Which factor is most likely to result in fetal hypoxia during a dysfunctional labor?

Effects of Hypoxia on Lung Development

Fetal hypoxemia can be caused by placental insufficiency, maternal anemia, maternal smoking, and living at high altitude. It is now known that hypoxia can induce persistent structural and functional alterations in the developing lung,165,166 but the effects will likely depend on the gestational timing of the hypoxia, its severity, and associated factors such as altered nutrition and chemical exposures.

Few studies have examined the effects of hypoxia alone on lung development. In explants of fetal lung, hypoxia stimulated branching morphogenesis and cell proliferation, potentially due to reduced activity of metalloproteinases (MMPs).167 However, in the intact ovine fetus, prolonged hypoxemia inhibits lung growth as indicated by a lower rate of pulmonary DNA synthesis.109 Similarly, in a rodent model of fetal hypoxia during the latter two-thirds of gestation, the lungs were small relative to body weight,168 although hypoxia starting at later stages of gestation did not appear to affect fetal lung growth168,169 In contrast, fetal sheep exposed to hypobaric hypoxia throughout much of gestation experienced no effect on fetal relative lung weight, or on protein or DNA concentrations.170 Postnatal hypoxia may affect the developing lung differently; for example, postnatal hypoxia in rodents led to lung hypertrophy and hyperplasia, with increased amounts of connective tissue.135

Prenatal hypoxia, induced by high altitude, has significant and lasting effects on the pulmonary vasculature, both structurally and functionally, that may contribute to pulmonary hypertension and altered alveolarization.166,171,172 The persistence of the effects of fetal hypoxia into adulthood may be a consequence of epigenetic changes in vascular smooth muscle.173

Fetal Hypoxemia

Fetal hypoxemia resulting from prolonged parturition or dystocia may be a cause or contributing factor to weak-calf syndrome. Various predisposing factors can cause prolonged interference with fetal blood or oxygen supply, which can result in death during delivery or shortly after.

Examination of blood-gas values in newborn calves has shown that a prolonged parturition or delivery terminated by forced extraction results in a severe acidemia as a result of oxygen deprivation and ensuing anaerobic glycolysis with lactate accumulation in combination with hypercapnia, resulting in respiratory acidosis. As blood pH drops, first vitality is reduced, subsequently vital organs such as the brain are damaged, and ultimately the fetus dies.

The bovine fetus appears relatively susceptible to hypoxia and hypercapnia, which has been studied experimentally by clamping the umbilical cords of fetuses for 4 to 8 minutes, at 24 to 48 hours before expected birth, followed by a cesarean section 30 to 40 minutes later. Calves born following this procedure may die in 10 to 15 minutes after birth or survive for only up to 2 days. Under these experimental conditions, fetuses can survive anoxia for 4 minutes, but most will die following 6 or 8 minutes of anoxia.6 During the clamping there is also increased fetal movement and a release of meconium that stains the calf and the amniotic fluid. Those that survive for a few hours or days are dull and depressed, cannot stand, and have poor sucking and swallowing reflexes, and their temperatures are usually subnormal. They respond poorly to supportive therapy. Some calves whose umbilical cords were clamped for 4 minutes were born weak and made repeated efforts to raise their heads and move onto the sternum, but they were unable to maintain an upright position for long. These calves become hypothermic and dull, and their sucking and swallowing reflexes are present but weak. These calves are usually too weak to suck the cow even when assisted, and they commonly develop diarrhea and other complications.

