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Acute reversible placental dysfunction and abnormal fetal heart rate at delivery
European Journal of Obstetrics & Gynecology and Reproductive Biology 110 (2003) 136–142
Acute reversible placental dysfunction and abnormal fetal heart rate at delivery Gabriel Carlesb, Nathalie Tobala, Henri Marreta, Philippe Arbeillea,* a
Inserm 316, Department of Medecine Nucle´aire & Ultrasons, CHU Trousseau, 37044 Tours, France b Sce. Obstet. & Gyne´col., Hopital Andre´-Bouron, St. Laurent du Maroni, French Guiana, France Received 31 May 2002; accepted 8 January 2003
Abstract Acute placental dysfunction induced by malaria is characterized by umbilical artery resistance increase and cerebral artery resistance decrease during the crisis. The objective was to evaluate the sensitivity and specificity of fetal Doppler indices and crisis duration for predicting abnormal fetal heart rate (aFHR) at delivery several weeks after the crisis. Method: Every day during the crisis, the umbilical and cerebral resistance indices were measured by Doppler. These indices allowed evaluation of the amplitude of the fetal flow redistribution (C/U ¼ cerebral resistance/umbilical resistance ratio), the duration of the flow redistribution period (i.e. crisis duration) and the Hypoxic index (HI) (mean %C/U change crisis duration). Results: Population: 46 pregnancies. Mean duration of the flow redistribution period 8 3:2 days, mean C/U change 9% 6; Hypoxic index 86 75; prematures 48%; aFHR 30%). Hypoxic index >150 predicted occurrence of aFHR with high sensitivity and specificity (83%/88%). The presence of abnormal flow distribution (C/U < 1:1) and the duration of the period with flow disturbance (>8 days) predicted aFHR at delivery with a sensitivity of 45 and 48% and a specificity of 82 and 84%. Conclusion: The Hypoxic index was more predictive of aFHR at delivery than the amplitude or the duration of the fetal flow redistribution triggered by placental insufficiency. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Malaria; Fetus; Doppler; Hypoxia; Heart rate
1. Introduction Chronic and sustained placental insufficiency often develop during pregnancy complicated by hypertension. Such insufficiency trigger fetal flow redistribution and is generally associated with premature birth and growth retardation, and risk of cerebral lesions of hypoxic origin. Doppler examination of the fetal blood vessels is widely used to confirm the existence of hemodynamic abnormalities at the placental level accompanying intra-uterine growth restriction, and to evaluate the cerebral vascular response to hypoxia. Several studies have shown the usefulness of the umbilical and cerebral resistance indices in the detection of intra-uterine growth restriction and hypoxia [1–10]. Acute and reversible placental insufficiency appears during malaria infection. The placenta acts as a filter by retaining the parasitized blood red cells. This infestation
*
Corresponding author. Tel.: þ33-2-4747-5939; fax: þ33-2-4747-5913; mobile: þ33-6-8010-5488. E-mail address: [email protected] (P. Arbeille).
causes a deterioration of the placenta consisting of: degeneration of the chorionic villi, formation of deposits of fibrin and malarial pigment, thickening of the basement membrane, and accumulation of macrophages in the intervillous space [11–16]. Malarial placental lesions result in a temporary and reversible decrease in feto-placental exchange. In early pregnancy, a severe acute hypoxia may be observed, which induces abortion or death of the fetus. Later on in the pregnancy, malaria crisis of long duration (1 week or more) may be associated with prematurity and abnormal fetal heart rate (aFHR) at delivery. As the crisis occurs several weeks before delivery one may suggest that their might be a relationship between the crisis characteristics (duration, hemodynamic disturbance, level of hypoxia, . . .) and the fetal outcome. The objective was (a) to evaluate the sensitivity and specificity of fetal Doppler indices for the prediction of abnormal fetal heart rate at delivery several weeks after the episode of acute placental insufficiency (malaria crisis), (b) to compare with the performances of the duration of the period with flow disturbance (i.e. crisis duration) for predicting aFHR.
0301-2115/$ – see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0301-2115(03)00089-7
G. Carles et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 110 (2003) 136–142
2. Materials and methods 2.1. Population The study, designed as a prospective and observational one, was carried out in the obstetric department of a government hospital in French Guiana. The population consisted of 46 pregnancies, all complicated by a malaria infection (Plasmodium falciparum). 2.2. Protocol The Hospital at Saint Laurent du Maroni (French Guiana) receives a substantial number of pregnancies complicated by malaria. These gestations originate from the inhabited areas distributed along the Maroni River. At the first clinical signs of malaria infection, the gravidas were treated and transferred to the obstetrics department at the Hospital. Admission of the cases and the monitoring of the growth and fetal circulation by ultrasound and Doppler were carried out according to a well-defined protocol: Doppler investigation consisted of uterine, umbilical, and cerebral arteries recording at admission, then cerebral and umbilical arteries recording every day during the crisis. Echography for examination of the placenta and amniotic fluid volume, and fetal biometry were performed every two days. This protocol started at admission and was continued until the end of the crisis (remission of the clinical, hematological, and hemodynamic signs). The diagnosis of malaria was based on the presence of fever, and the detection of parasitized cell in the maternal blood. The maternal blood analysis was performed every day during the crisis, and the treatment was stopped when no more parasites were present. After leaving the hospital, the gravida was seen as regularly as possible and at each visit underwent a complete ultrasound-Doppler examination. Following delivery, the perinatal data were collected. 2.3. Fetal hemodynamic data The uterine vascular resistance indices were measured at admission only, no notch was noticed. The distribution of the fetal flows (between the placental and cerebral regions) was evaluated using the cerebral–umbilical resistance ratio (C/U), which is the ratio between the cerebral and umbilical resistance indices [9,10]. This parameter is always greater than 1.1 during normal pregnancy but decreases in the case of hypoxia due to the umbilical resistance increase (increase placental resistance) and cerebral resistance decrease (cerebral vasodilation) [9]. The C/U ratio decreases proportionally with the fetal partial pressure of oxygen [pO2] and its minimum absolute value is proportional to the lowest level of the fetal pO2 [10,17]. In addition, it is not dependent on the fetal heart rate (as are the other Doppler indices), and has a cut-off limit between the normal and pathological zones which is constant throughout gestation and equal to 1.1 at least from 25 to 40 weeks.
