Effects of Gestational Intermittent Hypoxia on the Respiratory System: A Tale of the Placenta, Fetus and Developing Offspring

1. Introduction

Obstructive sleep apnea (OSA) is the most common sleep disorder worldwide [1]. It is associated with cardiovascular, cerebrovascular, metabolic, neoplastic and neurocognitive diseases [2,3]. OSA is characterized by repeated complete (apnea) or partial (hypoapnea) obstructions of the upper airway during sleep. With each obstruction, arterial oxygen pressure (PaO₂) and hemoglobin saturation for oxygen (SatO₂) decrease, making OSA a chronic recurrent intermittent hypoxia (IH) event, the severity of which is related to changes in SatO₂ [4]. The decrease in PaO₂ activates the carotid body (CB), which activates motor neurons of the inspiratory and dilator muscles of the upper airways and sleep-wake control areas at of the central nervous system [5]. Muscle action and sudden arousals overcome the obstruction, PO₂ is restored, and the cycle repeated, resulting in IH, hypercapnia and sleep fragmentation [6]. CB stimulation produces respiratory reflexes and cardiovascular responses to minimize the deleterious effects of hypoxia. Repeated stimulation sensitizes CB chemoreceptors, increasing sympathetic tone, leading to hypertension and cardiovascular and metabolic pathology [7].

Epidemiological data on OSA indicate the magnitude of the social, health and economic problem. Its prevalence is estimated to be 9-24% in men and 4-9% in women over 30 years of age, increasing with age [8]. In pregnant women, the prevalence is estimated to be around 8% in the first trimester and increases to nearly 20% in the third trimester of pregnancy [9,10].

Anatomical and physiological changes during pregnancy, or the presence of the disease prior to pregnancy, increase the prevalence of gestational OSA [11]. This pathology is associated with increased morbidity and mortality and can cause hypertension, pre-eclampsia and gestational diabetes mellitus [12]. Episodes of hypoxia-reoxygenation during pregnancy can affect fetal development and postnatal development, resulting in growth retardation, preterm delivery, low birth weight and even fetal death [13]. Adult changes, such as metabolic and epigenetic alterations in male offspring, have also been described in animal models where intermittent hypoxia exposure during pregnancy mimics the hypoxia-reoxygenation cycles of gestational OSA [14]. These episodes of hypoxia-reoxygenation increase the production of reactive oxygen species (ROS), causing tissue damage and an influx of inflammatory cells to the injured sites and into the fetus via the placenta [15].

The repeated episodes of IH that occur during sleep, and especially during pregnancy, can have significant respiratory effects on both, the mother, and the developing fetus. The following sections highlight the major respiratory effects of gestational intermittent hypoxia (GIH), and how they affect the pregnant woman, the fetus, and the developing offspring into adulthood.

2. Maternal Respiratory Disturbances

2.1. Hormonal changes

Pregnancy induces hormonal alterations, which are the main cause of changes in the respiratory pattern. Progesterone, which acts as a trigger for the primary respiratory center, gradually increases its plasma levels during pregnancy, going from 27 ± 1.5 ng/mL at week 13 to 146 ± 17.2 ng/mL at week 37, decreasing after delivery (3.5 ± 1.5 ng/mL) [16]. This remarkable increase is accompanied by an increase in the sensitivity of the respiratory center to CO₂ [17]. In addition, progesterone acts as a bronchodilator lessening airway smooth muscle tone and, by acting directly on the CB, increase the peripheral ventilatory response to hypoxia.

Pregnancy also affects estrogens levels, which rise in parallel with progesterone levels. It acts by increasing the number and sensitivity of progesterone receptors in the areas of the central nervous system associated with respiration, mainly the hypothalamus and medulla oblongata [18]. The prostaglandins have also been described to have a variety of various effects, with PGF2α causing bronchial smooth muscle constriction and PGE1 and PGE2 causing bronchodilation [18].

