Abstract
Objective: Fetal hypoxemia has been proposed to be one of the mechanisms of preterm labor (PTL) and delivery. This may have clinical implications since it may alter: (i) the method/frequency of fetal surveillance and (ii) the indications and duration of tocolysis to an already compromised fetus. The aim of this study was to examine whether there is a difference in the fetal blood gas analysis [pH, PaO2 and base excess (BE)] and in the prevalence of fetal acidemia and hypoxia between: (i) patients in PTL who delivered within 72 hours vs. those who delivered more than 72 hours after cordocentesis and (ii) patients with fetal inflammatory response syndrome (FIRS) vs. those without this condition. Study design: Patients admitted with PTL underwent amniocentesis and cordocentesis. Ninety women with singleton pregnancies and PTL were classified according to (i) those who delivered within 72 hours (n = 30) and after 72 hours of the cordocentesis (n = 60) and (ii) with and without FIRS. FIRS was defined as a fetal plasma concentration of IL-6 > 11 pg/mL. Fetal blood gases were determined. Acidemia and hypoxemia were defined as fetal pH and PaO2 below the 5th percentile for gestational age, respectively. For comparisons between the two study groups, ΔpH and ΔPaO2 were calculated by adjusting for gestational age (Δ = observed value – mean for gestational age). Non-parametric statistics were employed. Results: No differences in the median Δ pH (−0.026 vs. −0.016), ΔPaO2 (0.25 mmHg vs. 5.9 mmHg) or BE (−2.4 vs. −2.6 mEq/L) were found between patients with PTL who delivered within 72 hours and those who delivered 72 hours after the cordocentesis (p > 0.05 for all comparisons). Fetal plasma IL-6 concentration was determined in 63% (57/90) of fetuses and the prevalence of FIRS was 28% (16/57). There was no difference in fetal pH, PaO2 and BE between fetuses with and without FIRS (p > 0.05 for all comparisons). Moreover, there was no difference in the rate of fetal acidemia between fetuses with and without FIRS (6.3 vs. 9.8%; p > 0.05) and fetal hypoxia between fetuses with or without FIRS (12.5 vs. 19.5%; p > 0.05). Conclusions: Our data do not support a role for acute fetal hypoxemia and metabolic acidemia in the etiology of PTL and delivery.
Introduction
Spontaneous preterm parturition is a syndrome [Citation1–8] characterized by activation of the common pathway of parturition (uterine contractility, cervical ripening and membrane/decidual activation). Recruitment of the different components can be synchronous or asynchronous; hence, the clinical manifestations may be increased preterm uterine contractility, cervical insufficiency or a short cervix and rupture of membranes.
The clinical picture that characterizes the extreme phenotype of the syndrome(s) is well-known by obstetricians and is part of classical obstetrics (preterm labor [PTL] with intact membranes, preterm prelabor rupture of membranes [PROM] and cervical insufficiency). On the other hand, the fact that the syndrome(s) is/are due to multiple etiologies was proposed approximately 20 years ago [Citation9], but this has only gained acceptance recently [Citation2,Citation3,Citation10].
The multiple pathologic processes responsible for the preterm parturition syndrome include intrauterine infection/inflammation [Citation11–31], uterine overdistension [Citation32–35], allergic-like reaction [Citation36–40], cervical disorders (i.e. a short cervix [Citation41–45]), allogenic rejection [Citation46–50], endocrine disorders (i.e. a suspension of progesterone action [Citation51–54]), maternal or fetal stress [Citation55–59] and uterine ischemia [Citation60–68]. We have also proposed that other mechanisms of disease unique to the pregnant state may cause preterm birth, but remain to be discovered [Citation1].
