Introduction
Due to limitations of technology, clinicians are typically unable to assess human fetuses as normoxic or moderately hypoxic. Risk factors for chronic hypoxia include fetal growth restriction (FGR), in which fetuses also have an increased incidence of oligohydramnios and thus are at risk for umbilical cord occlusion (UCO) and variable fetal heart rate (FHR) decelerations. At delivery, FGR infants (<3rd percentile) have nearly twice the incidence of low Apgar scores and umbilical pH <7.0. Despite the risks of chronic hypoxemia, oligohydramnios, and intermittent UCO, there is little understanding of the rates of acidosis in this FGR subgroup as might occur during human labor.
In laboring patients at term, UCOs resulting in variable heart rate decelerations are the most common abnormality found on intrapartum FHR monitoring. Repeated fetal hypoxia due to complete UCO (ie, severe variable deceleration) may lead to concerning acidemia and tissue acidosis. We recently quantified the changes in base deficit (BD) in response to repetitive UCOs simulating variable FHR decelerations in normoxic, near-term ovine fetuses. These studies demonstrated an increased rate of acidosis with progression from mild to moderate to severe variable decelerations, although only severe variable decelerations resulted in a marked progression of metabolic acidosis.
We hypothesized that chronically hypoxic fetuses may have enhanced acidosis in response to UCO and variable decelerations. Utilizing an ovine model, our findings indicate the moderate variable decelerations result in a marked increase in BD in chronically hypoxic as compared to normoxic fetuses.
Materials and Methods
Surgical preparation
Fourteen near-term ovine fetuses (124 ± 1 days’ gestation, term = 145 days) were surgically instrumented. The anesthetic and surgical procedures and postoperative care of the animals have been previously described. Briefly, polyvinyl catheters were placed in the right and left brachiocephalic arteries, cephalic vein, and amniotic cavity. Stainless steel electrocardiogram electrodes were sewn onto the fetal chest. An inflatable silicon rubber cuff (In Vivo Metric, Healdsburg, CA) was placed around the proximal portion of the umbilical cord and secured to the abdominal skin. A catheter was also placed in the maternal femoral vein. Postoperatively, animals were allowed 4 days to recover and were 128 ± 1 days gestational age on the first day of study. Animal care was according to guidelines of the Canadian Council on Animal Care and was approved by the University of Western Ontario Council on Animal Care.
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 O 2 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). After a 1- to 2-hour baseline period, partial, intermediate, and complete series of repetitive UCOs were performed. UCO was induced in all series for 1-minute duration every 2.5 minutes by graduated inflation of the occluder cuff with a saline solution. During the first hour following baseline, mild variable decelerations were induced with partial UCO, with the goal of decreasing FHR by ∼30 beats per minute (bpm), corresponding to an approximate 50% reduction in umbilical blood flow. During the second hour, moderate variable decelerations were induced with an intermediate UCO with the goal of decreasing FHR by approximately 60 bpm, corresponding to an approximately 75% reduction in umbilical blood flow. Subsequently, animals underwent severe variable decelerations with complete UCO until the targeted fetal arterial pH of <7.00 was detected, at which point the repetitive UCOs were terminated. All animals were allowed to recover for 48 hours after the last series of UCO. Maternal venous blood samples were drawn at baseline and at completion of the UCO protocol. Fetal arterial blood samples were drawn at baseline, at 20-minute intervals (between UCOs) throughout each of the series, as well as at 1, 24, and 48 hours of recovery.
All blood samples were analyzed for blood gas values, pH, and glucose with an ABL-725 blood gas analyzer (Radiometer Medical, Copenhagen, Denmark) corrected to 39.0°C. After the 48-hour recovery blood sample, the ewe and the fetus were killed by an overdose of barbiturate and the location and function of the umbilical occluder were confirmed. Fetal weight was obtained at necropsy.