2.2. Anatomical changes

Pregnancy-induced uterine enlargement increases abdominal pressure, displacing the diaphragm upwards. As a result, pleural pressure increases, leading to small airways obstruction, which reduces functional residual capacity FRC (20-30%), expiratory reserve volume ERV (15-20%) and residual volume RV (20-25%). The shortening in chest height is accompanied by an increase in other dimensions to maintain total lung capacity (TLC) [19]. Along with these changes in FRC and ERV, pregnancy is associated with an increase in the tidal volume (30-50%) and minute ventilation (20-50%), with only a small increase in respiratory frequency.

As the diaphragm moves upwards, the thorax also undergoes significant changes during pregnancy. There is an increase in the subcostal angle of the rib cage (from 68 to 103 degrees) due to relaxation of the lower rib cage ligaments, and an increase in the circumference of the lower chest wall (5 to 7 cm). These anatomical changes peak at week 37, and largely return to normal by week 24 after delivery (although the subcostal angle remains 20% wider than at baseline) [16]. This increase in chest wall size also helps to compensate for the upward displacement of the diaphragm mentioned above.

In addition, pregnant women have significant upper airway narrowing during the third trimester of pregnancy [20]. This upper airway narrowing may be related to the increased incidence of snoring and sleep-disordered breathing in pregnancy. Alongside this observation, women with pre-eclampsia have also been described to have narrower upper airways in supine position than pregnant and non-pregnant women [21]. Besides this narrowing, they have larger neck circumferences, which may be due to differences in fat deposition around the neck, or tissue oedema, which is present in most women with pre-eclampsia. All these factors would certainly increase the severity of OSA.

Besides these effects, the mucosa of the upper airways is also affected during pregnancy, with an increase in mucopolysaccharide content and phagocytic activity, resulting in nasal congestion. This common nasal congestion is known as pregnancy rhinitis, and affects up to 65% of pregnant women, lasting 3 or more weeks [22] and resolving spontaneously 2 weeks after delivery. Although the etiology is unclear, some contributing factors may be smoking, nasal allergy or infections, with the potential of further complications. Nasal obstruction would exacerbate snoring and therefore sleep-disordered breathing.

2.3. Respiratory changes during labour and delivery

The respiratory muscles play a key role in pushing during labour. It has been described in animal models that a long period of stretching causes muscle fibers to add sarcomeres in the longitudinal direction, thereby increasing tension [23]. This may well be what happens to the diaphragm and abdominal muscles during the long stretching period of pregnancy, to improve their efficiency in developing expulsive force during labor.

Intrauterine pressure is increased by contracting the diaphragm during inspiration and the abdominal muscles during expiration. In the latter stages of labor, women may be asked to take deep inspirations and hold their breath while pushing. This maneuver, known as “closed-glottis” (or Valsalva) pushing, fixes the diaphragm in a low position. Alternatively, women may be instructed to maintain a more spontaneous pushing technique, emitting sounds and pushing with a slow exhalation without holding their breath. This second approach is called “open-glottis” pushing technique. Among first-time mothers with singleton pregnancies at term, there was no difference in the risk of assisted vaginal delivery between the two pushing techniques [24].

To conclude this section on maternal respiratory disorders associated with intermittent hypoxia, we mention a retrospective analysis of 4326 pregnant women diagnosed with obstructive sleep apnea in the United States [25]. This study found a direct association between sleep apnea and an increased likelihood of maternal-fetal complications. Along with higher rates of pre-eclampsia and cesarean delivery, there was also a higher prevalence of pulmonary edema, although no significant association with a higher risk of mortality.

3. Effects of Intermittent Hypoxia in the Placenta

The placenta is the first organ to form in mammals and is essential for feeding, breathing, protection and hormone production during the fetal development [26]. During pregnancy, the placenta is subject to a variety of environmental cues that can have an impact on the placental development, fetal growth, and postnatal phenotype of the offspring. These factors include low oxygen levels, which can be caused by maternal anemia, umbilical cord occlusion, or poor placental vascularization, as well as by all high-altitude pregnancies or maternal OSA [27-29]. Attempts to experimentally mimic such conditions in animals, including mice, rats, and guinea pigs, have shown that placental and fetal weights are altered (see [29]). In general, these studies show that the specific effects on placental appear to depend on the type and the severity of the challenge, and the duration and timing of the challenge in relation to placentation. However, an adverse maternal environment has a greater effect on fetal growth than on placental growth, suggesting that the placenta may be spared relative to other organs [30]. In addition, although placental growth and function are similar in females and males, sexually dimorphic phenotypes are observed, as reported by Kalisch-Smith et al. [31].

