No impact of gestational diabetes mellitus on pregnancy complications in women with PCOS, regardless of GDM criteria used

Stine Lyngvi Fougner; Eszter Vanky; Tone Shetelig Løvvik; Sven Magnus Carlsen

doi:10.1371/journal.pone.0254895

. 2021 Jul 23;16(7):e0254895. doi: 10.1371/journal.pone.0254895

No impact of gestational diabetes mellitus on pregnancy complications in women with PCOS, regardless of GDM criteria used

Stine Lyngvi Fougner ^1,^2,^*, Eszter Vanky ^2,³, Tone Shetelig Løvvik ^2,^3,^#, Sven Magnus Carlsen ^1,^2,^#

Editor: Stephen L Atkin⁴

PMCID: PMC8301673 PMID: 34297751

Abstract

Polycystic ovary syndrome (PCOS) is characterized by the presence of insulin resistance, and women with PCOS have high prevalence of gestational diabetes (GDM). Both conditions have been associated with increased risk for pregnancy complications such as preterm birth, preeclampsia and increased offspring birth weight. We aimed to estimate the prevalence of GDM in women with PCOS using both previous and new diagnostic criteria, and to analyse whether the risk of pregnancy complications increased with the presence of GDM. In addition, we aimed to assess the response to metformin treatment in PCOS women with GDM. We performed post-hoc analysis of three prospective, double blinded studies of altogether 791 pregnant women with PCOS randomized to either metformin or placebo treatment from first trimester to delivery. Glucose data allowing GDM classification after previous (WHO 1999) and new (WHO 2013 and Norwegian 2017) diagnostic criteria were available for 722 of the women. Complications such as preeclampsia, late miscarriage and preterm birth, birth weight and gestational age were correlated to the presence of GDM and metformin treatment. The prevalence of GDM was 28.3% (WHO 1999), 41.2% (WHO 2013) and 27.2% (Norwegian 2017). Having GDM already in first trimester associated with increased risk for late miscarriage (p<0.01). Having GDM according to newer criteria correlated to increased maternal age and BMI (p<0.001). Otherwise, having GDM (any criteria) correlated neither to the development of preeclampsia, nor to birth weight z-score or the proportion of offspring being large for gestational weight. Maternal age and BMI, parity and gestational weight gain, but not GDM or metformin treatment, were determinants for birth weight z-score. Conclusion: in pregnant women with PCOS, having GDM did not increase the risk for other pregnancy complications except for an increased risk for late miscarriage among those with GDM already in the first trimester.

Introduction

Gestational diabetes mellitus (GDM) is defined as glucose intolerance diagnosed in pregnancy. In most women with GDM, β-cell dysfunction due to chronic insulin resistance is present prior to pregnancy. The physiological insulin resistance seen in the second half of normal pregnancies adds to this chronic insulin resistance, leading to elevated glucose levels. Hence, factors increasing insulin resistance, such as advanced maternal age and increased body mass index (BMI), are known risk factors for the development of GDM [1,2]. According to the International Diabetes Federation (IDF), one out of seven pregnancies (14%) worldwide meets the WHO 2013 criteria for GDM (IDF Diabetes Atlas 2017).

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of fertile age, with a prevalence of up to 20% in European studies using the Rotterdam 2003 diagnostic criteria for PCOS [3]. In the non-pregnant state, most women with PCOS are characterized by the presence of both hyperandrogenemia and increased insulin resistance [4]. Insulin resistance has been found to be present in 44–70% of women with PCOS, depending on the method used [5]. A meta-analysis of clamp studies demonstrated an overall 27% reduction of insulin sensitivity in PCOS women compared to controls. Importantly, the insulin sensitivity was reduced also in lean women with PCOS compared to lean controls [6]. The risk for developing GDM is therefore expected to be increased in women with PCOS. A recent meta-analysis of 40 studies including 17 800 PCOS pregnancies found a relative risk of 2.78 for GDM compared to non-PCOS pregnancies. This increased risk was particularly among non-obese women [7]. However, another review demonstrated substantial heterogeneity among studies, suggesting that the results could depend on differences in BMI and study designs [8]. Two Nordic prospective cohort studies and review did not find any increased risk for GDM in PCOS per se, but rather that the risk of GDM depended on factors like ethnicity, BMI, age and the diagnostic criteria for GDM used [9,10].

Women with PCOS are also at an increased risk of developing other pregnancy complications such as preterm birth, hypertension and preeclampsia [7]. A recent study concluded, however, that the rate of perinatal complications such as preeclampsia and GDM was not increased in pregnant women with PCOS after adjusting for gestational weight gain [11]. Another study of pregnant women with GDM found that having PCOS in addition further increased the risk for pregnancy complications [12].

In the general pregnant population, GDM has been associated with increased risk for both maternal and foetal complications such as preeclampsia, preterm delivery, macrosomia and large for gestational age (LGA) babies [13,14]. The HAPO study demonstrated a positive association between glucose levels and the proportion of neonates with a birth weight above 4000 g, with no obvious cut-off level, but rather a continuous rise throughout the total glucose level range of both fasting and 1 and 2 hours after an oral glucose load [15]. Gestational weight gain was not registered in this observational study.

Given the increased prevalence of both GDM and other pregnancy complications in women with PCOS, we hypothesized that the increased risk for complications in pregnancies with PCOS is related to common underlying risk factors in this population and not to the concomitant presence of GDM per se. In this study, we present the prevalence of GDM in a large, pooled patient cohort from three randomized controlled studies of pregnant women with PCOS [16–18], using both former and present criteria for GDM. Further, we compared the risk of maternal and neonatal complications in PCOS women with and without GDM and examined whether treatment with metformin had any impact on pregnancy complications in women with GDM.

Patients and methods

Patients, randomization and treatment

The patients included in this post hoc analysis are pregnant women with PCOS who took part in three prospective, randomized, double blinded, placebo-controlled trials with similar designs. The first study was a pilot study of 40 women, all at St. Olavs Hospital, Trondheim University Hospital, Norway. The PregMet and PregMet2 studies were multicentre trials. PregMet included 273 women at eleven secondary study centres in Norway, while PregMet2 included 478 women in fourteen secondary study centres in Norway, Sweden and Iceland. The participants were randomized to treatment with either metformin or placebo. The target dose of metformin was 1700 mg daily in the pilot study and 2000 mg daily in the PregMet and PregMet2 studies. Women diagnosed with GDM were referred according to local guidelines for further assessment and treatment, without interfering with the study medication. The three studies are described in detail elsewhere [16–18].

According to the protocols, a 75 g oral glucose tolerance test (OGTT) was performed at inclusion in the first trimester (≤ week 12⁺⁶), and then in week 19 and 32 (Pilot and PregMet) or in week 28 (PregMet2) in the patients not diagnosed with GDM after the initial OGTT. However, for some patients the OGTT was omitted at one or several visits, due to reasons such as nausea, previous bariatric surgery, failing willingness, analysis failure or non-fasting participants. In this post hoc analysis of GDM in women with PCOS, only women with sufficient available data on glucose metabolism were included. Of the 791 women completing one of these trials, an OGTT had been performed at inclusion in 772 (97.6%) of the women. For evaluation of the impact of GDM in early pregnancy, these 772 women were included. However, for the rest of this post hoc study we included only women who had an OGTT either at week 28 or 32, or at the last visit prior to delivery, unless a fasting glucose alone or the OGTT at an earlier visit led to the diagnosis of GDM. In total, 722 women (91.3%) were included in the main analyses.

GDM classification

In the study protocols for all three studies, GDM was diagnosed in accordance with the WHO 1999 criteria. The new WHO 2013 criteria for diagnosing GDM were released during the PregMet2 study period, but this was implemented only in Iceland at the end of the study period. Hence, the great majority of patients were diagnosed and treated in accordance with the WHO 1999 criteria. In the present study, we classified GDM using three different criteria: (i) the WHO 1999 criteria (fasting plasma glucose (FPG) ≥7.0 mmol/L or 2 h plasma glucose ≥7.8 mmol/L), (ii) the WHO 2013 criteria (FPG 5.1–6.9 mmol/L or 2 h plasma glucose 8.5–11.0 mmol/L) based on the 1.75 SD in the HAPO study and (iii) the Norwegian 2017 criteria (FPG ≥ 5.3 mmol/L or 2 h plasma glucose ≥9.0 mmol/L) based on the 2.0 SD in the HAPO study [15,19].

Baseline data

Baseline data were recorded at the inclusion visit in the first trimester of pregnancy, and included maternal weight and age, parity, smoking status and comorbidities. BMI was calculated from maternal weight and height as kg/m². A 75 g oral glucose tolerance test (OGTT) was also performed at inclusion.

