In this study women with singleton pregnancies and diagnosed in the University Medical Center Groningen with GDM according to the Dutch national guidelines between January 2011 and January 2016, were included. In these women serum TSH and FT4 levels were assessed routinely at the first visit after being diagnosed with GDM. Women with pre-existing DM and women with known thyroid disease or thyroid medication usage were not included, as were women with a twin pregnancy (n=7) and women with missing data on pregnancy outcomes (n=2) or thyroid func-tion (n=14). The study has been conducted in accordance with the guideline of the Declaration of Helsinki and Good Clinical Practice. The study has been exempted for approval according to the Medical research involving Human Subjects Act.19 This report is based on patient data acquired during care-as-usual, the data has been analysed retrospectively and all the requirements for patient anonymity are in agreement with the regulations of the ethics committee. According to this and the Dutch law on Medical research with Human Subjects, no approval from an ethics committee is necessary.
Gestational diabetes mellitus
As previously described,20,21 women were screened for GDM between 24-28 weeks of gestation with a 75-g oral glucose tolerance test (OGTT) when they had one or more GDM risk factors according the Dutch national guideline.22 Screening was also performed in women with signs suggestive of GDM (e.g. polyhydramnios or foetal macrosomia). Abnormal blood glucose values were defined according to the diag-nostic criteria established by the World Health Organization 1999: a fasting plasma glucose ≥7.0 mmol/l and/or a 2-h value ≥7.8 mmol/l.23 Details regarding dietary and – if needed – insulin therapy and follow-up have been described previously.21
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Thyroid function
Thyroid function (TSH and FT4 levels) was measured at or around the first visit at the diabetes outpatient clinic at time of GDM diagnosis, between 24-29 weeks of gestation. Serum FT4 and TSH levels were analysed using an electrochemilumines-cence immunoassay on the Roche Modular E170 Analyzer using kits provided by the manufacturer (Roche, Switzerland). Normal values outside pregnancy for FT4 are 11-20 pmol/L, for TSH 0.4-4.5 mU/L.
Outcome measures
Maternal characteristics were recorded and all the data were obtained from review of the electronic medical and birth records. Ethnicity was divided into: Caucasian, African-American, Middle-Eastern/North-African descent, Asian (Indian or South-East Asian), and other. Weight gain was defined as the difference in weight between pre-pregnancy weight and weight at the first visit at the diabetes outpatient clinic. Pre-existing hypertension was defined as a systolic blood pressure (SBP) ≥140 mmHg, a diastolic blood pressure (DBP) ≥90 mmHg or the use of blood-pressure lowering drugs, before pregnancy or before 20 weeks of gestation.24
Neonatal and maternal outcomes
Neonatal outcomes included gestational age at birth, birth weight, expected birth weight at 40 weeks of gestation, large for gestational age (LGA) (birth weight above the 90th percentile, corrected for gestational age, gender, parity, and ethnicity),25 small for gestational age (SGA) (birth weight below the 10th percentile, corrected for gestational age, gender, parity, and ethnicity),25 macrosomia (birth weight >4000 grams), still birth/neonatal death, birth trauma (shoulder dystocia, fracture of hu-merus or clavicle), Apgar score below 7 after 5 minutes, preterm delivery (delivery before 37 weeks of gestation), and admission to the neonatology department.
Expected birth weight at 40 weeks was estimated with the Dutch reference curves for birth weight by gestational age, corrected for gender, parity and ethnicity.25 The calculated birth percentiles and birth weight were compared with the birth percentiles at 40 weeks of gestation. The percentage change between birth weight and the expected birth weight at 40 weeks for the individual percentile was added to the actual birth weight.
