Gestational diabetes mellitus complicated by preeclampsia in the Czech Republic: A case case study

doi:10.21203/rs.3.rs-5276817/v1

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Gestational diabetes mellitus complicated by preeclampsia in the Czech Republic: A case case study

https://doi.org/10.21203/rs.3.rs-5276817/v1

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Background

Gestational diabetes mellitus (GDM) and preeclampsia (PE) are serious complications of pregnancy. In a proportion of women, they coexist; however, it is not entirely clear whether they share common pathophysiological mechanisms. The reported incidence of PE in the Czech Republic is about 4–6% and its overlap with GDM has not been studied yet. The aim of the study was (i) to determine the prevalence of PE in healthy pregnant women and GDM patients, (ii) to determine the prevalence of PE in a group of patients with GDM with persisting glucose intolerance (PGI) postpartum and (iii) to determine whether GDM patients with PE have a higher risk of obstetric complications than other subgroups.

Methods

The study included 861 women enrolled in the period 2013–2019 (409 healthy women and 452 women with GDM) with data about delivery available in 74.8% (n = 644). GDM was diagnosed according to IADPSG criteria, PE according to ISSHP criteria. Following peripartal parameters were evaluated: the necessity of induction, the length of labour (protracted birth), the use of the instruments during delivery (section, pliers, vacuum extractor), Apgar Score (pathology), the weight of the child (macrosomia). Patients with GDM were monitored at the Diabetology Centre of the University Hospital Brno until birth. Postpartum, 48.5% (n = 219) of GDM patients underwent repeated oGTT up to 1 year after delivery, of which 11.4% (n = 25) were confirmed as PGI (according to WHO criteria).

Results

PE was diagnosed in 4.6% (n = 19) controls and 10.4% (n = 47) GDM patients (P 0.022, Chi square test. Occurrence of PE was 20% in PGI group. The presence of PE also affected the course of birth - patients with PE more often have a (planned) Caesarean delivery and childbirth was more often prematured.

Conclusion

The incidence of PE in GDM patients was statistically significantly higher (approx. doubled) than in the control group (p = 0.022 Chi square) and PE negatively affected the course of birth. In patients with PGI after delivery, the occurrence of PE was very high and PE can be considered an independent risk factor for PGI.

gestational diabetes mellitus

preeclampsia

pregnancy

adverse peripartal outcomes

Gestational Diabetes mellitus (GDM) is defined as any degree of glucose intolerance that arises or is first diagnosed during pregnancy and which usually disappears after delivery ¹. Some definitions strictly distinguish between GDM as a glucose intolerance that disappears after delivery and other forms of diabetes (or prediabetes) that were not merely diagnosed before pregnancy. When glucose levels stay abnormal after delivery, this is most likely not GDM but some other form of diabetes such as type 2 diabetes (T2DM), type 1 diabetes (T1DM), Late Autoimmune Diabetes of Adults (LADA) or Maturity-Onset Diabetes of the Young (MODY). Similarly, we can consider hypertension during pregnancy first diagnosed after the 20th week of pregnancy a gestational; however, if persisting after delivery, it can be considered primary hypertension that was not diagnosed before pregnancy².

Diabetes, whether gestational or other type, as well as (gestational) hypertension, can occur independently during pregnancy, but diagnoses may coexist in various combinations resulting from the previous definition of diabetes and hypertension during pregnancy. The diagnosis firmly associated with hypertension during pregnancy is preeclampsia (PE). There are several definitions of PE proposed by professional organisations that are preferred in countries worldwide. According to the International Society for Hypertension In Pregnancy (ISSHP), PE is defined as the presence of a new-onset hypertension (blood pressure more than 140/90mm Hg) after the 20th week of pregnancy accompanied by proteinuria (over 30 mg/mmol in single urine spot or above 0.3 g/24 hours) or by the kidney damage, liver dysfunction, neurological complications, haemolysis or thrombocytopenia or slowed foetal growth³.

Compared to normotensive pregnancies, women who develop preeclampsia often have increased insulin resistance in the first and second trimesters and also several years after the pregnancy³. Many risk factors specific to PE are associated with insulin resistance and GDM, too (incl. obesity, chronic hypertension, higher age, ethnicity, nulliparity or multiple pregnancies). These factors can contribute to increased oxidative stress, increased risk of inflammation and vascular dysfunction, all of which are involved in the etiology of preeclampsia⁴.

