Sleep Deprivation and Preterm Delivery

Insufficient sleep duration and poor sleep quality are considered to be endemic in modern society. Optimal sleep duration in pregnancy is not known. Insufficient sleep has been suggested to have effects on the health of mother and baby. Short sleep duration in pregnancy has been found to be associated with postpartum depression, preterm delivery, and the need for cesarean. When considering the general population, there is a significant correlation between short sleep duration and mortality. Possible reasons of this correlation are short sleep duration, impairing of the cognitive functions, increase in traffic and occupational accidents, and metabolic and endocrine dysfunctions . Short sleep duration alone can increase the risk for preterm delivery. As previously described, residency studies among female physician trainees were associated with increased risk of preterm delivery . In a study by Lee et al ., on polysomnography performed in the last four gestational weeks, a significant need for cesarean was seen in pregnant patients with a sleep duration under 6 h, compared to those with a sleep duration over 7 h.

Several studies with nonpregnant women indicate sleep disorders increase the level of inflammation indicators. In a study subjectively evaluating Pittsburgh sleep quality index and sleep diary, interleukin6 level was reported to be higher in the pregnant patient with sleep disorder defined in mid-pregnancy and last trimester . Inflammatory cytokines play a crucial role in the onset mechanism of the delivery and in addition, they affect the preterm delivery etiopathogenesis. Prostaglandins have a major role in the onset and maintenance of uterine contractions . Inflammatory cytokine concentrations in amniotic fluids have been reported to significantly increase in the pregnant patient with preterm delivery .

Sleep Deprivation and Postpartum Depression

Postpartum depression is defined as an episode of depression emerging within 4 weeks of delivery and lasting up to 6 months in duration. Previous studies suggest that the rate of the onset of depression increases threefold in the months after childbirth . Postpartum depression is seen in approximately 10–15% of all women giving birth. Postpartum depression prevalence has been reported as levels of 40–50% in the high-risk pregnancy in terms of depression . The main risk factors for postpartum depression are low socioeconomic class, lack of education, social isolation, poor family relations, unplanned pregnancy, preterm delivery, cesarean section, psychological stress, and previously experienced postpartum depression .

Sleep deprivation is a risk factor that is known to be associated with depression, but has not attracted enough attention. Past epidemiologic studies have described an association between sleep disturbance and depression . Goyal et al. followed 124 primiparous women from their last month of pregnancy through 3 months postpartum. In another study, Wolfson and colleagues examined self-reported depressive symptoms and sleep patterns from the late pregnancy to 1-year postpartum and observed an association between sleep patterns during the late pregnancy and depressive symptoms in the first few weeks of the postpartum period. Although both groups of women reported similar sleep patterns in the postpartum period, mothers who develop greater depressive symptoms at 2–4 postpartum weeks had significantly different sleep routines in late pregnancy compared to nondepressed mothers .

Various mechanisms for the development of postpartum depression have been suggested. The most accepted suggestion among these is the sudden drop of estrogen and progesterone hormones after birth that had progressively increased during the pregnancy period. However, various cytokines are also suggested to have a role in this situation. Changes occurring in cytokine levels due to sleep disturbances may play a role in the pathogenesis of depression by affecting neuorochemical transmission and/or the hypothalamic pituitary adrenal axis . Effects of sleep deprivation in pregnancy are summarized in Figure 10.1 .

Effects of sleep deprivation in pregnancy.

Sleep-Disordered Breathing

Sleep-disordered breathing (SDB) includes snoring, upper airway resistance syndrome, and obstructive sleep apnea (OSA). OSA is characterized by repetitive collapse of the upper airway during sleep, resulting in obstruction of airflow and oxygen desaturation, which cause arousal from sleep. OSA is a common disorder affecting at least 2–4% of the adult population . The prevalence of OSA is estimated to be 5–6% among women of reproductive age .

Apnea is defined as the complete cessation of airflow for a minimum of 10 s. A ⩾30% reduction of airflow associated with ⩾4% drop in oxygen saturation, or alternatively a ⩾50% reduction of airflow associated with ⩾3% drop in oxygen saturation, or associated with an electroencephalogram arousal is considered hypopnea according to American Academy of Sleep Medicine manual scoring system. The average number of apnea–hypopnea per hour is called apnea–hypopnea index (AHI). OSA is diagnosed when a patient has clinical symptoms in conjunction with an AHI >5 events per hour .