Pregnancy outcome

All late miscarriages (week 13⁺⁰ to 22⁺⁶) and preterm births (week 23⁺⁰ to 36⁺⁶) were recorded, as was the development of hypertension and preeclampsia during pregnancy. Maternal weight gain from inclusion until the gestational week 36, was recorded for the women attending the visit in week 36.

When glycaemic targets were not achieved through diet and lifestyle modifications, insulin treatment was initiated. The decision to initiate insulin treatment was based on local guidelines and practice, and not stated in the study protocols. For PregMet2, the practice for clinical GDM classification and criteria for insulin treatment changed in Iceland during the study period, but not in Norway or Sweden.

Neonatal outcome

Birth weight, gender and gestational age were recorded. For all live births after gestational week 24, a gestational age- and gender-adjusted birth weight z-score was calculated based on Niklasson’s standard values from a large Swedish population [20]. The z-scores express the deviation between observed values and the Swedish population mean birth weight, adjusted for sex and gestational age at birth. Small for gestational age (SGA) was defined as birth weight <10 percentile of the gestational age (z-score <-1.28), and large for gestational age (LGA) as a birth weight >90 percentile of the gestational age (z-score >1.28).

Statistical analyses

All analyses were performed using SPSS version 25 (IBM SPSS, Armonk, NY, USA). Comparisons between groups were performed with t-test for independent samples. Chi square test was used to analyse differences in proportions of dichotomized variables. Pearson correlation test was used to analyse correlation between continuous variables. Linear regression analysis was used to analyse the determinants of birth weight, and logistic regression analysis for analysis of determinants for late miscarriage. In the multiple regression, we included the parameters that either were significantly correlated with the outcome in the univariate analysis or were considered clinically relevant. For related variables, such as maternal weight and BMI or glucose data and GDM status, only one was included.

To adjust for multiple analyses, p-values ≤0.01 were considered significant, while p-values between 0.01 and 0.05 were regarded as a trend.

Ethics

The studies were approved by the Regional Committees for Medical Research Ethics (all three studies; project number 51–2000, 145.04 and 2011/1434), the Regional Ethical Review Board in Stockholm, Sweden (PregMet2, Dnmb: 2012/1200-31/2), and the National Bioethics Committee of Iceland (Pregmet2, VSNb2012100011/03.10). All studies were approved by the Medicines Agency in Norway, and for PregMet2 also approved in Sweden and Iceland.

They were conducted according to the Declaration of Helsinki II, and written informed consent was obtained from all patients.

The studies are registered at ClinicalTrials.gov (NCT 03259919, NCT 00159536, NCT 01587378). The first study was registered after the enrolment of participants because the study started in 2000, prior to the regular use of this web registry. The authors confirm that all ongoing and related trials for this intervention are registered.

Results

GDM and baseline characteristics

Of the 722 women with sufficient glucose data, 706 women could be classified in accordance with the WHO 1999 GDM criteria, 702 women by using the WHO 2013 criteria and 685 women by using the Norwegian 2017 criteria. Of the 706 women classified using the WHO 1999 criteria, 200 women (28.3%) had GDM. Using the WHO 2013 criteria, 289 out of 702 women (41.2%) had GDM, while 186 out of 685 women (27.2%) had GDM according to the Norwegian 2017 criteria.

Women with GDM according to WHO 1999 criteria tended to be older than women without GDM (p = 0.038), while with the newer GDM criteria (WHO 2013 and Norwegian 2017 criteria) a correlation between increasing age and the presence of GDM was found (p<0.01). BMI was significantly higher in women with GDM using all three criteria (p< 0.01). No difference in pre-existing comorbidity was found between women with and without GDM (47% vs 50%, ns) when using the WHO 1999 criteria, while a trend towards increased comorbidity in women with GDM was found using the WHO 2013 criteria (44% vs 53%, p = 0.024) and the Norwegian 2017 criteria (45% vs 54%, p = 0.038). The proportion of women with and without GDM, according to all criteria, was similar among women randomized to metformin and placebo treatment.

Detailed baseline data according to GDM status are presented in Table 1a and 1b (WHO criteria 1999 and 2013) and S1 Table (Norwegian 2017 criteria).

Table 1. Clinical characteristics and pregnancy outcome for women with and without gestational diabetes (GDM).

a) GDM in accordance with WHO 1999-criteria in 706 women with PCOS. b) GDM diagnosed in accordance with WHO 2013-criteria in 702 women with PCOS.

a) GDM in accordance with WHO 1999-criteria in 706 women with PCOS.
		Non-GDM	GDM	P-value
	N (%)	506 (72)	200 (28)
Randomization	Metformin	248 (49)	97 (49)	0.90
Baseline data	Age, years	29.6 ± 4.3	30.4 ± 4.6	0.038
	BMI, kg/m2	28.1 ± 6.2	29.6 ± 6.5	0.006
	Weight, kg	79.4 ± 18.2	81.8 ± 18.0	0.12
	Nulliparous	297 (59)	107 (54)	0.23
	Comorbidity	237 (47)	99 (50)	0.52
	Smoking	26 (5)	10 (5)	0.95
Maternal outcome	HT, debut in pregn.	28 (6)	6 (3)	0.09
	Preeclampsia	34 (7)	9 (5)	0.27
	Weight gain, Kg *	10.8 ± 4.9	8.2 ± 5.4	<0.001
Neonatal outcome	Birth weight, g	3576 ± 562	3445 ± 655	0.008
	Birth weight, z-score	-0.01 ± 1.02	-0.14 ± 1.08	0.16
	Gest. age, days	278 ± 18	273 ± 23	0.013
	SGA/LGA ^§	52 (10)/45 (9)	25 (13)/19 (10)	0.60
b) GDM diagnosed in accordance with WHO 2013-criteria in 702 women with PCOS.
		Non-GDM	GDM	p-value
	N (%)	413 (59)	289 (41)
Randomization	Metformin	197 (48)	139 (48)	0.94
Baseline data	Age, years	29.4 ± 4.2	30.3 ± 4.6	0.009
	BMI, kg/m2	27.2 ± 5.7	30.5 ± 6.6	<0.001
	Weight, kg	76.6 ± 16.7	85.1 ± 19.3	<0.001
	Nulliparous	242 (59)	165 (57)	0.33
	Comorbidity	183 (44)	153 (53)	0.024
	Smoking	21 (5)	15 (5)	0.96
Maternal outcome	HT, debut in pregn.	19 (5)	14 (5)	0.46
	PE	24 (6)	19 (7)	0.68
	Weight gain, kg *	10.9 ± 4.7	9.0 ± 5.6	<0.001
Neonatal outcome	Birth weight, g	3539 ± 564	3515 ± 680	0.60
	Birth weight, z-score	-0.08 ± 1.00	0.01 ± 1.07	0.28
	Gest. age, days	278 ± 16	274 ± 25	0.008
	SGA/LGA	47 (11)/33 (8)	29 (10)/29 (5)	0.56

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a) Values given as mean ± SD or N (%) as appropriate. * N = 647. HT hypertension, PE preeclampsia, SGA small for gestational age, LGA large for gestational age.

b) Values given as mean ± SD or N (%) as appropriate. HT hypertension, PE preeclampsia, SGA small for gestational age, LGA large for gestational age. * N = 635.

At inclusion in the first trimester, fasting glucose levels correlated to maternal BMI (R = 0.24, p<0.001) and maternal age (R = 0.15, p<0.001), while 2-hour glucose level during the OGTT correlated to maternal BMI (R = 0.17, p<0.001) and tended to correlate with maternal age (R = 0.08, p = 0.031).

Maternal outcomes

GDM during any stage of pregnancy

Women with and without GDM had similar prevalence of preeclampsia and pregnancy-induced hypertension, independent of the GDM criteria used. For all three GDM criteria, women with GDM gained less weight during pregnancy than women without GDM. For details, see Table 1a and 1b (WHO criteria 1999 and 2013) and S1 Table (Norwegian 2017 criteria). During the study, women diagnosed with GDM in accordance with the WHO 1999 criteria were informed of having GDM and advised about lifestyle and diet modifications to treat GDM. When those women were excluded from the analysis, there was no difference in gestational weight gain between women classified with GDM and those without, when the new WHO 2013 criteria were used (11.0 vs 10.2 kg, p = 0.12, n = 477).