Uteroplacental ischemia has been considered a mechanism of disease responsible for preeclampsia and intrauterine growth restriction (IUGR); yet, there is a growing body of evidence that uteroplacental ischemia can also result in PTL and delivery. The evidence for this includes:
| (1) | Biological plausibility: experimental studies in which uterine ischemia generated by narrowing the lumen of the uterine arteries in non-human primates (in an attempt to generate a model for preeclampsia) often failed because of the spontaneous onset of PTL/delivery [Citation63] | ||||
| (2) | Pathologic observations: placental bed biopsies of patients with PTL and preterm PROM who delivered preterm had a higher percentage of failure of physiologic transformation in the myometrial segment of the spiral arteries than women who delivered at term [Citation65,Citation66]. This lesion was generally associated with preeclampsia and IUGR, but is now known to be associated with spontaneous PTL [Citation65,Citation66] | ||||
| (3) | Vascular resistance in the uterine arteries: Doppler velocimetry studies of the uterine arteries indicate that a subgroup of patients with increased impedance to blood flow in the uterine arteries in the second trimester of pregnancy are at increased risk for preeclampsia and IUGR; however, a subgroup with neither of these two conditions is at increased risk for spontaneous PTL/delivery [Citation64] | ||||
| (4) | Increased impedance to flow in the uterine arteries of patients with PTL destined to deliver preterm: uterine artery Doppler velocimetry studies of patients in PTL indicate that women who deliver preterm are more likely to have abnormal Doppler indices than those with an episode of PTL who deliver at term [Citation61] | ||||
| (5) | Placental pathology: vascular lesions in the decidual vessels on the basal plate of the placenta are more common in patients with PTL and preterm PROM than in those who deliver at term [Citation60], and | ||||
| (6) | Evidence of an imbalance between angiogenic and anti-angiogenic factors in patients with PTL: results of a longitudinal study indicate that a subset of women destined to develop spontaneous PTL/delivery had an abnormal angiogenic/anti-angiogenic profile in maternal plasma before the onset of PTL [Citation62]. Of interest is that, in these patients, the most common pathologic lesions of the placenta were consistent with maternal underperfusion rather than acute chorioamnionitis, and that such patients had elevated concentrations of maternal plasma endoglin, a potent anti-angiogenic factor [Citation62]. | ||||
However, it is clear that the degree of ischemia observed in patients with PTL and preterm PROM is much less than that noted in patients with preeclampsia, IUGR and fetal death [Citation66]. Indeed, fetal acidemia and hypoxemia are rare in neonates born after PTL and preterm PROM, but this is not the case in patients with preeclampsia and IUGR. Yet, hypoxia has been proposed to be a cause of PTL.
The fetal inflammatory response syndrome (FIRS), originally described in pregnancies complicated by spontaneous PTL and preterm PROM, was operationally defined as an elevation of the fetal plasma IL-6 concentration of >11 pg/mL [Citation69–71]. It is now clear that FIRS develops in cases of intra-amniotic infection/inflammation [Citation20,Citation72–76]. Fetuses with FIRS have a higher rate of neonatal morbidity [e.g. respiratory distress syndrome (RDS [Citation69]), suspected or proven neonatal sepsis [Citation69,Citation73], pneumonia [Citation69], bronchopulmonary dysplasia [Citation77–79], intraventricular hemorrhage [Citation69], periventricular leukomalacia [Citation80] and cerebral palsy [Citation22,Citation80–88] and a shorter cordocentesis-to-delivery interval in patients presenting with preterm PROM [Citation70].
Intra-amniotic infection/inflammation is associated with changes in proinflammatory cytokines [Citation18,Citation89–98], anti-inflammatory cytokines [Citation99], caspase-1 (a component of an inflammasome [Citation100]), chemokines [Citation101–107], protease-antiprotease [Citation108], angiogenic factors [Citation109], adipocytokines [Citation110–113], hemostatic factors [Citation114,Citation115], complement products [Citation116,Citation117], anti-microbial peptides [Citation118–120], soluble pattern recognition receptors (pentraxin [Citation121]), damage-associated molecular patterns or alarmins and their receptors [Citation122–126], matrix degrading enzymes [Citation76,Citation127–136], arachidonate lipoxygenase metabolites and prostaglandins [Citation137–140] in amniotic fluid, and is a strong risk factor for neonatal morbidity in preterm neonates [Citation27,Citation30,Citation72,Citation73,Citation88,Citation141–143]. Moreover, fetuses with funisitis, the histologic hallmark of FIRS, have a higher rate of production of reactive oxygen radicals than those without funisitis [Citation144].