Both diagnoses (PE and GDM) are associated with an increased risk of adverse perinatal outcomes and are, therefore, at the centre of attention of the relevant medical disciplines and public health in general. PE is diagnosed in approx. 15–20% of pregnant women with T1DM and 10–14% of pregnant women with T2DM⁵. Very few studies focusing on PE and GDM coincidence have been published^6–8. We have not found any study in the central European and specifically Czech populations dealing with the coincidence of PE in women with GDM and we therefore try to contribute to the current gaps in our knowledge.

The aims of our current study were (i) to determine the prevalence of PE in healthy pregnant and GDM subjects, (ii) to determine the prevalence of PE in a group of GDM patients with persistent glucose intolerance/diabetes after delivery and (iii) to determine whether GDM patients with PE have a higher risk of obstetric complications (peripartal adverse outcomes) than GDM patients without PE, the same for patients with PE and without GDM.

Subjects and diagnostic criteria

The cross-sectional observational study included n = 861 pregnant women (all Caucasians of Czech nationality from the South Moravian Region, Czech Republic) enrolled from 2013–2019 (409 healthy women and 452 women with GDM). The study was approved by the Ethical Committee of the Faculty of Medicine, Masaryk University, Brno, Czech Republic (approval number 22/2010, date of approval 16 September 2010), and was conducted in accordance with the Declaration of Helsinki as revised in 2008. Each participant provided informed consent prior to being included in this study. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

All enrolled subjects underwent fasting plasma glucose (FPG) testing in the first trimester of pregnancy by their gynaecologists, and all of them had normal FPG values. Subsequently, all subjects underwent routine mid-gestational GDM screening by the oral glucose tolerance test (oGTT) with 75 g of glucose between 24th to 28th weeks of pregnancy (mid-trimester). GDM was diagnosed according to the IADPSG criteria (FPG ≥ 5.1 mmol/l, 1-h post-load glucose ≥ 10.0 mmol/l, and 2-h post-load glucose ≥ 8.5 mmol/l with any one of the three cut-off values qualifying for a GDM diagnosis).

Control subjects were pregnant women with negative screening for GDM (as described above) who were followed during their prenatal period in several gynaecological centres of Brno. Women diagnosed with GDM were followed from the time of GDM diagnosis to delivery at the Diabetes Centre of the Faculty Hospital Brno. The inclusion criteria were: positive screening for GDM by oGTT at mid-gestation, singleton pregnancy, and Caucasian origin. The exclusion criteria were pre-existing T1DM or T2DM or diabetes with established treatment before pregnancy (diagnosed according to recent WHO criteria⁹), non-Caucasian origin, and multiple pregnancies. At the time of GDM diagnosis at mid-gestation, other selected (co)morbidities were documented incl. hypothyroidism, allergies, polycystic ovary syndrome (PCOS) and anaemia.

PE was diagnosed according to ISSHP criteria (pressure more than 140/90mmhg) with a new onset after the 20th week of pregnancy accompanied by proteinuria (over 30 mg/mmol once or above 0.3 g/24 hours) or by laboratory signs of kidney damage (creatinine ≥ 90 µmol/L;1mg/dL), liver dysfunction (elevated transaminases e.g. ALT or AST > 40IU/L), neurological complications (incl. eclampsia, altered mental status, blindness, stroke, clonus, severe headaches, persistent visual scotomata), haemolysis or thrombocytopenia (platelet countbelow150,000/µL) or abnormal foetal growth³.

Of the total study sample (n = 861), 74.8% (n = 644) women delivered in Obstetrics and Gynaecology Clinics of the University Hospital Brno, and peripartal data were therefore available to be retrieved retrospectively (2014–2021) by investigators from electronic health records. The analysed peripartal parameters comprised data on (i) the length of delivery (≥ 480 min duration of all three stages of labour defined as prolonged), (ii) the mode of delivery (prematurity, the need for delivery induction, instrumental delivery, or Caesarean section), (iii) delivery complications (such as manual extraction of the placenta or uterine hypotonia) and, finally, (iv) the selected neonatal parameters (Apgar score, the pH of cord blood, base excess (BE), and child birth weight).