The pregnancies with GDM were on average 4 days shorter than the pregnancies without GDM when using the WHO 2013 criteria; however, using the WHO 1999 criteria there was only a tendency for shorter gestational age (Table 1). Again, when excluding the women who received a GDM diagnosis during pregnancy (using the WHO 1999 criteria), there was no difference in gestational age between the women classified with or without GDM when the WHO 2013 criteria were used (276 vs 278 days, p = 0.27).

GDM at inclusion

Women diagnosed with GDM already at inclusion in the first trimester had a higher risk of late miscarriage than the women with a normal OGTT, but there was no significant difference in the prevalence of preterm birth (Table 2a). In a logistic regression analysis, only 2-hour glucose level during the first trimester OGTT emerged as a risk factor for late miscarriage, while fasting glucose, smoking habits, metformin treatment, maternal age and BMI did not (Table 2b). Women with late miscarriage had significantly higher 2-hour glucose levels than women without late miscarriage (7.3 ± 1.6 versus 5.8 ± 1.5 mmol/l, p<0.001).

Table 2.

a) The risk of late miscarriage and preterm birth, according to GDM status at inclusion in 772/773 women. b) Determinants of late miscarriage, logistical regression.

a) The risk of late miscarriage and preterm birth, according to GDM status at inclusion in 772/773 women.
	GDM at inclusion (WHO 1999)		p-value	GDM at inclusion (WHO 2013)		p-value
	Yes	No		Yes	No
N (%)	77 (10)	695 (90)		160 (21)	613 (79)
Late miscarriage	4 (5.2)	7 (1.0)	0.003	6 (3.8)	5 (0.8)	0.005
Preterm birth	3 (3.9)	44 (6.3)	0.40	7 (4.4)	40 (6.5)	0.31
b) Determinants of late miscarriage, logistical regression.
	Late miscarriage
	Univariable			Multivariable
	OR (95% CI)		p-value	OR (95% CI)		p-value
Maternal age	1.13 (0.99–1.29)		0.07	1.13 (0.98–1.32)		0.10
Maternal BMI	1.06 (0.98–1.16)		0.14	1.06 (0.96–1.16)		0.24
Smoking	0.0^*		1.00	0.0^*		1.00
Randomization	2.65 (0.70–10.05)		0.15	2.56 (0.66–10.00)		0.18
Fasting glucose, incl.	1.31 (0.37–4.6)		0.67	0.46 (0.12–1.8)		0.27
2-hour glucose, incl.	1.71 (1.24–2.36)		<0.01	1.69 (1.20–2.39)		0.003
Total model (enter)						p = 0.009

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OR = odds ratio, CI = confidence interval.

*Confidence interval cannot be computed, as none of the women with late miscarriage did smoke (Fisher’s exact test p = 0.65). Multivariable logistical regression using model: Enter.

Data given as N (%).

Neonatal outcomes

When the WHO 1999 criteria were used, offspring born to mothers with GDM had significantly lower birth weight than did offspring born to mothers without GDM (p = 0.008); this lower birth weight was not found when the WHO 2013 the Norwegian 2017 GDM criteria were used. However, there was no difference in birth weight z-score or the proportion of SGA and LGA neonates between women with or without GDM using any of the GDM criteria, see Table 1a and 1b (WHO criteria) and S1 Table (Norwegian criteria).

Offspring birth weight z-score showed a positive correlation to maternal weight and BMI at inclusion, parity and maternal weight gain during pregnancy (p<0.001 for all), but only a trend towards correlation with fasting glucose level at inclusion (p = 0.045). In linear regression analysis, maternal age and BMI at inclusion, parity and maternal gestational weight gain during pregnancy correlated to offspring birth weight z-score. GDM according to WHO 1999 or WHO 2013 criteria, randomization to metformin treatment or smoking habits did not correlate to birth weight z-score (Table 3).

Table 3. Determinants of offspring birth weight (z-score) in women with PCOS, linear regression.

	Birth weight z-score
	Univariable		Multivariable¹		Multivariable²
	B	p-value	β (95% CI)	p-value	β (95% CI)	p-value
Maternal age	-0.03	0.40	-0.13 (-0,5–-0,01)	0.01	-0.12 (-0.05–-0.01)	0.002
Maternal BMI	0.14	<0.001	0.18 (0.02–0.04)	<0.001	0.19 (0.02–0.04)	<0.001
Maternal weight	0.19	<0.001
Smoking	-0,06	0.13	-0.07 (-0.70–0.14)	0.06	-0.07 (-0.69–0.02)	0.07
Parity	0.22	<0.001	0.27 (0.27–0.50)	<0.001	0.28 (0.29–0.51)	<0.001
Randomization	0.00	0.93	-0.00 (-0.16–0.15)	0.94	0.00 (-0.15–0.16)	0.97
Fasting glucose, incl	0.07	0.045
2-hour glucose, incl	0.03	0.46
GDM (WHO 1999)	-0.05	0.16			-0.05 (-0.28–0.70)	0.24
GDM (WHO 2013)	0.04	0.28	0.05 (-0.05–0.27)	0.19
Maternal weight gain	0.14	<0.001	0.22 (0.03–0.06)	<0.001	0.22 (0.03–0.06)	<0.001
Total			R² = 0.126		R² = 0.131

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¹GDM after WHO 2013 criterion,

²GDM after WHO 1999 criterion.

Early versus late GDM

Of the 195 women with GDM classified by the WHO 1999 criteria, 77 women (39%) had GDM already at inclusion in the first trimester; classified by the WHO 2013 criteria, however, as many as 160 of 284 women (56%) were diagnosed with GDM in the first trimester of pregnancy. The women with GDM diagnosed at inclusion were older and received insulin treatment more often during pregnancy than the women who developed GDM later in pregnancy (see Table 3). There were no differences between these GDM groups regarding maternal weight and BMI, parity, comorbidity or smoking. Women with early GDM tended to gain less weight during pregnancy than the women with late GDM (p = 0.015 for WHO 1999 and p = 0.031 for WHO 2013 criteria).

Among women with GDM in accordance with WHO 1999 criteria, early GDM tended to correlate to shorter gestational age (mean 269 vs 276 days, p = 0.032), but this was not found for those classified in accordance with the WHO 2013 criteria. There were no differences in offspring birthweight, birthweight z-score, proportion of SGA and LGA babies (Table 4a and 4b).

Table 4. GDM diagnosed at inclusion (in first trimester) compared to GDM diagnosed later in pregnancy.

a) GDM after WHO 1999 criteria, N = 195. b) GDM after WHO 2013 criteria, N = 284.

a) GDM after WHO 1999 criteria, N = 195:
		GDM		p-value
		Early GDM	Late GDM
	N (%)	77 (39)	118 (61)
Baseline data	Age, years	31.5 ± 4.2	29.6 ± 4.6	0.004
	Nulliparity	36 (46)	66 (55)	0.10
	BMI, kg/m2	30.5 ± 6.2	29.0 ± 6.7	0.11
	Weight, kg	83.8 ± 16.8	80.5 ± 18.8	0.21
	Comorbidity	32 (42)	62 (53)	0.13
	Smoking	4 (5)	6 (5)	0.97
Maternal outcome	HT	1 (1)	5 (4)	0.22
	PE	4 (5)	5 (4)	0.76
	Preterm birth	3 (4)	6 (5)	0.65
	Weight gain, kg *	7.0 ± 4.8	9.0 ± 5.7	0.015
	Gest. age, days	269 ± 34	276 ± 12	0.032
	Insulin treatment	17 (22)	6 (5)	<0.001
Neonatal outcome	Birth weight, g	3337 ± 793	3507 ± 552	0.08
	Birth weight, z-score	-0.19 ± 1.09	-0.10 ± 1.10	0.58
	SGA/LGA ^§	9 (12)/6 (8)	16 (14)/13 (12)	0.78
b) GDM after WHO 2013 criteria, N = 284:
		GDM		p-value
		GDM at incl	Late GDM
	N (%)	160 (56)	124 (44)
Baseline data	Age, years	30.8 ± 4.6	29.4 ± 4.4	0.008
	Nulliparity	90 (56)	72 (58)	0.61
	BMI, kg/m2	31.1 ± 6.4	29.9 ± 6.8	0.13
	Weight, kg	86.6 ± 18.4	83.4 ± 20.0	0.16
	Comorbidity	83 (52)	66 (53)	0.82
	Smoking	6 (4)	9 (7)	0.19
Maternal outcome	HT	7 (4)	7 (6)	0.73
	PE	9 (6)	10 (8)	0.41
	Preterm birth	7 (4)	9 (7%)	0.30
	Weight gain, kg *	8.3 ± 5.4	9.9 ± 5.7	0.031
	Gest. age, days	271 ± 30	276 ± 17	0.10
	Insulin treatment	20 (13)	4 (3)	0.005
Neonatal outcome	Birth weight, g	3505 ± 718	3518 ± 641	0.88
	Birth weight, z-score	0.03 ± 1.07	-0.02 ± 1.09	0.69
	SGA/LGA ^§	15 (10)/15 (10)	14 (11)/14 (11)	0.80

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a) Values given as mean ± SD or N (%) as appropriate. HT hypertension, PE preeclampsia, SGA small for gestational age, LGA large for gestational age. * N = 175, ^§ N = 191.

b) Values given as mean ± SD or N (%) as appropriate. HT hypertension, PE preeclampsia, SGA small for gestational age, LGA large for gestational age. * N = 247, ^§ N = 277.