The maternal characteristics and outcomes included fasting glucose level, 2-h glucose level after a 75-g oral glucose load, HbA1c, pre-gestational body mass index (BMI), weight gain during pregnancy, insulin use, and several obstetric outcomes:
mode of delivery (spontaneous, instrumental (forceps or vacuum extraction), cae-sarean section (planned or secondary)), PIH, and preeclampsia. PIH was defined as a SBP ≥140 mmHg and/or DBP ≥90 mmHg on two occasions at least four hour apart in
the second half of pregnancy in previously normotensive women, with the absence of proteinuria.24 Preeclampsia was defined as a combination of PIH and proteinuria (≥300 mg/24-h).24
Statistical analyses
Continuous variables are given as mean and standard deviation (SD) or as median and inter quartile range (IQR) in case of skewed distribution. Categorical variables are given as frequencies and percentages.
Neonatal and maternal outcomes were calculated across quartiles of serum FT4 and TSH levels. Differences between the quartiles were tested by analysis of variance (ANOVA) for normally distributed continuous variables, Kruskal-Wallis for non-normally distributed continuous variables, or Chi-square test or Fisher’s exact test for categorical variables. In addition, P for trend (tests of trend across quartiles) was calculated by treating FT4 and TSH levels as continuous linear term to use all the intra-categorical information that otherwise is ignored by mere categorical comparisons.26
All P-values were two-tailed, and P-values <0.05 were considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics (version 22.0. Armonk, NY: IBM Corp).
RESULTS
The maternal characteristics of the study population are presented in Table 1. A total of 222 women with GDM and completed thyroid function measures were included in the study. The mean maternal age was 32.5 ± 5.3 years, and the median pre-gestational BMI was 27.7 (IQR 24.1-32.0) kg/m2. The median weight gain dur-ing pregnancy was 8.0 (IQR 4.1-11.0) kg. The majority of the women was Caucasian (71%) and multiparous (56%).
The median gestational age at time of the OGTT was 26.9 (IQR 25.4-27.6) weeks.
The median fasting and 2-h glucose were 5.0 (IQR 4.6-5.4) mmol/l and 8.6 (IQR 8.1-9.2) mmol/l, respectively. The median gestational age at time of the thyroid function test was 27.6 (IQR 26.3-28.8) weeks. Median TSH level and FT4 levels were 1.5 (IQR 1.02-2.02) mU/L and 11.4 (IQR 10.3-12.3) pmol/L, respectively.
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TABLE 1. Maternal characteristics of the study population.
Characteristics N=222
Pre-gestational BMI (kg/m2) 27.7 [24.1-32.0]
Weight gain during pregnancy (kg) 8.0 [4.1-11.0]
Smoking during pregnancy, n (%) 23 (10.4)
First degree relative with DM, n (%) 110 (49.5)
History of GDM, n (%) 21 (9.5)
Previous infant weighing ≥4500 g at birth, n (%) 15 (6.8)
Pre-existing hypertension, n (%) 10 (4.5)
Gestational age at time of OGTT (wks) 26.9 [25.4-27.6]
Fasting glucose level (mmol/l) 5.0 [4.6-5.4]
2-h glucose level after a 75-g OGTT (mmol/l) 8.6 [8.1-9.2]
Gestational age at time of thyroid function test (wks) 27.6 [26.3-28.8]
TSH level (mU/L) 1.5 [1.02-2.02]
FT4 level (pmol/L) 11.4 [10.3-12.3]
Abbreviations: BMI, body mass index; DM, diabetes mellitus; GDM, gestational diabetes mellitus; OGTT, oral glu-cose tolerance test; TSH, thyroid stimulating hormone; FT4, free thyroxine.
Data are expressed as mean ± SD, median [IQR], or proportion n (%).
Data with respect to pre-gestational BMI, weight gain during pregnancy, family history of DM, are missing in 3 (1.4%), 14 (6.3%), 8 (3.6%) of the women, respectively.
Neonatal and maternal outcomes
FT4 quartiles
Neonatal and maternal outcomes according to quartiles of second trimester serum FT4 levels are given in Table 2. Between the quartiles of FT4, there were no sig-nificant differences with respect to most of the neonatal outcomes. Admission to the neonatology department was higher in the first quartile and was statistically significant between the quartiles (p=0.036). Preterm delivery tended to be higher in the lower quartiles but this was not statistically significant between the groups.
