Spontaneous hypoxia in multiple pregnancies is associated with early fetal decompensation and enhanced T-wave elevation during brief repeated cord occlusion in near-term fetal sheep

doi:10.1016/j.ajog.2005.03.024

American Journal of Obstetrics and Gynecology

Volume 193, Issue 4, October 2005, Pages 1526-1533

https://doi.org/10.1016/j.ajog.2005.03.024 Get rights and content

Objective

The purpose of this study was to examine the hypothesis that fetuses from multiple pregnancies who exhibited spontaneous, stable hypoxia would show more rapid development of metabolic acidosis and hypotension during short repeated episodes of umbilical cord occlusion than normoxic singleton or twin fetuses and, if this proved to be true, to determine whether this deterioration could be identified by changes in T/QRS height or ST waveform shape.

Study design

Chronically instrumented near-term sheep fetuses (124 ± 1 day) were subjected to 1-minute umbilical cord occlusions every 5 minutes (normoxic group, 8 fetuses; hypoxic group, 10 fetuses) for a total of 4 hours or until mean arterial blood pressure fell below 20 mm Hg for 2 successive occlusions.

Results

The spontaneous hypoxic, but not normoxic, fetuses had progressive compromise during repeated umbilical cord occlusions, with severe, progressive metabolic acidosis (pH, 7.07 ± 0.14; base deficit,13 ± 1.5 mmol/L vs 7.34 ± 0.07 mmol/L; base deficit after the final occlusion, 1.1 ± 1.4 mmol/L; P < .001), and hypotension (24 ± 2 mm Hg vs 45.5 ± 3 mm Hg; P < .0001); 4 hypoxic fetuses were unable to complete the 4-hour series of occlusions. The hypoxic group showed a much greater increase in T/QRS ratio during (P < .001) and between occlusions. Biphasic ST segment waveforms were not seen in either group either during or between occlusions.

Conclusion

Exaggerated elevation of the T/QRS ratio during decelerations in early labor may be a useful marker of greater myocardial anaerobic stress (eg, because of pre-existing spontaneous hypoxia), but not of the development of fetal acidemia or hypotension.

Section snippets

Surgical preparation and postoperative care

All animal procedures that were used were approved by the Animal Ethics Committee of the University of Auckland, New Zealand. Eighteen Romney/Suffolk fetal sheep (University of Auckland, Auckland) were fitted with instruments between 117 and 126 days gestation (term, 147 days) with general anesthesia (2% halothane in oxygen) by sterile techniques.¹² Food, but not water, was withdrawn 18 hours before surgery. Ewes were given 5 mL of Streptopen procaine penicillin (250,000 IU) and

Results

At postmortem examination, the hypoxic group was significantly smaller (P < .05, Mann-Whitney-U test: Table I) but of similar gestational age and sex. All animals survived to the end of the experimental protocol. Four experiments in the hypoxia group had to be stopped before the end of the protocol, at occlusion number 34, 38, 43, and 45, respectively, because MAP fell <20 mm Hg for 2 subsequent occlusions. Three animals in the hypoxic group were not able to be included in the electrocardiogram

Comment

The present study is the first systematic report of the physiologic responses to a labor-like insult in fetuses with chronic hypoxia. Near-term fetal sheep from multiple pregnancies with spontaneous, pre-existing stable hypoxemia rapidly developed progressive metabolic acidosis and arterial hypotension during variable decelerations that were induced by umbilical cord occlusion at a rate that was consistent with early labor. Indeed, 4 fetuses experienced severe hypotension before the end of the