Data acquisition and analysis
During the baseline, repetitive UCO, and the first 2 hours of the recovery period arterial and amniotic pressures were continuously monitored using Statham pressure transducers (Gould Inc, Oxnard, CA). Data acquisition and analysis were performed by PowerLab system and LabChart software (Chart 7 For Windows, ADInstruments Pty Ltd, Castle Hill, Australia). True arterial blood pressure (ABP) was determined as the difference between ABP and amniotic pressure.
FHR and ABP means were calculated from artifact-free baseline, repetitive variable FHR deceleration series (mild, moderate, severe), and the first hour of recovery. Nadirs of the FHR during decelerations in each of the UCO series and corresponding ABP were determined for each fetus during each deceleration and an average obtained for each series.
BD (mEq/L) was calculated as follows : BD = –[0.02786 × PCO 2 × 10 (pH–6.1) + 13.77 × pH –124.58] with PaCO 2 measured in mm Hg.
The rate of BD deterioration (mEq/L/min) was calculated for each period of mild, moderate, and severe variable decelerations and the first hour of recovery, as follows: Delta BD = 24X – 36Y, where 24X is number of minutes of UCO × the rate of BD increase and 36 is number of minutes of recovery × the rate of BD clearance.
We assessed the effect of a single 1-minute partial or complete UCO and associated variable deceleration on the change in BD associated with each UCO as follows: Y = (BD change at experiment end during 1-h recovery)/60 min, where Y is recovery of BD/min.
Statistical analysis
Normal data distribution was tested using Kolmogorov-Smirnov test followed by parametric or nonparametric tests, as appropriate. Baseline and recovery values of pH, pCO 2 , BD, and hemoglobin (Hgb) were normally distributed, are presented as mean ± SD, and were compared between the hypoxic and normoxic group using Student t tests. Repeated measures analysis of variance followed by Holm-Sidak (vs baseline) or Student-Newman-Keuls (pairwise) tests for multiple comparisons were used to assess differences in cardiovascular responses. No adjustment for multiple comparison was undertaken at this point.
The rates of change of BD between hypoxic and normoxic fetuses in response to individual mild, moderate, and severe variable decelerations were not normally distributed, analyzed with nonparametric Wilcoxon rank sum analysis, and reported as median values with interquartile ranges (IQR) of 25-75%. Statistical significance was assumed for P < .05.
Materials and Methods
Surgical preparation
Fourteen near-term ovine fetuses (124 ± 1 days’ gestation, term = 145 days) were surgically instrumented. The anesthetic and surgical procedures and postoperative care of the animals have been previously described. Briefly, polyvinyl catheters were placed in the right and left brachiocephalic arteries, cephalic vein, and amniotic cavity. Stainless steel electrocardiogram electrodes were sewn onto the fetal chest. An inflatable silicon rubber cuff (In Vivo Metric, Healdsburg, CA) was placed around the proximal portion of the umbilical cord and secured to the abdominal skin. A catheter was also placed in the maternal femoral vein. Postoperatively, animals were allowed 4 days to recover and were 128 ± 1 days gestational age on the first day of study. Animal care was according to guidelines of the Canadian Council on Animal Care and was approved by the University of Western Ontario Council on Animal Care.
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 O 2 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). After a 1- to 2-hour baseline period, partial, intermediate, and complete series of repetitive UCOs were performed. UCO was induced in all series for 1-minute duration every 2.5 minutes by graduated inflation of the occluder cuff with a saline solution. During the first hour following baseline, mild variable decelerations were induced with partial UCO, with the goal of decreasing FHR by ∼30 beats per minute (bpm), corresponding to an approximate 50% reduction in umbilical blood flow. During the second hour, moderate variable decelerations were induced with an intermediate UCO with the goal of decreasing FHR by approximately 60 bpm, corresponding to an approximately 75% reduction in umbilical blood flow. Subsequently, animals underwent severe variable decelerations with complete UCO until the targeted fetal arterial pH of <7.00 was detected, at which point the repetitive UCOs were terminated. All animals were allowed to recover for 48 hours after the last series of UCO. Maternal venous blood samples were drawn at baseline and at completion of the UCO protocol. Fetal arterial blood samples were drawn at baseline, at 20-minute intervals (between UCOs) throughout each of the series, as well as at 1, 24, and 48 hours of recovery.
