Sleep disorders during pregnancy: an underestimated risk factor for gestational diabetes mellitus

Sleep disorders are highly prevalent during pregnancy and significantly affect women’s health and quality of life. Gestational diabetes mellitus (GDM) is one of the most common metabolic complications during pregnancy and constitutes a significant risk factor for both mother and fetus in the short and the long term. While the association between sleep disorders and type 2 diabetes mellitus (T2DM) is indisputable, it is not clear whether there is a link between sleep disorders and GDM. The aim of this article was to investigate the association between sleep disorders and GDM and whether the treatment of sleep disorders may prevent GDM development. Insomnia, obstructive sleep apnea (OSA), restless legs syndrome (RLS), and narcolepsy were the most common sleep disorders identified during pregnancy and were related to poor sleep quality and short or prolonged sleep duration. They were all associated with an increased risk of GDM. The ideal sleep duration for pregnant women was determined at 8–9 h daily. In conclusion, sleep disorders constitute a risk factor for GDM. It is imperative that prospective studies be conducted to evaluate the effect of the early management of sleep disorders on GDM manifestation and control. Healthcare providers should highlight the importance of sufficient sleep to reinforce pregnancy outcomes.


Introduction
Sleep is an essential function that preserves life and supports mental and physical health.The absence of sleep is incompatible with life.Sleep disorders are common health conditions that usually affect the quality, timing, and duration of sleep resulting in dysfunction, fatigue, and sleepiness during the day [1].Sleep disorders are undermining the quality of life and have been associated with the development of various medical conditions, such as type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), non-alcoholic liver disease (NAFLD), and dyslipidemia [2].However, their association with gestational diabetes mellitus (GDM) is not yet established.GDM is the most common metabolic complication of pregnancy in which the advanced maternal age (≥35 years), maternal obesity (body mass index, BMI ≥ 30 kg/m 2 ), personal history of GDM in a previous pregnancy, or the family history of diabetes are the most prominent risk factors [3].GDM screening is performed in every pregnant woman between 24-28 gestational weeks with an Oral Glucose Tolerance Test (OGTT).The main diagnostic methods that are currently used are (1) the 75-g OGTT proposed by the International Association of Diabetes and Pregnancy Study Group (IADPSG), or (2) the older two-step approach of Carpenter and Coustan that includes an initial 50-g screening test, followed by 100-g OGTT for the positive subjects [4,5].GDM is related to multiple gestational, perinatal, and future complications for the mother and the offspring, and these pregnancies are classified as high-risk.The present study aims to investigate the association between sleep disorders and GDM.

Insomnia
Insomnia during pregnancy has a high incidence, reaching up to 61%, and deteriorates with the advance of gestational age.Reported insomnia has been associated with GDM, depression, pre-eclampsia, fetal growth restriction, preterm delivery, prolonged labor, cesarean section, and undiagnosed underlying psychiatric disease [6].In treating insomnia, efforts should focus on educating pregnant women on sleep hygiene, exercise, and behavioral therapy, while the aid of a psychologist-psychotherapist may be essential.Few pharmaceutical substances, such as the antihistamine diphenhydramine, could be used in pregnancy [7].

Sleep-related breathing disorders
The most common sleep-related breathing disorder during pregnancy is obstructive sleep apnea (OSA) or obstructive sleep apnea-hypopnea syndrome (OSAHS).Various questionnaires, such as Berlin Questionnaire (BQ), Epworth Sleepiness Scale (ESS), STOP and STOP-BANG, are used as screening tools; however, none of these has a high sensitivity [8].Fatigue and daytime sleepiness are the most common clinical features while snoring, awakenings with dyspnea, nocturnal polyuria, and apneas observed by partners are also present.OSA in pregnancy has been associated with various complications, such as GDM, hypertension, pre-eclampsia, premature labor, cardiomyopathy, congestive heart failure, low birth weight, reduced Apgar score, postpartum neonatal intensive care unit (NICU) hospitalization and prolonged hospitalization.However, a common confounder is the coexistence of obesity.In addition to OSA, even simple snoring, the incidence of which increases in pregnancy, has been associated with GDM, hypertension, and small-for-gestational-age (SGA) fetuses [9].