Similar to the postnatal role of the lung, the placenta is the organ where fetal blood gases are exchanged with the environment by a concentration gradient-dependent passive extraction of oxygen from maternal blood, similar to the process of diffusion and transfer of oxygen from alveolar gas. The human placenta consists of an extensively branched fetal villous tree that is bathed by maternal blood circulating in the intervillous space. The interface between fetal placental tissue and maternal blood is the syncytiotrophoblast, which acts as the endothelium for the intervillous space [32]. Oxygen transfer across the placental barrier is achieved as fetal blood circulates from the umbilical arteries to the capillaries within the placental villi and back to the umbilical vein [33], whereas maternal blood is filtered through a high-volume intervillous compartment, making the exchange process slower and less efficient than at the alveolar-capillary interface [34]. In addition, the placenta is a high consumer of oxygen, resulting in a PO₂ in fetal blood leaving the placenta through the umbilical vein that is significantly lower than the PO₂ in the maternal artery [34,35]. This fact, which is not a limitation under normal conditions of oxygenation, may compromise gas exchange during the intermittent hypoxia episodes that occur in OSA. Notably, there is evidence of hypoxia in the human placenta in OSA [36]. Fluctuations in oxygen delivery in the intervillous space following intermittent hypoxia during the process of gas exchange in the placenta result in hypoxia-reoxygenation events that can overwhelm local antioxidant defenses and lead to oxidative stress and pathological placental changes [37]. The effects of hypoxia-reoxygenation are well documented in other organs such as the heart, brain and intestine, where its detrimental effects are mainly due to its ability to generate high levels of ROS, oxidative stress and increased inflammation [32,38,39]. It is therefore biologically plausible that OSA, via one or more of these pathways, may adversely affect placental tissue perfusion and oxygenation, potentially predisposing to the development of placental-mediated adverse outcomes.

The severity of maternal oxygen deprivation seems affect the gross architecture of the placenta. Thus, maternal inspired hypoxia of 12-13% in the last third of pregnancy selectively expanded the labyrinthine zone [40,41]. Conversely, when maternal inspired oxygen is reduced to 10%, the labyrinthine zone is reduced with an associated increase in the volume density of the junctional zone [41,42]. Maternal intermittent hypoxia has been reported to alter the placental area [43]. Switching metabolism from aerobic to anaerobic by inhibiting mitochondrial oxidation early in blastocyst development also alters placentation in rats in the short term [44]. Hypoxia-induced changes in gross placental morphology have been associated with altered expression of genes and proteins involved in proliferation, apoptosis, oxidative stress, and cell lineage differentiation in which the hypoxia-inducible factors (HIF) appear to be essential [29,45].

In the same line, human trophoblasts proliferate in vitro under low O₂ conditions, but differentiate at higher O₂ levels, mimicking the developmental transition they undergo when invading the placental bed to establish the maternal-fetal circulation in vivo. Using a human trophoblast cell line (HTR8/SVneo) and primary extravillous trophoblast cells (EVTs), Song et al [46] reported that, in contrast to sustained hypoxia, intermittent hypoxia blocks trophoblast proliferation and induces excessive trophoblast apoptosis by activating the ER stress signaling pathway. They found that intermittent hypoxia can also significantly impair the invasive and migratory ability of trophoblasts which they attributed in part to the reduced secretion of matrix metalloproteinase-2. These changes in trophoblast function may have implications for proper pregnancy development [47].

Placental delivery of maternal nutrients and oxygen to the fetus is the primary determinant of intrauterine fetal growth. Therefore, pregnancy is associated with a continuous remodeling of the uteroplacental circulation to ensure adequate blood flow to provide sufficient nutrients and oxygen for fetal and placental growth [48,49]. As a result, human uterine perfusion increases from 50 ml/min at 10 weeks' gestation to as much as 1,300 ml/min at the end of pregnancy [50]. This increased blood flow is directly correlated with fetal growth and survival, as well as neonatal birth weight [49,51].