Infection is not the only cause of systemic inflammation or a systemic inflammatory response syndrome (SIRS): for example, patients with pancreatitis or burns have systemic inflammation in the absence of demonstrable infection. Moreover, ischemia and/or hypoxemia can also elicit changes that resemble systemic inflammation. Guinea pigs subjected to chronic hypoxemia have dramatically elevated levels of IL-6 and tumor necrosis factor-α concentrations in fetal blood [Citation145]. This observation led the authors to propose that FIRS may be an adaptive response of the fetus to chronic hypoxemia. Is it possible that hypoxemia plays a role in the generation of FIRS and PTL?
The aim of this study was to determine whether there is a difference in the fetal blood pH and gases (pH, PaO2 and base excess [BE]) between: 1) patients presenting with PTL who delivered within 72 hours and those who delivered more than 72 hours after the cordocentesis; and 2) patients with and without FIRS prior to delivery.
Materials and methods
Patients and eligibility
This retrospective cross-sectional study included ninety women who presented to Hutzel Women’s Hospital with PTL and intact membranes between March 1992 and June 1995. Women were offered amniocentesis for the diagnosis of microbial invasion of the amniotic cavity and the assessment of fetal lung maturity. Patients who consented to have an amniocentesis were asked to participate in a research protocol that included a cordocentesis to assess the fetal status. The inclusion criteria were: (i) PTL with intact membranes; (ii) consent to have an amniocentesis and cordocentesis; and (iii) availability of skilled medical staff to perform amniocentesis and cordocentesis. The exclusion criteria were: (i) clinical chorioamnionitis; (ii) multiple gestations; (iii) non-reassuring fetal heart rate pattern; and (iv) significant vaginal bleeding.
All patients provided written informed consent prior to the collection of samples. The collection and utilization of samples for research purposes was approved by the Human Investigation Committee of Wayne State University (Detroit, MI) and the Institutional Review Board of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD/NIH/DHHS). Many of these samples have been used in previous studies.
Clinical and laboratory definitions
The diagnosis of PTL was made in the presence of regular uterine contractions (at least 3 in 30 minutes) and documented cervical change assessed by digital examination in patients with a gestational age between 20 and 36 6/7 weeks. All patients had PTL and were classified according to the interval procedure-to-delivery in two groups: those who delivered within 72 hours of the cordocentesis (n = 30) and those who delivered more than 72 hours after the cordocentesis (n = 60). Gestational age was assigned on the basis of information obtained from the earliest available ultrasonographic examination and last known period. FIRS was defined as a fetal plasma concentration of IL-6 > 11 pg/mL [Citation69]. Intra-amniotic infection was defined as a positive microbiological culture of amniotic fluid and intra-amniotic inflammation was diagnosed when amniotic fluid, concentrations of IL-6 were >2.6 ng/mL [Citation143]. Fetal acidemia and hypoxemia were defined as fetal pH and PaO2 below the 5th centile for gestational age based on a previously published reference range [Citation146]. For comparisons between the two study groups, ΔpH and ΔPaO2 were calculated by adjusting for gestational age (Δ = observed value – mean for gestational age [Citation146]). Base excess was calculated using the following formula: 0.93 × HCO3 + (13.77 × pH) – 124.58.
Amniotic fluid and fetal blood sample collection
All patients had a detailed ultrasonographic examination before the amniocentesis and cordocentesis were performed. Electronic fetal monitoring was conducted before and after the procedure to evaluate fetal well-being. Amniocentesis/cordocentesis proce-dures were performed under ultrasound guidance with the “free-hand technique” [Citation147]. One percent lidocaine was given as a local anesthetic, but no sedative drugs were administered. A 22-gauge needle was used, and a path was chosen for needle insertion that allowed the Amniocentesis/cordocentesis procedures to be carried out with a single percutaneous needle insertion in approximately 95% of patients. Amniotic fluid was sent for Gram stain, microbiologic culture, IL-6 and fetal lung maturity studies when indicated. Fetal venous blood was collected in ethylenediaminetetra-acetic acid (EDTA) tubes. Kleihauer-Betke stains were performed on fetal blood, and all specimens were found to be free of maternal blood. In addition, fetal blood was analyzed for pH, gases (pO2 and BE) and IL-6. IL-6 concentrations were determined with commercially available enzyme-linked immunoassays obtained from R&D Systems (Minneapolis, MN, USA). Briefly, the immunoassay utilized the quantitative sandwich technique, and analyte concentrations were determined by interpolation from the standard curves. The sensitivity of the assay was 0.06 pg/mL. The inter- and intra-assay coefficients of variation for IL-6 were 8.3% and 3.3%, respectively.
