Prediction of Fetal Lung Maturity Using Ultrasound Evaluation of Thalamus Echogenicity By Mohamed N. Azam; Amal M. Al-Anwar; Hoda S. Abd-Al Salam; Randa M. and Ashraf M.M. El-Arini Obstetrics and Gynecology Department, Faculty of Medicine, Zagazig University

ABSTRACT Background: Neonatal respiratory distress syndrome (RDS) is the leading cause of death in the preterm babies, the WHO estimates its financial burden to be around ~40-50 billion$ per year worldwide. Because of the huge complications & huge financial burden of the RDS, confirming fetal lung maturity is important to determine the time of delivery, in order to avoid the development of RDS in the neonate after birth. The gold-standard methods to assess fetal lung maturity are still the chemical, biological and physical properties of amniotic fluid obtained by amniocentesis. Several attempts were conducted to find a suitable and less invasive technique to confirm fetal lung maturity including, measuring the fetal lung-to-liver signal intensity ratio (LLSIR) on T2-weighted images at magnetic resonance imaging (MRI), direct estimation of fetal lung volume & using the fetal pulmonary artery Doppler wave acceleration/ejection time ratio. Objectives: Evaluation of fetal thalamus echogenicity was studied to predict the maturity of fetal lung and it provided a less invasive and promising technique. Patients and methods: This study was conducted in zagazig university hospitals, on 100 pregnant women with singleton pregnancy, from 34-40w of gestation, with the mean age of the patients at 27.7 ys, and mean gestational age at 37w+4d. Results: After applying the appropriate statistical methods, thalamic echogenicity was not proven to have a high sensitivity, specificity, or overall accuracy regarding the prediction of the fetal lung maturity, and hence can’t be recommended as a part of routine surveillance of the fetal lung maturity. The placental maturity grade has the highest sensitivity, specificity, or overall accuracy regarding the prediction of the fetal lung maturity, and hence is recommended to be a part of routine surveillance of the fetal lung maturity. Conclusion: Thalamic echogenicity was not proven to have a high sensitivity, specificity, or overall accuracy as regarding the prediction of the fetal lung maturity. The placental maturity grading has the highest sensitivity, specificity, or overall accuracy as regarding the prediction of the fetal lung maturity.

Key Words: Lung development, thalamus development, infant respiratory distress

syndrome, fetal lung maturity INTRODUCTION

Premature delivery is one of the major health problems that is associated with huge health complications and a major financial burden, the WHO estimates its financial burden to be around ~ 4050 billion $ per year worldwide(1). There is no accurate estimation of the incidence or the

cause-specific mortality rate of the RDS worldwide, however there is a huge difference in the incidence of RDS between different countries. Respiratory distress syndrome - also known as hyaline membrane disease-occurs almost exclusively in premature infants. RDS is caused by the inadequate production of surfactant in the lungs, which is

normally produced by type II pneumocytes and has the property of lowering surface tension. Decreased surfactant levels causes alveoli to collapse on expiration and greatly increases the energy required for breathing, the additional interstitial edema makes the lung even less compliant. This leads to hypoxia and retention of carbon dioxide(2). It would be convenient to predict fetal lung immaturity before an elective birth noninvasively, to allow therapeutic protection against possible respiratory distress syndrome (RDS) in the neonate, or in some cases, to estimate the effect of steroid treatment of a preterm fetus by repeated tests that can be freely performed by noninvasive techniques. Prenatal diagnosis permits delivery by planned cesarean section sufficiently early to avoid the possible complications(3). The gold-standard methods to assess fetal lung maturity are still the chemical, biological and physical properties of amniotic fluid obtained by amniocentesis(4). Amniocentesis is an invasive technique that requires complex training and has many complications such as intraamniotic infection (chorioamnionitis), transmission of infection from the mother to the fetus, leakage of amniotic fluid, injury to the fetus and the occurrence of preterm labor(5). Because of the previously mentioned complications of amniocentesis, several studies were conducted to find a suitable and less invasive technique to confirm fetal lung maturity.