Restless legs syndrome (RLS)
Restless legs syndrome (RLS) is characterized by an unpleasant urge to move one's legs and affects the onset and maintenance of sleep.Hemoglobin values below 11 g/dl, family history of RLS, and age ≥35 years are some known risk factors.Moreover, RLS has been associated with a higher risk of GDM, poor sleep quality, daytime dysfunction, drowsiness, pre-eclampsia, preterm delivery, low birth weight, and depression.The treatment of choice is nonpharmaceutical, including exercise, massage, and the use of pressure devices.Iron administration to restore the ferritin value to at least 75 mcg/l is considered essential [10].

Narcolepsy and other sleep disorders
Narcolepsy is characterized by sudden involuntary sleep episodes.Women with an increased BMI before and those with excessive weight gain during pregnancy face a higher risk of developing narcolepsy type I or narcolepsy with cataplexy, a sudden muscle weakness triggered by laughing, crying or terror.There are no official recommendations for the treatment of narcolepsy with first onset during pregnancy since all the available medications are not authorized for such use [11].However, a recent consensus by sleep experts concluded that the risk of teratogenic effects from narcolepsy medications is extremely low [12].

Sleep duration and quality and risk of GDM
Sleep evaluation is performed with either subjective or objective measures.The subjective assessment includes structured or official questionnaires, while objective assessment is implemented with actigraphy or a sleep study, also known as polysomnography (PSG).

Sleep evaluation using questionnaires
Qiu et al. evaluated the association between sleep duration and snoring during pregnancy with the risk of GDM in 1290 pregnant women [13].After adjustment for maternal age and ethnicity, women who reported a sleep duration of ≤4 h per night at the beginning of pregnancy had a 5.56 times greater risk of developing GDM than women with a sleep duration of 9 h.It also appeared that even an extra hour of sleep reduced the risk for GDM by 15%.Moreover, women who reported sleep duration ≥10 h had higher plasma glucose concentrations, while snoring was related to a 1.86-fold increased risk of GDM.Rawal et al. published a study of 2581 pregnant women evaluating the association of sleep duration in the 1st and 2nd trimesters with GDM development using structured questionnaires [14].Sleep duration decreased gradually in ≤7 h from the 1st to the 2nd trimester, along with a reduction in daytime sleep intervals.There was no association of sleep duration in the 1st trimester with the onset of GDM.It was observed that non-obese pregnant women who slept more or less than 8-9 h in the 2nd trimester had twice the risk of developing GDM, indicating a U-shaped association between GDM and sleep duration.Followingly, Wang et al. studied sleep duration and quality in 12,506 Chinese women, showing that moderate and poor sleep quality during pregnancy was associated with a higher risk of GDM development (OR 1.62 and 1.77, respectively) [15].According to two recent studies, GDM prevalence was prominent in women with poor  [18].They filled out a structured questionnaire before the 16th gestational week to assess the duration and quality of morning and nocturnal sleep, with a repeat of the questionnaire at 24-28 weeks, when the OGTT was also performed.Poor sleep quality in early pregnancy combined with long sleep duration (≥8.5 h) was associated with an increased risk of GDM (OR 2.27).Another study, including 48,787 pregnant women, concluded that sleep duration less than 5 and more than 10 h was associated with a higher risk of GDM (OR 1.30 and 1.21, respectively) [19].Wang et al. studied 1300 women and showed that sleep duration <7 or >10 h and poor sleep quality were associated with a higher risk of GDM (OR 4.28, 4.42 and 1.75, respectively).The combination of poor sleep quality and duration of <7 h was related to a greater risk of GDM (OR 12.71) [20].Peivandi et al. concluded that women with poor sleep quality had significantly higher BMI levels and a higher risk of developing GDM (OR 2.99) [21].Furthermore, according to another study, no difference was detected in GDM prevalence in women with poor sleep quality, while short sleep duration was associated with an increased risk for GDM [22].Song et al. concluded that a positive BQ index increased the risk of GDM development from 27.5% to 66.7%, indicating an interaction of OSA with GDM [23].Conclusively, sleep duration and risk of GDM present a U-shaped association, indicating that the optimal sleep duration during pregnancy is 8-9 h.The various findings are summarized at Table 1.

