Perinatal outcomes and maternal clinical characteristics in IUGR with absent or reversed end-diastolic flow velocity in the umbilical artery

Abstract

Purpose

The aim of this study was to evaluate the effect of absent or reversed end-diastolic umbilical artery Doppler flow on neonatal outcome independent of oligohydramnios, gestational age, and maternal factors.

Methods

From January 2004 to March 2010 we reviewed 76 cases at our hospital, which were diagnosed with intrauterine growth restriction (IUGR). Among those cases, the existence of absent or reversed end-diastolic velocity of umbilical artery (AEDV) was considered abnormal. We set the group that had no abnormal signs as the control group (57 cases), and compared it with the AEDV group (19 cases). Logistic regression was used to control for oligohydramnios and gestational age.

Results

The gestational age was lower in the AEDV group compared to that of the control group. Neonatal weight, platelet count were also lower in the AEDV group and serum SGOT level, the frequency of non-reassuring fetal heart beat pattern were higher in AEDV group compared to that of the control group independent of gestational age. Perinatal outcomes such as Apgar score at 1 min below 4, use of a ventilator, admission to the neonatal intensive care unit (NICU), respiratory disease, neurologic disease, neonatal sepsis, anemia, thrombocytopenia, and neonatal mortality were statistically less favorable in the AEDV group compared to those in the control group independent of gestational age and presence of oligohydramnios. There were more intrauterine fetal death histories and preeclampsia in the AEDV group compared the control group.

Conclusion

The waveform of umbilical artery Doppler velocity is an informative parameter of perinatal outcomes independent of gestational age or the presence of oligohydramnios in IUGR patients. It is especially important to check the waveform of umbilical artery Doppler velocity in IUGR patients with preeclampsia and IUGR patients with FDIU history.

Introduction

The definition of intrauterine growth restriction (IUGR) is the failure to reach the growth potential diagnosed by serial ultrasonographic scan [1]. The standard varies depending on the investigator and cases whose estimated fetal weight by ultrasonography is lower than the 10th to 3rd percentile of the weight based on gestational age has been used as the cutoff for intrauterine growth restriction.

In intrauterine growth restriction, the incidence of intrauterine fetal death, birth asphyxia, meconium aspiration, neonatal hypoglycemia, and hypothermia is elevated [2], and thus the perinatal morbidity and mortality is increased. The cause of intrauterine growth restriction which ranges from fetal chromosomal abnormality, fetal deformity, infection, to maternal diseases, and, etc., is very diverse and therefore difficult to elucidate in many cases. Utero-fetal circulation insufficiency due to increased vascular resistance develops secondarily to these causes excluding fetal chromosomal abnormality and infection, utero-placental circulation resulting in intrauterine growth restriction. Therefore, evaluating the condition of the fetus, umbilical arterial Doppler flow becomes a useful index [3]. It is widely known that the absent or reversed end-diastolic flow velocity of the umbilical artery shown in the Doppler velocity pattern is associated with chronic fetal growth restriction, chronic fetal hypoxic condition, acidemia, increase of perinatal mortality, and other perinatal complications [4, 5]. Nevertheless, the absent or reversed end-diastolic flow velocity of the umbilical artery does not appear in all fetuses showing intrauterine growth restriction, and concurrent oligohydramnios and preterm birth may complicate effect of the flow velocity of the umbilical artery.

In our study, we investigated the effect of absent or reversed end-diastolic flow velocity of the umbilical artery on perinatal outcomes independent of oligohydramnios and gestational age.

Materials and methods

The research subjects

This study was a retrospective study. Among 3,919 women delivered in the Department of Obstetrics at the Catholic university, Saint Vincent hospital, from 1 January 2004 to 31 March 2010, 76 patients diagnosed as intrauterine growth restriction whose umbilical arterial blood flow was measured within 1 week prior to delivery were included. The study subjects were divided into two groups: the group with intrauterine growth restriction as well as the absent or reversed end-diastolic flow velocity of the umbilical artery (AEDV group, 19 cases) and the group with intrauterine growth restriction alone (control group, 57 cases). The study was approved by the clinical study medical ethics committee (VC10E1S10035).