Metformin treatment in women with GDM

When the WHO 2013 criteria were used, women with GDM who were randomized to metformin treatment had fewer late miscarriages and preterm births (combined) than women randomized to placebo treatment (2% versus 12%, p = 0.001), while only a trend was found when the other two GDM criteria were used. There were no differences in the prevalence of preeclampsia or hypertension. Gestational weight gain was significantly lower in the women treated with metformin than in the placebo group. A tendency was found towards reduced gestational age among the women with GDM treated with metformin, but no difference in offspring birth weight z-score. Metformin treatment did not affect the proportion of women receiving insulin treatment using any of the GDM criteria. For details, see Table 5 (WHO criteria) and S2 Table (Norwegian criteria).

Table 5. Pregnancy complications in patients treated with metformin and placebo, women with and without GDM.

		GDM			Non-GDM
		Metformin	Placebo	p-value	Metformin	Placebo	p-value
WHO 1999 criteria	N	97	103		248	258
	Hypertension	3 (3)	3 (3)	0.31	14 (6)	14 (6)	0.92
	Preeclampsia	6 (6)	3 (3)	0.26	14 (6)	20 (8)	0.34
	Late miscarriage/preterm birth	2 (2)	10 (10)	0.023	10 (4)	26 (10)	0.008
	SGA/LGA	9 (9)/9 (9)	16 (16)/10 (10)	0.33	29 (12)/24 (10)	23 (9)/21 (8)	0.47
	Birth weight, g	3527 ± 511	3366 ± 761	0.08	3580 ± 522	3571 ± 600	0.86
	Birth weight, z-score	-0.09 ± 1.05	-0.18 ± 1.11	0.09	-0.06 ± 1.07	0.04 ± 0.96	0.27
	Gest. age, days	277 ± 11	270 ± 30	0.036	278 ± 16	277 ±20	0.45
	Maternal weight gain, kg	6.6 ± 7.6	9.2 ± 5.2	0.009	9.8 ± 4.9	11.8 ± 4.7	<0.001
	Insulin treatment	9 (9)	14 (14)	0.339	1 (0.4)^*	0 (0)	0.31
WHO 2013 criteria	N	139	150		198	215
	Hypertension	9 (6)	5 (3)	0.23	8 (4)	11 (5)	0.78
	Preeclampsia	9 (6)	10 (7)	0.95	11 (6)	13 (9)	0.83
	Late miscarriage/preterm birth	3 (2)	18 (12)	0.001	9 (5)	20 (10)	0.06
	SGA/LGA	9 (6)/14 (10)	20 (14)/15 (10)	0.12	26 (13)/17 (9)	21 (10)/16 (8)	0.51
	Birth weight	3631 ± 480	3406 ± 811	0.005	3521 ± 533	3556 ± 592	0.54
	Birth weight, z-score	0.10 ± 1.03	-0.08 ± 1.11	0.17	-0.17 ± 1.05	0.01 ± 0.95	0.06
	Gest. age, days	277 ± 19	270 ± 30	0.022	278 ± 11	277 ± 20	0.49
	Maternal weight gain, kg	8.0 ± 5.4	10.0 ± 5.6	0.004	9.9 ± 4.8	11.8 ± 4.4	<0.001
	Insulin treatment	10 (7)	14 (9)	0.51	0	0

Open in a new tab

Values given as mean ± SD or N (%) as appropriate. SGA small for gestational age, LGA large for gestational age.

*One patient receiving metformin was treated with insulin due to GDM diagnosed using the new WHO 2013 criteria, but she did not have GDM using the WHO 1999 criteria.

Metformin treatment in women without GDM

When the WHO 1999 criteria for GDM were used, metformin treatment was associated with fewer late miscarriages and preterm birth (combined) than placebo treatment in the women without GDM (4% versus 10%, p = 0.008), but not when using the WHO 2013 criteria. A similar trend was found using the Norwegian 2017 GDM criteria. There were no differences in the prevalence of preeclampsia or hypertension. Gestational weight gain was significantly lower in the women treated with metformin than in the placebo group. Gestational age and birth weight z-score were independent of whether the women without GDM were treated with metformin or placebo. For details, see Table 5 (WHO criteria) and S2 Table (Norwegian criteria).

Discussion

The main findings in this large cohort of pregnant women with PCOS from three randomized placebo-controlled studies on metformin treatment are that: 1) the prevalence of GDM varied markedly with the criteria used, 2) the presence of GDM did not increase the incidence of pregnancy complications, except for an increased risk of late miscarriage in women with GDM already in first trimester, and 3) the use of metformin did not correlate to the presence of GDM, as previously described in this cohort [16]. However, metformin treatment reduced the composite endpoint of late miscarriages and preterm births in PCOS women both with and without GDM. Otherwise, metformin treatment did not correlate to the presence of other maternal or neonatal complications in women with GDM.

GDM prevalence

In the present study, a large proportion of the women with PCOS were diagnosed with GDM although the prevalence varied markedly with the criteria used. This is in accordance with previous reports on GDM in PCOS pregnancies [7]. However, a recent study from Finland concluded that PCOS is not an independent risk factor for GDM, but found that the increased risk mainly was related to adiposity, increased age, heritage for diabetes and maternal preterm birth [9]. Our cohort had no control group of women without PCOS, but the PCOS women with GDM were older and had higher BMI than the women without GDM. The mean BMI of our cohort of women with PCOS was 28.4 kg/m², markedly higher than previous studies on GDM in Norwegian cohorts [21,22], which might explain the high proportion of women with GDM in this study. Using the newer criteria for GDM, an even higher proportion of women was diagnosed with GDM, and it is noteworthy that the majority of these were diagnosed already in the first trimester. This increase in prevalence is mainly driven by a lower diagnostic limit of fasting glucose levels in the WHO 2013 criteria. Previous reports of unselected pregnant women indicate a stronger association between maternal BMI and fasting glucose than to glucose levels during an OGTT [23]. Also, in the present cohort of women with PCOS, both maternal age and BMI correlated stronger to fasting glucose level than to two-hour glucose level during an OGTT. In accordance with this, we observed that using the new WHO 2013 criteria revealed greater differences in maternal age and BMI between women with and without GDM.

GDM effect on complications

In the present study, the clinical outcomes did not differ between PCOS women with and without GDM. This observation was independent of the GDM criteria used. However, women with GDM in early pregnancy had a higher risk of late miscarriage; otherwise, having GDM did not associate with any maternal or neonatal complications such as development of preeclampsia or hypertension in pregnancy, or offspring birth weight.

This observation is noteworthy and contradicts the prevailing view that elevated glucose levels are the direct cause of pregnancy complications and poor pregnancy outcome. This finding is further supported by the observation that maternal BMI, but not glucose levels during pregnancy per se, correlated with birth weight z-score. Only a trend for univariate correlation with fasting glucose levels in the first trimester was observed. Importantly, and in contrast to maternal BMI, parity, age and gestational weight gain, having GDM was not a determinant for birth weight in the regression analysis. This importance of maternal BMI is in line with several previous reports demonstrating a positive association between maternal BMI and the risk of pregnancy complications such as preeclampsia and pregnancy outcomes such as increased infant birth weight and fat mass [23–27]. Several studies have also demonstrated that maternal pre-pregnancy BMI, independent of glucose levels, is an important risk factor for adverse pregnancy outcomes including macrosomia and LGA offspring [28–30]. The HAPO study reported a correlation between higher glucose levels and the prevalence of LGA offspring, but in the first publication of primary endpoint, birth size was not adjusted for maternal BMI [15]. More recent post hoc analyses of the HAPO study using the IADPSG criteria for GDM identified both maternal GDM and obesity at pregnancy week 28 (week 24–32) as independent risk factors for birth weight >90^th percentile [31,32].