All blood samples were analyzed for blood gas values, pH, and glucose with an ABL-725 blood gas analyzer (Radiometer Medical, Copenhagen, Denmark) corrected to 39.0°C. After the 48-hour recovery blood sample, the ewe and the fetus were killed by an overdose of barbiturate and the location and function of the umbilical occluder were confirmed. Fetal weight was obtained at necropsy.
Data acquisition and analysis
During the baseline, repetitive UCO, and the first 2 hours of the recovery period arterial and amniotic pressures were continuously monitored using Statham pressure transducers (Gould Inc, Oxnard, CA). Data acquisition and analysis were performed by PowerLab system and LabChart software (Chart 7 For Windows, ADInstruments Pty Ltd, Castle Hill, Australia). True arterial blood pressure (ABP) was determined as the difference between ABP and amniotic pressure.
FHR and ABP means were calculated from artifact-free baseline, repetitive variable FHR deceleration series (mild, moderate, severe), and the first hour of recovery. Nadirs of the FHR during decelerations in each of the UCO series and corresponding ABP were determined for each fetus during each deceleration and an average obtained for each series.
BD (mEq/L) was calculated as follows : BD = –[0.02786 × PCO 2 × 10 (pH–6.1) + 13.77 × pH –124.58] with PaCO 2 measured in mm Hg.
The rate of BD deterioration (mEq/L/min) was calculated for each period of mild, moderate, and severe variable decelerations and the first hour of recovery, as follows: Delta BD = 24X – 36Y, where 24X is number of minutes of UCO × the rate of BD increase and 36 is number of minutes of recovery × the rate of BD clearance.
We assessed the effect of a single 1-minute partial or complete UCO and associated variable deceleration on the change in BD associated with each UCO as follows: Y = (BD change at experiment end during 1-h recovery)/60 min, where Y is recovery of BD/min.
Statistical analysis
Normal data distribution was tested using Kolmogorov-Smirnov test followed by parametric or nonparametric tests, as appropriate. Baseline and recovery values of pH, pCO 2 , BD, and hemoglobin (Hgb) were normally distributed, are presented as mean ± SD, and were compared between the hypoxic and normoxic group using Student t tests. Repeated measures analysis of variance followed by Holm-Sidak (vs baseline) or Student-Newman-Keuls (pairwise) tests for multiple comparisons were used to assess differences in cardiovascular responses. No adjustment for multiple comparison was undertaken at this point.
The rates of change of BD between hypoxic and normoxic fetuses in response to individual mild, moderate, and severe variable decelerations were not normally distributed, analyzed with nonparametric Wilcoxon rank sum analysis, and reported as median values with interquartile ranges (IQR) of 25-75%. Statistical significance was assumed for P < .05.
Results
At baseline, hypoxic fetuses demonstrated a lower arterial pO 2 (16.1 ± 3.9 mm Hg vs 23.0 ± 1.7 mm Hg, P < .01) and O 2 Sat (41.4 ± 14.9% vs 64.5 ± 4.0%, P = .02), but similar pH, pCO 2 , BD, and Hgb compared to normoxic fetuses ( Table ). Baseline FHR (168 ± 12 bpm vs 159 ± 13 bpm) and mean ABP (48 ± 5 mm Hg vs 44 ± 5 mm Hg) showed no significant difference between the hypoxic and normoxic groups, respectively.