Even though, there were almost no statistical differences between the quartiles, there were statistical differences when we tested for a trend. FT4 quartiles were
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TABLE 2.Pregnancy outcomes according to quartiles of second trimester (24-29 weeks of gestation) FT4 levels in 222 women with gestational diabetes mellitus. Quartiles of FT4 (pmol/L) P-value*P-trend*1 n=51 <10.32 n=60 ≥10.3-11.33 n=52 ≥11.4-12.24 n=59 ≥12.3 Neonatal outcomes Gestational age at birth (wks)38.3 [38.1-39.7]38.4 [38.0-40.0]38.4 [38.0-39.9]39.0 [38.1-40.0]0.3110.040 Birth weight (g) 3346 ± 5563261 ± 5363396 ± 5523320 ± 5390.6180.883 Expected birth weight at 40 wks (g) 3632 ± 4153532 ± 4223661 ± 4233486 ± 4410.1050.172 Large for gestational age, n (%)9 (17.6)4 (6.7)9 (17.3)6 (10.2)0.2160.586 Macrosomia, n (%)4 (7.8)6 (10.0)5 (9.6)6 (10.2)0.9760.720 Small for gestational age, n (%)4 (7.8)6 (10.0)1 (1.9)4 (6.8)0.3880.466 Still birth/neonatal death, n (%)0000NANA Birth trauma, n (%)002 (3.8)3 (5.1)0.1510.031 Apgar score <7 after 5 min, n (%)2 (3.9)2 (3.3)0 (0.0)3 (5.2)0.4640.919 Preterm delivery, n (%)6 (11.8)4 (6.7)2 (3.8)1 (1.7)0.1370.022 Admission to the neonatology department, n (%)13 (25.5)6 (10.0)4 (7.7)7 (11.9)0.0360.051 Maternal outcomes Fasting glucose level (mmol/l)5.1 [4.6-5.5]4.9 [4.6-5.5]5.0 [4.6-5.5]4.9 [4.6-5.3]0.7970.503 2-h glucose level after a 75-gram OGTT (mmol/l)8.6 [8.0-9.4]8.6 [8.1-9.2]8.5 [8.0-9.1]8.4 [8.1-9.4]0.8110.937 HbA1c (%)5.6 [5.4-5.7]5.6 [5.3-5.8]5.5 [5.3-5.8]5.4 [5.3-5.6]0.2850.095 Pre-gestational BMI (kg/m2)28.9 [25.1-32.3]27.6 [24.3-30.2]28.2 [24.3-34.0]24.9 [21.7-30.5]0.0240.120 Weight gain during pregnancy (kg)9.0 [6.0-12.1]8.0 [4.8-12.0]7.0 [4.0-10.5]7.3 [2.8-11.0]0.1670.016 Insulin use, n (%)26 (51.0)25 (41.7)22 (42.3)21 (35.6)0.4450.132 Insulin dose, U/day20.0 [12.0-34.0]14.0 [7.8-39.5]25.5 [9.5-38.0]18.0 [12.0-22.0]0.7440.434 Insulin dose, U/kg0.2 [0.1-0.4]0.1 [0.1-0.3]0.3 [0.1-0.4]0.2 [0.1-0.3]0.6920.937
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TABLE 2.Pregnancy outcomes according to quartiles of second trimester (24-29 weeks of gestation) FT4 levels in 222 women with gestational diabetes mellitus. (continued) Quartiles of FT4 (pmol/L) P-value*P-trend*1 n=51 <10.32 n=60 ≥10.3-11.33 n=52 ≥11.4-12.24 n=59 ≥12.3 Delivery type, n (%) Spontaneous Instrumental Caesarean section Planned caesarean section 31 (60.8) 4 (7.8) 9 (17.6) 7 (13.7) 47 (78.3) 2 (3.3) 8 (13.3) 3 (5.0) 34 (65.4) 6 (11.5) 6 (11.5) 6 (11.5) 42 (71.2) 7 (11.9) 7 (11.9) 3 (5.1)
0.211 0.232 0.787 0.240