Meconium Passage in Utero

Fetal hypoxia may lead to meconium passage in utero secondary to increased intestinal peristalsis and, perhaps, also to relaxation of the anal sphincter. However, the increased vagal tone associated with fetal maturation may lead to meconium passage; approximately 10% to 20% of apparently normal pregnancies at term and 25% to 50% of postdate pregnancies are accompanied by meconium-stained amniotic fluid. Thus, although the presence of meconium-stained amniotic fluid during labor is a potentially ominous sign concerning fetal well-being, controversy exists over the relative importance of this sign.179-196 The discrepancy in conclusions may relate in part to the failure to assess the timing and quantity of meconium passed. In a prospective study of 2923 pregnancies, Meis and co-workers188 observed the presence of meconium-stained amniotic fluid in 646 (22%) of cases. Meconium passage was classified as either early (light or heavy) or late. Early passage referred to meconium noted on rupture of the fetal membranes before or during the active phase of labor; light or heavy designations were made on the basis of quantity (and color). Late passage referred to meconium-stained amniotic fluid passed in the second stage of labor, after clear fluid had been noted previously. Patients with early-light meconium-stained amniotic fluid constituted approximately 54% of the total group with stained fluid and were no more likely to be depressed at birth than were control patients. Patients with late passage of meconium constituted approximately 21% of the total group with stained fluid and exhibited 1- and 5-minute Apgar scores lower than 7 two to three times more often than did control patients, but this difference was not statistically significant. (In a subsequent study, the same investigators demonstrated that the presence of both late passage of meconium and certain intrapartum fetal heart rate abnormalities, i.e., loss of beat-to-beat variability and variable decelerations [see next section], sharply increased the likelihood of depressed Apgar scores.190) Finally, however, patients with early-heavy meconium-stained amniotic fluid, which constituted 25% of the total group, had a sharply increased likelihood of neonatal depression as well as intrapartum and neonatal death. Significantly, of this group 33% exhibited Apgar scores lower than 7 at 1 minute, and 6.3% had scores lower than 7 at 5 minutes. Early-heavy meconium-stained amniotic fluid was also associated with other signs of fetal distress (e.g., fetal heart rate abnormalities) and with antecedent obstetrical conditions that lead to neonatal morbidity. Thus, the data suggest that the timing and quantity of meconium passage are critical variables in attempting to assess the significance of this occurrence for fetal well-being. Presumably, these two aspects of meconium passage correlate with the duration and severity of the intrauterine insult. Clinical estimation of the timing of meconium passage in utero is aided by examination of placental membranes or of the newborn (Table 17.10).197 In general, in most cases, the finding of meconium-stained amniotic fluid is not of serious import concerning intrauterine asphyxia. Moreover, in view of the high rate of meconium passage without serious perinatal complications, the most prevalent current view is that “the presence of meconium per se does not imply fetal distress during labor until other parameters, e.g., fetal heart rate abnormalities, support such a contention.”196 However, a recent study continues to confirm the association of thick meconium with acute hypoxic-ischemic cerebral injury. In this study of 405 infants >35 weeks gestation with early encephalopathy, clinical markers, and neuroimaging consistent with hypoxic-ischemic injury, 29% had thick meconium at delivery versus 7% of controls. On multivariable analysis, thick meconium was one of seven intrapartum factors that was independently associated with hypoxic-ischemic injury.198

Neonatal Asphyxia

Chronic intrauterine asphyxia affects placental blood flow, and placental infarction adversely affects fetal growth. In cases of chronic intrauterine asphyxia, labor may be poorly tolerated and neonatal resuscitation may be necessary. When neonatal resuscitation is required, primary or secondary consequences of asphyxia, including acidosis, seizures, transient cardiac dysfunction (e.g., cardiomyopathy or tricuspid insufficiency), pulmonary hypertension, renal insufficiency (e.g., acute tubular necrosis), gastrointestinal/hepatic insults (e.g., necrotizing enterocolitis [NEC]), or clotting abnormalities may occur.

Postnatal asphyxia is often the result of a continuum of intrauterine events, but it may also be caused by events that occur during labor and delivery. Immature respiratory control mechanisms can predispose neonates, especially premature neonates, to life-threatening responses to asphyxia. For example, the response to hypoxia during the first 3 to 4 weeks of life can be paradoxical, in that hypoxia produces a brief period of hyperpnea that is followed by bradypnea (Cross and Oppe, 1952; Brady and Ceruti, 1966). Hypothermia and hypercapnea blunt the initial hyperpnea (Ceruti, 1966; Rigatto et al., 1975). The ventilatory response to carbon dioxide increases with both postnatal and gestational age (see Chapter 3, Respiratory Physiology in Infants and Children) (Rigatto et al., 1975).

