Fetal Lung Maturity Profile

The ability of the fetus to survive outside of the uterus is greatly dependent on proper pulmonary function. Pulmonary surfactant is needed to reduce the surface tension of the air-liquid interface of the alveolar lining, so that alveoli don’t collapse upon expiration.  Infants born with a deficiency of pulmonary surfactant are at increased risk of developing respiratory distress syndrome (RDS). The incidence of RDS is dependent on gestational age, with more RDS occurring in younger fetuses. For instance, the risk of RDS is 0% at 40 weeks, 2% at 36 weeks, and 8 to 23% at 34 weeks, depending on birth weight. RDS can occur at term, especially with Rh isoimmunization and maternal diabetes. 

Generally, fetal lung maturity testing was not necessary when the gestational age is >39 weeks because fetal lungs are usually mature. Unfortunately, complications such as diabetes and Rh isoimmunization retarded fetal lung development. Women with these complications may require testing. Testing was also not usually necessary when the gestational age was <30 weeks, because most fetuses are expected to have immature lungs. However, a number of disorders accelerate pulmonary maturity including maternal hypertension, preeclampsia, HELLP syndrome, premature rupture of the membranes, intrauterine growth restriction, maternal smoking and drug use, and maternal hemoglobinopathies. Women with one of these complications and preterm labor or premature rupture of the membranes may have required testing for fetal lung maturity (FLM).

Surfactant is a complex mixture of lipids, proteins, and carbohydrates.  Most of the lipids are phospholipids including lecithin (L), sphingomyelin (S), disaturated lecithin, phophatidyl inositol (PI), and phosphatidyl glycerol (PG). All of these phospholipids are manufactured by the fetal lung, possess surface tension activity, and are secreted into the amniotic fluid.  Lecithin is present in the lung in the highest concentration, but must be stabilized by PI and/or PG to have maximal surface tension reducing activity. The relative concentrations of these phospholipids determine the degree of fetal lung maturity.

In early pregnancy, the concentration of lecithin is very small, while that of sphingomyelin is much greater. Lecithin begins to be secreted into amniotic fluid by the developing fetal lung between 24 and 26 weeks of gestation. At 30 to 32 weeks, lecithin concentration remains relatively low, less than or equal to sphingomyelin. PI concentration is also low at this time and PG is nonexistent. Subsequently, sphingomyelin concentration levels off and lecithin begins to increase, with an abrupt rise at 35 weeks.  PI increases in parallel with lecithin until 35 weeks and subsequently declines. PG becomes detectable at 36 weeks. 

Initially, the fetal risk of RDS was estimated by measuring amniotic fluid phospholipid concentrations. The ratio of lecithin to sphingomyelin was measured by extraction of phospholipids from amniotic fluid and separation by chromatography. The percent of each phospholipid was determined by scanning the chromatography plate and measuring the area under each phospholipid peak. A lecithin to sphingomyelin (L/S) ratio of 2.2 or higher indicated fetal lung maturity.

Results were interpreted as follows.

An L/S ratio greater than 2.2 was considered mature. The combination of an L/S ratio >2.2, >50% disaturated lecithin, a high percentage of PI, and the presence of PG usually indicated maturity.  

Because PG appeared later in gestation, it was a good indicator of maturity. PG was detected using the AmnioStat-FLM test. The positive predictive value  was greater than 95%.

Because the L/S ratio procedure was so labor intensive, many laboratories adopted the FLM II assay from Abbott Laboratories to assess fetal lung maturity. However, Abbott ended production of FLM II on Dec 31, 2011 due to the retirement of their TDx and FLx instruments.

In response, some hospital laboratories validated Lamellar Body Counts (LBC) as a replacement for FLM II. Type II pneumocytes package surfactant into intracellular storage granules called lamellar bodies, which are excreted into the alveolar space. Lamellar bodies appear in the amniotic fluid at 28 to 32 weeks and increase exponentially as gestation continues. Thus, LBC is a direct measurement of surfactant production. Due to the similar size of lamellar bodies and platelets, automated hematology analyzers could accurately count amniotic fluid lamellar bodies using the platelet channel. 

Outcome-based studies demonstrated that LBC performed at least as well as the FLM II test. A meta-analysis calculated receiver-operating characteristic curves based upon data from six studies and showed the lamellar body count performed slightly better than the lecithin/sphingomyelin ratio in predicting respiratory distress.

Due to improvements in gestational age dating, maternal administration of corticosteroids that accelerate fetal lung maturity in at-risk pregnancies, and exogenous surfactant replacement therapies, the number of newborn deaths due to respiratory distress syndrome has declined considerably over the last 25 years. Most clinical laboratories in the United States have noted a steady decline in the number of fetal lung maturity tests that they perform each year. 

Many obstetricians in the United States have indicated that laboratory tests for fetal lung maturity are no longer needed for patient care. Furthermore, European physicians rarely, if ever, order these tests and yet the rates of infant death due to respiratory distress are no worse than they are in the US. Therefore, FLM testing is no longer indicated to guide timing of preterm or early-term delivery. This test should not be ordered for any clinical scenarios involving pregnant women.

References

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ACOG Committee Opinion No. 765: Avoidance of Nonmedically Indicated Early-Term Deliveries and Associated Neonatal Morbidities. Obstetrics and Gynecology 133(2) (2019) e156-e163.

ACOG Committee Opinion No. 764: Medically Indicated Late-Preterm and Early-Term Deliveries. Obstetrics and Gynecology 133(2) (2019) e151-e155.

Ghidini A, et al. Role of lamellar body count for the prediction of neonatal respiratory distress syndrome in non-diabetic pregnant women. Arch Gynecol Obstet 2005;271:325-8, 

Haymond S et al. A direct comparison between lamellar body counts and fluorescent polarization methods for predicting respiratory distress syndrome, Amer J Clin Pathol, 2006;126:894-899. 

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Wijnberger LD et al. The accuracy of lamellar body count and lecithin/sphingomyelin ratio in the prediction of neonatal respiratory distress syndrome: a meta-analysis, Brit J Obstet Gynecol,2001;108(6):583-588.

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