However, placental development during normal pregnancy occurs in a low-oxygen environment (~2-8 % O₂) and this "physiological hypoxia" appears to be critical for early placental development and angiogenesis [52,53]. Vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF2) are two potent angiogenic factors that have been implicated in placental angiogenesis [54,55]. It is well established that hypoxia increases the expression of VEGF and its receptors VEGFR-1 and VEGFR-2 in endothelial cells [56]. Hypoxia also increases the expression of FGF receptors and alters the distribution of FGF2 in different cellular compartments [57]. It has been reported that hypoxia may differentially modulate angiogenic factor-stimulated placental angiogenesis depending on the severity and duration of hypoxia exposure. Wang et al [58] showed in human placental artery endothelial (HPAE) cells that in vitro exposure to sustained hypoxia (3% O₂) enhanced FGF2 and VEGF-stimulated HPAE cell proliferation, but independently of the canonical MEK1/ERK1/2 and PI3K/AKT1 pathways, suggesting that hypoxia may induce a very complex signaling network in the placenta. Whether intermittent hypoxia adds further complexity is currently unknown.

Finally, how intermittent hypoxemia is transmitted from the mother to the fetus in OSA deserves some comment. By simultaneously measuring PO₂ in the maternal artery and umbilical vein, Almendros et al [59] showed in a sheep pregnancy model that the PO₂ fluctuations resulting from experimental maternal obstructive apnea are significantly smaller in fetal blood than those registered in maternal blood, due to the damping effect of oxygen transfer across the placenta. This work raises an important question about the potential effects of intermittent hypoxia on the fetus during pregnancy, as the placenta may attenuate the severity of hypoxemic changes in the fetus.

In addition to potential differences in the structure and physiology of the placenta in sheep and humans and, therefore, in the values of oxygen swing attenuation through the placenta in both species, the study by Almendros et al [59] rises several considerations when translating the findings to pregnant women. Since the severity of hypoxemic swings is attenuated in the fetus, it could be anticipated that hypoxia-reoxygenation, and thus the oxidative stress induced in the various fetal organs and tissues would be lower than those experienced by adult tissues [60].

It is also possible that the sensitivity and tolerance of fetal tissues to very short intermittent hypoxia, which have so far not been studied, are different from those in adults. Moreover, the impact of intermittent hypoxemia, even of low amplitude, could be different in the fetus and the adult, since fetal mechanisms to regulate the distribution of blood flow among organs are markedly different from those in adults [61,62,63]. These potential differences could modulate the epigenetic changes observed in the offspring after GIH [64-66].

4. Fetal Respiratory Distress

As a result of maternal GIH, and the recurrent episodes of intermittent hypoxia, there is a reduction in oxygen saturation in the maternal blood which could compromise oxygen delivery from the placenta to the fetus, leading to fetal hypoxemia. However, the extent to which the placenta provides protection to the fetus, and therefore the amount of oxygen that reaches the fetus is still unknown.

Although there is not a functional, fully developed gas exchange system in the lungs of the fetus, it doesn´t mean that they remain inactive. There are rhythmic contractions of the diaphragm and other respiratory muscles, known as fetal breathing movements (FBM), which play a key role in lung maturation. They are a distinctive adaptation to the intrauterine environment.

With completely unique characteristics that differ from neonatal and adult breathing, they also differ from maternal respiratory movements. In humans, FBM begin at around week-10 of gestation and increase in frequency with gestational age, reaching up to 35% of the time around week-30 of pregnancy [67,68]. They occur at a frequency of approximately 30-70 contractions/breaths per minute in each bout, followed by apneic periods that can last up to 2 hours near term [69]. Between 28 and 36 weeks, FBM are closely correlated with REM states, with less frequent FBM occurring in non-REM states [70]. The frequency of FBM episodes is also correlated with other factors, such as glucose levels, with a higher incidence described in humans after maternal meals [71]. In terms of respiratory gases, high levels of PaCO₂ (hypercapnia) increase the incidence of FBM, while low levels of PaO₂ (hypoxia) inhibit FBM in studies in ewes [72] and humans [73].