Besnard et al.(6) after performing a systematic review of 13 studies, recommended replacing the lecithin/sphingomyelin ratio (L/S ratio) as gold standard with the lamellar body count (LBC) since the LBC is easy to perform, rapid, inexpensive, and available to all hospitals 24 h per day, but it’s still an invasive technique. Takesin et al.(7) found that the echogenicity of the fetal lung showed a particular changing pattern during pregnancy, which corresponds to morphologic changes of the fetal lung development, and thence can be used to confirm the fetal lung maturity. Attempts have also been made to measure the fetal lung-to-liver signal intensity ratio (LLSIR) on T2-weighted images at magnetic resonance imaging (MRI) which was found to be accurate but not cost-effective so can’t be recommended for routine antenatal care(8). The amniotic fluid biomarkers were studied against the fetal pulmonary artery Doppler waveforms acceleration/ejection time ratio to evaluate its ability to predict fetal lung maturity and suggested that ultrasound evaluation of fetal pulmonary artery blood flow may be a promising new noninvasive technique to evaluate fetal lung maturity(9). Direct estimation of fetal lung volume was investigated as a marker for fetal lung maturity, , but this method was found to be affected by liquor volume, fetal congenital malformation & any

abnormalities in the utero-placental circulation, and it do not provide any additional information relating to potential physiological function of the fetal lung(10). Rasheed et al.(3) evaluated fetal thalamic echogenicity by ultrasound as a possible marker of fetal lung maturity and concluded that evaluation of echogenic thalamus is beneficial, and can be considered as a new marker of fetal lung maturity; however, further studies are required to strengthen such idea. The aim of this work is to predict fetal lung maturity using a non-invasive method, which is transabdominal ultrasound evaluation of thalamus echogenicity. PATIENTS AND METHODS

In this cohort study, 100 women attended the outpatient clinic in Zagazig University hospitals to be prepared for elective cesarean section. Inclusion criteria:  Elective C.S.  Age between 18-35 years.  Single viable intrauterine pregnancy.  Gestational age 36-40 weeks.  Rh-Positive patient. Exclusion criteria:  Any maternal medical disease either chronic, or pregnancy complicated.  Multiple pregnancies.  Abnormal fetal growth patterns.  Known fetal congenital malformations.

 Abnormal volume of the amniotic fluid.  Any case of rupture of membranes.  Any evidence of active maternal or fetal infection. Methods: All patients were subjected to thorough clinical evaluation with emphasis on: 1- Full medical and surgical history. 2- General clinical examination. 3- Laboratory investigations [complete blood picture (CBC), liver enzymes, serum BUN and creatinine levels, bleeding profiles & Fasting blood sugar (FBS)]. 4- Radiological studies (transabdominal 2D ultrasound with convex transducer (Using Samsung Medison SonoAce R5 machine equipped with the C2-8 Curved array transducer with 51mm footprint and set at a frequency of 3.5MHz) at Zagazig University within 1 week of planned time of L.S.C.S). The amniotic fluid particles (vernix) and the placental changes were also assessed as a part of fetal wellbeing assessment. The placental maturity grade was recorded according to the Grannum Classification system. The ultrasound parameters was compared with the neonatal outcomes (APGAR score, the need for admission to the NICU and any signs of respiratory distress) as determined by the neonatologist attending the labor, and confirmed by the findings of the neonatal chest

plain X-ray performed 12-48h after labor . In cases requiring NICU admission, the causes & duration of the admission was noted as determined by the neonatologist observing the case.

following tests were used to test differences for significance. Differences between frequencies (qualitative variables) and percentages in groups were compared by Chi-square test. Differences between means (quantitative variables) in parametric independent groups by T test in. P value was set at <0.05 for significant results & <0.001 for high significant result. RESULTS

Figure (1): Ultrasonograph shows echolucent fetal thalamus (T) at 36 weeks of gestation.

Figure (2): Ultrasonograph shows echogenic fetal thalamus (T) at 37 weeks of gestation.

Statistical analysis: Data collected throughout history, basic clinical examination, laboratory investigations and outcome measures coded, entered and analyzed using Microsoft Excel software. Data were then imported into Statistical Package for the Social Sciences (SPSS version 20.0) (Statistical Package for the Social Sciences) software for analysis. According to the type of data, the

Table (4) showed nonsignificant result in case of thalamus echogenicity, so there is a no association with RDS. Table (5) showed nonsignificant result in case of presence of vernix , so there is a no association with RDS. Table (6) showed high significant result in case of placental grading, so there is a significant association with RDS. Table (7) showed that the thalamic echogenicity has the lowest accuracy among all three ultrasound parameters used in this study in predicting the incidence of RDS. Table (8) showed that the thalamic echogenicity has the lowest accuracy among all three ultrasound parameters used in this study in predicting the need for NICU admission. Table (9) showed that P value is > 0.05, so the multiparity is a risk factor for RDS. Table (10) showed significant result in case of malpresentation so it can be considered risk factors for RDS.

Table (11) showed that P value is < 0.05, so the maternal age is not a risk factor for RDS. Table (12) showed that P value is > 0.001 (high significant

result), so the fetal gestational age is a major risk factor for RDS. Table (13) showed significant result) in case of indication of L.S.C.S and ERCS, so they can be considered risk factors for RDS.