Our finding that gestational weight gain correlated independently to offspring birth weight is in accordance with previous studies on pregnant women with GDM [33,34]. Truong et al. demonstrated that a higher gestational weight gain associated with several adverse pregnancy outcomes including offspring LGA and preeclampsia, despite significantly lower prevalence of GDM among women with high weight gain [35]. In the first treatment studies of GDM which concluded that untreated women with GDM had increased risk for offspring LGA, the treatment group had lower gestational weight gain during pregnancy [13,14]. In these studies, the untreated women were not informed about their glucose levels and therefore received no lifestyle advice. Hence, it is difficult to discriminate the effect of the pharmacological treatment for GDM from the effects of diet and lifestyle modifications. In our cohort, the women diagnosed with GDM according to the WHO 1999 criteria had a markedly lower weight gain during pregnancy than did women without GDM. These women were diagnosed with GDM in the study period and received additional diet and lifestyle advice. However, when these women were excluded from the analysis, there was no difference in weight gain between women who were retrospectively classified with or without GDM with the new WHO 2013 criteria. Most women with GDM achieved acceptable glucose levels with only diet and lifestyle intervention and did not need additional treatment with insulin. Therefore, we hold that the reduced weight gain seen in women with GDM is a consequence of the GDM diagnosis and the diet and lifestyle treatment, and not by GDM per se.

Studies on dietary intervention in pregnant overweight women have shown a decrease in macrosomia with dietary intervention, despite similar gestational weight gain [36,37] and an association between the glycaemic load of the maternal diet and the prevalence of LGA offspring [38]. A recent RCT of overweight women without GDM in late second trimester found that intensive lifestyle intervention resulted in lower gestational weight gain during pregnancy, yet no reduction in the development of GDM; nevertheless, there was a markedly lower incidence of LGA offspring [39]. This is in concordance with our findings that in women with PCOS, gestational weight gain and not GDM status associated with offspring birth size, and that the risk of having an LGA offspring did not associate with GDM status. As increased maternal BMI and high gestational weight gain are risk factors for pregnancy complications, we argue for an increased focus on overweight reduction and diet and lifestyle improvement in women with PCOS prior to conception. In addition, we suggest a focus on diet and gestational weight gain rather than strictly on GDM and glucose levels during pregnancy.

In the present study, having abnormal glucose metabolism already in the first trimester correlated to increased risk for late miscarriage. Since the insulin resistance due to pregnancy usually develops gradually from the second trimester, a pathological OGTT in the first trimester is compatible with insulin resistance and glucose intolerance prior to the actual pregnancy. However, in the regression analysis only 2-hour glucose level, and not fasting glucose, was a significant determinant for late miscarriage.

Metformin effect

The previously published pooled analyses of this study cohort concluded that metformin reduced the incidence of late miscarriage and preterm birth (combined) in women with PCOS [16]. This conclusion is affirmed in the present post hoc study using more stringent diagnostic criteria for GDM. Furthermore, the effect is found to be independent of GDM status; however, the risk of late miscarriage was significantly lower only for metformin treated women with GDM according to WHO 2013 criteria, and in women without GDM according to WHO 1999 criteria. The mechanism is unclear, but probably not related to an effect on glucose metabolism since metformin treatment did not affect the proportion of women with GDM or the need for insulin treatment.

For almost all women in the present study, the WHO 1999 criteria were used for diagnosing GDM during the clinical studies. Although 200 women (28%) were diagnosed with GDM, and a large proportion of them in the first trimester, only 24 women (12% of the women with GDM) were treated with insulin, irrespective of metformin treatment. Despite an even higher GDM incidence when classifying the study cohort after the new WHO 2013 criteria, treatment with metformin did not reduce the GDM rate. This lack of metformin-effect on glucose homeostasis in pregnancy is remarkable as it has a well-known effect in non-pregnant women with PCOS, and on impaired glucose tolerance and diabetes type 2. However, this lack of effect of metformin on glucose metabolism in pregnant women has also been observed in previous RCTs on cohorts of overweight and obese pregnant women [40–43] and in a recent meta-analysis of RCTs on cohorts of women with increased GDM risk [44]. Importantly, the effect of metformin on glucose metabolism has not been tested in placebo controlled RCTs in women with GDM. We hold that women with PCOS, overweight and obese women with increased risk of GDM make up a significant proportion of women who develop GDM during pregnancy. Given this, metformin at best has a very limited effect on glucose metabolism in pregnant women. The use of metformin for the treatment of GDM should therefore be postponed until metformin has been shown to improve glucose homeostasis and/or pregnancy outcomes in placebo controlled RCTs of women with GDM.

Strengths and limitations

The strengths of this study are the high number of participants included, where all women were diagnosed according to the same strict criteria before the actual pregnancy. This results in a well-defined population of pregnant women with PCOS. Further, the individual participant data analyses of three RCTs, the repeated longitudinal measurements of BMI and glucose levels, the meticulous collection of clinical information on co-morbidity, and strict registration and diagnoses of pregnancy outcomes add to the strengths of the study.

A main limitation of this study is that it is a post hoc analysis. In addition, the original studies included in the present analyses were not designed to primarily evaluate the effect of GDM on pregnancy outcome. For instance, data on neonatal hypoglycaemia was not reliably recorded, and could not be included in the analyses. Another main limitation regarding the impact on GDM, is that this study included only women with PCOS. The results can therefore not be directly extrapolated to the general population of pregnant women. However, as PCOS is common among women of fertile age and since women with PCOS more often develop GDM, a relatively high proportion of the women with GDM can be expected to have PCOS. Our cohort of pregnant women with PCOS could therefore be representative for a significant proportion of pregnant women with GDM.

Conclusion

In conclusion, in this large cohort of pregnant women with PCOS an additional GDM-diagnosis did not increase the risk for pregnancy complications except for an increased risk for late miscarriage among those with abnormal glucose metabolism already in the first trimester. Despite a lower maternal weight gain during pregnancy, metformin treatment neither affected the prevalence of GDM according to both old and new criteria for GDM, nor reduced the pregnancy complications in the women with GDM.

Supporting information

S1 Table. GDM in accordance with the Norwegian 2017-criteria in 685 women with PCOS.

(DOCX)

Click here for additional data file.^{(17.5KB, docx)}

S2 Table. Pregnancy complications in patients treated with metformin and placebo, women with and without GDM (according to Norwegian 2017 criteria).

(DOCX)

Click here for additional data file.^{(17KB, docx)}

S3 Table. Comparison of the prevalence between the different GMD classifications.

a. GDM diagnosed any time in pregnancy. b. GDM diagnosed in early pregnancy (at inclusion).

(DOCX)

Click here for additional data file.^{(16.3KB, docx)}

Data Availability

Data cannot be shared publicly because of restrictions due to Norwegian regulations. Since informed consent specifically on publication of individual data was not requested from the participants before inclusion, it is not allowed by the Norwegian regulations to publish individual data. This has been discussed with the leader of the Regional Committee for Health Research Ethics prior to submission and is in accordance with Norwegian national legislation, paragraph 20. Contact information, Regional Committee for Health Research Ethics of Central Norway: rek-midt@mh.ntnu.no.

Funding Statement

The pilot study had no external funding except for salary costs to the primary investigator (EV) from her institution (St. Olav’s University Hospital and the Norwegian University of Science and Technology). For the pilot study and the PregMet study, Metformin and placebo tablets were delivered free of charge by Weifa A/S, Oslo, Norway. The PregMet study also received grants from the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology. The PregMet2 study received funding from The Research Council of Norway. None of the funders had any role in the study design, data collection and analysis, decision to publish, or the preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0254895.r001

Decision Letter 0

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25 Jan 2021

PONE-D-20-31750

The impact of gestational diabetes mellitus on pregnancy complications in women with PCOS

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Partly

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

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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Reviewer #2: Yes

Reviewer #3: 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: This is an interesting paper, quite relevant to what are PLOS One's publication criteria.

It is becoming increasingly recognized that in GDM, maternal weight gain during the pregnancy is a major determinant of outcome, and may be more than important than hyperglycaemia.

The authors quite rightly make the point that no weight data was collected during the HAPO study, and is perfectly possible that the increased glucose levels associated with adverse outcomes may have been a very good correlate of increased body mass.

The authors have clearly demonstrated that in an (largely) obese and almost always insulin resistant group of pregnant women, given the label of PCOS, whatever level of new onset hyperglycaemia in pregnancy is found, then the outcome is no different. It is perhaps not surprising therefore then in those who were randomized to metformin there was little if any significant difference.

The major weakness of the study, acknowledged by the authors, is no control group of course.