Based on umbilical cord blood analysis, one study found that maternal snoring during pregnancy was associated with enhanced fetal erythropoiesis [74], suggesting that the fetus becomes hypoxic in utero, at least to some extent, during the repeated bouts of intermittent hypoxia. These episodes of fetal hypoxemia, if prolonged or severe, could impair fetal development and increase the risk of adverse perinatal outcomes.

Due to the increased metabolic demands of the fetus during pregnancy, increases in O₂ consumption (20%) and CO₂ production (35%) have been described in pregnant individuals when compared with their respective controls. These changes do not correlate exactly with the changes in minute ventilation described in the previous section which were around 20 and 50%. This greater increase in minute ventilation translates into an increase in the alveolar (PAO₂) and arterial partial pressures of O₂ (PaO₂) and a decrease in the corresponding partial pressures of CO₂ (PACO₂ and PaCO₂). These increases in oxygen tension are important to facilitate oxygen transfer across the placenta. Thus, measurements of PaO₂ during pregnancy found control values of PaO₂ around 93 mmHg raising to 105-106 mmHg during the first trimester, and 101-106 mmHg near term [75]. Despite this increase in oxygen tension, the oxygen reserves of pregnant women are lower, making them more susceptible to hypoxic episodes during periods of apnea, and consequently to the developing fetus.

As for the PaCO₂ levels, they went from 37 mmHg in the non-pregnant state to 28-29 mmHg in the first trimester and 26-30 mmHg near term. These low PaCO₂ values lead to chronic respiratory alkalosis, with compensatory renal mechanisms acting to excrete bicarbonate, whose endpoint is stimulating the 2,3-diphosphoglycerate (2,3-DPG) synthesis. The increase in 2,3-DPG levels reduces the affinity of maternal hemoglobin for O₂, allowing more O₂ to be delivered to the fetus, whose major hemoglobin, called fetal hemoglobin or HBf, has a higher affinity for O₂ than the adult hemoglobin or HbA.

The transition from fetal to postnatal breathing includes, among others, the absorption of lung fluid, gaseous expansion of the lungs, activation of the Hering-Breuer reflexes and the appearance of continuous respiration. Birth itself is a delicate process that has hindered more detailed research. Thus, many of the factors involved in the birth process are not yet fully understood. Asphyxia, umbilical cord occlusion or the rise in PaO₂ with the first postnatal breath may be involved [76,77], although neither the afferent input from the carotid sinus nerve [78] nor the interruption of umbilical circulation [79] seem to play a role in this process.

5. Offspring Respiratory Disorders

Although key components of the respiratory system begin to develop in utero, such as phrenic motoneurons and diaphragm muscle, there is also an important postnatal maturation process. After birth there is a transition from fetal breathing movements to functional gas exchange. With a less efficient respiratory system, infants develop a number of counteractive mechanisms to compensate for the increased vulnerability of their respiratory system.

Looking at the evolution of some respiratory values in humans it is known that respiratory rates fall progressively with age, going from 40 breaths/min in neonates to around 12-18 breaths/min in adults, with tidal volume values (adjusted by weight) remaining virtually identical throughout life.

In addition to these numbers, chemoreceptor pCO₂ sensitivity is almost mature at term, but minute ventilation is higher at any level of CO₂ in neonates and infants compared to adults [80]. However, preterm infants showed an attenuated sensitivity (and slower response) to CO₂ [81].

As for the peripheral pO₂ receptors, they need a few weeks of readjustment [82] to gain sensitivity to the higher levels of oxygen of the environment compared to the uterus. This adaptation results in a depression of ventilatory responses to hypoxia that can last up to 6 months after birth [83]. Immediately after birth, rats showed a weak ventilatory response to a hypoxic challenge [84], even though their ventilatory rate was relatively high, probably to compensate for their immature gas exchange machinery.