Both epidemiologic and sleep clinic-based studies indicate that OSA is more common in men than in women. There are a number of pathophysiologic differences to suggest why men are more prone to the disease than women. Although the exact mechanisms are unknown, differences in obesity, upper airway anatomy, breathing control, hormones, and aging are all thought to play a role . Ninety-three percent of women with moderate-to-severe OSA were not clinically diagnosed in the Wisconsin sleep cohort study . The diagnosis of OSA starts with a sleep history that typically is obtained in one of three setting; first as part of routine health maintenance evaluation, second as part of evaluation of symptoms of OSA, and third as part of the comprehensive evaluation of patients at high risk of OSA. Symptoms and signs most suggestive of OSA include habitual snoring, witnessed apneas, gasping and choking sensations during sleep, large neck, obesity, and hypertension. The classic OSA presentation and major symptoms may not be in female OSA patients. Female OSA patients referred for evaluation at sleep clinic more frequently, insomnia, nocturnal palpitation, depression, lack of energy, night sweats, fibromyalgia, irritable bowel syndrome, compared to men with OSA .

Effect of Pregnancy on SDB

Several physiologic changes that alter the functions of many organs and systems occur during pregnancy. Some of these changes may provide protection from SDB, whereas others may put women at risk. Anatomic changes such as progressive weight gain and the enlarging uterus up toward the diaphragm 3–4 cm, subcostal angle increases, and thorax transverse diameter increases by 2 cm, combined with the supine position during sleep may reduce functional residual capacity and predispose women to OSA .

A number of hormonal rhythms, some of which influence sleep, are altered by pregnancy. Estrogen and progesterone are progressively increasing in pregnancy and affect sleep. High levels of estrogen and progesterone are required to maintain pregnancy. Along with estrogen and progesterone, the changes occurring during pregnancy in prostaglandin and cortisol levels may also have an impact on the SDB physiology . Reduced upper airway dimensions during pregnancy have been demonstrated. Nasal zone is responsible for 50% of upper airway resistance. Estrogen induces changes in the airway mucosa consisting of hypersecretion, hyperemia, nasopharyngeal mucosal edema, and vasomotor rhinitis which can predispose to increased upper airway resistance, snoring, and upper airway obstructive events . Nasal obstruction has been shown to be an independent risk factor for OSA in the adult population . A study reported nasal congestion and rhinitis symptoms in 42% of the subjects at the 36th week of gestation. In fact, rhinitis symptoms have been reported to be higher even during the luteal phase of the menstrual cycle . Another factor that both protects against and is conducive to OSA is the elevated progesterone level that occurs during pregnancy. Progesterone enhances respiratory center sensitivity to CO ₂ , thereby up-regulating ventilatory drive and minute ventilation. This hyperventilation reduces arterial PaCO ₂ to a nadir of about 30 mmHg but blood pH and PaO ₂ remains normal. The increased respiratory drive protects against upper airway occlusion by enhancing responsiveness of upper airway dilator muscles to chemical stimuli during sleep. Furthermore, progesterone itself has been shown to increase upper airway dilator muscle electromyographic activity . On the contrary, increased ventilatory drive with resultant respiratory alkalosis has been predisposed to central apnea. Another effect of increased ventilatory drive is increased diaphragmatic activity. This can lead to greater negative inspiratory pressure and increased tendency for upper airway collapse . The factors increasing snoring and apnea frequency in pregnancy are summarized in Figure 10.2 .

The factors increasing snoring and apnea frequency in pregnancy.

SDB in Pregnant Women

The prevalence of SDB during pregnancy is unknown. There are several studies on snoring and other symptoms of OSA during pregnancy, all confirming an increase in OSA symptoms among pregnant women compared to prepregnancy status or nonpregnant women . Many studies were based on questionnaires and were limited by a lack of polysomnographic confirmation of OSA.