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The variation of the C/U ratio was expressed as a percentage compared to the normal value measured at the end of the crisis (remission of clinical and hematological signs). The Hypoxic index (HI) has been calculated from the mean variation in the C/U ratio (%C/U) during the crisis and the crisis duration (in days): Hypoxic index ¼ (mean %C/U change) (crisis duration). The decrease of the C/U ratio has been found to represents the decrease in fetal pO2, in animal model and human cases [10,17]. Thus, the area between the C/U ratio curve and the time axis represents the cumulated deficit in pO2 during the crisis. Therefore, the Hypoxic index combines information on the amplitude of the flow redistribution towards the brain (i.e. pO2 decrease), and the duration of the exposure to hypoxia. The cut-off value of 150 for the Hypoxic index was found on a retrospective study on pregnancies complicated by hypertension (personal unpublished data) and tested on the present study. At each daily Doppler examination we measured the umbilical and cerebral resistances, and then C/U ratio. The Hypoxic index was calculated at the end of the crisis. Doppler examinations were performed by the two obstetricians in charge of the pregnancies, using a Hitachi EUB 44. 2.4. Perinatal data The Doppler data were compared with the fetal and maternal perinatal data: fetal heart rate (FHR) monitoring at delivery, gestational age at delivery and type of delivery, Apgar score at 5 min and fetal weight after delivery, maternal parasitemia (grades 1–5), parity of the gravida, date of the onset of the crisis, crisis duration, number of days before treatment. The FHR patterns were defined as abnormal when one of the following was detected: persistent late deceleration, recurrent severe variable deceleration, prolonged deceleration, or loss of variability. FHR traces were evaluated blindly by the two obstetricians. The Apgar score at 5 min was considered as pathological when lower than 7. The parasitemia grade represents the concentration of parasitis/ mm3 of maternal blood (grade 1: 0–1000; grade 2: 1000– 2500; grade 3: 2500–10,000; grade 4: 10,000–50,000; grade 5: >50,000). Normal delivery was defined as at-term delivery, without any signs of fetal distress or maternal complication. Cesarean section were decided for fetal distress, dystocia, or maternal complication. 2.5. Data processing The Doppler parameters were calculated using frequency cursors for detecting systole and en diastolic amplitude on the Doppler spectrum, and averaged over 10 cardiac cycles. The Doppler parameters were compared with the fetal and maternal perinatal data. Normal or abnormal Doppler data were compared with the occurrence of abnormal fetal heart rate, prematurity, cesarean section, abnormal Apgar score at 1 min, using a chi-square test. The Doppler values were compared with the duration of the crisis (days), the grade of
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G. Carles et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 110 (2003) 136–142
parasitemia (1–5), the date of the crisis, the number of days before treatment using a Mann–Whitney non-parametric test. The limit for significance was set at P ¼ 0:05. The ability of the Doppler parameters (minimal C/U, HI) and the crisis duration to predict the occurrence of aFHR was expressed in terms of sensitivity, specificity, positive and negative predictive values.
3. Results The duration of the study was three years. One hundred pregnancies complicated by malaria were investigated, but the complete Doppler and clinical data needed for the study were collected in only 46 of them. The other pregnancies, assessed by Doppler during their stay at the hospital, returned to their villages, and their deliveries could not be monitored. Perinatal data are presented in Table 1. The fetal umbilical and cerebral Doppler traces were successfully recorded at each daily Doppler session. Doppler data at admission, and percentage changes of these parameters during the crisis are presented in Table 2. Fig. 1 shows the mean umbilical resistance increase (in %) and cerebral resistance and C/U ratio decrease. Fig. 2 gives examples of low HI (<150) and high HI (>150) as found in mild or severe malaria crisis. Fig. 3 shows the correspondence between HI or crisis duration and aFHR. Sensitivity, specificity, positive predictive and negative predictive values of the lowest C/U absolute value (abnormal when <1.1), crisis duration (>8days), Hypoxic index (>150) for predicting abnormal fetal heart rate at delivery are presented in Table 3. There was no significant correlation between the amplitude of the redistribution of the fetal flows (mean %C/U ratio variations), or the Hypoxic index, and the following
Table 1 Maternal and fetal parameters Parameters
Crisis (n ¼ 46)
Age (years, mean S.D.) Parity (mean S.D.) Crisis gestational age (years, mean S.D.) Crisis duration (days, mean S.D.) Days before treatment (mean S.D.) Parasitemia grade (mean S.D.) Delivery (weeks, mean S.D.) Cesarean section Oligoamnios during crisis Abnormal FHR Apgar score < 7 at 5 min Premature Intra-uterine growth retardation (<10 centile)
23 2.5 32 31.4 3.6 8 3.2 3 1.5 31 36 3 8 (17) 16 (35) 14 (30) 13 (28) 22 (48) 8 (17)
Values given in parenthesis are in percentage.
parameters: the grade of parasitemia, the parity of the pregnancy, the gestational age at the time of the crisis, the number of days before treatment, the gestational age at delivery, the mode of delivery, the time between crisis and delivery, the fetal weight at birth. The Hypoxic index (>150) predicted abnormal FHR at delivery with a good sensitivity and specificity. Conversely the lowest C/U value (<1.1) and crisis duration (>8days) did not predict aFHR with a good sensitivity nor specificity (Table 3).
