Objective: To determine if infants delivered after immature or indeterminate TDx-FLM II testing and a mature reflex test are at increased risk for neonatal respiratory complications. Methods: The primary analysis compared neonatal respiratory morbidity (RDS or TTN) in 34–39-week fetuses delivered after either (i) mature TDx-FLM II testing, or (ii) indeterminate or immature TDx-FLM II and a positive reflex test (PG or L/S ratio). Results: Fifty patients delivered after mature TDx-FLM II, and 30 after immature or indeterminate TDx-FLM II with an L/S ≥2.0. Respiratory morbidity was significantly higher in the group delivered after mature reflex testing compared with mature TDx-FLM II (23% vs. 2%, p < 0.01). When PG was present, there were no cases of RDS or TTN. Conclusions: Utilizing L/S ratios as a reflex test to confirm lung maturity was associated with a high risk for respiratory morbidity, particularly when PG was not present.
Keywords: LS ratio, lung maturity testing, cascade testing
IntroductionFetal lung maturity tests may aid clinicians in determining when delivery can occur. In clinical practice, many providers use a cascade approach to fetal lung maturity testing. If an initial test shows immature or indeterminate lung maturity, reflex tests are performed, and if they in turn demonstrate fetal lung maturity, the likelihood of respiratory distress syndrome (RDS) is presumed to be low, even though the initial test did not predict maturity.
The rationale for this management strategy is based on the fact that while most fetal lung maturity tests perform well in predicting maturity, they are poor at predicting respiratory morbidity including RDS and TTN [1–3]. The ACOG Practice Bulletin on fetal lung maturity notes, “The negative predictive value for mature neonatal lung function is high, and if one of these test results for fetal lung maturity is positive, RDS is unlikely. The main value for fetal lung maturity testing is predicting the absence of RDS. An immature test result for fetal lung maturity is less reliable in predicting the presence of RDS” [3].
The most popular initial test for assessing fetal lung maturity is the TDx-FLM II surfactant-to-albumin ratio assay marketed by Abbott Laboratories (Abbott Park, Illinois) because of its speed, ease, and high sensitivity [4,5]. If this test returns indeterminate or negative, other studies such L/S ratio or PG presence may then
be performed. A potential concern with this cascade approach is that the negative predictive value may be decreased in reflex testing. As Luo and Norwitz point out, “the predictive value of any test is dependent on the prevalence of the disease in the popula-tion,” in addition to the intrinsic characteristics of the test [6]. With the cascade approach patients who have an indeterminate or immature initial test are a subgroup at higher risk of respiratory morbidity than the initial unselected cohort.
An additional concern is that a lung maturity test may perform poorly (and not demonstrate the same sensitivity and specificity) when used as a reflex test. Karcher et al. reported on 13 infants who developed RDS after fetal maturity testing in a cohort of 238 women delivered after lung maturity testing. While TDx-FLM II testing demonstrated mature values in 0/13 RDS cases, L/S provided false reassurance. It returned ≥2.0 in 9/13 cases and ≥2.5 in 5/13 cases of RDS [7].
The purpose of this study was to determine if infants delivered after immature or indeterminate TDx-FLM II testing but mature reflex testing with L/S and/or PG were at increased risk for RDS or transient tachypnea of newborn compared to infants delivered after mature TDx-FLM II.
Materials and methodsThis retrospective cohort study was performed after institutional review board approval was obtained. Potential maternal–neonatal pairs were identified by querying an inpatient coding database and the maternal–fetal medicine ultrasound database at the Hospital of the University of Pennsylvania. This allowed capture respec-tively of inpatient and outpatient amniocentesis procedures.
Eligibility criteria included singleton pregnancies undergoing amniocentesis at 34–39-weeks gestation between 7/1/02–12/31/08. Exclusion criteria included multiple gestations, congenital anom-alies compromising respiratory function, incomplete neonatal chart documentation, amniocentesis performed >72 h prior to delivery, no test indicating lung maturity, and neonatal diagnosis of pneumonia.