All enrolled GDM subjects were invited to participate in the postpartum oGTT and 48.5% (n = 219) of them underwent repeated oGTT up to 1 year after delivery. Persistence resp. early conversion to permanent glucose intolerance (PGI = prediabetes or diabetes diagnosed according to WHO criteria for non-pregnant subjects: FPG ≥ 7 mmol/l alone or 2-h post-load glucose ≥ 11.1 mmol/l for diabetes mellitus or 5.6–6.9 mmol/l or 7.8–11.0 mmol/L for, respectively, prediabetes) was confirmed in 11.4% (n = 25) of GDM cases. In the case of a positive postpartum test of PGI, urinary ketone bodies, C-peptide, and the selected antibodies (anti-glutamic acid decarboxylase, anti-tyrosine phosphatase–2, and insulin autoantibodies) were measured to exclude eventual T1DM.

Statistical analyses

Data were expressed as medians and interquartile ranges (IQR). Nonparametric tests were used for comparison between and within the groups (Mann-Whitney test and chi-square test). Software Statistica (StatSoft, Tulsa, Oklahoma, USA) was used for all analyses. P < 0.05 was considered statistically significant.

Prevalence of PE

PE was diagnosed in 4.6% (n = 19) controls and 10.4% (n = 47) GDM patients (p = 0.022, Chi square test). For those with PGI after birth, the occurrence of PE was 20%. For more details on GDM groups see Table 1.

Table 1

**Comparison of clinical and biochemical parameters of GDM women with PE and without PE.**
Parameters	GDM without PE (n = 405)	GDM with PE (n = 47)	P
Age (years) in 2nd trimester	33 (30–36)	33 (29–35)	NS
Weight before pregnancy (kg)	71 (62–84)	85 (75–98)	3x 10^− 6
Weight gain before 28th week (kg)	7 (4–10)	6 (5–10)	NS
BMI before pregnancy	25.7 (22.4–30.0)	30.8 (27.2–33.9)	2x10^− 6
SBP in 2nd trimester (mmHg)	116 (108–124)	130 (123–141)	< 1x10^− 6
DBP in 2nd trimester (mmHg)	74 (68–81)	87 (80–94)	< 1x10^− 6
FPG in 2nd trimester (mmol/l)	5.0 (4.6–5.4)	5.2 (4.8–5.8)	0.008
oGTT 2nd hr 1st trim. (mmol/l)	10.1 (8.9–10.6)	9.9 (8.9–10.7)	NS
oGTT 2nd hr 2nd trim. (mmol/l)	8.7 (7.9–9.3)	8.9 (8.2–9.7)	NS
Primipara	38.7%	40.4%	NS
Insulin therapy	36.3%	55.3%	NS
Comorbidities – PCOS	0.25%	4.2%	0.002
Comorbidities – obesity	25.2%	59.6%	0.008
Comorbidities – hypothyroidism	15.6%	19.1%	NS
Comorbidities – asthma	27.4%	34.0%	NS
PGI	10.2% (from n = 195)	20.4% (from n = 23)	NS

Data are expressed as median (IQR), Mann-Whitney test, or as frequencies (chi-square test)

BMI - body mass index, DBP – diastolic blood pressure, FPG - fasting plasma glucose, GDM - gestational diabetes mellitus, oGTT - oral glucose tolerance test, PCOS – polycystic ovary syndrome, PGI – postpartum glucose intolerance, SBP - systolic blood pressure.

Peripartal adverse outcomes

Of the total study sample (n = 861), data about delivery were available in the 74.8% (n = 644) women. Table 2 shows a comparison of peripartal outcomes between all groups of pregnant women (with or without GDM combined with PE or without). Subjects with PE, independently of GDM, more often had a (planned) Caesarean delivery and childbirth was more often premature. Furthermore, GDM patients with PGI had statistically significantly more common instrumental delivery (vacuum extractor, obstetric pliers, non-planned Caesarean section), independently of PE co-existence (p = 0.01, Chi square test).

