Serum cytokines in second trimester pregnancy and their relationship with preterm births in the Ribeirão Preto and São Luiz cohorts

doi:10.21203/rs.3.rs-2459101/v1

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Research Article

Serum cytokines in second trimester pregnancy and their relationship with preterm births in the Ribeirão Preto and São Luiz cohorts

https://doi.org/10.21203/rs.3.rs-2459101/v1

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published 21 Jun, 2023

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Objective: To evaluate the association between second trimester plasma cytokine levels in asymptomatic pregnant women and preterm births (PTB) in an attempt to identify a possible predictor of preterm birth.

Methods: Cohort case-control study including women with singleton pregnancies between 20 and 25 weeks and 6 days of gestation from two Brazilian cities. The patients were interviewed and venous blood samples were collected. The participants were again evaluated at birth. A total of 197 women with PTB comprised the case group. The control group was selected among term births (426 patients). Forty-one cytokines were compared between groups.

Results: When only spontaneous PTB were analyzed, GRO, sCD40L and MCP-1 levels were lower in the case group (p < 0.05). Logarithmic transformation was performed for cytokines with discrepant results, which showed increased levels of IL-2 in the group of spontaneous PTB (p < 0.05). In both analyses, the incidence of maternal smoking and of a history of preterm delivery differed significantly between the case and control groups. In multivariate analysis, only serum GRO levels differed between the case and control groups.

CONCLUSION: Lower second trimester serum levels of GRO in asymptomatic women are associated with a larger number of PTB. This finding may reflect a deficient maternal inflammatory response.

Cytokines

Preterm birth

Prenatal cohorts

Preterm birth (PTB) is defined as birth before 37 weeks of gestation, which may or may not be preceded by labor, and is independent of the newborn’s weight (1). Its incidence varies widely between developed and developing countries and has shown a significant global increase in recent years (2). Preterm births are responsible for about 75% of neonatal deaths and the surviving newborns are susceptible to numerous complications, including respiratory disorders, delayed neuropsychomotor development, cerebral palsy. and other neurological sequelae such as vision, hearing and motor deficits (3, 4).

The physiopathology of PTB is not fully understood but appears to be the result of a multifactorial process in which the interaction of numerous factors transforms the quiescent uterus into an effectively contracting uterus (5). Preterm labor can be caused by activation of the normal labor process or be the consequence of risk conditions and pathological processes (6). The isolated or simultaneous occurrence of some of these pathological processes will lead to a common pathway that is characterized by degradation of the extracellular matrix of the cervix and fetal membranes and by myometrial stimulation, accompanied by uterine contractions, cervical dilatation and membrane rupture (7). Studies have suggested the involvement of some cytokines in the onset of labor and in the pathological processes (8).

Several studies have reported a strong association of high concentrations of inflammatory biomarkers with a short cervix (9) and consequently with PTB, which may be caused by increased levels of the cytokines that triggers rupture of the cervical connective tissue (10). Interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) stimulates the production of prostaglandins in the myometrium. Interleukin 6 (IL-6) stimulates the production of acute-phase proteins and enzymes necessary for prostaglandin production, while IL-8 is important for modification and preparation of the uterine cervix (11).

Cytokines are hydrosoluble glycoproteins or polypeptides that are synthesized and released by different cells types in the organism in response to different stimuli. They can be divided into interleukins (IL-1 to IL-35), chemotactic cytokines (chemokines), tumor necrosis factors, mesenchymal growth factors, and interferons (12). During pregnancy, cytokines trigger contractions and are involved in the onset of labor, in addition to balancing the inflammatory response during the period. Cytokines are also responsible for the maintenance of pregnancy and for the fact that the fetus is not recognized as a foreign body by the maternal immune system (8).

The well-established relationship between inflammation and myometrial contraction that underlies the mechanism of contractions and subsequent progression to labor (preterm or term) allows us to question whether the early emergence of inflammatory markers in maternal venous blood may be an indicator of PTB and whether these markers may be used for population screening because of the easy application of this method and noninvasive sample collection. In view of this association, studies have attempted to determine the role of cytokines in the diagnosis of labor by measuring their levels in vaginal secretions, amniotic fluid, and/or maternal blood. However, these studies are conflicting since their results are variable and inconsistent (13).

The aim of this study was to establish the relationship between serum cytokine levels in asymptomatic women in the second trimester of gestation and PTB, and to identify cytokines that could be used as risk indicators of prematurity in asymptomatic patients in the second trimester.