4. Discussion The fetal Doppler performed during the crisis showed that the malarial infection induced a range of transient hemodynamic changes at the placental and cerebral level. In all cases, there was an increase of the umbilical resistance,
Table 2 Doppler data at admission and during the crisis Doppler at admission Uterine resistance index (UTRI) at admission (mean S.D.) Cerebral/umbilical (C/U ¼ CRI/URI) ratio at admission (mean S.D.) Umbilical resistance index (URI) at admission (mean S.D.) Cerebral resistance index (CRI) at admission (mean S.D.) Doppler changes during crisis Abnormal uterine resistance (UTRI) index Abnormal umbilical resistance (URI) index Abnormal cerebral resistance (CRI) index Both URI & CRI abnormal Abnormal cerebral/umbilical (C/U) ratio Cerebral/umbilical (C/U) ratio decrease >10% Lowest cerebral/umbilical (C/U) ratio in crisis (mean S.D.) Largest cerebral/umbilical (C/U) ratio decrease (mean S.D.) Days with flow redistribution (C/U < 1.1, mean S.D.) % Cerebral/umbilical (C/U) change during the crisis (mean S.D.) Hypoxic index (HI, mean S.D.) Values given in parenthesis are in percentage.
Crisis (n ¼ 46) 0.47 1.13 0.67 0.75
0.08 0.17 0.08 0.08
19 (41) 11 (24) 24 (52) 7 (15) 30 (65) 32 (70) 1.02 0.14 18 8.5 8 3.2 9 6 86 75
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Fig. 1. Mean variations of umbilical resistance index (URI), cerebral resistance index (CRI), and cerebral/umbilical ratio (C/U) during malaria induced placental insufficiency. Changes expressed in % of the end crisis value. All change significant (P < 0:05) except for ‘‘URI 6 days’’ and ‘‘CRI 5–7 days’’).
probably in relation with the degradation of the vascular bed as observed and reported in previous studies [3–8]. Relatively high uterine resistance indices were also found but only in 41% of the pregnancies, which is in agreement
with other studies which reported the existence of placental lesion in 50% of cases [11–16]. The Uterine resistance at admission was not correlated either with the parasitemia grade, or the fetal cerebral and umbilical hemodynamic changes during the crisis, or with the crisis duration. Umbilical and cerebral resistance and C/U ratio became abnormal during the crisis in 24, 52, and 65% of the cases, respectively. During all crisis, umbilical resistance index increased, and cerebral resistance index decreased but the changes of one of these was higher than 10% in 32 out of the 46 cases (70%) and both indices were abnormal in 15% of the cases. This confirm that malaria triggers a fetal hemodynamic disturbance in all cases and that only the investigation of both umbilical and cerebral flows can detect it. As a response to the deterioration of the feto-maternal exchanges, a reduction of the cerebral vascular resistance by vasodilation was observed, which resulted in an increase in the cerebral perfusion and thus of oxygen supply. Previous studies on pregnancies complicated by hypertension showed that the C/U ratio which measures the flow redistribution, varies proportionally to the fetal pO2 [10–17]. As it decreases during malaria crisis one can only suggest that the fetal pO2 reduces during the crisis, as the fetal pO2 could not be measured during the crisis. The mean C/U value (1:13 0:17) at admission was close to the cut-off limit (1.1) which suggests that the level of hypoxia was not very
Fig. 2. Graphic representation of the Hypoxic index (HI) as induced by mild or severe malaria crisis. The area between the C/U ratio curve and the time axis is the Hypoxic index value. As the C/U ratio changes proportionately to the fetal pO2, this area represents the cumulated deficit in pO2 over the crisis. Note that HI (area) may increase by increasing the amplitude of the flow redistribution (%C/U on Oy axis) or by increasing the duration of the exposure to the flow redistribution (days on Ox axis). (HI ¼ 80 could correspond, for example to eight days with 10% pO2 reduction (8 10), or four days with 20% pO2 reduction (4 20); HI ¼ 200 could correspond, for example to 10 days with 20% pO2 reduction (10 20) or five days with 40% pO2 reduction (5 40)).
Table 3 Sensitivity, specificity, positive and negative predictive value for HI (Hypoxic index <150 or > 150), lowest C/U during the crisis (proportionate to the lowest level pO2; abnormal <1.1 or normal >1.1), crisis duration (< or >8 days) in predicting abnormal fetal heart rate (aFHR) Parameters
Sensitivity (%)
Specificity (%)
Positive predictive value (%)
Negative predictive value (%)
HI > 150 vs. abnormal FHR C/U < 1.1 vs. abnormal FHR Crisis duration > 8 days vs. abnormal FHR
83 45 48
88 82 84
71 81 71
94 47 66
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G. Carles et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 110 (2003) 136–142
Fig. 3. (a) Abnormal fetal heart rate (aFHR) vs. crisis duration (days). Note that crisis below eight days may lead both to either normal FHR or abnormal FHR at delivery. Thus, the duration of the crisis is not a reliable parameter for predicting abnormal FHR at delivery. (b) Abnormal fetal heart rate vs. Hypoxic index value. Note that most of the abnormal FHR are associated with Hypoxic index higher than 150, also the majority of normal FHR correspond to HI < 150. Thus, the HI is a reliable parameter for predicting (since the end of the crisis) abnormal FHR to occur at delivery days or weeks later.