0.561 0.187 0.371 0.265 PIH, n (%)1 (2.0)1 (1.7)1 (1.9)2 (3.4)0.9220.593 Preeclampsia, n (%)2 (3.9)2 (3.3)1 (1.9)2 (3.4)0.9460.796 Abbreviations: BMI, body mass index; FT4, free thyorixine; OGTT, oral glucose tolerance test; PIH, pregnancy- induced hypertension. Data are expressed as mean ± SD, median [IQR], or proportion n (%). Data with respect to HbA1c, pre-gestational BMI, weight gain during pregnancy, insulin dose U/day and insulin dose U/kg are missing in 2 (0.9%), 3 (1.4%), 14 (6.3%), 5 (5.3%), 13 (13.9%) of the women, respectively. * P-values were based on analysis of variance (nonskewed continuous variables), Kruskal-Wallis (skewed continuous variables) or Chi-square test/Fisher’s exact test (categorical variables). Test across quartiles (P for trend) were based on linear regression (continues variables) or Chi-square (categorical variables, linear-by-linear association)
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TABLE 3.Pregnancy outcomes according to quartiles of second trimester (24-29 weeks of gestation) TSH levels in 222 women with gestational diabetes mellitus. Quartiles of TSH (mU/L) P-value*P-trend*1 n=54 <1.022 n=56 ≥1.02-1.483 n=57 ≥1.49-2.014 n=55 ≥2.02 Neonatal outcomes Gestational age at birth (wks)38.1 [38.0-39.6]39.1 [38.1-40.0]38.4 [38.1-40.0]38.4 [38.0-40.0]0.2670.869 Birth weight (g)3263 ± 4763216 ± 5853438 ± 6623391 ± 3840.0990.570 Expected birth weight at 40 wks (g)3534 ± 4153411 ± 4823732 ± 4113611 ± 3400.0010.400 Large for gestational age, n (%)6 (11.1)6 (10.7)13 (22.8)3 (5.5)0.0420.820 Macrosomia, n (%)4 (7.4)4 (7.1)11 (19.3)2 (3.6)0.0260.949 Small for gestational age, n (%)3 (5.6)9 (16.1)1 (1.8)2 (3.6)0.0120.176 Still birth/neonatal death, n (%)0000NANA Birth trauma, n (%)01 (1.8)2 (3.5)2 (3.6)0.5350.160 Apgar score <7 after 5 min, n (%)1 (1.9)2 (3.6)2 (3.5)2 (3.7)0.9390.608 Preterm delivery, n (%)3 (5.6)3 (5.4)5 (8.8)2 (3.6)0.7040.874 Admission to the neonatology department, n (%)5 (9.3)8 (14.3)10 (17.5)7 (12.7)0.6400.510 Maternal outcomes Fasting glucose level (mmol/l)5.0 [4.6-5.5]5.0 [4.5-5.3]4.9 [4.6-5.4]5.0 [4.6-5.5]0.7680.746 2-h glucose level after a 75-gram OGTT (mmol/l)8.7 [8.1-9.2]8.6 [8.1-9.1]8.5 [8.0-9.1]8.6 [8.0-9.4]0.9470.764 HbA1c (%)5.5 [5.2-5.8]5.4 [5.3-5.7]5.5 [5.3-5.8]5.6 [5.4-5.8]0.3800.404 Pre-gestational BMI (kg/m2)25.5 [21.9 -30.5]28.0 [22.4-33.6]27.7 [24.4-31.4]29.4 [25.0-33.5]0.0790.002 Weight gain during pregnancy (kg)7.0 [5.0-11.0]6.5 [2.8-10.0]10.0 [5.0-12.0]9.0 [4.3-12.3]0.0270.385 Insulin use, n (%)28 (51.9)17 (30.4)28 (49.1)21 (38.2)0.0800.475 Insulin dose, U/day18.0 [9.3-26.0]18.0 [10.0-32.5]17.0 [7.5-36.5]24.0 [12.3-37.5]0.6620.898 Insulin dose, U/kg0.2 [0.1-0.4]0.2 [0.1-0.3]0.1 [0.1-0.3]0.3 [0.1-0.4]0.2330.796
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TABLE 3.Pregnancy outcomes according to quartiles of second trimester (24-29 weeks of gestation) TSH levels in 222 women with gestational diabetes mellitus. (continued) Quartiles of TSH (mU/L) P-value*P-trend*1 n=54 <1.022 n=56 ≥1.02-1.483 n=57 ≥1.49-2.014 n=55 ≥2.02 Delivery type, n (%) Spontaneous Instrumental Caesarean section Planned caesarean section 44 (81.5) 5 (9.3) 1 (1.9) 4 (7.4) 40 (71.4) 3 (5.4) 8 (14.3) 5 (8.9) 33 (57.9) 7 (12.3) 12 (21.1) 5 (8.8) 37 (67.3) 4 (7.3) 9 (16.4) 5 (9.1)
0.058 0.411 0.024 0.989