Study design

This is a case-control study nested within a convenience cohort that is part of a project entitled “Etiological factors of preterm birth and consequences of perinatal factors in child health: birth cohorts in two Brazilian cities” (BRISA project). The BRISA project was approved by the Ethics Committee under number 4116/2008.

The participants were recruited through the municipal health system in Ribeirão Preto (SP) and São Luís (MA) between February 2010 and February 2011. The patients were invited to participate in the project during regular prenatal consultations and those who showed interest were asked to come to the hospitals responsible for data collection in their respective cities: University Hospital of the Ribeirão Preto Medical School (HCRP) in Ribeirão Preto, State of São Paulo, and three maternity units in São Luís, State of Maranhão, Brazil. Only pregnant women with a single fetus and a gestational age between 20 and 25 weeks and 6 days (confirmed by obstetric ultrasound performed at less than 20 weeks of gestation) were included. All patients who agreed to participate in the study signed the free informed consent form. Women with multiple pregnancies and fetuses with congenital malformations or chromosome syndromes diagnosed before 20 weeks or on the occasion of prenatal data collection (confirmed by ultrasound) were excluded.

The pregnant women eligible for the study answered a standard questionnaire and underwent an interview and examinations, including gynecological examination, morphological and transvaginal obstetric ultrasound for the measurement of cervical length (except for pregnant women from São Luís where the uterine cervix is not measured routinely), and collection of a venous blood sample. The team responsible for the collection and processing of the data was adequately trained to ensure homogeneity and applicability of the assessment.

The study involved 2,864 pregnant women from Ribeirão Preto and São Luís. Based on the responses of the birth cohort in the BRISA project, it was possible to identify and exclude from the case.

Group patients who progressed to PTB because of obstetric indications (n = 82), constituting a new group (n = 115) of cases that contained only spontaneous PTB (spontaneous PTB group). Spontaneous PTB was defined as that resulting from preterm labor or chorioamniorrhexis.

The control group (pregnant women who delivered at term, ≥ 37 weeks) was selected by simple random drawing without replacement from the remaining cohort at a proportion of 2:1 in their respective cities (426 patients). Thus, the total sample of the study consisted of 623 patients.

For cytokine analysis, venous blood samples were collected at the time of assessment of the prenatal cohort and sent to the laboratory for centrifugation and separation of serum. The serum samples were stored in a freezer for subsequent analysis in the case and control groups. The serum inflammatory markers (IL-1ß, IL-6, IL-8, IL-10 and TNF-α, among other cytokines, totaling 41 different markers) were measured using a high-sensitivity assay (Milliplex Map Human Cytokine/Chemokine Panel, Cat HCYTOMAG-60K-PX41, Millipore Corporation, Billerica, MA, USA) according to manufacturer recommendations. The analytes were quantified in a Luminex 200 analyzer (Millipore Corporation, Billerica, MA, USA) using the Analyst Software and the results are expressed as pg/ml.

The seven most studies cytokines associated with PTB were measured: TNF, IFN-γ, IL-1, IL-6, IL-17 (proinflammatory), and TGF-ß and IL-10 (anti- inflammatory), added to the 41 markers available in the commercial kit used in the study.

Variables that could influence the number of PTB were also analyzed (14): maternal age (< 20, 20 to 34, ≥ 35 years), parity (1, 2–3, ≥ 4 births), history of PTB (yes and no), smoking (yes, if the patient had smoked at least one cigarette per day during pregnancy, and no), and genitourinary infection (urinary tract infection confirmed by urine culture and/or bacterial vaginosis confirmed by clinical and microscopic examination). Cervical length was not considered since this parameter was not evaluated in patients from São Luís. The following data were collected at birth: city and hospital of birth, date of birth, and gestational age at birth in days.

Statistical analysis

Statistical analysis was performed in two steps. First, all women with PTB that had their cytokines measured in the prenatal cohort of the BRISA project were included and comprised the case group (PTB group). The following variables were compared between the case and control groups: maternal age, parity, history of PTB, smoking and presence of genitourinary infection, as well as the 41 inflammatory markers. Second, based on the responses of the birth cohort in the BRISA project, it was possible to identify and exclude from the case group patients who progressed to PTB because of obstetric indications (n = 82), constituting a new group (n = 115) of cases that contained only spontaneous PTB (spontaneous PTB group). Spontaneous PTB was defined as that resulting from preterm labor or chorioamniorrhexis.