low, but values equal or lower than 0.9 were found in 10 out of the 46 cases (39%) which lead to suspect that those fetuses were submitted to a drop in pO2 of more than 20% from cutoff limit. The C/U ratio has been tested on hypertensive pregnancies, on pregnancies with idiopathic growth restriction, and on twin pregnancies [18–20] and in all cases the sensitivity of this parameter (abnormal when <1.1) for the detection of intra-uterine growth restriction was comparable (sensitivity 85%, specificity 98%). This parameter was subsequently tested as a predictor of the occurrence of acute fetal distress at birth and of neonatal complications. In this application the sensitivity was of 90% for the C/U ratio, 78% for the cerebral index, and 80% for the umbilical index [20]. The present study confirms the superiority of the C/U ratio for detecting fetal vascular abnormalities associated with hypoxia. The minimum C/U ratio (<1.1) was used to predict the occurrence of FHR abnormalities at the end of gestation, but
the sensitivity (45%) and specificity (82%) of this parameter for predicting occurrence of aFHR was not very high (Table 3). Another factor for evaluating hypoxia is the mean C/U ratio variation during the crisis. This variation, expressed as a percentage of the normal value at the end of the crisis, measures the mean flow redistribution amplitude and thus the mean drop in pO2 [10,17]. The mean C/U variation during the crisis was of 9% 6 but this parameter did not predict occurrence of aFHR. Moreover, there was no direct relation between the amplitude of the C/U ratio variation and the following data: grade of parasitemia, parity, gestational age at crisis, date and mode of delivery, fetal weight. The duration of the crisis was partially correlated with aFHR at delivery but the sensitivity of the crisis duration (>8 days) for predicting aFHR was rather modest (48%) (Table 3). One may notice that the distribution range of the crisis duration (8 3:2 days) was rather large. On the other hand there was no correlation between the crisis
G. Carles et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 110 (2003) 136–142
duration and the increase in placental resistance or decrease in cerebral resistance. The Hypoxic index, combining both the amplitude of the C/U ratio variation (porportional to fall in pO2) and the crisis duration (flow redistribution duration i.e. period with C/U < 1:1) has thus been calculated and tested as a factor for predicting aFHR at delivery. The mean Hypoxic index (% change of C/U ratio crisis duration in days) is supposed to represent the cumulated lack of pO2. Thus, a Hypoxic index ¼ 80 could correspond, for example to eight days with 10% pO2 reduction (8 10), or four days with 20% pO2 reduction (4 20). A Hypoxic index ¼ 200 could correspond, for example to 10 days with 20% pO2 reduction (10 20) or five days with 40% pO2 reduction (5 40) (Fig. 2). Only crises of long duration and with substantial C/U decrease (flow redistribution) can provide a HI > 150. The limit of 150 was found retrospectively on a populations of pregnancies complicated by hypertension (personal unpublished data) and tested in the present study (Tables 1 and 2). In fact, the Hypoxic index when higher than 150 was the best parameter for predicting the occurrence of aFHR in both acute and chronic placenta insufficiency. The Hypoxic index (>150) predicted the occurrence of aFHR with a high sensitivity and specificity (83 and 88%) (Table 3). Lastly even the short crisis were less frequently associated with aFHR than long crisis, the duration of the crisis was not sufficient to predict aFHR at delivery. Only the HI was found to be a good predictor of such functional abnormality. There was no severe fetal distress at delivery and no sign of neurological handicap after delivery which supports the hypothesis that consequences of the transient hypoxia induced by malaria are limited to functional disturbances like aFHR. On the other hand the transient placental insufficiency (i.e. hypoxia) had a limited effect on the fetal growth (17% of the cases between 5 and 10 centile). Moreover, the duration of the crisis was not correlated with the degree of growth restriction. This observation is in agreement with the fact that the crisis took place several weeks before delivery, a period of time during which the fetus could have a normal growth, even if part of the fetal physiological systems (autonomic nervous system) did not recover in between. The crisis duration, the amplitude of the fetal flow redistribution, and the occurrence of abnormal FHR were not correlated with the gestational age at which the crisis occurred. Moreover, the parasitemia grade was not related to the gestational age. These observations suggest that the capacity of the fetus to respond to acute hypoxia and the vulnerability of the fetal physiological functions were similar between 27 and 36 weeks. Thus, one may have to consider that the capacity of the fetus to respond to hypoxia is not influenced by the development or the maturation of its nervous system. In the population studied, malaria affected multiparas and primiparas equally, which tends to show that successive pregnancies do not induce any protection against malaria.
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Moreover, the crisis with short-duration flow redistribution were not necessarily those who were treated before three days of crisis. Thus, only the absence of large and extended flow redistribution as measured by cerebral and umbilical Doppler, can guaranty that the fetus will not be severely affected by the maternal malaria infection. This idea is supported by the fact that fetal flow redistribution towards the brain do not prevent against brain damage if the flow redistribution period exceed some weeks [21,22].
5. Conclusion Close monitoring of the fetal circulation by Doppler during an acute and reversible placenta insufficiency allow to measure the duration and the amplitude of the induced fetal vascular disturbance, which can predict the consequences of this aggression on the fetal development and outcome.
Acknowledgements This work was supported by INSERM (Institut National de la Sante et de la Recherche Medicale) and CNES (Centre National d’Etudes spatiales) Tele-Medecine grants.
