Can first trimester pregnancy-associated plasma protein-A predict the surfactant needs of preterm neonates?

Abstract

BACKGROUND:

Low values of pregnancy associated plasma protein A (PAPP-A), have been shown to be associated with some poor gestational outcomes, especially those related to placental deficiency such as pre-eclampsia and fetal growth restriction as well as preterm labor. The aim of this study was to compare first trimester PAPP-A MoM values with the surfactant needs of newborns of pregnant women who had a preterm delivery.

METHODS:

This study included 216 pregnant women who had a preterm delivery, who were found to be in the low-risk group based on their aneuploidy screening. The women were separated into two groups based on the surfactant receipts of their newborns. A record was made of the obstetric history, birth characteristics of the preterm infants, and whether or not there was a need for surfactant.

RESULTS:

A comparison of the PAPP-A values of the two groups revealed that the group that received surfactant had statistically significantly lower PAPP-A values (t(–3.97) = 0.203, p < 0.001). When the cut-off value of PAPP-A was taken as 1 MoM and the gestational age was analyzed together with the birth weight, PAPP-A alone was found to be a significant independent variable for the prediction of respiratory distress syndrome (RDS) (p = 0.031; OR:8.2 (1.2–55.6)).

CONCLUSIONS:

The result of this study demonstrated that PAPP-A MoM values may be significant in predicting the need for surfactant in RDS, which is a frequently seen condition in the neonatal period.

Keywords

IGF-1 pregnancy associated plasma protein a respiratory distress syndrome surfactant

1 Introduction

The causes of morbidity and mortality in newborns today are short and long term complications arising from and accompanying preterm labor [1]. Respiratory problems and particularly respiratory distress syndrome (RDS) are the most common of these in the short term. A deficiency of surfactant, whose primary function is to prevent collapse by reducing alveolar surface tension, results in RDS and surfactant is used for in treatment [2]. The prevalence of RDS in the infants of diabetic mothers is six times higher compared to the normal population and it is known to originate from the inhibition of surfactant protein by insulin and insulin growth factors 1 and 2 (IGF-1, IGF-2) mediated by IGF receptor (IGF-1R) [3].

Pregnancy-associated plasma protein A (PAPP-A) is a zinc-binding metalloproteinase with a high molecular weight that is produced in placental syncytiotrophoblasts. Low values of PAPP-A, one of the biochemical markers in first trimester aneuploidy screening tests, have been shown to be associated with some poor gestational outcomes, especially those related to placental deficiency such as pre-eclampsia and fetal growth restriction as well as preterm labor [4 –6]. The primary substrate of PAPP-A enzyme is the insulin-like growth factor binding protein-4 (IGFBP-4) that acts as a modulator by inhibiting and stimulating IGF-mediated cell growth [7]. PAPP-A cleaves IGFBP-4 only when IGFBP-4 is bound to IGF-1. IGF 1 and 2 are known to inhibit surfactant, leading to increased surfactant deficiency in the infants of diabetic mothers. PAPP-A protein also affects the IGF system. Hence, PAPP-A and surfactant can be thought to influence each other through a common molecular system. The aim of this study was to explore whether or not there was a relationship between the first trimester PAPP-A MoM values and the surfactant needs of the newborns of pregnant women who had a preterm delivery.

2 Methods

2.1 Study design

This retrospective study was carried out at Ankara Dr. Zekai Tahir Burak Women’s Health Training and Research Hospital, a reference site for tertiary care, between January 2018 and January 2019. Approval for the study was granted by a Local Institutional Review Board was obtained. The research complied with all the relevant national regulations, institutional policies and in accordance with the tenets of the Helsinki Declaration.

2.2 Study population

This study included 216 pregnant Turkish women who had a preterm delivery, who were found to be in the low-risk group based on their first trimester aneuploidy screening and whose detailed ultrasound findings and gestational diabetes screenings in the second trimester were found to be normal. The preterm newborns admitted to neonatal intensive care unit (NICU) were separated into two groups based on the requirement for surfactant.

2.3 Exclusion criteria

To obtain the most homogenous study group the newborns meeting the following criteria were excluded from the study: a) Presence of maternal chronic systemic disease (chronic hypertension, diabetes mellitus, type 1 or type 2 asthma, connective tissue diseases, autoimmune diseases); b) Presence of gestational diabetes; c) Being in the high-risk group with an abnormal karyotype as a result of the first trimester aneuploidy screening; d) Diagnosis of aneuploidy in previous pregnancies; e) Multiple pregnancy; f) Women who had a term delivery; g) Smoking; h) Pregnancies from in-vitro fertilization (IVF).