Sleep evaluation using actigraphy
Actigraphy is a non-invasive and objective diagnostic method of sleep duration and quality [24].Twedt et al. showed that shorter sleep duration has been related to worse glycemic control [25].Nocturnal sleep duration <7 h and later sleep midpoint were associated with statistically significant increased risk for GDM [26].Finally, in another study short sleep duration was related to impaired glucose tolerance [27].The findings are summarized at Table 2.

Sleep evaluation using polysomnography
Polysomnography (PSG) is the diagnostic gold standard for the majority of sleep disorders.Reutrakul et al. investigated the relationship between OSA and GDM using PSG [28].GDM was related to shorter sleep duration, higher microarousal index, 4-fold ΑΗΙ, and increased risk for OSA (OR 6.6) compared to women without GDM.OSA was correlated with increased insulin resistance, pancreatic beta-cell  [30].Insulin sensitivity and secretion were improved in the CPAP subgroup.Alonso-Fernandez et al. evaluated 177 pregnant women with and without GDM in the 3rd trimester of pregnancy.Although women with GDM had greater BMI and increased insulin resistance, OSA prevalence did not differ between the two groups [31].Bublitz et al. focused on the role of inflammation in OSA and GDM.They conducted a sleep study in 23 women with GDM and detected increased levels of interleukins 6, 8, and TNF-a.The researchers suggested that there is an elevated inflammatory profile in this population [32].Balserak et al. concluded that OSA prevalence, snoring frequency, and REM sleep duration, were significantly higher in women with GDM [33].In another study in women with GDM, the elevated ΑΗΙ was related to increased nocturnal glucose levels [34].Sanapo et al. proved that women with OSA presented increased fasting glucose levels, C-peptide, and insulin resistance [35].Serednytskyy et al. evaluated the coexistence of OSA and GDM and supported that they were related to increased sympathetic activity and IL-1β levels [36].Conclusively, GDM was more common in women with OSA, while there is also a higher incidence of OSA in pregnant women with GDM.The findings are summarized at Table 2.

Other sleep disorders and GDM
The association of narcolepsy, circadian rhythm disorders, and RLS with the risk of GDM was evaluated below (Table 3).

Narcolepsy
The incidence of GDM was higher in women diagnosed with narcolepsy type I before or during pregnancy compared to women diagnosed postpartum [37].Besides, Calvo-Ferrandiz et al. concluded that GDM was more frequent in women with narcolepsy with cataplexy [38].In a nationwide study performed in the USA, 7742 women with narcolepsy were detected (88% were diagnosed with narcolepsy type II or narcolepsy without cataplexy).However, no association between narcolepsy and GDM was observed [39].

Circadian rhythm disorders
Weschenfelder et al. evaluated 235 women with a history of GDM and concluded that pregnant women raising children and having unfavorable work conditions had a higher need for long-acting insulin therapy [40].

Restless legs syndrome (RLS)
A recent study revealed a higher frequency of RLS women with GDM [41].Bisson et al. compared 26 pregnant women with GDM with 26 controls, concluding that there was a higher incidence of RLS in the GDM subgroup (46% vs 19%) [42].

Conclusions
In conclusion, the available evidence indicates an association between sleep disorders during pregnancy and GDM.
The interaction mechanisms between sleep disorders and GDM are directed towards the presence of systemic inflammation and stimulation of the sympathetic nervous system.It is crucial to design prospective studies using both subjective and objective sleep assessment methods to recognize sleep disorders during the first trimester of pregnancy.Therefore, early medical intervention will be provided, and GDM prevalence and pregnancy complications will be diminished, ensuring an improvement in public health and the quality of life of pregnant women.Healthcare providers should highlight the importance of sufficient sleep to reinforce pregnancy outcomes.The literature reports of other sleep disorders in pregnancy are scarce, making this field an area of particular interest for future studies.The underlying mechanisms correlating sleep disorders with GDM development should be investigated with further research.

Table 1
Association of sleep disorders with the risk of GDM using questionnaires

Table 3
Association of narcolepsy, circadian rhythm disorders, and RLS with the risk of GDM