References [1] Adamson SL, Morrow RJ, Langille BL. Site-dependent effects of increases in placental vascular resistance on the umbilical arterial velocity waveform in fetal sheep. Ultrasound Med Biol 1990;16(1):19–27. [2] Maulik D, Yarlagadda P, Nathanielsz PW. Hemodynamic validation of Doppler assessment of feto-placental circulation in a sheep model system. J Ultrasound Med 1989;8:177–81. [3] Brar HS, Platt LD. Reverse end-diastolic flow on umbilical artery velocimetry in high-risk pregnancies: an ominous finding with adverse pregnancy outcome. Am J Obstet Gynecol 1988;159: 559–61. [4] Cameron AD, Nicholson SF, Nimrod CA, Harder JR, Davies DM. Doppler waveforms in the fetal aorta and umbilical artery in patients with hypertension in pregnancy. Am J Obstet Gynecol 1988;158: 339–45. [5] Fleischer A, Schulmann M, Farmakides G. Umbilical artery velocity waveform and intra-uterine growth retardation. Am J Obstet Gynecol 1995;151:50–505. [6] Trudinger BJ, Giles WB, Cook CM. Fetal umbilical artery flow velocity waveforms and placental resistance: clinical significance. Br J Obstet Gynaecol 1985a;92:20–3. [7] Arbeille Ph. Cerebral Doppler in the assessment of the IUGR, and the fetal hypoxia. J Matern Fetal Invest 1991;1:51–6. [8] Arbeille P, Maulik D, Fignon A, Stale H, Bodard S, Locatelli A. Assessment of the fetal pO2 changes by cerebral and umbilical Doppler on lamb fetuses during acute hypoxia. Ultrasound Med Biol 1995;21(7):861–70. [9] Menendez C. Malaria during pregnancy: a priority area of malaria research and control. Parasitol Today 1995;11:178–83. [10] Galbraith RM, Fox H, His B, Galbraith GMP, Bray RS, Faulk WP. The human materno-fetal relationship in malaria. II. Histological,
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[16] Arbeille P, Maulik D, Stree JL, Amyel C, Deufel M. Fetal renal, and cerebral Doppler in small for gestational age fetuses in hypertensive pregnancies. Eur J Obstet Gyn Reprod Biol 1994;56:111–6. [17] Wladimiroff JW, van de Wijngaard JA, Degani S. Cerebral and umbilical arterial blood flow velocity waveform in normal and growth retarded pregnancies. Obstet Gynaecol 1987;69:705–9. [18] Gramellini D, Folli MC, Raboni S, Vadora E, Merialdi M. Cerebral– umbilical Doppler ratio as predictor of adverse outcome. Obstet Gynecol 1992;79:416–20. [19] Fignon A, Salihagic A, Akoka S, Laurini R, Arbeille P. Twenty days cerebral, twenty days cerebral & umbilical Doppler monitoring on a growth retarded & hypoxic fetus. Eur J Obst Gyn Reprod Biol 1996;66:83–6. [20] Arbeille P, Maulik D, Salihagic A, Locatelli A, Lansac J, Platt LD. Effect of long term cocaine administration to pregnant ewes on the fetal hemodynamics, oxygenation, and growth. Obstet Gynecol 1997;90:795–802.
Acute reversible placental dysfunction and abnormal fetal heart rate at delivery Gabriel Carlesb, Nathalie Tobala, Henri Marreta, Philippe Arbeillea,* a
Inserm 316, Department of Medecine Nucle´aire & Ultrasons, CHU Trousseau, 37044 Tours, France b Sce. Obstet. & Gyne´col., Hopital Andre´-Bouron, St. Laurent du Maroni, French Guiana, France Received 31 May 2002; accepted 8 January 2003
Abstract Acute placental dysfunction induced by malaria is characterized by umbilical artery resistance increase and cerebral artery resistance decrease during the crisis. The objective was to evaluate the sensitivity and specificity of fetal Doppler indices and crisis duration for predicting abnormal fetal heart rate (aFHR) at delivery several weeks after the crisis. Method: Every day during the crisis, the umbilical and cerebral resistance indices were measured by Doppler. These indices allowed evaluation of the amplitude of the fetal flow redistribution (C/U ¼ cerebral resistance/umbilical resistance ratio), the duration of the flow redistribution period (i.e. crisis duration) and the Hypoxic index (HI) (mean %C/U change crisis duration). Results: Population: 46 pregnancies. Mean duration of the flow redistribution period 8 3:2 days, mean C/U change 9% 6; Hypoxic index 86 75; prematures 48%; aFHR 30%). Hypoxic index >150 predicted occurrence of aFHR with high sensitivity and specificity (83%/88%). The presence of abnormal flow distribution (C/U < 1:1) and the duration of the period with flow disturbance (>8 days) predicted aFHR at delivery with a sensitivity of 45 and 48% and a specificity of 82 and 84%. Conclusion: The Hypoxic index was more predictive of aFHR at delivery than the amplitude or the duration of the fetal flow redistribution triggered by placental insufficiency. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Malaria; Fetus; Doppler; Hypoxia; Heart rate
1. Introduction Chronic and sustained placental insufficiency often develop during pregnancy complicated by hypertension. Such insufficiency trigger fetal flow redistribution and is generally associated with premature birth and growth retardation, and risk of cerebral lesions of hypoxic origin. Doppler examination of the fetal blood vessels is widely used to confirm the existence of hemodynamic abnormalities at the placental level accompanying intra-uterine growth restriction, and to evaluate the cerebral vascular response to hypoxia. Several studies have shown the usefulness of the umbilical and cerebral resistance indices in the detection of intra-uterine growth restriction and hypoxia [1–10]. Acute and reversible placental insufficiency appears during malaria infection. The placenta acts as a filter by retaining the parasitized blood red cells. This infestation
*
Corresponding author. Tel.: þ33-2-4747-5939; fax: þ33-2-4747-5913; mobile: þ33-6-8010-5488. E-mail address: [email protected] (P. Arbeille).
causes a deterioration of the placenta consisting of: degeneration of the chorionic villi, formation of deposits of fibrin and malarial pigment, thickening of the basement membrane, and accumulation of macrophages in the intervillous space [11–16]. Malarial placental lesions result in a temporary and reversible decrease in feto-placental exchange. In early pregnancy, a severe acute hypoxia may be observed, which induces abortion or death of the fetus. Later on in the pregnancy, malaria crisis of long duration (1 week or more) may be associated with prematurity and abnormal fetal heart rate (aFHR) at delivery. As the crisis occurs several weeks before delivery one may suggest that their might be a relationship between the crisis characteristics (duration, hemodynamic disturbance, level of hypoxia, . . .) and the fetal outcome. The objective was (a) to evaluate the sensitivity and specificity of fetal Doppler indices for the prediction of abnormal fetal heart rate at delivery several weeks after the episode of acute placental insufficiency (malaria crisis), (b) to compare with the performances of the duration of the period with flow disturbance (i.e. crisis duration) for predicting aFHR.