Research methods

Based on the review of medical records, the age, parity, delivery methods, the past history of mother (intrauterine fetal death, recurrent miscarriages, preeclampsia, preterm delivery), diseases associated with pregnancy (preeclampsia, gestational diabetes, preterm labor) and oligohydramnios were noted. Preeclampsia was defined as gestational hypertension (systolic pressure of ≥140 mmHg or diastolic blood pressure of ≥90 mmHg on two or more occasions after gestational week 20) with proteinuria (≥0.3 g/day or ≥dipstick 1+). Gestational diabetes was confirmed by 100 g oral glucose tolerance test. Preterm birth was defined as giving birth before gestational age 37). In order to compare the prognosis of neonates, gestational age, the presence or absence of fetal distress, intrauterine fetal death, neonatal birth weight, the gender of neonate, 1- and 5-min Apgar scores, and the umbilical arterial and venous pH were examined. The development of hyperbilirubinemia, use of mechanical ventilation, presence of cardiovascular, neurological, gastrointestinal hematological, or respiratory abnormalities, and the presence of sepsis were used as markers of neonatal complications. Intrauterine growth restriction, according to the definition of Seeds et al. [6], based on the weight of the corresponding gestational week, was defined as weight lower than fifth percentile, and the umbilical arterial blood flow velocity was measured avoiding the cord area close to placental origin. Neonatal anemia was defined as hemoglobin (Hb) less than 14.5 g/dL, and thrombocytopenia was defined as platelets count lower than 150,000 (109/L). Apnea, respiratory distress syndrome (RDS), pneumonia, transient tachypnea (TTN), and pulmonary hemorrhage were classified as respiratory diseases. RDS was diagnosed when a blood gas analysis shows low oxygen and excess acid in the body fluids and a chest X-ray shows have a characteristic “ground glass” appearance. Patent ductus arteriosus (PDA), atrial septal defect (ASD), interventricular septal defect (VSD), coarctation of aorta, and supraventricular tachycardia were classified as heart diseases. Gastroesophageal reflux, upper GI hemorrhage, meconium ileus, Hirschsprung’s disease, and cases with omental necrosis were classified as gastrointestinal tract diseases. Cerebral hemorrhage and facial nerve palsy were classified as diseases of the nervous system. Oligohydramnios was defined according to the four-quadrant technique used by Phelan et al. [7] as amniotic fluid index (AFI) of less than 5. A 3.5 MHz ultrasonography (ACCUVIX XQ-3D, Medison, Korea) was used for the measurement of the size of fetus, amniotic fluid index, and umbilical arterial flow velocity. All observations were made by one author.

Statistical methods

For statistical analysis, the SAS version 8 (SAS institute Inc, USA) was used. In examining the difference of maternal age, independent t test was performed. For the difference of parity and gestational age, the non-parametric method, Mann–Whitney test was applied. To assess the difference of maternal past history and incidence of diseases associated with pregnancy, Fisher exact test was used. For comparison of the mean value of neonatal weight, 1-min Apgar score, 5-min Apgar score, umbilical arterial and venous pH, the period of admission to neonatal intensive care, and values of neonatal blood tests, the gestational age was adjusted by ANCOVA. On analysis of the difference of disease incidence between the two groups of gestational age, the presence or absence of oligohydramnios, and the age of mother were adjusted for using logistic regression analysis. Cases with p < 0.05 were determined as statistically significant.

Results

The maternal characteristics of the AEDV group and the control group were compared. The maternal age was 31.95 ± 4.28 and 31.82 ± 4.31 years, and parity was 0.89 ± 0.94 and 0.74 ± 0.92, respectively. Statistically significant differences between the two groups were not detected. Histories of preterm labor, recurrent miscarriages, and preeclampsia between the two groups were not statistically significantly different. Nonetheless, the incidence of previous intrauterine fetal death was 3/19 (15.8%) and 0/57 (0%), respectively, and a significant difference between the two groups was observed (p = 0.014). The incidence of previous total maternal obstetric disease of the two groups was 3/19 (15.8%) and 0/57 (0%), and a statistically significant difference was shown (p = 0.014).