Regarding the airways, they are a component of the respiratory system that also showed differences between neonates and adults. Thus, the pediatric upper and lower airways are characterized by a higher resistance to flow, mainly due to a smaller diameter, higher collapsibility, and lower pharyngeal muscle tone [85]. Focusing on the upper airways, they have an elliptical shape in neonates. From the subglottic to the cricoid ring, the airways are narrower in the transverse dimension than in the anteroposterior dimension [86]. Observations of airways in children over 1 year of age showed a circular shape. Smaller and softer, they are more prone to inspiratory collapse. The closure of newborn upper airways is behind central apneas, with values of 3 obstructive events per hour during the first 3 months of life [87]. This closure may be due to either passive pharyngeal collapse or active laryngeal closure [88]. Nevertheless, the cartilaginous structure lengthens and stiffens with maturation during childhood.

Respiratory immaturity is associated with breathing instability, while immature breathing control manifests as central apneas. Both events have been linked, although controversially, to the sudden infant death syndrome [89]. There is an improvement with progressive maturation, with the frequency and duration of central apneas decreasing during the first 12 months of life, with values of 15 apneas longer than 3 seconds per hour reported at 12 months [90].

Chest wall properties are also affected. Thus, newborns have up to 3 times higher compliance levels than adults to allow for greater expansion during breathing. The ribs also contribute to this end, as they are more flexible in the newborn, while they are positioned more horizontally than in the adults, moving only upwards, and not upwards and outwards, as in the adult rib cage. This difference is the main limitation to increase tidal volumes and the reason why infants under 12 months of age rely mainly on diaphragmatic breathing [91].

The values of the functional reserve capacity (FRC) are also subjected to significant changes, with values that increase rapidly after birth [92]. FRC is directly related to the number of alveoli; fewer alveoli in immature lungs provide less support and can lead to peripheral airways collapse. During lungs growth, they undergo a process of alveolarization which also contributes to increase the surface area available for gas exchange.

Exposure to adverse conditions in utero, such as those caused by GIH, may lead to epigenetic changes that affect the postnatal development of the respiratory control. Animal studies have shown that prenatal exposure to intermittent hypoxia can alter respiratory control mechanisms and increase the susceptibility to respiratory diseases later in life [93]. However, the effects of intermittent hypoxia protocols during pregnancy on the developing respiratory system are not yet fully understood.

The first study of the effects of GIH on respiratory responses in neonatal rats found that normoxic ventilation was increased in the GIH offspring compared to their respective controls (1- and 4-months of age), although hypoxic responses were similar [94]. They postulated that this maladaptive response to postnatal hypoxia could contribute to events such as the sudden death syndrome. Nevertheless, this study had several limitations because it didn´t distinguish between male and female pups. Our group found similar differences in basal normoxic ventilation between GIH and control rats at 1 month of age, in both, males and females (Valverde-Pérez et al., unpublished data). However, following the same rats at 3 months of age, minute ventilation values were higher only in the female GIH animals, being this ventilation decreased in the male GIH compared to their respective controls.

A study of inflammatory status in neonatal GIH-treated rats recorded respiratory motor burst in brainstem-spinal cord preparations [93]. In newborn rats (0-3 days old) burst frequency was unchanged in GIH animals, although the rhythm was more regular and the rise time tended to be faster, with no sex effects on these variables in any of the groups. When testing the respiratory motor output elicited by an inflammatory challenge, males showed a significantly reduced burst frequency compared to normal conditions, with no differences between control and GIH animals. However, in preparations from female animals, only the control preparations showed a decrease in burst frequency with the inflammatory challenge, while the GIH group showed no change. Although GIH didn´t alter the expression of pro-inflammatory factors tested in the brainstem or spinal cord (IL-1β, TNFα and COX-2), it did affect the offspring response to a later postnatal inflammatory challenge, in a sex-dependent manner. Their hypothesis is that GIH reprogrammed the neuroinflammatory response pathways in the female animals so that there is less cytokines production during inflammatory challenges. Cytokines are linked to the sensitivity of the brainstem respiratory centers, which modulate the respiratory frequency in a complex way, ranging from hyperventilation and even respiratory stress syndrome (as in the worst cases of Covid-19, associated with “storm” of cytokines) [95], to respiratory depression. If this were the case, female GIH offspring would have an impaired ability to trigger an immune response against infection, from birth, and perhaps even into adulthood, especially at the level of respiratory system pathologies.

