,549	8,634	915
Subtotal	10,892	9,015	1,877
Direct non-medical and indirect costs per subject	3,184	3,005	179
Total cost per subject
Health system perspective*	10,892	9,015	1,877
Social perspective*	14,076	12,020	2,056

All costs were reported in Chinese yuan (CNY, ¥) (1 CNY: 0.159 USD, 31 December 2012).

* Health system perspective cost only included the direct medical costs; societal perspective cost included direct medical cost, direct non-medical cost, and indirect cost.

From the health system perspective, the total cost per study participant was ¥10,892 in the SC group and ¥9,015 in the UC group, and the incremental cost was ¥1,877. From the societal perspective, the cost per study participant in the SC/UC groups was ¥14,076/¥12,020, and the incremental cost was ¥2,056 (Table 3). Thus, from the health system perspective, the cost to prevent a case of macrosomia/LGA was ¥30,032/¥26,278, calculated by multiplying NNT by the incremental cost. From the societal perspective, the corresponding cost-effectiveness ratio was ¥32,896/¥28,784 per prevented case of macrosomia/LGA (Table 4).

Table 4

Effectiveness and cost-effectiveness of a lifestyle intervention program for women with gestational diabetes in China.

	Effectiveness of intervention		Incremental cost (CNY, ¥)		Incremental effectiveness, Macrosomia /LGA (NNT)‡	Incremental cost-effectiveness ratio (CNY, ¥)
	Macrosomia Incidence (%)	LGA† Incidence (%)	Health care system	Society		Health care system		Society
						Macrosomia	LGA†	Macrosomia	LGA†
Main analysis
Shared care	11.2	13.0	1,877	2,056	16/14	30,032	26,278	32,896	28,784
Usual care	17.5	19.9	--	--	--	--	--	--	--
Sensitivity analysis
Including all 936 women
Shared care	12.5	14.0	1,701	1,925	32/20	54,432	34,020	61,600	38,500
Usual care	15.6	18.9	--	--	--	--	--	--	--
Doubling the intervention cost
Shared care	11.2	13.0	2,840	3,019	16/14	45,440	39,760	48,304	42,266
Usual care	17.5	19.9	--	--	--	--	--	--	--

All costs were reported in Chinese yuan (CNY, ¥) (1 CNY: 0.159 USD, 31 December 2012).

‡ NNT, Number needed to treat to prevent one case.

† LGA, Large for gestational age was defined by gender and gestational age-specific 90th percentiles.

In the sensitivity analysis, the NNT to prevent one macrosomia/LGA was 32/20. The incremental cost was ¥1,701 and the ICER was ¥54,432/¥34,020 for macrosomia/LGA from the health system perspective. The corresponding estimates from the societal perspective were ¥1,925 for the incremental cost and ¥61,600/¥38,500 for the ICER (Table 4). Doubling the intervention led to a higher incremental cost and ICERs (Table 4).

Discussion

Intensive lifestyle intervention among women with GDM is effective in improving pregnancy outcomes in China [14], but whether this intervention is cost-effective is unclear. Our study results demonstrate that such intervention costs less than ¥33,000 ($5,247) to prevent one macrosomia or LGA. Whether or not implementing this intervention among all women with GDM in China is an efficient use of health care resources depends on the future health and economic consequences of preventing a case of macrosomia or LGA and ultimately society’s willingness to pay for avoiding such adverse outcomes.

Spending less than ¥33,000 ($5,247) to prevent a macrosomia/LGA infant seems to represent a good value in terms of efficient use of limited health care resources in China or elsewhere in the world. First, macrosomia/LGA has both short-term and long-term adverse health complications. The immediate adverse health effects include preterm birth, higher rates of postpartum hemorrhage, increased risk of caesarean delivery, birth trauma, as well as low 1-min Apgar scores [15, 16]. Macrosomia/LGA also has long-term adverse health risks for the offspring. A prospective study using a population-based sample of 21,315 mother-child pairs in China examined the risk factors and long-term health consequences of macrosomia, and found that macrosomic infants showed an increased susceptibility to being overweight and/or obesity in childhood [17]. Obesity among children is a significant risk factor for the development of insulin resistance in a dose-response manner [18]. Moreover, macrosomia is an independent risk factor for developing metabolic syndrome in childhood, and even type 2 diabetes [19] and hypertension [20] later in life.

The long-term adverse health outcomes associated with macrosomia/LGA lead to high future health costs. A literature review reported that a child with obesity bears an extra lifetime medical cost of $19,000 as compared to a child of normal weight in the USA [21]. Persons with diabetes have substantially higher lifetime medical expenditures. Zhuo X. et al showed that in the United States the excess lifetime medical costs for people with diabetes diagnosed at ages 40, 50, 60, and 65 years were $124,600, $91,200, $53,800, and $35,900, respectively [22]. Preventing macrosomia/LGA may lead to a reduction in those long-term medical costs.