Nonetheless I feel strongly that these findings add more to our understanding of the omportance of non-glycaemic factors in GDM.

Reviewer #2: Here is a list of specific comments. Note: line and page numbering in reviews and comments is based on ruler applied in Editorial Manager-generated PDF.

1. Page 7, lines 133–135: Per lines 106–107, data from the OGTT test at baseline were also available. I suggest including it in the Baseline Data section.

2. Page 8, lines 149–153: I did not understand what the z-scores represent (i.e., z-scores of what). I assumed it was birth weight. Did you mean to state the following? ‘For all live births after gestational week 24, a gestational age- and gender-adjusted birth weight was calculated based on Niklasson’s standard values from a large Swedish population. The z-score transformed birth weight express the deviation between observed birth weight and the Swedish population mean birth weight, adjusted for sex and gestational age at birth.’

3. Page 9, lines 160–162: In multivariable regressions, I suggest elaborating how determinants were selected into the regressions.

4. Page 10, line 183: Between the first and second paragraphs in the GDM and Baseline Characteristics section, it might be interesting to see a comparison between the WHO 1999 criteria and the WHO 2013 criteria using a 2x2 table with McNemar’s test statistics. Please feel free to add the Norwegian 2017 criteria to the mix but it certainly increases the number of comparisons.

5. Page 10, lines 195–198: I suggest specifying which correlation statistic was used (i.e., what R represented) in the Statistical Analyses section.

6. Page 11, line 221: In the logistic regressions in Table 2b, what was the rationale for not including GDM? Up to this point, all comparisons were centered around GDM. It would be interested to see how GDM associated with late miscarriage.

7. Page 13, line 257: The analyses in the Metformin Treatment in Women with and without GDM sections may be biased. The analyses were separated by GDM, a post Metformin variable. Analyses stratified by a post-baseline variable would require a more careful analytic approach or require a cautious note regarding the potential bias the analyses may infer.

8. Table 2b:

(8a) For both univariable and multivariable logistic regressions, I suggest reporting odds ratios and their 95% confidence intervals (instead of B). Also, I suggest replacing “multivariate” with ‘multivariable’.

(8b) Lines 569–570: For continuous variables, t-test was not appropriate in this case. I suggest reporting p-values using univariable logistic regressions. Note that the univariable logistic regressions can be used for dichotomous variables as well where p-values should be the same as the p-values from chi-square tests.

9. Table 3:

(9a) Please clarify what R represented.

(9b) Instead of beta/t, I suggest reporting regression coefficients (betas) and their 95% confidence intervals.

Reviewer #3: I have reviewed this submission by Fougner et al. The study included three cohorts of PCOS women randomized in three different trials in three different eras to receive metformin versus placebo. The study is comparing the pregnancy outcomes between women with and without GDM. The study has significant issues that question it's validity.

Major points

1. The study title indicates that the focus of the paper is on pregnancy outcomes. However, the manuscript includes lengthy details describing the difference in women's prevalence and characteristics with GDM using three different criteria. In my view, this could be the main focus of the manuscript. The title should reflect this part of the study.

2. The authors did not outline what the three diagnostic criteria in the manuscript are. In particular – what is the Norwegian criteria?

3. There was no standardized management protocol for women with GDM. Hence, it cannot be assumed that all women were treated to a unified target. The glycaemic management of women with GDM is quite critical to pregnancy outcomes.

4. The authors used different criteria and applied them to the whole cohort and then classified them as GDM or no GDM based on three different criteria. However, this is a messy and untidy way to define GDM. It essentially means that some women classified with GDM using one classification were essentially classified as Normal Glucose Tolerant ( NGT) during pregnancy and did not receive any treatment.

5. Glycaemic control is the most critical factor in the pregnancy outcomes of GDM. There was neither unified management protocol nor consistency in the women's classification during pregnancy- hence the pregnancy outcomes are not valid.

6. Hence, If the authors would like to proceed with this paper, I will advise them to drop the pregnancy outcomes and only report the prevalence of GDM using three different criteria. Alternatively, they can do a re-analysis using the actual classification of the women during pregnancy.

Minor points

1. Under the abstract, the authors wrote, "having GDM according to newer criteria correlated to increased maternal age and BMI (p<0.001), while GDM already in the first trimester associated with increased risk for late miscarriage (p<0.01)." What does this mean?

2. In the introduction, the authors wrote "IFD diabetes atlas" is IDF- diabetes atlas.

3. They stated, "The HAPO study demonstrated a positive association between glucose levels and the proportion of neonates with a birth weight above 4000 g". This is not correct; the HAPO showed correlation with birth weight > 90th percentile.

4. The HAPO trial reported on Gestational weight gain. The authors can refer to some of their publications.

5. The authors should report all the p-values and not only mention ns.

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Reviewer #1: Yes: Stephen Beer

Reviewer #2: No

Reviewer #3: Yes: Mohammed Bashir

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PLoS One. 2021 Jul 23;16(7):e0254895. doi: 10.1371/journal.pone.0254895.r002

Author response to Decision Letter 0

5 Apr 2021

We thank the Editor and the Reviewers for their time and effort spent on reviewing the manuscript. Below are the responses to the comments by each of the reviewers.

Reviewer #1: This is an interesting paper, quite relevant to what are PLOS One's publication criteria. It is becoming increasingly recognized that in GDM, maternal weight gain during the pregnancy is a major determinant of outcome, and may be more than important than hyperglycaemia.

The major weakness of the study, acknowledged by the authors, is no control group of course.

Nonetheless I feel strongly that these findings add more to our understanding of the importance of non-glycaemic factors in GDM.

Answer: Thank you for thorough reading of our manuscript and your positive review.

We appreciate your comment on the importance of gaining more knowledge on the factors not related to hyperglycemia in women with GDM, which we now believe to be more important than previously regarded.

Reviewer #2: Here is a list of specific comments. Note: line and page numbering in reviews and comments is based on ruler applied in Editorial Manager-generated PDF.

1. Page 7, lines 133–135: Per lines 106–107, data from the OGTT test at baseline were also available. I suggest including it in the Baseline Data section.

Answer: Thank you for your suggestion. We agree and have included the information in the Baseline Data section.

Answer: Thank you for pointing out some unclarity in our text. We have now adjusted the text as suggested.

3. Page 9, lines 160–162: In multivariable regressions, I suggest elaborating how determinants were selected into the regressions.

Answer: Thank you for your correct notification. This is now included in the Statistics section.

Answer: We agree and have added this 2x2 table in the Supplemental file (Suppl. Table 3).

5. Page 10, lines 195–198: I suggest specifying which correlation statistic was used (i.e., what R represented) in the Statistical Analyses section.

Answer: Thank you for the notification of omitted important information. This is now included in the Statistics section

Answer: For this regression analysis, we wanted to include the glucose data (fasting glucose and 2h-glucose) instead of the dichotomized parameter GDM. This was possible since the glucose data were collected at one time point in pregnancy. We found it more interesting to analyze if fasting glucose was more important than 2h-glucose, or vice versa, than using the “double” dichotomized parameter GDM. Using continuous data (fasting and 2 h glucose) instead of dichotomized data (GDM) in general also increase the statistical power and possibility to identify possible biologic associations. For the regression analysis of birth weight, however, we had glucose data from different time points in the pregnancy, and this was not possible. For this analysis, we had to use the dichotomized parameter GDM sometime in the pregnancy and perform two analyses, one for each GDM criterion (WHO 1999 and WHO 2013).

Answer: For the analyses of parameters registered late on pregnancy or at birth like preeclampsia and, we agree with the reviewer. There is a potential bias when looking at the GDM and non-GMD group separately, where we cannot be sure if the treatment with Metformin during second and third trimester influence the later development of GDM. However, we did not find any effect of Metformin regarding the glucose levels or the prevalence of GDM. There is still a theoretically risk for Metformin influencing which women who develop GDM, however, we hold this as less possible. In this regard, it is interesting that the observed effects of metformin are similar for both groups (GDM and non-GMD). However, for birth weight, this was accounted for in the regression analyses where both Metformin and GDM status were included (please see page 12).

In addition, regarding the risk for late miscarriage and preterm birth combined, the risk for this potential bias is even less likely, since most women with GDM in this group were diagnosed at inclusion. Of the 6 women diagnosed with GDM later in pregnancy after any criteria, three had received Metformin and three placebo treatment. We have not included these details in the paper, but we can do so if indicted by Editor.

8. Table 2b:

Answer: Thank you for the correct notification on parameters reported. The Table is now updated.