Table 2

**Comparison of peripartal adverse outcomes in women with and without PE**
Parameter	Women without GDM and without PE (n = 314)	Women without GDM and with PE (n = 17)	P	Women with GDM and without PE (n = 275)	Women with GDM and with PE (n = 38)	P
Prematurity (delivery in week less than 37th )	2.9%	23.5%	< 1x10^− 4	5.5%	18.4%	0.034
Induction of delivery	28%	29.4%	NS	36%	44.7%	NS
Instrumental delivery (section, vacuum extractor, obstetric pliers)	23.9%	64.7%	0.0002	28.7%	50%	0.0008
Caesarean section	14%	35.3%	0.017	16.4%	26.3%	NS
Protracted delivery (≥ 480 min.)	4.8%	0%	NS	5.8%	0%	NS
Macrosomia (birth weight ≥ 4000 g)	5.4%	0%	NS	8.7%	0%	NS
Abnormal Apgar score (in 5th min. <5)	0.3%	5.9%	0.04	0.4%	2.6%	NS
Abnormalities in base excess (≤ -11)	2.2%	0%	NS	0.4%	5.2%	0.003
Abnormalities in pH of cord blood (≤ 7.0)	1%	5.9%	NS	1.1%	2.6%	NS

Data are expressed as frequency, chi-square test.

Preeclampsia complicates about 2–8% of pregnancies, and the occurrence of GDM is reported in about 14% of pregnancies worldwide¹⁰. In the Czech Republic, the reported incidence of PE is about 4–6%¹¹ and the incidence of GDM is about 9–24% depending on the used criteria^12,13. It is well documented that the occurrence of GDM is rising worldwide. Several studies report GDM being associated with a higher PE incidence ^6,8,14. For example, German study comprising more than 600,000 pregnant women⁶ found that in women with GDM, the risk of preeclampsia was about 20% higher compared to the normal population. Another study on the Korean population has shown that the risk of GDM in the second pregnancy after the first pregnancy complicated by PE is about 20% higher than in the normal population⁷. Our study in the Czech (Caucasian) population showed 10.4% prevalence of PE in a group of GDM patients vs. 4.6% in control pregnant subjects. Those with persisting glucose intolerance after birth had the occurrence of PE as high as 20%. Women with GDM complicated by PE were significantly more obese and had a higher prevalence of polycystic ovary syndrome than those without PE in GDM complicated pregnancies.

Possible pathophysiological mechanisms contributing to PE and GDM coincidence can be ascribed to insulin resistance, inflammation and endothelial dysfunction, but GDM etiopathogenesis itself has not yet been fully clarified. While increased insulin sensitivity is typical of the first trimester of physiological pregnancy, in the second and third trimester, sensitivity decreases and women develop a certain degree of insulin resistance due to increasing concentrations of mainly placental hormones in the mother's body (such as estrogen, progesterone, leptin, cortisol, prolactin, human placental lactogen and growth hormone)¹⁵. Women with the physiological course of pregnancy are able to increase the production of insulin (with the desirable anabolic effect) and compensate for sensitivity changes (through hypertrophy and β-cell hyperplasia and increased glucose by stimulated insulin secretion). Maladaptation to the insulin sensitivity decline is later manifested as GDM.

Although both diseases - GDM and PE - share some risk factors and pathophysiological pathways, we are still in a very early stage to understand how one disease can facilitate another. What seems obvious is, that fundamental regulation takes place in the placenta, however, disease mechanisms likely operate quite differently in each disease. Increased pro-angiogenic status was described in GDM¹⁶ contrary to anti-angiogenic status in PE¹⁷. Whether GDM may act as another independent risk factor for PE because it causes a shift between pro-angiogenic and anti-angiogenic factors secreted by placenta still needs to be investigated¹⁸.

Apart from the placental dysfunction, inflammation can play a role in PE development.

Longer hyperglycaemia causes the release of cytokines (mainly tumour necrosis factor alpha (TNFα), which can play an important role in the pathogenesis of endothelial dysfunction leading to PE development. Hyperglycaemia and/or increased TNFα level lead to a higher production of peroxide radicals and reduced cell proliferation, however, it is not quite clear what cellular and molecular mechanisms are involved in this phenomenon¹⁹.

Moreover, inflammation may be also responsible for a higher occurrence of prematurity in pregnancies complicated by PE, independently of GDM. Maybe this factor can explain the finding in our study, that patients with PE more often delivered by assistance of instruments or Caesarean section.

Research aimed at PE in women with diabetes is complicated by several factors. The first problem is a sufficient sample size (i.e. coincidence of GDM with PE). Therefore, very often all forms of diabetes are studied together, or women with broader definition of hypertension are included (e.g. chronic hypertension, history of hypertension/PE in previous pregnancies, etc.). The relevance of results could be thus significantly affected. Another problem is the lack of standardized criteria for diagnosis of PE in women who have proteinuria before conception (which can apply to women with diabetes⁵).