Table (1): Frequency distribution of the patients’ ages & gestational Ages: Std. Mean Median Minimum Maximum Deviation 27.76 29.0 5.62 18.0 38.0 Age 37.73 38.0 1.12 36.0 40.0 Gestational age

Table (2): Frequency & percentage of the parity, indications of C.S. & fetal presentation: N % Parity M 84 84.0 PG 16 16.0 Indication 1ry infertility 11 11.0 ERCS 68 68.0 Mal- presentation 21 11.0 Presentation Breech 15 15.0 Cephalic 79 79.0 Oblique 6 6.0 Total 100 100.0

Table (3): Frequency & percentage of the neonatal outcome: Frequency st APGAR score Low 1 min ( >5 ) 31 th Low 5 min ( >7 ) 29 NICU YES 29 NO 71 NO 71 CAUSE Hypoglycemia 5 RDS 20 TTN 4 RDS RDS 20 No RDS 80 Total 100

Percent 31.0 29.0 29.0 71.0 71.0 5.0 20.0 4.0 20.0 80.0 100.0

Table (4): Comparison between the state of thalamus echogenicity & the incidence of RDS:

RDS 12 8 20

Echolucent Echogenic

RDS No RDS 33 47 80

Total 45 55 100

X2

P

2.27

0.13

Table (5): Comparison between the vernix & the incidence of RDS:

vernix

absent presence

Total

RDS RDS No RDS 5 17 15 63 20 80

Total

X2

P

22 78 100

0.13

0.71

Table (6): Comparison between the placental grade maturity incidence of RDS:

Placenta grade

RDS RDS No RDS 10 10 10 70 20 80

I II & III

Total

& the

Total

X2

P

20 80 100

14.06

0.00**

Table (7): Comparison between the sensitivity and the specificity of the three ultrasound parameters in our study as a sign of fetal lung maturity (absence of RDS). Sensitivity Specificity Echogenic Thalamus Vernix presence Placenta grade II & III

+VE Predictive

-VE predictive

Accuracy

58.8%

60.0%

85.4%

26.6%

59.0%

78.8%

25.0%

80.7%

22.7%

68.0%

87.5%

50.0%

87.5%

50.0%

80.0%

Table (8): Comparison between the sensitivity and the specificity of the three ultrasound parameters in our study as a sign of fetal lung maturity (no need for NICU). +VE -VE Sensitivity Specificity Accuracy Predictive predictive Echogenic 58.8% 60.0% 85.4% 26.6% 59.0% Thalamus 78.8% 25.0% 80.7% 22.7% 68.0% Vernix presence Placenta grade II 87.5% 50.0% 87.5% 50.0% 80.0% & III

Table (9): Comparison between the parity & the incidence of RDS: RDS Total T p RDS NO RDS parity m 20 64 84 4.76 0.029* PG 0 16 16 Total 20 80 100 * significant

Table (10): Comparison between fetal presentation & the incidence of RDS: RDS Total T P RDS NO RDS Presentation b 6 9 15 14.57 0.001** c 10 69 79 o 4 2 6 Total 20 80 100 * significant

Table (11): Comparison between the maternal age & the incidence of RDS: Std. RDS N Mean t P Deviation Age No RDS 80 27.9000 5.58162 .496 .621 RDS 20 27.2000 5.92586

Table (12): Comparison between the gestational age & the incidence of RDS: Gestational Age by weeks Total t p 36.00 37.00 38.00 39.00 40.00 Maturity RDS 6 12 0 2 0 20 No RDS 9 19 24 24 4 80 19.9 0.001** Total 15 31 24 26 4 100 ** highly significant

Table (13): Comparison between the indication of L.S.C.S & the incidence of RDS: RDS Total t P RDS NO RDS 1ry infertility 3 8 11 Indication ERCS 7 61 68 14.7 0.005* malpresentation 10 11 21 Total 20 80 100 * significant ** highly significant