0.044 0.863 0.015 0.774 PIH, n (%)2 (3.7)2 (3.6)0 (0.0)1 (1.8)0.5090.301 Preeclampsia, n (%)1 (1.9)2 (3.6)1 (1.8)3 (5.5)0.6480.400 Abbreviations: BMI, body mass index; PIH, pregnancy-induced hypertension; OGTT, oral glucose tolerance test; TSH, thyroid stimulating hormone. Data are expressed as mean ± SD, median [IQR], or proportion n (%). Data with respect to HbA1c, pre-gestational BMI, weight gain during pregnancy, insulin dose U/day and insulin dose U/kg are missing in 2 (0.9%), 3 (1.4%), 14 (6.3%), 5 (5.3%), 13 (13.9%) of the women, respectively. * P-values were based on analysis of variance (nonskewed continuous variables), Kruskal-Wallis (skewed continuous variables) or Chi-square test/Fisher’s exact test (categorical variables). Test across quartiles (P for trend) were based on linear regression (continues variables) or Chi-square (categorical variables, linear-by-linear association).
negatively associated with gestational age at birth (p-trend=0.040) and preterm de-livery (p-trend=0.022) and positively associated with birth trauma (p-trend= 0.031).
For the maternal outcomes, both pre-gestational BMI and weight gain during pregnancy (p-trend=0.016) were highest in the lowest FT4 quartile. For the other maternal outcomes there were no statistical differences between the FT4 quartiles.
TSH quartiles
Neonatal and maternal outcomes according to quartiles of second trimester serum TSH levels are given in Table 3. Neonates born from mothers with TSH levels in the third and fourth quartile were more likely to have a higher expected birth weight at 40 weeks (p=0.001). LGA neonates and macrosomia were more frequent in the third quartile. SGA neonates were more frequent in the lowest quartiles. There were no significant differences between the TSH quartiles with respect to gestational age at birth, birth weight, still birth/neonatal death, birth trauma, Apgar score <7 after 5 min, preterm delivery, and admission to the neonatology department.
For the maternal outcomes, pre-gestational BMI was highest in the fourth TSH quartile and weight gain during pregnancy was higher in the third and fourth quar-tiles. When we tested for a trend, there was a significant trend across the quartiles for pre-gestational BMI (p-trend= 0.002), spontaneous delivery (p-trend= 0.044), and caesarean section (p-trend= 0.021). There were no significant differences in ma-ternal outcomes for weight gain during pregnancy, instrumental delivery, planned caesarean section, gestational hypertension, and preeclampsia.
DISCUSSION
In this study in patients with singleton euthyroid GDM pregnancies, we showed no major differences in unfavourable neonatal outcomes across quartiles of FT4 and TSH levels within the normal range. However, women with low FT4 levels were more likely to have a higher pre-gestational BMI and showed a trend towards a higher weight gain during pregnancy. This last finding is in agreement with our hypothesis.
Similarly, we observed that high TSH levels were also associated with a high pre-gestational BMI and larger weight gain during pregnancy.