The incidence of preeclampsia during present pregnancy was 68.4 and 35.1%, respectively, and a statistically significant difference was shown (p = 0.016). Other diseases were not statistically different. The incidence of all diseases associated with pregnancy was 84.2 and 52.6%, respectively, and statistically different (p = 0.016).

In comparison to the neonatal characteristics, gestational age at the time of delivery was 32.02 ± 3.23 and 36.96 ± 1.71 weeks, respectively, and it was statistically significantly different (p = 0.000). The incidence of unstable fetal heart beat pattern was 14/19 (73.7%) and 9/57 (15.8%), and it was statistically different (p = 0.000). Nevertheless, the ratio of male to female was not different. At the time of birth, neonatal weight was 1.15 ± 0.38 and 2.04 ± 0.49 kg (p = 0.003), the neonatal platelet count was 150.06 ± 87.83 (109/L) and 199.59 ± 58.15 (109/L) (p = 0.01), serum SGOT was 79.33 ± 156.25 and 44.32 ± 37.28 IU/L (p = 0.035), respectively, and they were statistically different even after adjustment for gestational age. Nonetheless, 1-min Apgar score, 5-min Apgar score, umbilical arterial and venous pH, neonatal hemoglobin (Hb), hematocrit (Hct), serum SGPT, and the duration of admission in neonatal intensive care were not significantly different.

In comparison to the incidence of neonatal complications, the presence or absence of oligohydramnios and gestational weeks at birth were adjusted using logistic regression analysis. The results showed that 1-min Apgar score of lower than 4 (OR = 24.883, p = 0.004), endotracheal intubation (OR = 6.839, p = 0.005), with or without admission to neonatal intensive care unit (OR = 8.471, p = 0.002), respiratory diseases (OR = 4.828, p = 0.022), diseases in the nervous system (OR = 23.748, p = 0.021), neonatal sepsis (OR = 14.933, p = 0.020), anemia (OR = 6.453, p = 0.019), thrombocytopenia (OR = 5.392, p = 0.005), neonatal morbidity (OR = 24.829, p = 0.003), and neonatal mortality (OR = 31.571, p = 0.002) showed statistically significant differences. There were no statistically significant differences in the incidence of 5-min Apgar score of less than 4 gastrointestinal diseases, heart diseases, neonatal disseminated intravascular coagulation disorder, hypoglycemia, and jaundice between the two groups (Tables 1, 2, 3).

Table 1 Maternal characteristics in IUGR with AEDV and IUGR (control)

Table 2 Neonatal characteristics in IUGR with AEDV and IUGR without AEDV (control)

Table 3 Odds ratio for developing neonatal morbidity and mortality after gestational age at birth and oligohydramnios are adjusted by logistic regression

Discussion

Fetal growth restriction is the failure to achieve normal growth potential due to maternal, fetal and/or external factors [8], and measurement of the umbilical arterial blood flow has been accepted as a very useful method of fetal evaluation. Umbilical arterial blood flow is primarily affected by the villous vascular architecture [4]. When the placental artery is obstructed due to various causes, impairment of the utero-placental blood flow develops which rearranges fetal cardinal ejection resulting in increased blood flow resistance and fetal growth impairment. This phenomenon is manifested as a decrease in blood flow during the umbilical arterial diastolic phase, and with further progression of this impairment of the blood flow of the umbilical arterial diastolic phase becomes undetectable. When more than 70% of the placental artery is obstructed, the reverse phenomenon during the diastolic phase of the umbilical artery develops resulting in an increase in complications of the fetus and neonates [5, 9].

Similarly, in the results of our research, when the absent or reversed end-diastolic flow velocity of the umbilical artery were present, the gestational week at the time of birth and neonatal weight were significantly different. Also, a significant decrease in neonatal platelet count and significant increase in serum SGOT values and unstable fetal heart beat pattern were detected. Despite adjustment of the gestational age, neonatal weight was significantly different, which implies that in cases with absent or reversed end-diastolic flow velocity of the umbilical artery, more severe intrauterine growth restriction occurs [18].