The incidence of snoring in a US population of healthy pregnant women was found to be 14%, significantly greater than the 4% incidence found in age-matched nonpregnant population . In a similar study carried out by Franklin et al. in Sweden, 502 pregnant women were asked to complete a questionnaire. They found that during the last week of pregnancy, 23% of the women reported snoring every night. Only 4% reported snoring before their pregnancy. Guilleminault et al. investigated 267 pregnant women in a two-stage study. All subjects underwent ambulatory monitoring of their sleep with a six-channel recorder at the 6-month prenatal visit. Prepregnancy snoring prevalence was reported to be 3.7%, while it was observed to be 11.8% during the last trimester. In the second stage of the study, 26 subjects underwent polysomnography, 13 based on symptoms, blood pressure values, and the ambulatory monitoring results; and 13 chosen at random from the group. Abnormal respiratory patterns were detected but none of the subjects were determined to have apnea or hypopnea. Age, obesity, and smoking predispose to snoring and other sleep-related breathing disorders. The prevalence of habitual snoring in middle-aged French males was reported at 32%. Age, neck circumference, tobacco consumption, excess weight, and large soft palate were independently associated with snoring . Resta et al. investigated the prevalence of snoring and OSA in obese subjects. They showed that neck circumference in men and body mass index (BMI) in women were the strongest predictors of the severity of OSA. Maasilta et al. recruited 11 obese and 11 control women. Overnight polysomnography was performed in early and late pregnancy. They showed that early and late pregnancy AHIs, oxygen desaturations, arousal indexes, and snoring times were significantly higher in the obese pregnant women as compared to the nonobese pregnant controls. The results of a large questionnaire study indicate that age, smoking during pregnancy, and weight before delivery were independent risk factors for habitual snoring in pregnancy, according to logistic regression analysis. Furthermore, neck circumference is higher in habitual snorers when compared to nonhabitual snorers in univariable analysis .

SDB, Gestational Hypertension, and Pre-eclampsia

SDB has been proposed as a risk factor for adverse maternal and fetal outcomes such as fetal heart rate abnormalities, fetal growth retardation, fetal death, pregnancy-induced hypertension (gestational hypertension), pre-eclampsia, pulmonary hypertension, and gestational diabetes. Some studies also suggested that SDB was associated with adverse pregnancy outcomes; however, other studies did not indicate significant association. These inconsistent results may be due to the fact that most of the studies were of small sample size and had an absence of polysomnographic data .

The National Heart, Lung, Blood Institute working group defines gestational hypertension as a new onset of systolic blood pressure ⩾140 mmHg or a diastolic blood pressure ⩾90 mmHg after mid-pregnancy. When associated with proteinuria, it is called pre-eclampsia . Gestational hypertension complicates 6–8% of pregnancies . OSA is an independent risk factor for hypertension in the general population. Observational studies indicate that untreated OSA is associated with an increased risk of prevalent hypertension, whereas prospective studies of normotensive cohorts suggest that OSA may increase the risk of incident hypertension in the nonpregnant adult population . Nocturnal blood pressure values are higher when compared with daytime values in pre-eclampsia and diurnal variations are observed . Moreover, diurnal variations are observed in hypertension in such patients as well. Therefore, an association between pre-eclampsia and SDB has been postulated. Risk factors for pre-eclampsia include nulliparity, pre-existing hypertension, diabetes, obesity, dyslipidemia, depression, renal disease, asthma, history of gestational hypertension, multifetal gestation, insulin resistance, thrombophilia, living in high altitude, collagen vascular disease, and hydatidiform mole . There is some evidence that maternal snoring is a poor prognostic factor for the mothers who have a greater risk of hypertension and pre-eclampsia . Izci et al. investigated 167 healthy pregnant, 82 pre-eclamptic pregnant, and 160 nonpregnant women. They reported that 32% of control, 55% of pregnant, and 85% of pre-eclamptic women snored. Franklin et al. reported that snoring pregnant women had a twofold (odds ratio of 2.03) greater incidence of hypertension and pre-eclampsia than did nonsnorers. In another study, snoring was a risk factor for gestational hypertension with an adjusted odds ratio of 1.82 after adjustments for prepregnancy BMI, weight gain during pregnancy, smoking, alcohol, age, and neck circumference . Snoring was a risk factor for gestational hypertension but not pre-eclampsia, and neck circumference was an independent risk factor for gestational hypertension and pre-eclampsia, according to logistic regression analysis in a case–control study . A recent study of 1000 subjects indicated that factors used in the regression analysis included age, BMI, diabetes, chronic hypertension, multifetal gestations, smoking, and renal disease. Symptoms of SDB were associated with a higher likelihood of pregnancy-induced hypertension and pre-eclampsia (OR 2.38, 95% CI 1.4–4.1); gestational diabetes (OR 2.1, 95% CI 1.3–3.4); and unplanned cesarean sections (OR 3.80 95% CI 2.2–6.7) after multivariable regression analysis . In conclusion, snoring during pregnancy may be an important finding, as it has been associated with gestational hypertension and pre-eclampsia.