Besides macrosomia and LGA, other maternal and infant clinical outcomes in the SC group were also less prevalent as compared with the UC group, including preterm birth (18/339 vs. 28/361), Apgar score at 1 min<7 (0/339 vs. 7/361), premature rupture of membrane (49/339 vs. 69/361) and more [14]. We did not include these potential health benefits in our cost-effectiveness analysis as they were not statistically significant between the two groups in our trial, possibly due to inadequate statistical power to detect a difference. Adding these potential health benefits to the possible benefit from improvement in lifestyle for the mothers and their offspring could further improve the cost-effectiveness of the lifestyle intervention in this population.

Previous cost-effectiveness analyses showed that intensive management of mild GDM was cost-effective in other countries and populations. Moss et al. conducted a cost-consequence analysis of the ACHOIS Trial and reported that intensive management of mild GDM was more expensive compared to routine care but cost-effective at $2,186/quality adjusted life years (QALY) [23]. Ohno, et al. used a decision analytic model to compare treating vs. not treating mild GDM in the United States and showed that the cost per QALY was $20,412 [24]. We did not measure health outcomes using QALY, thus we cannot compare our study results directly with results from these previous studies.

Our study has some limitations. First, we did not evaluate the cost-effectiveness of the intervention measured in cost per QALY as we did not collect quality–of-life data due to a limited study budget. If the lifestyle intervention could improve the quality of life for women with GDM, the intervention could be more cost-effective. Second, the direct non-medical and indirect cost estimates might be subject to recall bias, as the costs associated with travelling to follow-up visits, changes in diet, time lost due to outpatient services, and morbidity were collected from a questionnaire at 4–6 weeks after delivery. However, as the main cost items were collected from the Pregnant Women Health Records electronic database records of each participant, the effect of this recall bias would be minimal. Finally, our findings may not be generalizable to other low- and high-income countries due to different clinical diabetes management across countries.

In conclusion, our study was one of the first to evaluate the cost-effectiveness of lifestyle intervention in women with GDM. We found that lifestyle intervention cost less than ¥33,000 for prevention of a macrosomia/LGA infant in China. Considering the potential severe long-term health and economic consequences of GDM and macrosomia/LGA, intensive lifestyle intervention may be an efficient use of health care resources in China, or possibly in other developing countries.

Study flow chart of a lifestyle intervention for women with gestational diabetes in Tianjin, China.

(DOCX)

Click here for additional data file.

Baseline clinical and biochemical characteristics of study participants, by assignment.

Abbreviations: BMI, body mass index; BP, blood pressure; GDM, gestational diabetes mellitus; GCT, glucose challenge test; HbA1c, hemoglobin A1c; OGTT, oral glucose tolerance test; PG, plasma glucose. † P values were derived from Chi-square Test, Fisher’s Exact Test, or Student T Test unless otherwise specified. ‡ Data were reported as median (interquartile range) and P values were derived from Wilcoxon Two-Sample Test.

(DOCX)

Click here for additional data file.

Costs associated with routine surveillance, obstetric and neonatal complications due to gestational diabetes, per study participant, by study arm.

All costs were reported in Chinese yuan (CNY, ¥) (1 CNY: 0.159 USD, 31 December 2012). MI, Maternity insurance. IP, Individual payment.

(DOCX)

Click here for additional data file.

19 May 2020

PONE-D-20-12277

Within-trial cost-effectiveness of lifestyle intervention using a 3-tier shared care approach on pregnancy outcomes in Chinese women with gestational diabetes

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Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Major comment:

1. Could you provide more details about how you randomly assigned the women into SC or UC group? Or provide some statistics to show no other factors would cause the differences regarding the pregnancy outcomes between two groups.

Minor comment:

1. Some numbers in table 3 are not correct.

2. What are the p-values of : macrosomia [the SC group vs. the UC group: 11.2% (38/339) vs. 17.5% (63/361)] and LGA [the SC group vs. the UC group: 13.0% (44/339) vs. 19.9% (72/361)]

Reviewer #2: Based on the data from one of the biggest city in CHINA, the authors evaluated the cost-effectiveness of lifestyle intervention in women with GDM and found that lifestyle intervention cost less than ¥33,000 for prevention of a macrosomia/LGA infant in China, so intensive lifestyle intervention may be an efficient use of health care resources in China. Although this paper provides potentially interesting new observations, there are some significant issues that need to be addressed for it to be suitable for publication.

Major point:

1. Only 339 from the SC and 361 from UC are availabel finally, its a very important information , should be shown in the abstract.

2. The p value need to be shown in the first paragraph of the results between different groups, without that how to say "the SC significantly reduced the rates of macrosomia....."