Diagnoses of TTN or RDS were made by a neonatologist by reviewing electronic medical records of infants admitted to the NICU. Neonatal RDS was defined by the following criteria: early onset (<24 h) clinical symptoms (retractions, grunting, cyanosis), chest x-ray findings consistent with RDS, oxygen requirement for greater than 24 h, and administration of surfactant. TTN was
Performance of lecithin-sphingomyelin ratio as a reflex test for documenting fetal lung maturity in late preterm and term fetuses
Corina Tennant1, Alexander M. Friedman1, Emmanuelle Pare1, Christie Bruno2 & Eileen Wang1
1Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania and 2Division of Neonatology, Children’s Hospital of Philadelphia
Correspondence: Alex Friedman MD, Hospital of the University of Pennsylvania, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, 2000 Ravdin Court, 3400 Spruce Street, Philadelphia, PA 19104. Tel: (215) 662–6913. Fax: (215) 349–5625. E-mail: [email protected]
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LS ratio as a reflex test for fetal lung maturity 1461
defined by early onset of clinical symptoms (<24h) severe enough to require admission to the intensive care unit, oxygen require-ment, and quick resolution of symptoms. Maternal and neonatal medical and demographic data was collected by electronic medical record review.
Fetal lung maturity by TDx-FLM II was defined as ≥ 55 mg surfactant/g albumin. Indeterminate lung maturity was defined as 40–54 mg surfactant/g albumin, and fetal lung immaturity was defined as <40 mg surfactant/g albumin. Fetal lung maturity by reflex testing was defined as either an L/S ratio ≥ 2.0 or PG presence. For this study, trace PG presence was considered to be evidence of immaturity.
Positive and negative predictive values for different testing combinations were determined. We performed Fisher’s exact test to determine whether infants delivered after immature or inde-terminate TDx-FLM II testing but mature reflex testing with L/S and/or PG were at significantly increased risk for RDS or transient tachypnea of newborn compared to infants delivered after mature TDx-FLM II (Stata 10.1).
ResultsOf 169 patients initially identified, 41 were excluded for under-going amniocentesis >3 days prior to delivery. An additional 38 patients were excluded because of fetal anomalies. Eighty patients were included in the final analysis. Fifty patients were delivered after mature TDx-FLM II testing, and 30 patients were delivered after immature or indeterminate TDx-FLM II testing and a mature reflex test (PG and/or L/S; Figure 1). Maternal demographic data and indication for delivery are presented in Table I. L/S testing was done in all 30 cases of immature of inde-terminate TDx-FLM and PG testing was performed in 29/30 cases (Table II).
A total of 8/80 neonates developed respiratory morbidity (three cases of RDS and five cases of TTN). TDx-FLM II testing revealed immature or indeterminate values for 7/8 cases with respiratory morbidity. For pregnancies with immature or inde-terminate TDx-FLM II results, L/S ratios proved to be falsely reassuring and returned ≥ 2.0 in all seven of these cases. PG did not demonstrate maturity in any of these seven cases (Table III). In the 11 cases where PG was present, no respiratory morbidity occurred (Table II). Blood and meconium were not noted in the 80 patients included in the final analysis. There was one case
with indeterminate TDx-FLM and immature L/S testing and PG absence that was delivered and did not suffer respiratory morbidity that was not included in this analysis. Mean birth weights and gestational ages did not differ significantly between patients with and without respiratory morbidity (Table IV). Mean NICU length
Table I. Maternal demographic characteristics. No morbidity RDS/TTNCesarean, n (%) 8 (100%) 64 (89%)Diabetes, n (%) 2 (2%) 1 (13%)Indication for amniocentesis, n (%) Prior cesarean 45 (63%) 7 (88%) Myomectomy 12 (17%) 0 Placenta previa 4 (6%) 0 Isoimmunization 2 (3%) 1 (13%) Other 9(13%) 0Maternal age, mean (SD) 31.2 (6.5) 28.8 (5.0)
Table II. Respiratory morbidity by test result.