Although hypoxia may inflict long-term consequences on the fetus and newborn, hyperoxia can also cause significant morbidity, especially for preterm infants. For example, hyperoxia exposes preterm infants, especially those born before 32 weeks' gestation, to a significant risk for retinopathy of prematurity (ROP; see below) and, in some cases, blindness (see Chapter 27, Anesthesia for Ophthalmic Surgery) (Sylvester, 2008). The normal Pao2 of a fetus is 20 to 30 mm Hg. After birth, a Pao2 of 60 mm Hg is probably hyperoxic for infants born at 24 to 36 weeks' gestation. To avoid the effects of oxidative stress in the newborn, the oxygen saturation for premature infants is usually maintained between 88% and 93% (Pao2 of 45 to 60 mm Hg) in the NICU, and similar Sao2 levels are appropriate in the operating room. Continuous measurement of Sao2 makes it easier to maintain the desired oxygen saturation. Of note is one preterm infant, who never had an elevated Pao2 except in the operating room, but who developed ROP after surgery (Betts et al., 1977).

E. Fetal Electrocardiography Monitoring

Animal and human studies have shown that fetal hypoxemia can alter the shape of the fetal electrocardiogram waveform, particularly ST-segment elevation or depression.20 A Cochrane review supports the use of fetal ST waveform analysis via internal fetal scalp electrode as an adjunct to EFM when nonreassuring FHR patterns are present.

The FDA approved the STAN S31 (Neoventa Medical, Mölndal, Sweden) fetal heart monitoring system in 2006. This computer-enhanced fetal monitor records an “ST Event Flag” on the monitor tracing when fetal ECG changes are detected. ACOG will not endorse the system until further evidence is available that it is efficacious.

Thrombocytopenia secondary to chronic fetal hypoxia, maternal diabetes, pregnancy-induced hypertension, or intrauterine growth retardation

Neonatal thrombocytopenia may be caused by chronic intrauterine hypoxia resulting in placental insufficiency in association with pregnancy-induced hypertension, preeclampsia, HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome, maternal diabetes mellitus, and IUGR. These may be due in part to increased platelet destruction, but typically there is impaired megakaryopoiesis and an elevated thrombopoietin level. Neonates can increase the number of megakaryocytes but typically do not increase their size, which may limit their platelet-producing capability in an emergency setting. Thrombocytopenia from hypoxia is usually not severe and is self-limited. The nadir tends to occur around days 3–4 with recovery by days 7–10. Often no treatment is required. In the setting of preeclampsia, even with maternal thrombocytopenia, neonatal leukopenia is more common than neonatal thrombocytopenia.

Surgical Models

Uterine Vessel Ligation

Another well-established animal model of intrauterine hypoxia employs the Wigglesworth system, a method for the ligation of uterine vessels for the induction of ischemia. Named for a technique initially described by Dr J.S. Wigglesworth in 1964,54 this procedure is widely performed to faithfully mimic key aspects of IUGR and chronic hypoxia in pregnancy.

This model takes advantage of the fact that the rodent uterus is bicornuate (it is comprised of a right horn and a left horn). Thus, manipulation of a single uterine horn has no direct effect on the reproductive potential of the other horn. In the original Wigglesworth technique, on the 17th day of pregnancy, rats are anesthetized and one of the uterine horns is carefully selected for the presence of five or more fetuses. This selection of the more-crowded uterine horn for ligation is often modified by researchers to avoid bias. Two silk ligatures are placed around the lower portion of the uterine horn, about 0.5 cm apart from each other. A third ligature is placed at the base of the uterine vessels in the mesometrium, the goal of which is to restrict blood flow from the uterine vessels into the entire uterine horn, resulting in chronic hypoxia.54 Figure 1 illustrates this procedure for a mouse.

Figure 1. Illustration of the procedure for uterine artery ligation on the right uterine horn of a pregnant mouse.

Dashed-red lines indicate sites of uterine artery ligation.

Adapted from J.S. Wigglesworth, 1964: experimental growth retardation in the foetal rat.

Since the procedure was first reported, many studies have been performed in mouse models and the technique has been refined by use of technologically advanced materials and stringent controls. For instance, procedures now include the use of warming plates to maintain the dam’s body temperature constant during surgery, advanced surgical grade suture material, and the inclusion of sham surgeries on the control horn. In conclusion, the Wigglesworth technique provides researchers with a powerful tool to study the effects of utero-placental ischemia on a variety of reproductive tissues in rodent models of pregnancy, in addition to providing insights into the importance of adequate blood flow and tissue oxygenation for healthy pregnancy.