Minor point:

3. The unit in the sentence ‘35 kcal/day/kg for one kilogram body weight per day for those

with BMI at <18.5 kg/m2; 30–35 kcal/day for those with BMI at 18.5-23.9 kg/m2;

25-30 kcal/day/kg for those with BMI at 24.0-27.9 kg/m2; 25 kcal/day/kg for those

BMI at 28.0 kg/m2 and more” is not clear.

4. macrosomia should be a special kind of LGA, so the defination of LGA need to exclude macrosomia.

5. the language of this manuscript need to be improved.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

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Reviewer #1: No

Reviewer #2: No

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17 Jul 2020

PONE-D-20-12277

Response to Reviewer #1

Reviewer #1: Major comment:

1. Could you provide more details about how you randomly assigned the women into SC or UC group? Or provide some statistics to show no other factors would cause the differences regarding the pregnancy outcomes between two groups.

Response: Thank you for your comment. Details of the randomization were described in our previous publication. Following the suggestion, we now added more details of randomization as follows: “A simple randomization procedure without replacement (i.e., by the time sequence of visits to the clinic and a list of priori computer-generated random assignment status by X.Y.) was used to perform the random assignment by the intervention team members.” We also added a sentence to show no significant differences regarding the pregnancy outcomes between two groups as “There were no significant differences between the two groups for the baseline clinical and biochemical characteristics.”.

Minor comment:

1. Some numbers in table 3 are not correct.

Response: Thank you for the careful reading . We have corrected the error. .

2. What are the p-values of : macrosomia [the SC group vs. the UC group: 11.2% (38/339) vs. 17.5% (63/361)] and LGA [the SC group vs. the UC group: 13.0% (44/339) vs. 19.9% (72/361)]

Response: We have added the p values in the first paragraph of the results.

Response to Reviewer #2

Reviewer #2: Based on the data from one of the biggest city in CHINA, the authors evaluated the cost-effectiveness of lifestyle intervention in women with GDM and found that lifestyle intervention cost less than ¥33,000 for prevention of a macrosomia/LGA infant in China, so intensive lifestyle intervention may be an efficient use of health care resources in China. Although this paper provides potentially interesting new observations, there are some significant issues that need to be addressed for it to be suitable for publication.

Major point:

1. Only 339 from the SC and 361 from UC are availabel finally, its a very important information , should be shown in the abstract.

Response: Thank you for your comment. We have added this information in the abstract.

2. The p value need to be shown in the first paragraph of the results between different groups, without that how to say "the SC significantly reduced the rates of macrosomia....."

Response: Thank you for your comment. We have added the p values in the first paragraph of the results.

Minor point:

3. The unit in the sentence ‘35 kcal/day/kg for one kilogram body weight per day for those with BMI at <18.5 kg/m2; 30–35 kcal/day for those with BMI at 18.5-23.9 kg/m2;

25-30 kcal/day/kg for those with BMI at 24.0-27.9 kg/m2; 25 kcal/day/kg for those

BMI at 28.0 kg/m2 and more” is not clear.

Response: Thank you for your comment. We have revised this sentence.

Now it reads as “35 kcal per day for one kilogram of body weight (35 kcal/day/kg) for women with BMI at <18.5 kg/m2; 30–35 kcal/day/kg for women with BMI at 18.5-23.9 kg/m2; 25-30 kcal/day/kg for women with BMI at 24.0-27.9 kg/m2; 25 kcal/day/kg for women with BMI at 28.0 kg/m2 and more”

4. macrosomia should be a special kind of LGA, so the defination of LGA need to exclude macrosomia.

Response: We thank the reviewer for this insight. We agree that macrosomia is a special kind of LGA. However, in our original RCT design, we used the two outcomes as sperate outcome measures for the trial. We defined LGA as birth weight above the gender- and gestational age- specific 90th percentiles using the Tianjin local references, while macrosomia as birth weight ≥4,000 gram. The two measures were both prior defined primary endpoints for our RCT. We reported the effectiveness of intervention using both endpoints in our previous published main analysis. So we preferred not to exclude macrosomia from LGA to keep consistency with the main report.

5. the language of this manuscript need to be improved.

Response: Thank you for your comment. Now, a native English editor has copyedited the paper.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

3 Aug 2020

Within-trial cost-effectiveness of lifestyle intervention using a 3-tier shared care approach for pregnancy outcomes in Chinese women with gestational diabetes

PONE-D-20-12277R1

Dear Dr. Li

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Linglin Xie

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: My commets to author has been responsed in the new version this time, not only the data but also the statistical analysis been performed appropriately, the language also been improved, its valuable to be published.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

10 Aug 2020

PONE-D-20-12277R1

Within-trial cost-effectiveness of lifestyle intervention using a 3-tier shared care approach for pregnancy outcomes in Chinese women with gestational diabetes

Dear Dr. Li:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

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on behalf of

Dr. Linglin Xie

Academic Editor

PLOS ONE