0301-2115/$ – see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0301-2115(03)00089-7
G. Carles et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 110 (2003) 136–142
2. Materials and methods 2.1. Population The study, designed as a prospective and observational one, was carried out in the obstetric department of a government hospital in French Guiana. The population consisted of 46 pregnancies, all complicated by a malaria infection (Plasmodium falciparum). 2.2. Protocol The Hospital at Saint Laurent du Maroni (French Guiana) receives a substantial number of pregnancies complicated by malaria. These gestations originate from the inhabited areas distributed along the Maroni River. At the first clinical signs of malaria infection, the gravidas were treated and transferred to the obstetrics department at the Hospital. Admission of the cases and the monitoring of the growth and fetal circulation by ultrasound and Doppler were carried out according to a well-defined protocol: Doppler investigation consisted of uterine, umbilical, and cerebral arteries recording at admission, then cerebral and umbilical arteries recording every day during the crisis. Echography for examination of the placenta and amniotic fluid volume, and fetal biometry were performed every two days. This protocol started at admission and was continued until the end of the crisis (remission of the clinical, hematological, and hemodynamic signs). The diagnosis of malaria was based on the presence of fever, and the detection of parasitized cell in the maternal blood. The maternal blood analysis was performed every day during the crisis, and the treatment was stopped when no more parasites were present. After leaving the hospital, the gravida was seen as regularly as possible and at each visit underwent a complete ultrasound-Doppler examination. Following delivery, the perinatal data were collected. 2.3. Fetal hemodynamic data The uterine vascular resistance indices were measured at admission only, no notch was noticed. The distribution of the fetal flows (between the placental and cerebral regions) was evaluated using the cerebral–umbilical resistance ratio (C/U), which is the ratio between the cerebral and umbilical resistance indices [9,10]. This parameter is always greater than 1.1 during normal pregnancy but decreases in the case of hypoxia due to the umbilical resistance increase (increase placental resistance) and cerebral resistance decrease (cerebral vasodilation) [9]. The C/U ratio decreases proportionally with the fetal partial pressure of oxygen [pO2] and its minimum absolute value is proportional to the lowest level of the fetal pO2 [10,17]. In addition, it is not dependent on the fetal heart rate (as are the other Doppler indices), and has a cut-off limit between the normal and pathological zones which is constant throughout gestation and equal to 1.1 at least from 25 to 40 weeks.
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The variation of the C/U ratio was expressed as a percentage compared to the normal value measured at the end of the crisis (remission of clinical and hematological signs). The Hypoxic index (HI) has been calculated from the mean variation in the C/U ratio (%C/U) during the crisis and the crisis duration (in days): Hypoxic index ¼ (mean %C/U change) (crisis duration). The decrease of the C/U ratio has been found to represents the decrease in fetal pO2, in animal model and human cases [10,17]. Thus, the area between the C/U ratio curve and the time axis represents the cumulated deficit in pO2 during the crisis. Therefore, the Hypoxic index combines information on the amplitude of the flow redistribution towards the brain (i.e. pO2 decrease), and the duration of the exposure to hypoxia. The cut-off value of 150 for the Hypoxic index was found on a retrospective study on pregnancies complicated by hypertension (personal unpublished data) and tested on the present study. At each daily Doppler examination we measured the umbilical and cerebral resistances, and then C/U ratio. The Hypoxic index was calculated at the end of the crisis. Doppler examinations were performed by the two obstetricians in charge of the pregnancies, using a Hitachi EUB 44. 2.4. Perinatal data The Doppler data were compared with the fetal and maternal perinatal data: fetal heart rate (FHR) monitoring at delivery, gestational age at delivery and type of delivery, Apgar score at 5 min and fetal weight after delivery, maternal parasitemia (grades 1–5), parity of the gravida, date of the onset of the crisis, crisis duration, number of days before treatment. The FHR patterns were defined as abnormal when one of the following was detected: persistent late deceleration, recurrent severe variable deceleration, prolonged deceleration, or loss of variability. FHR traces were evaluated blindly by the two obstetricians. The Apgar score at 5 min was considered as pathological when lower than 7. The parasitemia grade represents the concentration of parasitis/ mm3 of maternal blood (grade 1: 0–1000; grade 2: 1000– 2500; grade 3: 2500–10,000; grade 4: 10,000–50,000; grade 5: >50,000). Normal delivery was defined as at-term delivery, without any signs of fetal distress or maternal complication. Cesarean section were decided for fetal distress, dystocia, or maternal complication. 2.5. Data processing The Doppler parameters were calculated using frequency cursors for detecting systole and en diastolic amplitude on the Doppler spectrum, and averaged over 10 cardiac cycles. The Doppler parameters were compared with the fetal and maternal perinatal data. Normal or abnormal Doppler data were compared with the occurrence of abnormal fetal heart rate, prematurity, cesarean section, abnormal Apgar score at 1 min, using a chi-square test. The Doppler values were compared with the duration of the crisis (days), the grade of
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parasitemia (1–5), the date of the crisis, the number of days before treatment using a Mann–Whitney non-parametric test. The limit for significance was set at P ¼ 0:05. The ability of the Doppler parameters (minimal C/U, HI) and the crisis duration to predict the occurrence of aFHR was expressed in terms of sensitivity, specificity, positive and negative predictive values.
3. Results The duration of the study was three years. One hundred pregnancies complicated by malaria were investigated, but the complete Doppler and clinical data needed for the study were collected in only 46 of them. The other pregnancies, assessed by Doppler during their stay at the hospital, returned to their villages, and their deliveries could not be monitored. Perinatal data are presented in Table 1. The fetal umbilical and cerebral Doppler traces were successfully recorded at each daily Doppler session. Doppler data at admission, and percentage changes of these parameters during the crisis are presented in Table 2. Fig. 1 shows the mean umbilical resistance increase (in %) and cerebral resistance and C/U ratio decrease. Fig. 2 gives examples of low HI (<150) and high HI (>150) as found in mild or severe malaria crisis. Fig. 3 shows the correspondence between HI or crisis duration and aFHR. Sensitivity, specificity, positive predictive and negative predictive values of the lowest C/U absolute value (abnormal when <1.1), crisis duration (>8days), Hypoxic index (>150) for predicting abnormal fetal heart rate at delivery are presented in Table 3. There was no significant correlation between the amplitude of the redistribution of the fetal flows (mean %C/U ratio variations), or the Hypoxic index, and the following
Table 1 Maternal and fetal parameters Parameters
Crisis (n ¼ 46)
Age (years, mean S.D.) Parity (mean S.D.) Crisis gestational age (years, mean S.D.) Crisis duration (days, mean S.D.) Days before treatment (mean S.D.) Parasitemia grade (mean S.D.) Delivery (weeks, mean S.D.) Cesarean section Oligoamnios during crisis Abnormal FHR Apgar score < 7 at 5 min Premature Intra-uterine growth retardation (<10 centile)
23 2.5 32 31.4 3.6 8 3.2 3 1.5 31 36 3 8 (17) 16 (35) 14 (30) 13 (28) 22 (48) 8 (17)
Values given in parenthesis are in percentage.