Intrapartum Glycemic Management

Maintenance of intrapartum metabolic homeostasis is essential to avoid fetal hypoxemia and promote a smooth postnatal transition. Strict maternal euglycemia during labor does not guarantee newborn euglycemia in infants with macrosomia and long-established islet cell hypertrophy. Nevertheless, the use of a combined insulin and glucose infusion during labor to maintain maternal blood glucose in a narrow range (80 to 110 mg/dL) during labor is a common and reasonable practice. Typical infusion rates are 5% dextrose in lactated Ringer’s solution at 100 mL/hr and regular insulin at 0.5 to 1.0 U/hr. Capillary blood glucose levels are monitored hourly in such patients.

For patients with diet-controlled gestational diabetes in labor, avoiding dextrose in all intravenous fluids normally maintains excellent blood glucose control. After 1 to 2 hours, no further assessments of capillary blood glucose are typically necessary.

Fetal Metabolic Acidosis

The most frequent cause of fetal metabolic acidosis is fetal hypoxemia due to abnormalities of uteroplacental function, blood flow, or both. Primary maternal hypoxemia or maternal metabolic acidosis secondary to maternal diabetes mellitus, sepsis, or renal tubular abnormalities are unusual causes of fetal metabolic acidosis. During the course of fetal hypoxemia, metabolism becomes anaerobic, and large quantities of lactic acid accumulate. H+ ions are buffered by the extracellular and intracellular buffering systems, and pH drops as plasma bicarbonate decreases. Because of the unhindered diffusion of carbon dioxide through the placenta,20 restoration of fetal pH toward normal initially occurs through elimination of the volatile element of the carbonic acid-bicarbonate system via the maternal lungs. Lactate and other fixed acids cross the placenta more slowly,13 however, resulting in a delay of effective maternal renal compensation of fetal metabolic acidosis. If fetal oxygenation improves, the products of anaerobic metabolism are also metabolized by the fetus.

As described earlier, the respiratory compensatory mechanism in utero does not contribute to effective compensation of fetal metabolic acidosis. However, in the absence of fetal hypercarbia or hypoxemia, isolated metabolic acidosis still stimulates fetal breathing movements, with significant delay in the onset of activation.21

Several lines of evidence indicate that the fetal kidney is able to excrete acid22-24 and organic acids25 and to reabsorb more bicarbonate.26 Studies in fetal sheep have found age-dependent increases in glomerular filtration rate (GFR), urinary titratable acid, ammonium, and net acid excretion.22 Furthermore, a positive relationship has been demonstrated between changes in GFR and bicarbonate, sodium, and chloride excretions.22,23 The fetal kidney, however, has a developmentally regulated limited ability to adapt to changes in fetal acid-base balance. In fetal sheep, in response to metabolic acidosis induced by the infusion of hydrochloric acid, systolic blood pressure increases but the GFR does not change. Urinary titratable acid, ammonium, and net acid excretion increase without significant changes in renal bicarbonate absorption.24 Evidence also indicates that the fetal kidney has the ability to increase bicarbonate reabsorption, at least during periods of volume depletion.26 With regard to the human fetus, only limited information is available concerning renal acidification.27 The physiologic importance of these adaptive fetal renal responses, however, is limited when compared with those in the postnatal period because the acid load excreted in the fetal urine remains within the immediate fetal environment and still has to be eliminated by the placenta or metabolized by the fetus.

General Historical/Clinical Background

Acute catastrophic demise is a consequence of profound, rapidly evolving intrauterine hypoxia, from sudden disruption of umbilical or uteroplacental circulation. The common etiologies, and those covered herein, include acute cord “accidents,” such as prolapse (see Chapter 31 for discussion of spontaneous umbilical cord hematoma), placental abruption, transected vasa previa, uterine rupture, and amniotic fluid embolism. These conditions are almost always unforeseen and may result in fetal death within minutes to hours. Acute modes of demise are almost always sporadic and are thus without risk of recurrence in future pregnancies.