In our study, to examine the independent effect of AEDV on neonatal diseases, gestational age and oligohydramnios were adjusted for by logistic regression analysis.

Yoon et al. have reported that even if gestational age and the level of preeclampsia were adjusted for, abnormal umbilical arterial flow could be a potent neonatal prognostic factor [19]. Sun et al. have reported that even after adjustment for gestational age, abnormal Doppler flow waveforms reflected significantly poor perinatal prognosis [20]. Ferrazzi et al. have reported that independent of gestational age and fetal weight, Doppler flow waveform is the best prognosis factor for perinatal fetal death [21]. On the other hand, Sezik et al. [22] have reported in a study conducted on preeclampsia patients that the results of Yoon et al. were due to intrauterine growth restriction and oligohydramnios not being considered, and thus adjusted for fetal growth restriction and oligohydramnios, and found that the correlation of the absence of diastolic flow of the umbilical artery to neonatal prognosis was weak, and that neonatal complications excluding hypoglycemia and increased platelet count were due to complex causes such as gestational age, the presence or absence of intrauterine growth restriction, oligohydramnios, and, etc.

Placenta dysfunction is a cause of oligohydramnios [10], and it is accompanied by intrauterine growth restriction [11–14]. It has also been reported that the presence of oligohydramnios alone without other diseases does not imply fetal distress [15], and when it is accompanied by intrauterine fetal growth retardation, perinatal prognosis is very poor [16, 17].

Therefore, we applied logistic regression analysis to our results, in order to rule out the effect of preterm delivery [23], and oligohydramnios [11–13] which are frequently present in patients with intrauterine growth restriction, on neonatal complications. The results showed that the incidence of a 1-min Apgar score of less than 4, endotracheal intubation, admission to the intensive care unit, respiratory diseases, neurological diseases, anemia, thrombocytopenia, and neonatal mortality were significantly increased. This is different from the results reported by Sezik et al., and implies the importance of the measurement of umbilical blood flow in mothers with intrauterine growth restriction.

The correlation of maternal past history and the presence of other concurrent diseases to abnormal umbilical arterial blood flow was examined, and a significant association was observed in patients with an absence of the diastolic flow of the umbilical artery, a past history of intrauterine fetal death and patients currently afflicted with preeclampsia. On the other hand, patients with a past history of recurrent miscarriages, preterm labor, or preeclampsia did not show a significant association. With regard to intrauterine fetal death, Torres et al. [24] have reported that in mothers with hypertension, sensitivity of the absence of the diastolic blood flow of the umbilical artery in predicting intrauterine fetal death was 100%. Gerber et al. [25] have reported that in cases with intrauterine growth restriction, if appropriate treatments are not administered despite detection of an absent or reversed end-diastolic flow velocity of the umbilical artery, the time to intrauterine fetal death was an average of 6.3 days, and thus a strong association was predicted. Nonetheless, association with a past history of intrauterine fetal death has rarely been reported, and thus more studies are required on this subject. Concerning the development of preeclampsia, Kofinas et al. [26] have reported that the early development of preeclampsia may induce pathological changes of the umbilical arterial waveforms. However, most studies are conducted based on the association with the uterine arterial blood flow [27–29], and studies on the association of abnormal findings of the umbilical arterial blood flow with the incidence of preeclampsia are insufficient, therefore, it was found that this subject also requires additional studies.

The limitation of this study is that our results are based on a small series, so further multicenter large randomized study is required to confirm it.

Conclusion

In our study, it was found that in mothers with intrauterine growth restriction, absent or reversed diastolic flow of the umbilical artery affected neonatal prognosis independent of preterm delivery or the presence of oligohydramnios. It was concluded that for cases with intrauterine fetal growth restriction, umbilical arterial blood flow should be measured, and its results applied not only to obstetrical management but also to the evaluation and management of the neonate. This is particularly important for mothers with preeclampsia or a past history of intrauterine fetal death and more studies are required on this part.