parameters: the grade of parasitemia, the parity of the pregnancy, the gestational age at the time of the crisis, the number of days before treatment, the gestational age at delivery, the mode of delivery, the time between crisis and delivery, the fetal weight at birth. The Hypoxic index (>150) predicted abnormal FHR at delivery with a good sensitivity and specificity. Conversely the lowest C/U value (<1.1) and crisis duration (>8days) did not predict aFHR with a good sensitivity nor specificity (Table 3).
4. Discussion The fetal Doppler performed during the crisis showed that the malarial infection induced a range of transient hemodynamic changes at the placental and cerebral level. In all cases, there was an increase of the umbilical resistance,
Table 2 Doppler data at admission and during the crisis Doppler at admission Uterine resistance index (UTRI) at admission (mean S.D.) Cerebral/umbilical (C/U ¼ CRI/URI) ratio at admission (mean S.D.) Umbilical resistance index (URI) at admission (mean S.D.) Cerebral resistance index (CRI) at admission (mean S.D.) Doppler changes during crisis Abnormal uterine resistance (UTRI) index Abnormal umbilical resistance (URI) index Abnormal cerebral resistance (CRI) index Both URI & CRI abnormal Abnormal cerebral/umbilical (C/U) ratio Cerebral/umbilical (C/U) ratio decrease >10% Lowest cerebral/umbilical (C/U) ratio in crisis (mean S.D.) Largest cerebral/umbilical (C/U) ratio decrease (mean S.D.) Days with flow redistribution (C/U < 1.1, mean S.D.) % Cerebral/umbilical (C/U) change during the crisis (mean S.D.) Hypoxic index (HI, mean S.D.) Values given in parenthesis are in percentage.
Crisis (n ¼ 46) 0.47 1.13 0.67 0.75
0.08 0.17 0.08 0.08
19 (41) 11 (24) 24 (52) 7 (15) 30 (65) 32 (70) 1.02 0.14 18 8.5 8 3.2 9 6 86 75
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Fig. 1. Mean variations of umbilical resistance index (URI), cerebral resistance index (CRI), and cerebral/umbilical ratio (C/U) during malaria induced placental insufficiency. Changes expressed in % of the end crisis value. All change significant (P < 0:05) except for ‘‘URI 6 days’’ and ‘‘CRI 5–7 days’’).
probably in relation with the degradation of the vascular bed as observed and reported in previous studies [3–8]. Relatively high uterine resistance indices were also found but only in 41% of the pregnancies, which is in agreement
with other studies which reported the existence of placental lesion in 50% of cases [11–16]. The Uterine resistance at admission was not correlated either with the parasitemia grade, or the fetal cerebral and umbilical hemodynamic changes during the crisis, or with the crisis duration. Umbilical and cerebral resistance and C/U ratio became abnormal during the crisis in 24, 52, and 65% of the cases, respectively. During all crisis, umbilical resistance index increased, and cerebral resistance index decreased but the changes of one of these was higher than 10% in 32 out of the 46 cases (70%) and both indices were abnormal in 15% of the cases. This confirm that malaria triggers a fetal hemodynamic disturbance in all cases and that only the investigation of both umbilical and cerebral flows can detect it. As a response to the deterioration of the feto-maternal exchanges, a reduction of the cerebral vascular resistance by vasodilation was observed, which resulted in an increase in the cerebral perfusion and thus of oxygen supply. Previous studies on pregnancies complicated by hypertension showed that the C/U ratio which measures the flow redistribution, varies proportionally to the fetal pO2 [10–17]. As it decreases during malaria crisis one can only suggest that the fetal pO2 reduces during the crisis, as the fetal pO2 could not be measured during the crisis. The mean C/U value (1:13 0:17) at admission was close to the cut-off limit (1.1) which suggests that the level of hypoxia was not very
Fig. 2. Graphic representation of the Hypoxic index (HI) as induced by mild or severe malaria crisis. The area between the C/U ratio curve and the time axis is the Hypoxic index value. As the C/U ratio changes proportionately to the fetal pO2, this area represents the cumulated deficit in pO2 over the crisis. Note that HI (area) may increase by increasing the amplitude of the flow redistribution (%C/U on Oy axis) or by increasing the duration of the exposure to the flow redistribution (days on Ox axis). (HI ¼ 80 could correspond, for example to eight days with 10% pO2 reduction (8 10), or four days with 20% pO2 reduction (4 20); HI ¼ 200 could correspond, for example to 10 days with 20% pO2 reduction (10 20) or five days with 40% pO2 reduction (5 40)).