The data were tabulated in an Excel spreadsheet and then exported to the SAS 9.3 program (SAS Institute, Inc., 2010). First, exploratory analysis was performed using measures of central tendency and dispersion and box plots. The Student t-test was used to compare mean values of the variables of interest between the two groups. The level of significance was set at 5%. The proc ttest procedure of the software was used for all tests. For variables showing wide variability whose distribution was not symmetrical, logarithmic transformation was performed and the results were compared to those obtained with the tests without transformation to evaluate the influence of outliers. Variables that differed between the case and control groups were then submitted to multivariate analysis.

A total of 2,864 pregnant women from Ribeirão Preto and São Luís were included in the study. There were 242 women with PTB (8.7% of all patients, n = 2,757). Forty-five PTB were excluded from the study because of insufficient data or the impossibility of analyzing inflammatory markers (not collected, inadequate sample). Spontaneous PTB group was n = 115 of cases. The control group (pregnant women who delivered at term, ≥ 37 weeks) was selected by simple random drawing without replacement at a proportion of 2:1 in their respective cities (426 patients). Thus, the total sample of the study consisted of 623 patients. In the group that included only spontaneous PTB (spontaneous PTB group), the mean age at birth was 239.8 days.

Exclusive comparison between the spontaneous PTB group (n = 115) and the control group revealed no expressive changes in relation to those observed in the PTB group as a whole. A significant difference was only observed for maternal smoking and a history of preterm delivery in previous pregnancies. Maternal age, parity or infections did not differ between the two groups (Table 1).

Table 1

Clinical characteristics of women with spontaneous preterm birth (spontaneous PTB group) and women who delivered at term (control group). BRISA Cohort, Ribeirão Preto and São Luís, 2010.
Variables	Spontaneous PTB group		Control group		p¹
	n	%	n	%
Maternal age (years)
≤ 20	11	9.6	35	8.2	0.5362
20–34	95	82.7	368	86.4
≥ 35	9	7.7	23	5.4
Total	115	100	426	Total
Parity
1	51	44.3	200	46.9	0.8412
2–3	51	44.3	184	43.2
≥ 4	13	11.4	42	9.9
Total	115	100	426	100
Smoking
Yes	26	22.6	63	14.8	0.0447
No	89	77.4	363	85.2
Total	115	100	426	100
Previous preterm delivery
Yes (1 or more)	74	64.3	29	6.8	≤ 0.0001
No	41	35.7	397	93.2
Total	115	100	426	100
Genitourinary infections*
Yes	38	33.1	102	23.9	0.0653
No	77	66.9	324	76.1
Total	115	100	426	100
¹ Chi-squared test.
*Urinary tract infection confirmed by urine culture and/or bacterial vaginosis confirmed by clinical and microscopic examination.

A significant difference between the two groups was also observed for cytokines GRO, with lower levels in patients with spontaneous PTB. On the other hand, this analysis revealed a significant difference in MCP-1 (monocyte chemoattractant protein 1), whose levels were also lower in the spontaneous PTB group (Table 2).