Several studies aimed at a question, how to prevent a prematurity in pregnancies complicated by PE, and treatment of low dose of aspirin or metformin was able to prolong the gestation^20–22. The mechanisms by which metformin may prevent PE are unknown and we just speculate they include a reduction of the production of antiangiogenic factors (soluble vascular endothelial growth factor receptor-1 and soluble endoglin) or the improvement of endothelial dysfunction, probably through an effect on the mitochondria. Another potential mechanism whereby metformin may play a role in the prevention of PE is its ability to modify cellular homeostasis and energy disposition, mediated by rapamycin, a mechanistic target²³. Those findings indicate, the metformin could be a great candidate for treatment of GDM complicated by PE with better peripartal outcomes than insulin, however, no such comparative study has been performed yet. In our study metformin was not used for GDM treatment in any patient, insulin was used exclusively when diet itself was not effective enough. We found no statistical differences in need of insulin treatment in GDM patients with or without PE, although a trend of increased insulin use in those with PE was present.

In our study the incidence of PE in GDM patients was statistically significantly higher – approx. doubled - than in the control group (p = 0.022 Chi square), In patients with any form of persistent glucose intolerance after delivery, the occurrence of PE was high (20%) and the risk of other peripartal complications was higher too. PE negatively affected the course of birth independently of GDM, so the delivery was more often ended by Cesarean section. Patients with co-incidence of GDM and PE should be monitored carefully with a tight cooperation of gynaecologists and diabetologists.

Metformin could be a great candidate for GDM treatment in pregnancies complicated by PE.

1-hr PPG – 1-hr post-load plasma glucose

2-hr PPG – 2-hr post-load plasma glucose

ALT – alanine amino transferase

AST – aspartate amino transferase

BE – base excess

BMI – body mass index

DBP – diastolic blood pressure

DM – diabetes mellitus

FPG – fasting plasma glucose

GDM – gestational diabetes mellitus

IADPSG – International Association of Diabetes in Pregnancy Study Group

ISSHP - International Society for Hypertension In Pregnancy

IQR – interquartile range

LADA - Late Autoimmune Diabetes of Adults

MODY - Maturity-Onset Diabetes of the Young

oGTT – oral glucose tolerance test

PE - preeclampsia

PGI – postpartum glucose intolerance

PCOS - polycystic ovary syndrome

SBP – systolic blood pressure

T1DM - type 1 diabetes mellitus

T2DM - type 2 diabetes mellitus

VEX – vacuum extractor

WHO - World Health Organization

Ethics approval and consent to participate

The study was approved by the Ethical Committee of the Faculty of Medicine, Masaryk University, Brno, Czech Republic (approval number 22/2010, date of approval 16 September 2010), and was conducted in accordance with the Declaration of Helsinki as revised in 2008.

Consent for publication

Each participant provided informed consent prior to being included in this study.

Availability of data and material (Please ensure it is identical with the submission system; If not applicable, please state so.)

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests

Funding

The work was supported by the Grant of the National Institute for Research of Metabolic and Cradio-vascular Diseases (Exceles Program, Project No. LX22NPO5104) funded by the European Union -Next Generation EU within the National Renewal Plan and by the project NW24-01-00285 from the Czech Health Research Council of Ministry of Health of Czech Rep.

Authors' contributions

VB designed the study, was a major contributor in writing the manuscript

KCH did statistical analyses,

LP wrote manuscript, did an administration of project

VT was a coordinator of patients,

PJ was a supervisor,

KK revised the manuscript, obtained a project support

All authors read and approved the final manuscript

Clinical Trial

Not applicable

Acknowledgements

The authors would like to thank Jana Belobradkova for the identification of study subjects and for facilitating the biological sample collection process.

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No competing interests reported.

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You are reading this latest preprint version

Gestational diabetes mellitus complicated by preeclampsia in the Czech Republic: A case case study

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Version 1

Abstract

Background

Methods

Results

Conclusion

Introduction

Material and methods

Subjects and diagnostic criteria

Statistical analyses

Results

Prevalence of PE

Data are expressed as median (IQR), Mann-Whitney test, or as frequencies (chi-square test)

Peripartal adverse outcomes

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1