At birth, the newborn comes into an oxygen-rich environment, and oxygenation through the lungs instead of the placenta raises tissue oxygenation within minutes. Same of oxygen forms reactive oxygen species (ROS), which are normally neutralized by antioxidant defense systems. In preterm infants, these defenses are immature, making them more prone to oxidative tissue injury. Thus, more than 65% of preterm infants suffer at least one infection during their hospitalization [96]. In addition to this, preterm infants with inflammation also have an increased incidence of apnea and are at a greater risk for adverse neurodevelopmental outcomes and mortality rates (see [97]).

The frequent episodes of intermittent hypoxia associated with preterm birth have been linked to adverse respiratory outcomes, with a recent article [98] linking them to high levels of oxidative stress. By measuring noninvasively lipids, proteins, and DNA oxidative stress biomarkers in urine samples from 1 week and 1 month old premature babies (<31 weeks of gestation), they found a direct association between intermittent hypoxia and the various oxidative products quantified. In this sense, it could be possible that most of the effects of GIH on the offspring are indirectly caused by the maternal stress. Thus, OSA events in pregnant women were associated with higher levels of systemic inflammation, which was related to the number of obstructive events, especially during the REM phases of sleep [99].

It is known that gestational stress can induce permanent epigenetic changes in the offspring, as shown by an increase in the levels of some chemokines and altered expression of their receptors in a rat model [100]. In this context, sex-specific effects of stress during gestation and development of respiratory control have been described (Fournier S et al., 2013), with a higher rate of pathological apneas in newborn male rats, which was associated with a deficit of medullar-derived serotonin (5-HT). A recent study [101] has found that GIH impairs endothelial NO synthesis in rat offspring vessels, highlighting the fact that some detrimental effects of gestational hypoxia may persist well into adulthood.

Underscoring the importance of inflammation in the neonatal respiratory system, even low levels of inflammation have been proved to impair respiratory control networks in neonatal rats [102]. Using brainstem spinal cord preparations, these authors found differential sensitivities of the respiratory control areas to inflammation. Lower levels of inflammation were more disruptive, affecting amplitude and frequency, while more severe inflammation affected frequency only.

Neonatal inflammation also affected carotid body chemosensitivity, induced spontaneous apneas in vivo and caused significant O₂ desaturation [103]. Dopamine, an inhibitor of CB activity, increased its levels in the CB due to neonatal inflammation. Neonatal inflammatory responses may mirror those of adults, although it could be that neonatal signaling pathways are different (see [104]). Nevertheless, the paucity of scientific studies on GIH exposure and respiratory control makes it difficult to draw firm conclusions.

Not many studies are available either on the role of the respiratory muscles, the final effectors in the respiratory control system. A study of the diaphragm function in rats exposed to GIH found no effect on the force-generating capacity of the diaphragm [105], in either male or female animals. Similar results were observed in the same study when the animals were subjected to intermittent hypoxia shortly after birth (postnatal days 22 and 42), suggesting a relative resilience of the diaphragm muscle to hypoxic stress during the perinatal period. However, when examining the sternohyoid, one of several pharyngeal dilator muscles, the same authors found evidence of weakness in the postnatally exposed animals [106]. This effect persisted into adulthood (16 weeks of age). They suggested that this mismatch between the diaphragm and sternohyoid muscles could contribute to a higher risk of airway collapse.

6. Conclusions

Overall, gestational intermittent hypoxia can have remarkable effects on both maternal and fetal health, with a concomitant risk of adverse pregnancy outcomes (Figure 1).

Multidisciplinary care involving obstetricians, sleep specialists, and respiratory therapists should be the approach adopted by national health services for the comprehensive management of sleep apnea during pregnancy. Early detection of OSA during pregnancy should be an essential tool for timely intervention. Questionnaires and polysomnography should be first line tools to help clinicians identify women at higher risk for OSA and respiratory disturbances.

Once identified, Continuous Positive Airway Pressure (CPAP) therapy is usually the treatment of choice. It helps improve upper airway patency and maternal oxygenation. Other interventions include lifestyle changes, such as weight management, positional therapy, and avoidance of sedatives and alcohol.