Statistical analysis
The Kolmogorov–Smirnov or Shapiro–Wilk test was used to determine whether the data were normally distributed. A two-tailed Mann–Whitney U test was used to compare continuous non-normally distributed variables. Comparisons between proportions were performed using χ-square or Fisher’s exact tests. Correlation between two continuous variables was determined using Spearman’s rank correlation test. A p value <0.05 was considered statistically significant. Analysis was performed with SPSS, version 12 (SPSS Inc., Chicago, IL, USA).
Results
Patients who delivered within 72 hours (n = 30) had a lower gestational age at cordocentesis than those who delivered more than 72 hours (n = 60) after the cordocentesis (p < 0.01; see ). By design, gestational age at delivery and birthweight were significantly lower in patients who delivered within 72 hours of the procedure (both p <0.001, see ). Among patients who delivered more than 72 hours after the cordocentesis, 76.7% (46/60) delivered at term. Among patients who delivered at term (n = 46) or those without FIRS (n = 41), there was no correlation between gestational age at cordocentesis and fetal plasma IL-6 concentrations.
Table I. Clinical and demographic characteristics of the study population.
Fetal pH, PaO2 and BE in patients who delivered within 72 hours and those who delivered more than 72 hours after the cordocentesis
There were no significant differences in the median fetal blood pH or ΔpH between those who delivered within 72 hours after the cordocentesis and those who delivered 72 hours after the cordocentesis (fetal blood pH median 7.38, interquartile range [IQR] 7.35–7.40 vs. median 7.38, IQR 7.36–7.40, respectively; p = 0.7 and fetal blood Δ pH median −0.026, IQR −0.4 to −0.005 vs. median −0.016, IQR −0.042 to −0.0005, respectively; p = 0.8; see and ). There was no difference in the rate of fetal acidemia between patients who delivered before or after 72 hours of the cordocentesis (delivered within 72 hours; 16.7% (5/30) vs. delivered after 72 hours; 18.3% (11/60); p = 0.8).
Figure 1. Fetal pH in patients who delivered within 72 hours after the cordocentesis and those who delivered more than 72 hours after the cordocentesis. There was no difference in the median fetal blood ΔpH between those who delivered within 72 hours after the cordocentesis and those who delivered 72 hours after the cordocentesis [median: −0.026, (IQR −0.4–−0.005) vs. median: −0.16, (IQR −0.042–−0.0005); p > 0.05].
![Figure 1. Fetal pH in patients who delivered within 72 hours after the cordocentesis and those who delivered more than 72 hours after the cordocentesis. There was no difference in the median fetal blood ΔpH between those who delivered within 72 hours after the cordocentesis and those who delivered 72 hours after the cordocentesis [median: −0.026, (IQR −0.4–−0.005) vs. median: −0.16, (IQR −0.042–−0.0005); p > 0.05].](/cms/asset/707a8d00-aa4a-4bd6-9b08-9f930149c61c/ijmf_a_629247_f0001_b.gif)
Table II. pH, gas analysis and IL-6 concentrations in the study population.
In addition, there was no significant difference in the median fetal PaO2 or ΔPaO2 between those who delivered within 72 hours after the cordocentesis and those who delivered more than 72 hours after the cordocentesis (PaO2 median 40.3 mmHg, IQR 27.5 to –49.1 vs. median 44.5 mmHg, IQR 33.4–52.9, respectively; p = 0.2 and ΔPaO2 median 0.25 mmHg, IQR −9.57–9.12 vs. median 5.9 mmHg, IQR −3.21–16.2, respectively; p = 0.06); see and ). Moreover, there was no difference in the rate of fetal hypoxia between patients who delivered before or after 72 hours of the cordocentesis (delivered before 72 hours; 20% (6/30) vs. delivered after 72 hours; 6.7% (4/60); p = 0.08).