OSA during pregnancy was first reported in 1978 by Joel-Cohen et al. . After this case report, there are several studies about OSA during pregnancy consisting largely of case reports, questionnaire, or small sample size case–control studies. Subsequent case–control studies using overnight recordings were used. In the first case–control study, Connolly et al. enrolled 15 healthy and 15 pre-eclamptic pregnant women along with 15 nonpregnant women in their study. The subjects were monitored overnight for blood pressure and respiration. They were also monitored with an oximeter. While none of the subjects was found to have significant sleep apnea syndrome, pre-eclamptic pregnant women were observed with significant inspiratory flow limitation. Episodic inspiratory flow limitation observed in upper airway resistance syndrome was brief and resulted in arousal. However, these subjects were observed with long episodes of minutes at a time. Champagne et al. performed tests involving 17 pregnant women with gestational hypertension and 33 pregnant women without hypertension. The crude odds ratio for the presence of OSA given the presence of gestational hypertension was 5.6. The odds ratio was 7.5 (95% CI 3.5–16.2), based on a logistic regression model with adjustment for maternal age, gestational age, prepregnancy BMI, prior pregnancies, and previous live births.

While it now appears clear that there is an association between the existence of SDB and hypertension during pregnancy, the primary causal abnormality has not been proved. Increased edema in the upper airway resulting from the generalized vascular changes found in pre-eclampsia may precipitate SDB . Upper airway diameters of 37 pre-eclamptic and 13 nonpre-eclamptic pregnant women in the third trimester, as well as 50 nonpregnant women were measured by using acoustic reflection method and then compared. Upper airway diameters in pre-eclamptic pregnant women were observed to be significantly narrower than those of the nonpregnant women and those of the nonpre-eclamptic pregnant women . However, it has been speculated that intermittent maternal hypoxia induced by SDB could cause placental ischemia, triggering oxidative stress, and endothelial activation. Oxidative stress and endothelial activation are implicated in the pathogenesis of gestational hypertension . The relationship between snoring, OSA, gestational hypertension, and pre-eclampsia is shown in Figure 10.3 .

The relationship among snoring, OSA, and pre-eclampsia.

SDB and Gestational Diabetes Mellitus

SDB may be a risk factor for gestational diabetes. Several epidemiologic and experimental studies showed that chronic partial sleep loss is associated with increased risk of obesity and obesity-related disorders such as impaired glucose tolerance. The estimated OSA prevalence in diabetic cohort is 17.5% (24.7% in men, 10.3% in women). OSA is associated with prevalent glucose intolerance and insulin resistance even after adjustment for confounders, especially obesity in the general population . Although the exact mechanisms underlying these associations have yet to be elucidated, evidence from experimental studies suggests that insufficient habitual snoring and sleep apnea result in metabolic and neuroendocrine alteration. Moreover, there has been data that long-term intermittent hypoxia and sleep fragmentation increase sympathetic activity, which in turn leads to disorders of glucose metabolism . The oxygen desaturation index (number of episodes of reduction in oxygen saturation by >4%, per hour of sleep) is a better predictor of insulin resistance than BMI . There are very little data about how insufficient sleep and SDB during gestation contribute to increased risk of medical complications of pregnancy, including gestational diabetes mellitus. Youssef et al. analyzed through 2003 health care cost utilization project nationwide inpatient data of all pregnant women. Controlling for race, gender, and obesity, OSA conferred twice the likelihood of having gestational diabetes. A recent cohort study of 1290 women was interviewed during early pregnancy. After adjusting for maternal age and ethnicity, gestational diabetes mellitus risk was increased among women sleeping ⩽4 h compared with those sleeping 9 h/night. Snoring was associated with a 1.86-fold increased risk of gestational diabetes mellitus. The risk of gestational diabetes mellitus was elevated particularly among overweight women who snored .