Table 2

Comparison of the mean levels and standard deviation of 41 cytokines between women with spontaneous preterm birth (PTB group) and women who delivered at term (control group). BRISA Cohort, Ribeirão Preto and São Luís, 2010
Cytokine	Group	Mean (pg/ml)	SD	p	Cytokine	Group	Mean (pg/ml)	SD	p
EGF	Spontaneous PTB	176.5	121.8	0.7054	IL-17A	Spontaneous PTB	34.7405	58.5471	0.4246
EGF	Control	171.7	122.5	0.7054	IL-17A	Control	41.6835	88.0351	0.4246
FGF-2	Spontaneous PTB	141.4	84.4845	0.7167	IL-1Ra	Spontaneous PTB	104.7	103	0.6848
FGF-2	Control	138	91.4382	0.7167	IL-1Ra	Control	114	237.5	0.6848
Eotaxin	Spontaneous PTB	110.4	77.0536	0.4453	IL-1 alpha	Spontaneous PTB	53.5263	57.5685	0.7778
Eotaxin	Control	117.2	86.1486	0.4453	IL-1 alpha	Control	55.8531	83.126	0.7778
TGF-alpha	Spontaneous PTB	17.5826	22.0619	0.1721	IL-9	Spontaneous PTB	5.1318	5.4218	0.3738
TGF-alpha	Control	21.3524	27.2512	0.1721	IL-9	Control	7.8791	32.9569	0.3738
G-CSF	Spontaneous PTB	153.4	106.5	0.6318	IL-1 beta	Spontaneous PTB	5.5833	5.048	0.782
G-CSF	Control	159.8	131	0.6318	IL-1 beta	Control	5.8939	11.7356	0.782
Flt-3L	Spontaneous PTB	59.6808	62.4317	0.3428	IL-2	Spontaneous PTB	15.5117	40.3502	0.2089
Flt-3L	Control	69.3022	103.7	0.3428	IL-2	Control	11.0445	31.7993	0.2089
GM-CSF	Spontaneous PTB	64.388	76.1811	0.625	IL-3	Spontaneous PTB	3.5501	3.1609	0.44
GM-CSF	Control	60.3111	80.1452	0.625	IL-3	Control	3.1752	4.9347	0.44
Fractalkine	Spontaneous PTB	87.7148	60.4493	0.8997	IL-4	Spontaneous PTB	52.2345	92.5687	0.4713
Fractalkine	Control	88.7183	79.2915	0.8997	IL-4	Control	45.4329	89.0372	0.4713
IFN-A2	Spontaneous PTB	79.2312	53.3346	0.8098	IL-5	Spontaneous PTB	4.4548	7.2135	0.6437
IFN-A2	Control	77.7269	60.968	0.8098	IL-5	Control	4.9761	11.4787	0.6437
IFN-gamma	Spontaneous PTB	55.5616	87.3259	0.5201	IL-6	Spontaneous PTB	20.3197	24.027	0.9203
IFN-gamma	Control	64.1897	136.4	0.5201	IL-6	Control	19.8816	45.1858	0.9203
GRO	Spontaneous PTB	1560.1	809.5	0.0022	IL-7	Spontaneous PTB	37.8736	48.6891	0.8619
GRO	Control	1950.6	1295.9	0.0022	IL-7	Control	38.8954	57.6335	0.8619
IL-10	Spontaneous PTB	9.9393	10.6842	0.3814	IL-8	Spontaneous PTB	59.9677	94.6081	0.6751
IL-10	Control	14.156	51.2865	0.3814	IL-8	Control	64.1658	95.4174	0.6751
MCP-3	Spontaneous PTB	58.2181	69.1722	0.562	IP10	Spontaneous PTB	413.4	245.5	0.5403
MCP-3	Control	53.9615	69.9875	0.562	IP10	Control	428.9	238.3	0.5403
IL-12P40	Spontaneous PTB	48.2861	47.7999	0.2179	MCP-1	Spontaneous PTB	377.5	206.7	0.0169
IL-12P40	Control	42.2234	46.4873	0.2179	MCP-1	Control	433.1	224.2	0.0169
MDC	Spontaneous PTB	1628.3	790.7	0.247	MIP-1A	Spontaneous PTB	35.6473	99.1318	0.4056
MDC	Control	1745.7	1005.3	0.247	MIP-1A	Control	76.0285	517.3	0.4056
IL-12P70	Spontaneous PTB	28.987	62.8652	0.4488	MIP-1B	Spontaneous PTB	86.133	85.9299	0.7682
IL-12P70	Control	49.556	289	0.4488	MIP-1B	Control	83.445	86.9795	0.7682
PDGF-AA	Spontaneous PTB	50.6634	51.43635	0.4126	RANTES	Spontaneous PTB	10062.5	5834.2	0.313
PDGF-AA	Control	1077425	6968028	0.4126	RANTES	Control	10784.8	7044.1	0.313
IL-13	Spontaneous PTB	14.925	18.8452	0.9919	TNF-alpha	Spontaneous PTB	16.3717	24.7215	0.7801
IL-13	Control	14.8995	24.943	0.9919	TNF-alpha	Control	17.0187	21.2659	0.7801
PDGF-BB	Spontaneous PTB	27225.8	12172.9	0.1604	TNF-beta	Spontaneous PTB	26.2545	36.9784	0.6261
PDGF-BB	Control	28924.3	11311.4	0.1604	TNF-beta	Control	29.518	69.135	0.6261
IL-15	Spontaneous PTB	17.2228	48.6253	0.3712	VEGF	Spontaneous PTB	319.1	272.3	0.4898
IL-15	Control	13.3801	38.5093	0.3712	VEGF	Control	361.8	646.6	0.4898
SCD40L	Spontaneous PTB	343608	285042	0.0082
SCD40L	Control	426611	301208	0.0082
* Student t-test.
Cytokines: EGF: epidermal growth factor; FGF2: fibroblast growth factor; TGF-alpha: transforming growth factor alpha; G-CSF: granulocyte colony-stimulating factor; Flt-3L: Fms-related tyrosine kinase 3; GM-CSF: granulocyte macrophage colony stimulating factor; IFN-A2: interferon alpha 2; IFN-gamma: interferon gamma; GRO: growth related oncogene; IL-10: interleukin 10; MCP-3: monocyte chemoattractant protein 3; IL12p40: interleukin 12p40; MDC: monocyte chemotactic protein; IL12p70: interleukin 12p70; PDGF-AA: platelet-derived growth factor AA; IL-13: interleukin 13; PDGF-BB: platelet-derived growth factor BB; IL-15: interleukin 15; SCD40L: soluble CD40-ligand; IP10: interferon gamma-induced protein 10; MCP1: monocyte chemoattractant protein 1; MIP: macrophage inflammatory protein; TNF: tumor necrosis factor; VEFG: vascular endothelial growth factor; RANTES: regulated on activation, normal T cell expressed and secreted.