Thyroid function and pregnancy outcomes
Overt maternal thyroid dysfunction is associated with adverse outcomes occurring before, during and after pregnancy. Hyperthyroidism has been associated with an increased risk of spontaneous abortion, intrauterine growth retardation,
low-birth-5
weight infants and foetal death.2 In addition, hypothyroidism has been associated with PIH, placenta abruption, and low-birth-weight infants.2
Several studies have demonstrated that both low and high FT4 levels in first or second trimester within the normal range are associated with unfavourable pregnancy outcomes, e.g. preterm delivery, low-birth weight, and hypertensive disorders.5,7,8 In the present study we examined the combined effect of GDM and variation in normal thyroid function on pregnancy outcomes. Although there were almost no statistically significant differences found between thyroid function and pregnancy outcomes, there was a trend towards a higher frequency of preterm delivery in women with low FT4 and neonates born to mothers with the lowest FT4 levels were more often admitted to the neonatology department. This finding is in line with the finding of Korevaar et al.,7 who showed in a large cohort of 5971 pregnant women that low FT4 levels in first or second trimester of pregnancy are as-sociated with an increased risk of premature delivery, which is independent of TSH level.7 In the present study we found no associations between low FT4 and other neonatal and obstetric outcomes. Furthermore, we could not demonstrate associa-tions between high FT4 and low-birth-weight infants and hypertensive disorders.
This may in part due to the low number of participants.
Thyroid function and maternal weight
The present study showed that euthyroid women with GDM and with lower FT4 levels in second trimester of pregnancy were more likely to have a higher pre-gestational BMI and there was a trend towards a higher weight gain during pregnancy. A num-ber of previous studies have addressed the association between low FT4 throughout pregnancy and maternal weight or BMI.27-29 These studies demonstrated a reciprocal relationship between FT4 and maternal weight. Moreover, studies have also shown associations between low FT4 levels during the second and third trimesters and the incidence of GDM.14-18 A recent study investigated the association between FT4, maternal weight, and GDM in a large cohort of more than 9000 euthyroid women.16 This study demonstrated that high maternal weight was associated with both low FT4 and a higher GDM rate in second trimester of pregnancy.16 The reciprocal find-ing of maternal weight and FT4 is consistent with the findfind-ings of our study.
Haddow et al.,16 discussed the possible biologically explanation for these find-ings. Some studies showed a reciprocal relationship between maternal FT4 and BMI and a direct relationship between the FT3/FT4 ratio and BMI, which suggests an in-crease in peripheral deiodinase activity.28,29 Studies have also shown that the rate of peripheral transformations of T4 to T3 increased with excessive energy intake, sug-gesting that peripheral deiodinase activity is affected by energy intake.30 As a high BMI is associated with increased risk of GDM, increased caloric intake and higher
weight connect with increased deiodinase activity on one hand and increased GDM incidence on the other.16
Comparable to the trend of FT4, the present study also showed that women with higher TSH were more likely to have a higher pre-gestational BMI and weight gain.
The study by Han et al.,31 demonstrated in a large euthyroid pregnant population that TSH was significantly higher in overweight group compared with the normal weight group (2.11 mU/L vs. 1.86 mU/L).
Strengths and limitations
To our knowledge this is the first study that investigated the combined effect of thyroid function and GDM on several maternal and neonatal outcomes, including maternal weight.
There are several potential limitations in this study that deserve attention. Due to the sample size there may not have been enough statistical power to find sig-nificant differences between the quartiles for relatively rare obstetric and neonatal outcomes, e.g. preeclampsia, stillbirth/neonatal death, birth trauma. Moreover, this was an observational retrospective study and this has resulted in missing obser-vations for some variables, e.g. HbA1c, pre-gestational BMI, weight gain during pregnancy and insulin dose.
CONCLUSIONS
In summary, this study showed no major differences between FT4 and TSH levels within the normal range and neonatal outcomes in women with GDM. However, women with the lowest FT4 levels and higher TSH levels had higher pre-gestational BMI and larger weight gain during pregnancy.
Acknowledgements
The authors wish to thank the endocrinologists and gynaecologists of the University Medical Center Groningen.
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