SDB in Pregnancy and Fetal Outcome

The clinical fetal outcome of SDB during pregnancy remains controversial. Some early reports suggest that it may represent a new risk factor to intrauterine growth restriction and lower Apgar scores at birth . However, other studies did not precisely support this association .

Repetitive episodes of obstructive respiratory events during sleep give rise to cyclic episodes of maternal hypoxemia. It is also known that hypoxia is observed in pregnant women particularly in the last trimester due to physiologic changes occurring in the respiratory system. It has been reported that PaO ₂ levels dropped below 90 mmHg in the supine position in 25% of pregnant women in the last trimester. As hypoxia can occur even during wakefulness, a minor alteration in respiration pattern during sleep may impair maternal and fetal oxygenation severely . Previous studies conducted on pregnant subjects living in higher altitudes or those with hypoxia due to pulmonary parenchyma demonstrated that maternal hypoxia led to retarded fetal development . Experimental rat studies revealed that prenatal hypoxia impaired the development of the chemoafferent pathway, as well as the ventilatory and metabolic responses to hypoxia . Gozal et al. demonstrated that newborns of pregnant rats exposed to intermittent hypoxia, a hallmark of sleep apnea syndrome, had lower birth weight when compared with newborns of pregnant rats exposed to normoxia. The same study also established that normoxic ventilation was higher in newborn rats whose mothers had been exposed to intermittent hypoxia.

Questionnaire-based investigations were performed to address the association between snoring and fetal outcome. The results of these studies are contradictory. Franklin et al. established impaired fetal development in 8 (7.1%) of the 113 pregnant women with habitual snoring and 10 (2.6%) of the 379 pregnant women with no habitual snoring. The difference was statistically significant, indicating that snoring was a risk factor for intrauterine growth restriction and low Apgar scores. In contrast, Loube et al. reported that pregnant women who were snorers did not have deliveries resulting in infants with evidence of an increase in compromised outcomes. A recent questionnaire study also indicated that there was no significant relationship between snoring and fetal outcome . Polysomnography and fetal heart monitoring-based studies were also performed to investigate fetal outcome in pregnant OSA patients. A case–control study included 57 pregnant women with confirmed OSA and 114 healthy pregnant controls. OSA patients had more pre-eclampsia (19.3% versus 7.0%) and preterm births (29.8% versus 12.3%). Controlling for comorbid conditions, OSA was associated with an increased risk of preterm birth (OR 2.6), mostly secondary to pre-eclampsia (63%). Cesarean delivery (OR 8.1) and OSA were associated with maternal morbidity (OR 4.6) . Sahin et al. simultaneously investigated the polysomnography and nonstress test (NST) records of 35 pregnant women. OSA was diagnosed in four, of which three with adequate NST had fetal heart decelerations associated with maternal desaturation. Apgar scores and birth weights were lower for the four women with confirmed OSA. However, a similar recent study indicated that no association was observed between fetal heart rate monitoring abnormalities and OSA parameters . However, there are some studies that did not find association, and preliminary reports suggest that OSA may cause fetal deceleration and lower birth weight and Apgar scores.

Evaluation and Treatment of OSA in Pregnancy

There are no specific guidelines for screening pregnant women for OSA because the data are limited in this population. The incidence of SDB in normal and complicated pregnancy is not defined. Most symptoms of OSA are nonspecific and may overlap normal pregnancy symptoms such as fatigue, sleepiness, or insomnia . In pregnancy, the Berlin questionnaire poorly predicts OSA . Consequently, the decision to investigate and treat must be individualized according to intensity and spectrum of symptoms, impact on quality of life, risk of accidents, comorbidities, concomitant disease, and acceptability of diagnostic testing . Some authors recommended that excessive daytime sleepiness, loud snoring, and witnessed apneas in pregnant women should be evaluated by overnight polysomnography (evidence C) . However, others have proposed that the indication for polysomnography in pregnant women probably should be expanded to include those with hypertension, pre-eclampsia, previous babies with unexplained intrauterine growth restriction, persistant insomnia, or hypersomnia associated with snoring and obesity (evidence C) . Several studies indicated that nocturnal polysomnography was successfully performed in pregnant women. Sleep studies in pregnant women can be applied similarly to nonpregnant women .