Logarithmic transformation was performed for cytokines with very discrepant values from the mean (outliers) and the results were compared with those obtained by tests without transformation to identify the possible influence of these outliers. Among the reevaluated cytokines, a significant difference was observed for Log IL-2 in the group involving only spontaneous PTB (p = 0.03) (Table 3).

Table 3

Comparison of IL-2 between women with preterm birth (PTB and spontaneous PTB groups) and women who delivered at term (control group).
	Group	Mean	SD	p
IL-2 (only spontaneous PTB)	Spontaneous PTB group	15.5117	40.3502	0.2089
IL-2 (only spontaneous PTB)	Control group	11.0445	31.7993
Log IL-2 (only spontaneous PTB)	Spontaneous PTB group	1.7283	1.1927	0.0326
Log IL-2 (only spontaneous PTB)	Control group	1.4544	1.2225
SD: standard deviation

In multivariate analysis, only a history of preterm delivery and GRO were associated with PTB. Patients with a history of preterm delivery had an almost 7 times higher risk of PTB (RR: 7.63; 95%CI: 5.20, – 11.23). As the measurement unit of GRO increased, the risk of PTB decreased. Since the marker-related variables are continuous, the estimates were very close to 1 (Table 4).

Table 4

Unadjusted and adjusted relative risk, 95% confidence interval and p-value of multivariate analysis involving inflammatory factors and clinical characteristics.
Variable	Unadjusted RR	95% CI		p	Adjusted RR	95% CI		p
		LL	UL			LL	UL
Previous preterm delivery	7.63	5.20	11.23	< .0001	7.19	4.90	10.52	< .0001
Smoking	1.48	0.95	2.29	0.077	1.25	0.80	1.96	0.323
GRO	1.00	1.00	1.00	0.006	1.00	1.00	1.00	0.033
IL-2	1.00	1.00	1.01	0.269	1.00	1.00	1.01	0.587
SCD40L	1.00	1.00	1.00	0.019	1.00	1.00	1.00	0.064
MCP-1	1.01	1.00	1.01	0.034	1.01	1.00	1.01	0.118
RR: relative risk; 95% CI: 95% confidence interval; LL: lower limit; UL: upper limit

The present study evaluated characteristics throughout the prenatal period that could be associated with PTB, more specifically spontaneous PTB, i.e., that resulting from preterm labor or rupture of the chorioamniotic membranes. For this purpose, maternal characteristics and serum cytokine concentrations were analyzed in two groups of patients for subsequent calculation of the relative risk in univariate and multivariate analyses.

Studies have investigated risk factors of prematurity and the most important maternal risk factors include extreme ages (14, 15), smoking (14, 16, 17), genitourinary infections (18), and a history of preterm delivery (14, 19). The last is the main risk factor associated with prematurity; the larger the number of previous PTB, the greater the risk of prematurity (14, 20).

Our results only identified a history of at least one preterm delivery as a risk factor for spontaneous PTB, while no association was observed with maternal age, parity, smoking or genitourinary infection. These discrepant findings might be related to the small sample size, the choice of the control group, and the fact that a convenience cohort was studied.