Figure 2. Fetal PaO2 in patients who delivered within 72 hours after the cordocentesis and those who delivered more than 72 hours after the cordocentesis. There was no difference in the median ΔPaO2 between those who delivered within 72 hours after the cordocentesis and those who delivered 72 hours after the cordocentesis [median: 0.25 mmHg, (IQR −9.57 to –9.12) vs. median: 5.9 mmHg, (IQR −3.21 to –16.2); p > 0.05].
![Figure 2. Fetal PaO2 in patients who delivered within 72 hours after the cordocentesis and those who delivered more than 72 hours after the cordocentesis. There was no difference in the median ΔPaO2 between those who delivered within 72 hours after the cordocentesis and those who delivered 72 hours after the cordocentesis [median: 0.25 mmHg, (IQR −9.57 to –9.12) vs. median: 5.9 mmHg, (IQR −3.21 to –16.2); p > 0.05].](/cms/asset/e86522e5-a4ff-4084-9ff8-2ccdf225a0ab/ijmf_a_629247_f0002_b.gif)
Similarly, there was no significant difference in the median fetal BE between those who delivered within 72 hours of the cordocentesis and those who delivered after 72 hours of the cordocentesis (median −2.4 mEq/L, IQR −3.3 to −1 vs. median −2.6 mEq/L, IQR −4.2 to −1.3; p = 0.7; see ). Furthermore, there was no significant relationship between the procedure-to-delivery interval and the fetal blood pH, ΔpH, PaO2 or ΔPaO2 (all p > 0.05).
Figure 3. Fetal base excess in patients who delivered before 72 hours after the cordocentesis and those who delivered more than 72 hours after the cordocentesis. There was no difference in the median fetal base excess between those who delivered before 72 hours of the cordocentesis and those who delivered after 72 hours of the cordocentesis [median: −2.4 mEq/L, (IQR −3.3–−1) vs. median: −2.6 mEq/L, (IQR −4.2–−1.3); p > 0.05].
![Figure 3. Fetal base excess in patients who delivered before 72 hours after the cordocentesis and those who delivered more than 72 hours after the cordocentesis. There was no difference in the median fetal base excess between those who delivered before 72 hours of the cordocentesis and those who delivered after 72 hours of the cordocentesis [median: −2.4 mEq/L, (IQR −3.3–−1) vs. median: −2.6 mEq/L, (IQR −4.2–−1.3); p > 0.05].](/cms/asset/e5d50cd9-f8ea-42a5-9f60-30b621394e90/ijmf_a_629247_f0003_b.gif)
Similar results were obtained when patients were classified according to the procedure-to-delivery interval into those who delivered within 24 hours and those who delivered >24 hours after the procedure or according to the gestational age at delivery into those who delivered preterm (n = 44) and those who delivered at term (n = 46); all p > 0.05.
FIRS and fetal pH, gas analysis and timing of delivery
The fetal plasma IL-6 concentration was determined in 63% (57/90) of fetuses. The prevalence of FIRS was 28% (16/57). Fetuses with FIRS had a lower median gestational age at cordocentesis and delivered earlier than those without FIRS (both p < 0.001; see ). Among fetuses with FIRS, 68.8% (11/16) delivered within 3 days of the cordocentesis. In contrast, among fetuses without FIRS, 82.9% (34/41) delivered more then 72 hours after the cordocentesis. There was no difference in the rate of hypoxia between fetuses with or without FIRS (6.3 (1/16) vs. 9.8% (4/41); p = 1.0); similarly, there was no statistical difference in the rate of acidemia between fetuses with and without FIRS (12.5 (2/16) vs. 19.5% (8/41); p = 0.7).
Table III. Clinical and demographic characteristics of the study population of fetuses with and without FIRS.