| Baseline | End mild | End moderate | End severe | 1-h Recovery | 24-h Recovery | ||
|---|---|---|---|---|---|---|---|
| pO2, mm Hg | HYP | 16.1 ± 3.9 a | 16.1 ± 4.5 | 16.6 ± 4.6 | 18.4 ± 3.8 | 17.1 ± 3.7 a | 17.3 ± 2.5 a |
| NOR | 23.0 ± 1.7 | 21.0 ± 2.2 | 20.0 ± 2.4 | 22.2 ± 3.1 | 22.4 ± 1.7 | 22.1 ± 2.0 | |
| O2sat, % | HYP | 41.4 ± 14.9 a | 37.9 ± 14.9 | 31.9 ± 9.1 | 28.5 ± 6.7 | 30.5 ± 11.4 a | 48.5 ± 12.1 |
| NOR | 64.52 ± 4.0 | 48.6 ± 5.6 | 44.5 ± 8.1 b | 33.1 ± 10.4 b | 47.2 ± 5.1 b | 53.0 ± 5.8 | |
| pCO2, mm Hg | HYP | 53.3 ± 3.8 | 52.0 ± 4.2 | 55.4 ± 2.7 | 64.1 ± 8.2 b | 49.7 ± 4.7 | 50.4 ± 3.6 |
| NOR | 50.0 ± 3.4 | 50.4 ± 4.5 | 53.8 ± 5.5 | 68.0 ± 11.7 b | 49.8 ± 4.2 | 51.8 ± 6.8 | |
| Hgb, g/dL | HYP | 12.3 ± 2.6 | 12.7 ± 2.5 | 12.6 ± 1.7 | 12.9 ± 2.6 | 12.1 ± 2.7 | 11.9 ± 2.3 |
| NOR | 11.0 ± 2.1 | 11.1 ± 2.2 | 11.5 ± 1.6 | 11.5 ± 2.2 | 10.8 ± 2.3 | 10.7 ± 2.1 | |
| pH | HYP | 7.34 ± 0.02 | 7.32 ± 0.02 | 7.20 ± 0.11 b | 7.01 ± 0.01 b | 7.21 ± 0.07 b | 7.35 ± 0.02 |
| NOR | 7.35 ± 0.03 | 7.33 ± 0.02 | 7.28 ± 0.03 b | 7.00 ± 0.12 b | 7.23 ± 0.04 b | 7.31 ± 0.10 | |
| BD, mEq/L | HYP | –2.1 ± 1.5 | 0.64 ± 1.5 | 5.9 ± 5.6 b | 15.5 ± 0.6 b | 10.6 ± 0.8 a , b | –0.6 ± 1.1 |
| NOR | –1.6 ± 1.9 | 0.5 ± 1.5 | 2.6 ± 1.9 b | 13.6 ± 3.1 b | 7.1 ± 1.5 b | 0.3 ± 4.5 |
a P < .05 compared to normoxic group within same time period
Increasing degree (partial, intermediate, and severe) of UCO resulted in progressively deeper FHR decelerations from the baseline heart rate in both groups as intended ( Figures 1 and 2 ), although there was no statistically significant difference in the depth of decelerations between the hypoxic vs normoxic groups: mild (29 ± 26 bpm vs 39 ± 16 bpm), moderate (54 ± 24 bpm vs 59 ± 8 bpm), and severe (77 ± 30 bpm vs 99 ± 14 bpm). The time to FHR nadir ( Figure 3 ) was significantly shorter between hypoxic and normoxic groups during mild variable decelerations (19 ± 6 seconds vs 26 ± 4 seconds, P < .05); moderate and severe variable decelerations showed no significant difference between the groups (33 ± 11 seconds vs 32 ± 6 seconds and 39 ± 15 seconds vs 35 ± 9 seconds, respectively). Both moderate and severe variable decelerations resulted in significantly longer time to FHR nadir than the respective mild decelerations within each group. The mean FHR between UCOs was not different between groups, nor did it change from baseline in response to mild, moderate, and severe FHR decelerations. However, mean FHR increased in both groups during the first hour of recovery ( Figure 4 ).
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