In addition to maternal characteristics, we examined the serum concentrations of inflammatory markers (cytokines, chemokines, and growth factors) in asymptomatic pregnant women in the second trimester and compared them between patients with PTB and a group of patients who delivered at term. Among the 41 cytokines analyzed, only GRO was a risk factor for spontaneous prematurity. The mean level of this cytokine was lower in the PTB group, although the literature shows an association between increased serum proinflammatory cytokines and PTB (21).

GRO is a chemokine that consists of three subunits: GRO𝛼/CXCL1, GRO𝛽/CXCL2, and GRO𝛾/CXCL3. This chemokine is produced by different cell types such as synovial cells, monocytes, fibroblasts, and endothelial cells. Its production is directly influenced by 7 IL-8, which is responsible for neutrophil activation and chemotaxis of inflammatory cells (22). Some studies have shown that an increase in chemokines (23) of the CXC family in maternal serum (24) and in amniotic fluid of patients with chorioamnionitis (24) was associated with PTB.

Our findings are biologically plausible. Laudanski et al. (25) also found significantly lower serum GRO concentrations in pregnant women with preterm labor compared to women who delivered at term (> 37 weeks of gestation), but did not establish a causal relationship between the serum concentration of this cytokine and progression to prematurity. On the other hand, Hsu et al. (24) detected higher concentrations of the alpha subunit of this cytokine in patients who progressed to PTB. Low serum GRO levels may reflect a deficient inflammatory response and increased susceptibility to infections, increasing the risk of triggering a myometrial contractile response and PTB. Some studies have demonstrated that lower serum or cervical concentrations of proinflammatory cytokines can predispose to infection and chorioamnionitis, which can cause PTB (26), in agreement with the findings of the present study.

The analysis of this study may be compromised by the fact that it was not possible to assess changes in the plasma concentrations of the inflammatory markers throughout pregnancy, which would allow to identify critical periods during which cytokine levels would reflect the real increase in the risk of prematurity. Another limitation of the study is the impossibility of evaluating cervical characteristics and their association with serum levels of the inflammatory markers since the patients from São Luís did not undergo specific ultrasound examination to measure cervical length in the prenatal cohort. Normal cut-off values for the cytokines are not available in the literature for direct comparison with the outcome (prematurity). The results of different studies are still insufficient to indicate the serum concentration of inflammatory markers in asymptomatic patients in the second trimester as a parameter to predict PTB or to identify at-risk populations.

Ethics approval and consent to participate.

"The Ethics Committee of the University Hospital of the Ribeirão Preto Medical School approved this study under protocol number 4116/2008 and our methods are in accordance with the guidelines and regulations of the Declaration of Helsinki and that informed consent was obtained from all subject’s participants of the analysis used in this study".

Consent for publication

Not Applicable.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Competing interests

We authors affirm that in our manuscript there is no conflict of interest.

Funding

We authors declare there is no funding.

Authors' contributions

Suzana Eggers Turra - Project Administration, Data Curation, Formal Analysis, Writing – Original Draft, Writing – Review & Editing

Ênio Luis Damaso - Writing – Original Draft, Writing – Review & Editing

Eduardo Carvalho de Arruda Veiga - Writing – Original Draft, Writing – Review & Editing

Viviane Cunha Cardoso - Writing – Original Draft, Writing – Review & Editing

Heloísa Bettiol - Writing – Original Draft, Writing – Review & Editing

Ricardo Carvalho Cavalli - Project Administration, Data Curation, Formal Analysis, Writing – Original Draft, Writing – Review & Editing

Acknowledgements

We authors would like Acknowledgments to FAPESP, CAPES, Cnpq and FAEPA.

We authors would like to confirm that our methods are in accordance with the guidelines and regulations of the Declaration of Helsinki

We authors would like to confirm that in our work there was only data collected with people of legal age, over 18 years old in our country.

Availability of Data and Materials

We authors would like to confirm that the “Availability of Data and Materials” section will be on the website that the journal prefers in case of publication.

• The datasets used and/or analyses during the current study available from the corresponding author on reasonable request.

• Not applicable. If your manuscript does not contain any data as no datasets were generated or analyses during the study, please state 'Not applicable' in this section.

We authors declare • Not applicable for all this section.

The correct name of the co-author is Eduardo Carvalho de Arruda Veiga

Conflicts of interests

The authors have no conflict of interest to declare.

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No competing interests reported.

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Serum cytokines in second trimester pregnancy and their relationship with preterm births in the Ribeirão Preto and São Luiz cohorts

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