2.4 Data collection

A preterm delivery was defined as one that occ-urred between gestational weeks 23 and 34 regardless of the birth weight. The gestational week for each patient was calculated based on the crown-rump length (CRL) taken at the time of performing the first trimester aneuploidy screening. The venous blood samples drawn on the day of ultrasonographical examination were centrifuged for 10 minutes at 5000 rpm in tubes containing ethylenediamine tetra-acetic acid (EDTA) (IMMULITE® 2000XPI immunoassay system- Siemens). In the first trimester aneuploidy screening, an adjustment was made for maternal weight to standardize the PAPP-A multiple of median (MoM) value. The obstetric history (gravida, parity, abortus, living-child), maternal ages, and maternal weights of the pregnant women included in the study were obtained from the hospital database.

The birth characteristics of preterm newborns (birth week, birth weight, sex, APGAR Minute 1 and 5 scores) and whether or not they had a need for surfactant were recorded. Antenatal steroids were used for all preterm deliveries. According to our clinical practice, antenatal steroids were administered to all pregnant women at 23–33^*6 weeks of gestation who were at increased risk of preterm delivery within the next one to seven days and the selection of pregnancies was made as a clinical judgement based on high probability of induction or cesarean delivery for obstetrical and medical indications. Newborns that were admitted to NICU for respiratory distress and needed surfactant were diagnosed with RDS. The RDS diagnosis was made according to the chest X-Ray, blood tests, echocardiography, and clinical signs. The diagnosis of RDS was made for newborns with clinical signs such as tachypnea, nasal flaring, subcostal retractions and cyanosis, a chest X-Ray showing diffuse ground-glass appearance with air bronchograms and hypo expansion, and blood gas measurements that showed hypoxemia and acidosis. These data were obtained from the NICU database and patient files. The surfactant protocol for neonates was determined according to the Turkish Neonatology Society clinical practice guideline [8]. Treatment was applied to the newborns with severe RDS.

2.5 Statistical analysis

Data obtained in the study were analyzed statistically using SPSS vn. 21® for Windows software. In the statistical analyses, the Pearson Chi-Square test and two independent samples t-test were used as well as the Student’s t-test for parametric values and the Mann Whitney U-test for non-parametric values. The Wald test was used to evaluate if the presence of each independent variable was significant. The Levene test was applied to determine whether the variances of both groups were equal. Categorical variables were stated as number (n) and percentage (%), and continuous variables as mean±standard deviation (SD) values. Spearman correlation analysis was performed for the assessment of the relationship between PAPP-A and surfactant therapy. A value of p < 0.05 was considered statistically significant.

3 Results

Of the 216 newborns included in the study, 172 (80%) did not require surfactant and 44 (20%) were in need of surfactant. No statistically significant difference was found between the two groups in respect of the maternal demographic characteristics and obstetric parameters. These findings are summarized in Table 1.

Table 1
Maternal demographic characteristics of the study groups. (BMI body mass index, kg/m²)

Receiving surfactant (n:44) Not receiving surfactant (n:172) P value

Age, years 25.3±4.2 26.4±3.3 0.803

Gravidity, n 3.1±0.7 3.4±1.2 0.754

Parity, n 1.8±0.6 1.9±0.4 0.784

Live-birth, n 1.7±0.7 1.8±0.9 0.707

BMI, kg/m² 27.1±3.8 26.8±4.2 0.881

	Receiving surfactant (n:44)	Not receiving surfactant (n:172)	P value
Age, years	25.3±4.2	26.4±3.3	0.803
Gravidity, n	3.1±0.7	3.4±1.2	0.754
Parity, n	1.8±0.6	1.9±0.4	0.784
Live-birth, n	1.7±0.7	1.8±0.9	0.707
BMI, kg/m²	27.1±3.8	26.8±4.2	0.881

A comparison of the PAPP-A values of the two groups revealed that the group that received surfactant had statistically significantly lower PAPP-A values (t (–3.97) = 0.203, p < 0.001) (Fig. 1). The mean birth weight and gestational age at birth of the group that received surfactant were statistically significantly lower than those of the group that did not receive surfactant (p < 0.001). The PAPP-A, birth weight, birth week and APGAR scores are summarized in Table 2.

Fig. 1

PAPP-A MoM values of the study groups.

Table 2

Birth characteristics and PAPP-A MoM values of the study groups. (PAPP-A: Pregnancy associated plasma protein A)

	Receiving surfactant (n:44)	Not receiving surfactant (n:172)	P Value
PAPP-A, MoM	0.76±0.20	1.12±0.59	0.001.
Birth weight, g	1151±530.1	2502±543	0.001.
Gestational week, w	27.50±3.06	34.57±1.47	0.001.
APGAR 1. Min.	7.1±1	7.3±0.9	0.711.
APGAR 5. Min.	8.2±0.3	8.4±0.5	0.802.

When the cut-off value of PAPP-A was taken as 1 and the gestational age was analyzed together with the birth weight, PAPP-A alone was found to be a significant independent variable for the prediction of RDS (p = 0.031; OR:8.2 (1.2–55.6)). A negative low to moderate statistically significant correlation was found between PAPP-A and surfactant therapy at 28–34 gestational weeks (p: 0.013; r:–0.261).