There was no significant difference in the median fetal blood pH or ΔpH between fetuses with or without FIRS (pH median 7.38, IQR 7.36–7.39 vs. median 7.39, IQR 7.35–7.40, respectively; p = 0.6 and ΔpH median −0.028, IQR −0.033 to −0.020 vs. median −0.012, IQR −0.04 to −0.0008, respectively; p = 0.3; see and ). Similarly, there was no significant difference in the median PaO2 or ΔPaO2 between fetuses with and without FIRS (PaO2 median 48.4 mmHg; IQR 39.7–56.8 vs. median 43 mmHg; IQR 32.1–50.6, respectively; p = 0.8 and ΔPaO2 median 5.2 mmHg, IQR −1.2–18 vs. median 7.8 mmHg, IQR −5.5–14.2; p = 0.5, respectively; see and ). Moreover, there was no significant difference in the median fetal BE between fetuses with and without FIRS (median −3.3 mEq/L, IQR −5.3–1.8 vs. median −2.3 mEq/L, IQR −4.1 to −1.4; p = 0.2, see and ).
Figure 4. Fetal pH in fetuses with and without FIRS. There was no difference in the median fetal blood pH between fetuses with and without FIRS [median: 7.38, (IQR 7.36–7.39) vs. median: 7.39, (IQR 7.35–7.40); p > 0.05].
![Figure 4. Fetal pH in fetuses with and without FIRS. There was no difference in the median fetal blood pH between fetuses with and without FIRS [median: 7.38, (IQR 7.36–7.39) vs. median: 7.39, (IQR 7.35–7.40); p > 0.05].](/cms/asset/04af8ded-bc44-473d-8866-c8e568d3e9a8/ijmf_a_629247_f0004_b.gif)
Figure 5. Fetal PaO2 in fetuses with and without FIRS. There was no difference in the median fetal PaO2 between fetuses with FIRS and without FIRS [median: 48.4 mmHg, (IQR 39.7–56.8) vs. median: 43 mmHg, (IQR 32.1–50.6); p > 0.05].
![Figure 5. Fetal PaO2 in fetuses with and without FIRS. There was no difference in the median fetal PaO2 between fetuses with FIRS and without FIRS [median: 48.4 mmHg, (IQR 39.7–56.8) vs. median: 43 mmHg, (IQR 32.1–50.6); p > 0.05].](/cms/asset/8e0d3413-01b8-468a-bbea-bce331bd033f/ijmf_a_629247_f0005_b.gif)
Figure 6. Fetal base excess in fetuses with and without FIRS. There was no difference in the median fetal base excess between fetuses with and without FIRS [median: −3.3 mEq/L, (IQR −5.3–−1.8) vs. median: −2.3 mEq/L, (IQR −4.1–−1.4); p > 0.05].
![Figure 6. Fetal base excess in fetuses with and without FIRS. There was no difference in the median fetal base excess between fetuses with and without FIRS [median: −3.3 mEq/L, (IQR −5.3–−1.8) vs. median: −2.3 mEq/L, (IQR −4.1–−1.4); p > 0.05].](/cms/asset/93de3b32-9e06-4f51-b24b-4a067882beb4/ijmf_a_629247_f0006_b.gif)
Table IV. pH, PaO2, base excess and IL-6 concentrations in the study population of fetuses with and without FIRS.
Discussion
Principal findings of the study
(i) There was no significant difference in the median fetal pH, ΔpH, fetal PaO2, ΔPaO2 and fetal BE between patients with PTL who delivered within 72 hours and those who delivered more than 72 hours after the cordocentesis. Similar results were obtained between women with PTL who delivered preterm and those who delivered at term; (ii) there was no significant relationship between the procedure-to-delivery interval and the fetal blood pH, ΔpH, PaO2, ΔPaO2 or BE; (iii) there was no significant difference in the median fetal pH, fetal ΔpH, fetal PaO2, fetal ΔPaO2, BE as well as the frequency of fetal acidemia or fetal hypoxia between patients with and without FIRS and (iv) there is no evidence that a change in fetal pH, fetal PaO2 or BE is associated with spontaneous PTL/delivery.