Table 3 Sensitivity, specificity, positive and negative predictive value for HI (Hypoxic index <150 or > 150), lowest C/U during the crisis (proportionate to the lowest level pO2; abnormal <1.1 or normal >1.1), crisis duration (< or >8 days) in predicting abnormal fetal heart rate (aFHR) Parameters
Sensitivity (%)
Specificity (%)
Positive predictive value (%)
Negative predictive value (%)
HI > 150 vs. abnormal FHR C/U < 1.1 vs. abnormal FHR Crisis duration > 8 days vs. abnormal FHR
83 45 48
88 82 84
71 81 71
94 47 66
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Fig. 3. (a) Abnormal fetal heart rate (aFHR) vs. crisis duration (days). Note that crisis below eight days may lead both to either normal FHR or abnormal FHR at delivery. Thus, the duration of the crisis is not a reliable parameter for predicting abnormal FHR at delivery. (b) Abnormal fetal heart rate vs. Hypoxic index value. Note that most of the abnormal FHR are associated with Hypoxic index higher than 150, also the majority of normal FHR correspond to HI < 150. Thus, the HI is a reliable parameter for predicting (since the end of the crisis) abnormal FHR to occur at delivery days or weeks later.
low, but values equal or lower than 0.9 were found in 10 out of the 46 cases (39%) which lead to suspect that those fetuses were submitted to a drop in pO2 of more than 20% from cutoff limit. The C/U ratio has been tested on hypertensive pregnancies, on pregnancies with idiopathic growth restriction, and on twin pregnancies [18–20] and in all cases the sensitivity of this parameter (abnormal when <1.1) for the detection of intra-uterine growth restriction was comparable (sensitivity 85%, specificity 98%). This parameter was subsequently tested as a predictor of the occurrence of acute fetal distress at birth and of neonatal complications. In this application the sensitivity was of 90% for the C/U ratio, 78% for the cerebral index, and 80% for the umbilical index [20]. The present study confirms the superiority of the C/U ratio for detecting fetal vascular abnormalities associated with hypoxia. The minimum C/U ratio (<1.1) was used to predict the occurrence of FHR abnormalities at the end of gestation, but
the sensitivity (45%) and specificity (82%) of this parameter for predicting occurrence of aFHR was not very high (Table 3). Another factor for evaluating hypoxia is the mean C/U ratio variation during the crisis. This variation, expressed as a percentage of the normal value at the end of the crisis, measures the mean flow redistribution amplitude and thus the mean drop in pO2 [10,17]. The mean C/U variation during the crisis was of 9% 6 but this parameter did not predict occurrence of aFHR. Moreover, there was no direct relation between the amplitude of the C/U ratio variation and the following data: grade of parasitemia, parity, gestational age at crisis, date and mode of delivery, fetal weight. The duration of the crisis was partially correlated with aFHR at delivery but the sensitivity of the crisis duration (>8 days) for predicting aFHR was rather modest (48%) (Table 3). One may notice that the distribution range of the crisis duration (8 3:2 days) was rather large. On the other hand there was no correlation between the crisis
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duration and the increase in placental resistance or decrease in cerebral resistance. The Hypoxic index, combining both the amplitude of the C/U ratio variation (porportional to fall in pO2) and the crisis duration (flow redistribution duration i.e. period with C/U < 1:1) has thus been calculated and tested as a factor for predicting aFHR at delivery. The mean Hypoxic index (% change of C/U ratio crisis duration in days) is supposed to represent the cumulated lack of pO2. Thus, a Hypoxic index ¼ 80 could correspond, for example to eight days with 10% pO2 reduction (8 10), or four days with 20% pO2 reduction (4 20). A Hypoxic index ¼ 200 could correspond, for example to 10 days with 20% pO2 reduction (10 20) or five days with 40% pO2 reduction (5 40) (Fig. 2). Only crises of long duration and with substantial C/U decrease (flow redistribution) can provide a HI > 150. The limit of 150 was found retrospectively on a populations of pregnancies complicated by hypertension (personal unpublished data) and tested in the present study (Tables 1 and 2). In fact, the Hypoxic index when higher than 150 was the best parameter for predicting the occurrence of aFHR in both acute and chronic placenta insufficiency. The Hypoxic index (>150) predicted the occurrence of aFHR with a high sensitivity and specificity (83 and 88%) (Table 3). Lastly even the short crisis were less frequently associated with aFHR than long crisis, the duration of the crisis was not sufficient to predict aFHR at delivery. Only the HI was found to be a good predictor of such functional abnormality. There was no severe fetal distress at delivery and no sign of neurological handicap after delivery which supports the hypothesis that consequences of the transient hypoxia induced by malaria are limited to functional disturbances like aFHR. On the other hand the transient placental insufficiency (i.e. hypoxia) had a limited effect on the fetal growth (17% of the cases between 5 and 10 centile). Moreover, the duration of the crisis was not correlated with the degree of growth restriction. This observation is in agreement with the fact that the crisis took place several weeks before delivery, a period of time during which the fetus could have a normal growth, even if part of the fetal physiological systems (autonomic nervous system) did not recover in between. The crisis duration, the amplitude of the fetal flow redistribution, and the occurrence of abnormal FHR were not correlated with the gestational age at which the crisis occurred. Moreover, the parasitemia grade was not related to the gestational age. These observations suggest that the capacity of the fetus to respond to acute hypoxia and the vulnerability of the fetal physiological functions were similar between 27 and 36 weeks. Thus, one may have to consider that the capacity of the fetus to respond to hypoxia is not influenced by the development or the maturation of its nervous system. In the population studied, malaria affected multiparas and primiparas equally, which tends to show that successive pregnancies do not induce any protection against malaria.
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Moreover, the crisis with short-duration flow redistribution were not necessarily those who were treated before three days of crisis. Thus, only the absence of large and extended flow redistribution as measured by cerebral and umbilical Doppler, can guaranty that the fetus will not be severely affected by the maternal malaria infection. This idea is supported by the fact that fetal flow redistribution towards the brain do not prevent against brain damage if the flow redistribution period exceed some weeks [21,22].
5. Conclusion Close monitoring of the fetal circulation by Doppler during an acute and reversible placenta insufficiency allow to measure the duration and the amplitude of the induced fetal vascular disturbance, which can predict the consequences of this aggression on the fetal development and outcome.
Acknowledgements This work was supported by INSERM (Institut National de la Sante et de la Recherche Medicale) and CNES (Centre National d’Etudes spatiales) Tele-Medecine grants.
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