Treatment guidelines for pregnant women with OSA are similar to that of the general population. In nonpregnant OSA patients, a number of treatment options are available, including various types of positive airway pressure (PAP) therapy, oral appliances, surgery, and conservative approach. All pregnant women should follow conservative precautions, such as avoiding weight gain, sleeping in a lateral position, elevating the head end of the bed, treating nasal obstruction with external nasal dilators, inhaling corticosteroids, avoiding allergens in the context of allergies, and restraining the use of sedatives and alcohol. Oral appliances usually are not initiated during pregnancy because of the delay required for optimization of therapy. It may be an option in patients who cannot tolerate PAP. Moreover, if treatment is already adjusted before pregnancy, it should be continued. Upper airway surgical therapies are not recommended routinely due to increased surgical risk during pregnancy .

Continuous positive airway pressure (CPAP) remains the predominant therapy for the treatment of patients with OSA and has been shown to resolve SDB levels and improve several clinical outcomes. CPAP is conventionally delivered via a nasal mask at a fixed pressure that remains constant throughout the respiratory cycle. CPAP’s proposed mechanism of action is as a pneumatic splint that maintains the patency of the upper airway in a dose-dependent fashion ( Figure 10.4 ). CPAP therapy is currently indicated for the treatment of moderate-to-severe OSA and for patients with mild OSA and associated symptoms, and/or associated cardiovascular disease . From the summary of case reports and small sample size studies, evidence showed that CPAP was safe and well tolerated during pregnancy. No adverse events were reported among pregnant women with OSA who were treated with nasal CPAP therapy . In a case series of twelve pregnant women with OSA (seven diagnosed before pregnancy and five diagnosed in the first trimester of pregnancy) in whom CPAP was initiated before early pregnancy, there was an improvement OSA symptom, all babies were healthy, and side effects were not different than the ones observed in other CPAP users . Some studies found nasal CPAP to be particularly useful in reducing nocturnal blood pressure increments in women with pre-eclampsia. Guilleminault and colleagues investigated the possibility of using nasal CPAP early in pregnancy for prevention of pre-eclampsia. In the first study, 12 women with either chronic hypertension or obesity were recruited in the first trimester to utilize CPAP throughout pregnancy. All of the women were able to utilize CPAP throughout pregnancy. There were some small differences in episodes of tachypnea when CPAP was used, but none of the chronic hypertensive patients developed pre-eclampsia or needed to increase their dosage of antihypertensive medication. One of the obese patients developed pre-eclampsia . Only one randomized controlled trial of CPAP among pregnant women was retrieved. This study compared the addition of nasal CPAP treatment to standard prenatal care or to standard prenatal care alone in hypertensive women treated with alpha-methyldopa during early pregnancy. Subjects were randomized to receive either CPAP with standard prenatal care (treatment group) or standard prenatal care alone (control group) with routine obstetric follow-up. Nocturnal polysomnography was performed in all patients randomized to the treatment group for initial CPAP titration. In the control group ( n =9), a progressive rise in blood pressure with a corresponding increase in alpha-methyldopa doses was observed, beginning at the sixth month of pregnancy. There was also an increase in the number of nonscheduled postnatal visits during the first postpartum month. Pre-eclampsia occurred in one subject; the remaining eight patients had normal pregnancies and infant deliveries. In the treatment group ( n = 7), blood pressure was noted to decrease significantly as compared to the control group with associated decreases in doses of antihypertensive medications at 6 months of gestation. All treated patients experienced uncomplicated pregnancies and delivered infants with higher Apgar scores at 1 min postdelivery compared to those of controls . Because delivery is associated with a decrease in severity of OSA, some reports recommended performing a postpartum polysomnography once weight is stabilized . Recommendations for the evaluation and treatment of pregnant women suspected of having SDB are shown in Figure 10.5 .

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