DISCUSSION Up to our knowledge, this is the second study in this field, the study evaluated the use of thalamic echogenicity as a predictor of fetal lung maturity, after a previous study that was conducted during the period from April 2010 to March 2011, in Bagdad, by Rasheed et al.(3). This study was conducted in Zagazig University Hospitals, on 100 pregnant women with singleton pregnancy, from 36 to 40weeks of gestations, with the mean age of the patients at 27.7 ys, and mean gestational age 37w+4d. In comparison Rasheed et (3) al. 's study was done on 142 pregnant women with singleton pregnancy, from 36 to 42 weeks of

gestations, with the mean gestational age 38w+6d. In our study, out of the 100 fetuses delivered, 29 babies required NICU admission, 5 for hypoglycemia, 4 for TTN (transient tachypnea of newborn) & 20 for RDS, 4 were admitted for less than 24h, 5 for 24-48h & 20 for more than 48h. While in Rasheed et al.(3)'s study out of the 142 fetuses delivered, 52 babies required NICU admission, 4 for hypoglycemia, 39 for TTN (transient tachypnea of newborn) & 9 for RDS, 31 fetuses were admitted for less than 24h, 16 fetuses 24-48h & 5 fetuses for more than 48h. Both the studies did not report any neonatal mortality up to

discharge of new born babies from the NICU. In this study the echogenic thalmai were 55, compared with 45 echolucent ones. The amniotic fluid particles (vernix) were found in 78 cases & the placental grade II & III were found in 80 cases. While in Rasheed et al.(3)'s study, the echogenic thalmai were 64, compared with 78 echolucent ones. The amniotic fluid particles (vernix) were found in 105 cases & the placental grade II & III were found in 61 cases. After applying the appropriate statistical methods, regarding the prediction of RDS, the thalamic echogenicty was found to have the lowest Sensitivity (58.8%) moderate Specificity (60.0%), moderate +VE Predictive value of (85.4%) & -VE predictive (26.6%). The amniotic fluid particles (Vernix) were found to have good Sensitivity (78.8%), the lowest Specificity (25.0%), the lowest +VE Predictive value of (80.7%) & -VE predictive (22.7%). The placental maturity grade II & III were found to have the highest Sensitivity (87.5%), high Specificity (50.0%), the highest +VE Predictive value of (87.5%) & the highest -VE predictive (50.0%). While in Rasheed et al.(3)'s study, the thalamic echogenicty was found to have sensitivity (63.2%) the highest Specificity (86.53%), the highest +VE Predictive value of (89.6%) & it has a -VE predictive value of (57.69%). The amniotic fluid particles (Vernix) were found to have the highest Sensitivity (86.66%), Specificity (48.07%), the +VE

Predictive value of (74.28%) & -VE predictive (67.56%). The placental maturity grade II & III were found to have the lowest Sensitivity (51.11%), moderate (71.15%), moderate +VE Predictive value of (75.40%) & the moderate -VE predictive (45.67%). The gestational age rather than the maternal age was found to be a major risk factor for both development of RDS & NICU admission with P value of 0.00 & 0.621 respectively. Malpresentation, indication of L.S.C.S & the multiparty were found to be risk factors for the development of RDS with P value of 0.006, 0.034 & 0.023 respectively. The results of this study is inconsistent with what Rasheed et al.(3) found that the evaluation of the thalamic echogenicity is of high sensitivity & +ve predictive value & can serve as a noninvasive marker in evaluation of fetal lung maturity. Meanwhile, the high accuracy (79%) for predicting fetal lung maturation in of infants in grade II and III group justifies using this group to indicate fetal lung maturity before repeat caesarean section in woman with reasonable certainty to reach 38 weeks of gestation and has no complicating diseases, such finding seems compatible with that reported previously by Shweni and Moodley(11). Regarding evaluation of the presence of free-floating particles (FFPs or the Vernix) in the amniotic fluid as a predictor of fetal lung maturity, Gross et al. correlate this ultrasound finding with fetal lung maturity in 1985 and suggest that

presence of FFPs on real-time ultrasound could be used to confirm fetal lung maturity(12). Our data is consistent with what Altman et al.(13), reported in 2013, that the multiparity is a risk factor for development of RDS. We agree with Goodman et al.(14) who stated in 2013, that the non-cephalic presentation of the fetus resulted in adverse fetal outcome, such as RDS, so the malpresentation is indeed a risk factor for RDS.

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CONCLUSION

1- Thalamic echogenicity, although showed simple and non-invasive technique to evaluate the fetal lung maturity, was not proven to have a high sensitivity, specificity, or overall accuracy as regarding the prediction of the fetal lung maturity, and hence can’t be recommended as a part of routine surveillance of the fetal lung maturity. 2- The placental maturity grading has the highest sensitivity, specificity, or overall accuracy as regarding the prediction of the fetal lung maturity, and hence is recommended to be a part of routine surveillance of the fetal lung maturity before any elective delivery. REFERENCES 1- WHO. Department of Health Statistics and Information Systems (WHO, Geneva) and WHO-UNICEF Child Health Epidemiology Reference Group (CHERG), CHERGWHO methods and data

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