Answer: Thank you for the correct notification on parameters reported. We have now reported the p-values using univariable logistic regression, in addition to reporting odds ratio and confidence interval (except for one parameter where confidence interval did not give any sense – please see revised Table legend).

9. Table 3:

(9a) Please clarify what R represented.

Answer: Thank you for the correct notification on parameters reported. R represented the Pearson correlation coefficient but is now replaced with beta and confidence interval from univariable linear regression.

(9b) Instead of beta/t, I suggest reporting regression coefficients (betas) and their 95% confidence intervals.

Answer: Thank you for the correct notification on parameters reported. The Table is now updated.

Major points

Answer: We hold the view that the title should reflect our hypothesis (the reason for performing the study) and/or the most important observation. Our main focus of this study was to evaluate the impact of GDM on pregnancy complications. However, to do this in detail, we had to classify the patients according to the criteria for GDM which has recently been changed. Our opinion is that an analysis with only old and now outdated criteria would not be sufficient. With our almost complete glucose data we choose to evaluate this question using the newer GDM criteria now widely used, in addition to the older criteria used at the time of the studies. At the same time, we had the opportunity to compare both the old and the new GDM criteria to pregnancy outcome in this large, well defined patient cohort and also to evaluate the possible difference between the GDM criteria. We state that pregnancy outcome is the most important part of our publication, and that the title therefore is correct. We consider the prevalence of GDM and the clinical characteristics of women with GDM according to the different criteria more to be a necessary and interesting introduction to analysis of the main hypothesis in this work. We are not aware that any data similar to our data on the missing association between glucose levels and pregnancy outcomes has been presented before. That is the novelty of the present study and not the difference in GDM according to different criteria. However, we have adjusted the title, now indicating the use of different CGM criteria.

2. The authors did not outline what the three diagnostic criteria in the manuscript are. In particular – what is the Norwegian criteria?

Answer: Information on all GDM criteria used were, and still are, stated in the Methods section, under the subsection GDM Classification. No adjustments of the manuscript have been made at this point.

Answer: All women were classified as having GDM and treated for GDM according to national standard and guidelines at the time. Thus, none were deprived of standard GDM treatment.

We agree that the management of GDM are important, but our data on missing association between glucose levels and pregnancy outcomes in a well-defined cohort of pregnant women with PCOS challenge the view that glycaemic management is most critical.

4. The authors used different criteria and applied them to the whole cohort and then classified them as GDM or no GDM based on three different criteria. However, this is a messy and untidy way to define GDM. It essentially means that some women classified with GDM using one classification were essentially classified as Normal Glucose Tolerant (NGT) during pregnancy and did not receive any treatment.

Answer: All women were classified as having GDM and treated for GDM according to national guidelines, thus, no women were deprived of standard GDM treatment. For almost all included women, the same GDM classification and clinical practice for management were used (WHO 1999 criteria). Only very few of the women in the last study (PregMet 2), that is only the last 10-15 included women in Iceland, were classified according to the new WHO 2013 criteria. Of them, only 3 women were diagnosed with GDM after new criteria, and only one patient received insulin treatment (from pregnancy week 36).

We hold that the fact that some women in these studies, according to criteria developed after their pregnancy, would have been classified as having GDM today, or vice versa, do not change the importance of these evaluations. Since almost all women in these studies were included prior to implementation of the newer GDM criteria, we also had the possibility to evaluate the group of women that did not get a GDM diagnose in pregnancy (according to the old GDM criteria) and therefore no treatment, but would have been diagnosed with GDM today, according to the new criteria. In this way, we argue that differences in gestational age and gestational weight gain is a result of the treatment and not the condition itself.

Answer: We agree that the common wisdom hold by most physicians is that glycemic control is the most critical factor influencing on outcomes in GDM. However, this is what our data and our paper challenge. Regarding diagnose and management of GDM, see answers above.

Answer: With all respect, we do not agree with this suggestion. We find it important to study the impact of glucose levels and the presence of gestational diabetes on pregnancy outcomes in a well-defined patient cohort. The fact that our data challenge the previous opinion that glucose levels are the most critical factor influencing outcome, makes it important to publish our data and make the findings available.

In fact, the analyses of GDM according to the WHO 1999 criteria is the analyses using the actual classification of the women used during pregnancy, as the Reviewer suggest, please see the answer to pt. 4 above. Together with other studies, our data might lead to an increased focus on the total risk profile of the pregnant women and not only on the glucose levels.

Minor points

Answer: Having GDM anytime during pregnancy correlated to increased maternal age and BMI. Having GDM already at inclusion in the first trimester associated with risk of late miscarriage. For the women with late miscarriage, only glucose data from the inclusion in the late first trimester was available. We have rephrased the sentences and hope this is clearer now.

2. In the introduction, the authors wrote "IFD diabetes atlas" is IDF- diabetes atlas.

Answer: Thank you for pointing out our misspelling. This has been corrected.

Answer: The original publication from the HAPO study, ref. 15, found an association with birth weight above 4000 g, but a newer post hoc analysis of the HAPO material correctly found a correlation with birth weight >90th percentile. This is already discussed in the Discussion section, and with ref. 31.

4. The HAPO trial reported on Gestational weight gain. The authors can refer to some of their publications.

Answer: We have both read and referred to several of the HAPO publications. However, we have not been able to find any publication referring data on maternal gestational weight gain. We will be happy to discuss and refer a publication from this large and important study reporting weight data if there are publications that we have not found. Please, see also the comment made by Reviewer #1 on this topic.

5. The authors should report all the p-values and not only mention ns.

Answer: We agree and have added the exact p-value to the Table.

Attachment

Submitted filename: Response to reviewers.PlosOne_2_mars2021.docx

Click here for additional data file.^{(25.2KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0254895.r003

Decision Letter 1

Stephen L Atkin

30 Apr 2021

PONE-D-20-31750R1

No impact of gestational diabetes mellitus on pregnancy complications in women with PCOS, regardless of GDM criteria used.

PLOS ONE

Dear Dr. Fougner,

==============================

Please address the comments of the reviewers particularly on the queries raised on the methodology by reviewer 2

==============================

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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: (No Response)

Reviewer #4: (No Response)

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

Reviewer #1: Yes

Reviewer #4: Yes

**********

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

Reviewer #1: Yes

Reviewer #4: Yes

**********

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

Reviewer #1: Yes

Reviewer #4: Yes

**********

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

Reviewer #1: No

Reviewer #4: Yes

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6. Review Comments to the Author

Reviewer #1: Having reviewed the submission carefully, and the comments of reviewer 3 in particular, I do still feel that this study should be published. I think it would be a better paper if it was presented as a study of different classifications of GDM, but the authors are being perfectly reasonable in sticking to their original hypothesis. I think they have justified this decision, and as such satisfy, in their revisions, much of the original concerns. I do have one or two major issues though.

I apologise to the Editor and the authors. The HAPO study does present data on weight in pregnancy in GDM, but not weight gain. Hyperglycaemia and Adverse pregnancy outcome (HAPO) study: Association with maternal body mass index BJOG 2010 117(5): 577-84

This concludes 'higher maternal BMI, independently of maternal glycaemia is strongly associated with increased frequency of pregnancy complications'.

Secondly, The Hyperglycaemia and Adverse Pregnancy outcome Study. Association of GDM and obesity with pregnancy outcomes. Diabetes Care 2012 35(4): 780-786 which concludes 'both maternal GDM and obesity are independently associated with adverse pregnancy outcomes.

These references should be included.

I think is incorrect to state that metformin use should be suspended until placebo controlled RCTs are performed in GDM, this isn't going to happen.

Finally as a minor point there is a tangle in the use of English, line 164 it should say parameters that either were instead of either was and in line 166 it should say only one was rather than only one were.

Reviewer #4: Title: No impact of gestational diabetes mellitus on pregnancy complications in women with PCOS, regardless of GDM criteria used.

Authors: Fougner et al.

Manuscript ID: PONE-D-20-31750R1

I accepted to review the paper by Fougner et al. in second revision.

The authors in this subanalysis of three RCTs concluded that, in pregnant women with PCOS, the GDM diagnosis did not increase the risk of late pregnancy complications. This data is surprising and it may be explained in only two ways: the risk of pregnancy complications in women with PCOS is per se so high that it is difficult to increase it and/or pregnant women with PCOS have different response to GDM in comparison with non-PCOS populations.

The introduction section should be reduced in length of about 30%.

The authors define the GDM “criteria” using only glucose values at OGTT irrespective from gestational age (when assays were taken). Please complete the methods section and discuss.