4 Discussion

In this study, which assessed whether or not there was a relationship between the first trimester PAPP-A values and the surfactant needs of the newborns of pregnant women who had a preterm delivery, the infants of the pregnant women with low PAPP-A values were found to have increased a greater need for surfactant. Therefore, it was concluded that PAPP-A alone was significant for the prediction of RDS.

RDS still appears to be a major cause of morbidity and mortality in preterm infants across the world. The etiological basis of RDS seems to be surfactant deficiency. Surfactant protein expression varies depending on the gestational week, with the earliest expression occurring in week 26 with a marked increase in week 32 [9]. The RDS incidence in Turkey has been reported to be 70.3%in deliveries before week 32 and 86.5%in deliveries before week 28 [10]. The same survey reported that the rates of surfactant use were 58.7%at < 32 weeks and 78.8%at week 28 and such high rates were attributed to infrequent use of antenatal steroids [9]. In the current study, 20.3%of the preterm newborns received surfactant for a diagnosis of RDS. This low rate compared to the general rate in Turkey can be linked to the more frequent and effective use of antenatal steroids in our clinical practice.

As a protease produced in the placenta and particularly in extravillous trophoblasts, PAPP-A is a biochemical marker used in first trimester aneuploidy screenings. In normal physiology, PAPP-A uses IGFBP4 as a primary substrate and inhibits it while increasing IGF bioavailability and inducing IGF-mediated growth [7]. Insulin-like growth factors are secreted from the placenta and these play a role in trophoblast invasion, fetal growth and development, and tissue-specific cell proliferation during the early gestational weeks [11]. Insulin and IGF-1 are the fundamental mediators in lung development in fetuses. IGF 1 and 2 bind to IGF-1 receptors and enable cell proliferation, and the presence of an abnormality in the pathways of these factors leads to serious pulmonary complications in the neonatal period [12]. Another molecule in this pathway is IGFBP. Binding proteins other than IGFBP1 are broken down by proteases, thereby reducing their affinity to IGF. Moreover, PAPP-A cleaves IGFBP-4 only when IGFBP-4 is bound to IGF-1. In a study that first revealed the relationship between the IGF system and surfactant protein, IGF-2 deficiency was shown to result in decreased airspace formation in fetal lungs, less alveolar separation, decreased SP-A expression, increased SP-B expression, and a compensatory increase in IGF-1 mRNA [13].

Low PAPP-A values are known to be associated with unfavorable gestational outcomes due to an abnormal karyotype and impaired placentation [4 , 14–16]. These unfavorable gestational outcomes include abortus, pre-eclampsia, fetal growth restriction and low birth weight [4 , 14–17]. A PAPP-A value < 0.4 –0.5 MoM has been considered as a low PAPP-A cut-off value in many studies [18, 19]. The probability of having gestational complications increases at the same rate as the PAPP-A value decreases. A PAPP-A value < 10th centile is known to be associated with unfavorable gestational outcomes but has a poor predictive value [20]. No single marker has yet been shown to have a high sensitivity and specificity in predicting preterm labor and no study has provided clear evidence of an apparent relationship between PAPP-A values and increased risk of preterm labor [21, 22]. Although the PAPP-A cut-off value was taken as 1 MoM in the current study, which was higher than in other studies, it was still found to be effective in predicting RDS. The group receiving surfactant was also found to have an earlier gestational week and a lower birth weight. This result supports the finding in the literature that the PAPP-A value is lower in preterm deliveries [5 , 23]. It also supports the fact that lower PAPP-A values are associated with earlier gestational weeks.

A study in the literature that explored the ratio of IGF-1 to PAPP-A in respect of bronchopulmonary dysplasia in preterm infants showed that the proportion of free IGF-1 increased while PAPP-A concentration decreased [24]. Another study investigating the role of PAPP-A MoM values in predicting RDS in pregnancies over 37 weeks showed that a PAPP-A MoM cut-off value ≦1.02 was associated with significant outcomes [25]. As previously stated, the results of the current study demonstrated that any PAPP-A MoM value less than the accepted PAPP-A cut-off value of 1 MoM was significant in predicting neonatal RDS and the need for surfactant, which was consistent with the results of the studies in the literature.

This study is one of the very few studies in literature to have shown the relationship of the PAPP-A value with RDS and surfactant need as one of the poor neonatal outcomes. The retrospective design of this study was not considered as a limitation, but the number of newborns in need of surfactant was small, rendering it insufficient to make a comparison between the weeks.

In conclusion, low values of PAPP-A, a biochemical marker in first trimester screening tests, have been shown to be associated with poor gestational outcomes in many studies conducted to date. This study can be considered to have demonstrated that PAPP-A MoM values may be significant in predicting the need for surfactant in RDS, a frequently seen condition in the neonatal period. Nevertheless, there is a need for further studies with larger patient cohorts to assess surfactant need according to gestational weeks.

Conflict of interests

The authors have no conflict of interests to declare.

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