Test N totalMean GA
(SD)Cases RDS and TTN
Morbidity (%)
Mature TDx-FLM 50 37.2 (0.6) 1 2.0Immature or indeterminate
TDx-FLM and reflex L/S ≥2
30 37.0 (0.5) 7 23.3
Immature or indeterminate TDx-FLM and PG present
11 37.1 (0.5) 0 0.0
Immature or indeterminate TDx-FLM, absent PG, reflex L/S ≥ 2
18 36.9 (0.4) 7 38.9
Table III. Test characteristics of patients with pulmonary morbidity.Diagnosis GA TDx-FLM II L/S PGRDS 35w4d 37 2.3 TraceRDS 37w0d 19 2.5 Not detectedRDS 39w0d 44 3.0 TraceTTN 37w0d 47 2.8 TraceTTN 37w4d 45 3.0 TraceTTN 36w3d 44 2.2 TraceTTN 37w0d 43 2.5 TraceTTN 38w6d 58 — —
Figure 1. Study inclusion.
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1462 C. Tennant et al.
The Journal of Maternal-Fetal and Neonatal Medicine
of stay for infants with RDS was 8.3 days +/− 1.5 days. Mean length of NICU stay for infants with TTN was 2.3 days +/− 0.5 days. Patients with immature or indeterminate TDx-FLM II fetal lung maturity testing but mature reflex testing were significantly more likely to develop respiratory morbidity compared to patients with mature TDx-FLM II testing (23.3% vs. 2.0% p = 0.01). Cesarean delivery rates were not significantly different between the two groups (Table I).
The negative predictive value for immaturity (i.e. the likeli-hood of no RDS with a mature test) for TDx-FLM II was 98% in this population. As a reflex test, the negative predictive value of PG for immaturity was 100%. Conversely, after immature or indeterminate TDx-FLM II and negative PG, the negative predic-tive value for LS ≥ 2 was only 61.1% (Table II).
DiscussionWhile elective delivery prior to 39 weeks is associated with signifi-cantly increased risks for adverse neonatal outcomes even if fetal lung maturity is documented [8–10] and delivery prior to this gestational age in the absence of maternal or neonatal indications is contraindicated, fetal lung maturity testing may still be useful in certain clinical circumstances, although it appears to be being used less frequently [5].
An optimal strategy for fetal lung maturity testing would identify the maximum number of infants safe for delivery while minimizing false reassurance. Data is limited regarding the use of different combinations and sequences of fetal lung maturity tests to achieve this goal. In this cohort, using TDx-FLM II as an initial test allowed delivery of 62% of fetuses with a 2% risk of respiratory morbidity. When PG testing was performed as a reflex test on indeterminate or immature TDx-FLM II cases, 58% of remaining fetuses were able to be safely delivered with 0% respi-ratory morbidity. The high percentage of cases with PG present was likely due to the late average gestational age in the cohort. In comparison, using L/S ratios provided false reassurance, and 7/7 reflex cases with respiratory morbidity had an L/S ratio ≥2.0 and 3/7 cases had an L/S ratio >2.5.
A strength of this study is that it reflects actual clinical deci-sions made by providers in the late third trimester. An additional strength is that the fetuses in the pregnancy were primarily late preterm and early term and had a high a priori likelihood for not developing respiratory morbidity. This lends further evidence to the fact that L/S ratios may not function well as a reflex test for lung maturity in this age range. Our study also has significant weaknesses that limit its generalizability. The study excluded fetuses with anomalies and those that underwent delivery >72 h from amniocentesis. Additionally, the patients included in this study were in a narrow gestational age range and it is plausible
that using L/S ratios may be a better predictor of lung maturity for fetuses at earlier gestational ages. Last, the majority of patients in our study delivered by cesarean section. It is possible that in a cohort of women with vaginal delivery, L/S ratios may perform better in confirming lung maturity.
Our data adds to prior published data by Karcher at al. that L/S ratios may provide false reassurance when used after immature or indeterminate TDx-FLM II testing [7]. The poor performance of L/S ratios may be due to increased disease prevalence in the population undergoing reflex testing as well as qualities of the test that lead to decreased sensitivity and specificity in the subset of patients with indeterminate or immature TDx-FLM II values. With the retirement of the TDx-FLM II system, additional scru-tiny of the L/S in ratio cascade FLM assessment for late term and early preterm fetuses is warranted.
AcknowledgmentsThis research was presented at 2011 Society for Maternal-Fetal Medicine Annual Meeting.
Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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Table IV. Gestational age and birth weight of outcome group. No morbidity RDS/TTNGA mean (wk) 37.1 ± 0.5 37.2 ± 1.2Birth weight mean (g) 3091 ± 506 2928 ± 313