Have you excluded patients with an abnormal OGTT at 12 weeks? Please clarify and discuss.

Can you give data on pregnancy complications on both populations (with GDM and pregestational diabetes)?

Please clarify if all patients had a natural pregnancy or ART pregnancy (including medications/drugs).

Please clarify where the patients were followed. One of the main concerns in terms of pregnancy complications in infertile e/o PCOS patients is the Hospital for obstetric management.

In my opinion, the analysis should be restricted to PCOS patients who did not use metformin (non-randomized to metformin) in order to avoid a potential confounder. Data on metformin should be analyzed as secondary aim in another different population and substudy.

The authors should clarify how the maternal weight gain was calculated and analyzed as risk factor. The increase in body weight throughout pregnancy is physiologic and different in obese and non-obese women (suggestions of the international guidelines).

**********

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: Yes: Stephen Beer

Reviewer #4: No

PLoS One. 2021 Jul 23;16(7):e0254895. doi: 10.1371/journal.pone.0254895.r004

Author response to Decision Letter 1

14 Jun 2021

Dear Editor,

Thank you for considering our manuscript “No impact of gestational diabetes mellitus on pregnancy complications in women with PCOS, regardless of GDM criteria used” for publication in PLOS ONE.

We thank the Editor and the Reviewers for their time and effort spent on reviewing the manuscript. Below are the responses to the comments by each of the reviewers.

This concludes 'higher maternal BMI, independently of maternal glycaemia is strongly associated with increased frequency of pregnancy complications'.

These references should be included.

Answer: We agree that data on maternal weight measured in third trimester have been published in later publications from the HAPO study. The study published in Diabetes Care 2012 was already included and discussed in the Discussion section (reference 31). We have now included also the HAPO publication in BJOG 2010 (new reference 32).

I think is incorrect to state that metformin use should be suspended until placebo controlled RCTs are performed in GDM, this isn't going to happen.

Answer: We agree that this maybe is not going to happen, at least worldwide. However, our opinion is still that further studies, RCTs, on the efficacy of metformin is necessary before treating pregnant women with a medication passing the placenta and being present in fetal blood at the same level as in the mother. Several studies suggest that metformin-exposed children have higher BMI and more often overweight during childhood (Hanem JCEM 2018, Rowan BMJ Open Diab Res Care 2018). RCTs on the efficacy of metformin treatment in pregnant women are now only available in women with PCOS, women with hypertension, women with insulin resistance prior to pregnancy and obese women. In these studies, despite the high risk for GDM in these women, metformin treatment did not influence the glucose homeostasis nor reduced the incidence of GDM.

Answer: We are sorry for the grammatical errors. Thank you for noticing, they are now corrected.

Reviewer #4: The authors in this subanalysis of three RCTs concluded that, in pregnant women with PCOS, the GDM diagnosis did not increase the risk of late pregnancy complications. This data is surprising and it may be explained in only two ways: the risk of pregnancy complications in women with PCOS is per se so high that it is difficult to increase it and/or pregnant women with PCOS have different response to GDM in comparison with non-PCOS populations.

Answer: We agree that our data could be surprising, however, as discussed in the Introduction and the Discussion sections other studies have also suggested that underlying factors can be more important than the glucose level per se. We agree that the two mentioned explanations both are possible. We cannot know whether women with PCOS have a “different GDM” or a different response to GDM compared to women without PCOS, since all women in these studies have PCOS. But as PCOS is a common condition and the prevalence of GDM is markedly increased in PCOS, these women probably constitute a significant proportion of all women with GDM. This is discussed at the end of the Discussion section.

The introduction section should be reduced in length of about 30%.

Answer: We feel that all parts of the introduction now is necessary to explain our rationale for this substudy. The length of the introduction has not been commented by the other three reviewers. However, we will try to shorten the section if the Editor find it best.

The authors define the GDM “criteria” using only glucose values at OGTT irrespective from gestational age (when assays were taken). Please complete the methods section and discuss.

Answer: As described in the Methods section, an OGTT was performed after protocol at two or three different visits during the pregnancy. We classified GDM using the glucose levels at each time point. It is correct that we use the same glucose levels at the different study visits.

Have you excluded patients with an abnormal OGTT at 12 weeks? Please clarify and discuss.

Can you give data on pregnancy complications on both populations (with GDM and pregestational diabetes)?

Answer: Patients with known pregestational diabetes and with fasting glucose ≥7 mmol/l at screening were not included in the randomized studies (exclusion criteria – please see the referred original publications). Women included in the RCTs that had an abnormal OGTT at the inclusion visit at appr. 12 weeks were not excluded in this substudy. They were registered as having early GDM. For data on pregnancy complications in the population with abnormal versus normal OGTT at 12 weeks, please see the sections “GDM at inclusion” and “Early versus late GDM”.

Please clarify if all patients had a natural pregnancy or ART pregnancy (including medications/drugs).

Answer: Of the 722 women included in this substudy, 312 women (43 %) had a spontaneous pregnancy, while the remaining 410 women had received assistance. Detailed information on this is given in the original publication for each RCT.

Please clarify where the patients were followed. One of the main concerns in terms of pregnancy complications in infertile e/o PCOS patients is the Hospital for obstetric management.

Answer: The women were followed with regular clinical and study visits at the Department of Gynaecology and Obstetrics of each study hospital. Detailed information on this is given in the original publication for each RCT.

Answer: Metformin could be a potential confounder. However, we did not find any difference between the women treated with metformin or not, except for the combined endpoint late miscarriage and preterm birth. Particularly, there were absolutely no difference in glucose levels or GDM incidence between the groups receiving metformin or placebo. This question is also taken into account with the analyses done separately for the two groups (metformin and placebo), see table 5, and also in the regression analyses where randomization was included as variable. Also, for the analyses of early GDM, the women had not yet started with study medication.

Answer: As described in the Methods section, Pregnancy outcome, maternal weight gain was calculated as the difference between maternal weight at the visit in pregnancy week 36 and the maternal weight at the inclusion visit in week 12, given in kilogram. We did not relate the weight gain in kg to the IOM guideline according to prepregnant maternal BMI.

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PLoS One. doi: 10.1371/journal.pone.0254895.r005

Decision Letter 2

Stephen L Atkin

7 Jul 2021

No impact of gestational diabetes mellitus on pregnancy complications in women with PCOS, regardless of GDM criteria used.

PONE-D-20-31750R2

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PLoS One. doi: 10.1371/journal.pone.0254895.r006

Acceptance letter

Stephen L Atkin

14 Jul 2021

PONE-D-20-31750R2

No impact of gestational diabetes mellitus on pregnancy complications in women with PCOS, regardless of GDM criteria used.

Dear Dr. Fougner:

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. GDM in accordance with the Norwegian 2017-criteria in 685 women with PCOS.

(DOCX)

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S2 Table. Pregnancy complications in patients treated with metformin and placebo, women with and without GDM (according to Norwegian 2017 criteria).

(DOCX)

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S3 Table. Comparison of the prevalence between the different GMD classifications.

a. GDM diagnosed any time in pregnancy. b. GDM diagnosed in early pregnancy (at inclusion).

(DOCX)

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Data Availability Statement

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PERMALINK

No impact of gestational diabetes mellitus on pregnancy complications in women with PCOS, regardless of GDM criteria used

Stine Lyngvi Fougner

Eszter Vanky

Tone Shetelig Løvvik

Sven Magnus Carlsen

Roles

Abstract

Introduction

Patients and methods

Patients, randomization and treatment

GDM classification

Baseline data

Pregnancy outcome

Neonatal outcome

Statistical analyses

Ethics

Results

GDM and baseline characteristics

Table 1. Clinical characteristics and pregnancy outcome for women with and without gestational diabetes (GDM).

Maternal outcomes

GDM during any stage of pregnancy

GDM at inclusion

Table 2.

Neonatal outcomes

Table 3. Determinants of offspring birth weight (z-score) in women with PCOS, linear regression.

Early versus late GDM

Table 4. GDM diagnosed at inclusion (in first trimester) compared to GDM diagnosed later in pregnancy.

Metformin treatment in women with GDM

Table 5. Pregnancy complications in patients treated with metformin and placebo, women with and without GDM.

Metformin treatment in women without GDM

Discussion

GDM prevalence

GDM effect on complications

Metformin effect

Strengths and limitations

Conclusion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Stephen L Atkin

Roles

Transfer Alert

Author response to Decision Letter 0

Decision Letter 1

Stephen L Atkin

Roles

Author response to Decision Letter 1

Decision Letter 2

Stephen L Atkin

Roles

Acceptance letter

Stephen L Atkin

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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