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As even short periods of hypoxia can quickly deplete cerebral and cardiac glycogen by up to 80%,64 any limitation in placental transfer of nutrients and oxygen renders these fetuses vulnerable to IFC and injury. Progressive hypoxia in labor results in a further reduction of myocardial glycogen stores, impaired cardiac function,100,101 and, ultimately, profound systemic hypotension and irreversible multiorgan injury.63,64 Cardiac function is further aggravated by the associated systemic hypotension, limiting coronary blood flow and causing subendocardial myocardial injury.102
Uterine contractions in labor result in a 60% reduction in uteroplacental perfusion, causing transient fetal and placental hypoxia. A healthy term fetus with a normally developed placenta is able to accommodate this transient hypoxia by activation of the peripheral chemoreflex, resulting in a reduction in oxygen consumption and a centralization of oxygenated blood to critical organs, namely the heart, brain, and adrenals. Providing there is adequate time for placental and fetal reperfusion between contractions, these fetuses will be able to withstand prolonged periods of intermittent hypoxia and avoid severe hypoxic injury. However, there exists a cohort of fetuses in whom abnormal placental development in the first half of pregnancy results in failure of endovascular invasion of the spiral arteries by the cytotrophoblastic cells and inadequate placental angiogenesis. This produces a high-resistance, low-flow circulation predisposing to hypoperfusion, hypoxia, reperfusion injury, and oxidative stress within the placenta. Furthermore, this renders the placenta susceptible to fluctuations and reduction in uteroplacental perfusion in response to external compression and stimuli (as occurs in labor), further reducing fetal capillary perfusion, placing the fetus at risk of inadequate gas/nutrient exchange. This placental dysfunction predisposes the fetus to intrapartum fetal compromise. In the absence of a rare catastrophic event, intrapartum fetal compromise occurs as a gradual process when there is an inability of the fetal heart to respond to the peripheral chemoreflex to maintain cardiac output. This may arise as a consequence of placental dysfunction reducing pre-labor myocardial glycogen stores necessary for anaerobic metabolism or due to an inadequate placental perfusion between contractions to restore fetal oxygen and nutrient exchange. If the hypoxic insult is severe enough and long enough, profound multiorgan injury and even death may occur. This review provides a detailed synopsis of the events that can result in placental dysfunction, how this may predispose to intrapartum fetal hypoxia, and what protective mechanisms are in place to avoid hypoxic injury.
Neonatal encephalopathy and hypoxic–ischemic encephalopathy
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For example, studies using near-infrared spectroscopy (NIRS) show a progressive fall in cerebral oxygen saturation when contractions occur more frequently than every 2.3 min (Peebles et al., 1994). The effects of repeated hypoxia may be amplified in vulnerable fetuses, for example in those with preexisting placental insufficiency (Westgate et al., 2005; Wassink et al., 2013) or fetal inflammation leading to sensitization of the brain to hypoxia–ischemia (Eklind et al., 2005; Osredkar et al., 2014). Conversely, even a normal fetus with normal placental function may be unable to fully adapt to tonic contractions or uterine hyperstimulation related to oxytocin infusion used for induction or augmentation or prostaglandin preparations for induction of labor (Winkler and Rath, 1999).
Acute hypoxic–ischemic encephalopathy around the time of birth remains a major cause of death and life-long disability. The key insight that led to the modern revival of studies of neuroprotection was that, after profound asphyxia, many brain cells show initial recovery from the insult during a short “latent” phase, typically lasting approximately 6 h, only to die hours to days later after a “secondary” deterioration characterized by seizures, cytotoxic edema, and progressive failure of cerebral oxidative metabolism. Studies designed around this framework showed that mild hypothermia initiated as early as possible before the onset of secondary deterioration and continued for a sufficient duration to allow the secondary deterioration to resolve is associated with potent, long-lasting neuroprotection. There is now compelling evidence from randomized controlled trials that mild to moderate induced hypothermia significantly improves survival and neurodevelopmental outcomes in infancy and mid-childhood.
Understanding Fetal Heart Rate Patterns That May Predict Antenatal and Intrapartum Neural Injury
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However, in practice, antenatal complications may occur in combination, or be followed by profound hypoxemia during labor. This leads to a number of complex interactions, for example FGR is associated with impaired adaptation to labor and a greater risk of fetal compromise,9,118,120 whereas prior inflammation can either exacerbate or attenuate neural injury depending on timing.136-139 Evidence is also accumulating that other factors such as hyperglycemia,140 antenatal glucocorticoids,140,141 and magnesium sulfate142 may affect the adaptation to hypoxemia.
Electronic fetal heart rate (FHR) monitoring is widely used to assess fetal well-being throughout pregnancy and labor. Both antenatal and intrapartum FHR monitoring are associated with a high negative predictive value and a very poor positive predictive value. This in part reflects the physiological resilience of the healthy fetus and the remarkable effectiveness of fetal adaptations to even severe challenges. In this way, the majority of “abnormal” FHR patterns in fact reflect a fetus’ appropriate adaptive responses to adverse in utero conditions. Understanding the physiology of these adaptations, how they are reflected in the FHR trace and in what conditions they can fail is therefore critical to appreciating both the potential uses and limitations of electronic FHR monitoring.
Accelerated acidosis in response to variable fetal heart rate decelerations in chronically hypoxic ovine fetuses
2016, American Journal of Obstetrics and Gynecology
Citation Excerpt :
Animals in this study were identified as normoxic or spontaneously hypoxic during the postoperative recovery period, and were studied over a 2-day period. Hypoxic fetuses were identified as those with an arterial O2 saturation of ≤55% on postoperative days 1-4, similar to the criteria utilized in a previous study of spontaneously hypoxic ovine fetuses (17 mm Hg).5 After a 1- to 2-hour baseline period, partial, intermediate, and complete series of repetitive UCOs were performed.
Due to limitations of technology, clinicians are typically unable to determine if human fetuses are normoxic or moderately, chronically hypoxic. Risk factors for chronic hypoxia include fetal growth restriction, which is associated with an increased incidence of oligohydramnios and thus a risk for umbilical cord occlusion (UCO) and variable fetal heart rate (FHR) decelerations. At delivery, fetal growth restriction infants (<3rd percentile) have nearly twice the incidence of low Apgar scores and umbilical pH <7.0. Despite the risks of oligohydramnios and intermittent UCO, there is little understanding of the acid/base responses rates of chronically hypoxic fetuses to variable FHR decelerations as might occur during human labor.
We sought to compare the increase in base deficit (BD) among chronically hypoxic as compared to normoxic ovine fetuses in response to simulated mild, moderate, and severe variable FHR decelerations.
Near-term ovine fetuses were chronically prepared with brachial artery catheters and an inflatable umbilical cuff occluder. Following a recovery period, normoxic (n = 9) and spontaneously hypoxic (n = 5) fetuses were identified (arterial O₂ saturation ≤55%). Both animal groups underwent graded, 1-minute occlusions every 2.5 minutes with 1 hour of mild (∼30 beats/min [bpm] decrease from baseline), 1 hour of moderate (∼60 bpm decrease from baseline), and up to 2 hours of severe (∼90 bpm decrease from baseline) variable FHR decelerations until fetal arterial pH reached 7.00, when occlusions were stopped.
Repetitive UCO resulted in development of acidosis (pH <7.0) in both groups. Hypoxic and normoxic fetuses demonstrated similar BD increases in response to both mild (0.39, interquartile range [IQR] 0.28-0.45 vs 0.26, IQR 0.01-0.30 mEq/L/10 min, P = .25) and severe (1.97, IQR 1.50-2.43 vs 1.51, IQR 0.97-2.45 mEq/L/10 min, P = .63) variable decelerations. However, moderate variable decelerations increased BD in hypoxic fetuses at 2.5 times the rate of normoxic fetuses (0.97, IQR 0.52-1.72 vs 0.39, IQR 0.23-0.47 mEq/L/10 min, P = .03). During the recovery period, hypoxic fetuses cleared BD slower than normoxic fetuses (0.08 ± 0.02 vs 0.12 ± 0.03 mEq/L/min, P = .02).
In comparison to normoxic fetuses, hypoxic fetuses can more rapidly progress to significant metabolic acidosis in response to moderate FHR variable decelerations, and more slowly recover with in utero resuscitation, likely a consequence of impaired placental function and fetal physiologic responses.
The Fetal Heart Rate Response to Hypoxia: Insights from Animal Models
2009, Clinics in Perinatology
Fetal Hypoxia Insults and Patterns of Brain Injury: Insights from Animal Models
2009, Clinics in Perinatology

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General Obstetrics and Gynecology: ObstetricsSpontaneous hypoxia in multiple pregnancies is associated with early fetal decompensation and enhanced T-wave elevation during brief repeated cord occlusion in near-term fetal sheep

Objective

Study design

Results

Conclusion

Section snippets

Surgical preparation and postoperative care

Results

Comment

Diagnostic value of blood sampling in fetuses with growth retardation

N Engl J Med

Blood gases, pH, and lactate in appropriate- and small-for-gestational-age fetuses

Am J Obstet Gynecol

Fetal oxygenation at cordocentesis, maternal smoking and childhood neuro-development

Eur J Obstet Gynecol Reprod Biol

Responses of the growth-retarded fetus to acute hypoxemia

Am J Obstet Gynecol

Effects of prevailing hypoxaemia, acidaemia or hypoglycaemia upon the cardiovascular, endocrine and metabolic responses to acute hypoxaemia in the ovine fetus

J Physiol

Changes in the ST waveform of the fetal lamb electrocardiogram with hypoxemia

Am J Obstet Gynecol

Myocardial metabolism in relation to electrocardiographic changes and cardiac function during graded hypoxia in the fetal lamb

Acta Physiol Scand

The relationship between circulating catecholamines and ST waveform in the fetal lamb electrocardiogram during hypoxia

Am J Obstet Gynecol

Randomised trial of cardiotocography alone or with ST waveform analysis for intrapartum monitoring

Lancet

Cardiotocography only versus cardiotocography plus ST analysis of fetal electrocardiogram for intrapartum fetal monitoring: a Swedish randomised controlled trial

Lancet

ECG waveform, short term heart rate variability and plasma catecholamine concentrations in response to hypoxia in intrauterine growth retarded guinea-pig fetuses

J Dev Physiol

General Obstetrics and Gynecology: Obstetrics
Spontaneous hypoxia in multiple pregnancies is associated with early fetal decompensation and enhanced T-wave elevation during brief repeated cord occlusion in near-term fetal sheep