The changes of fetal blood gases and fetal PaO2 in normal pregnancy
Several studies have evaluated the fetal acid–base status and PaO2 in normal pregnancies by cordocentesis [Citation146–150]. There are conflicting results regarding whether the fetal PaO2 and fetal blood pH change as a function of gestational age. In fetal venous blood, several authors reported that fetal pO2 [Citation146,Citation148–150], and, to a lesser extent, fetal pH, decreases with gestational age [Citation146,Citation150], whereas other authors have reported a non-significant trend of decreasing fetal pH with advancing gestational age in normal pregnancy [Citation149]. In contrast, fetal PaCO2 has been reported to be either increased [Citation146,Citation148] or not changed with gestational age [Citation149]. Only one study measured PaO2 and pH in the umbilical artery and reported a decrease with advancing gestational age [Citation146]. Therefore, for comparisons of the fetal pH and fetal PaO2 between the two study groups in the current study, the fetal ΔpH and fetal ΔPaO2 were calculated by taking into account the gestational age at cordocentesis.
Fetal hypoxia and PTL/delivery
The presence of fetal hypoxia in the context of IUGR, but not in PTL, has been studied extensively in the past using cordocentesis [Citation146,Citation147,Citation151–153]. In one of the largest studies, Nicolaides et al. [Citation146] compared the umbilical arterial and venous pH, PaO2, PaCO2 and LDH in small for gestational age (SGA) fetuses with appropriate for gestational age (AGA) fetuses. The authors found that SGA fetuses were more acidotic, had a lower PaO2 and a higher PaCO2 than AGA fetuses [Citation146]. They proposed that the acidosis and hypercapnia in the SGA fetuses may be the result of reduced gas exchange between the uteroplacental and fetal circulation due to reduced blood flow.
Our findings indicate that there was no significant difference in the fetal acid–base status and fetal PaO2 between patients with PTL who delivered within 72 hours and those who delivered more than 72 hours after the cordocentesis, or between women with PTL who delivered preterm and those who delivered at term are consistent with a previous study in patients with preterm PROM [Citation154]. Carroll et al. [Citation154] determined by cordocentesis the umbilical fetal blood pH and fetal PaO2 in patients with PPROM and reported no significant differences in the fetal pH or PaO2 between fetuses with a positive or negative fetal blood culture or between patients with a positive or negative amniotic fluid culture in patients with preterm PROM [Citation154]. Moreover, there were no differences in the mean pulsatility index of the umbilical artery, middle cerebral artery and thoracic aorta between those with or without intrauterine infection, suggesting that there was no significant change in the impedance to blood flow in the placenta or fetal brain [Citation154]. In another study, the umbilical arterial cord pH, PaO2, and PaCO2 obtained at the time of delivery in preterm or term newborns with clinical chorioamnionitis was not significantly different regardless of gestational age at delivery [Citation155].
Evidence supporting that chronic fetal hypoxia may not be a cause of spontaneous PTL/delivery derives from several observational studies in pregnant women residing at a high altitude. These patients are generally chronically exposed to a low level of oxygen tension in the atmosphere and tend to have an increased incidence of SGA neonates, but not spontaneous PTL/delivery [Citation156,Citation157]. Similar observations have been reported in animals [Citation158]. In fact, near-term pregnant rats exposed to hypoxia have a reduction of the myometrial contractility and oxytocin binding sites in the uterus, suggesting that hypoxia may delay, instead of shorten, parturition [Citation158,Citation159].
Fetal hypoxia and FIRS
The original definition of FIRS was described in fetuses with PTL and preterm PROM, and was often associated with microbial invasion of the amniotic cavity [Citation69,Citation70]. To date, FIRS has been largely observed in pregnancy complications involving infection. However, similar to SIRS [Citation160], the fetus may also mount a systemic inflammatory response to non-microbial-related insults, such as Rh isoimmunization [Citation161] and damage-associated molecular patterns (DAMPs; e.g. release of endogenous mediators when there is tissue injury [Citation123–125]).
Our finding that there was no significant difference in fetal acid–base status or PaO2 between fetuses with and without systemic inflammation is consistent with observations made in an animal study in which bacterial endotoxin or saline was infused intravenously into fetuses over a 5-day period of time [Citation162]. There was no significant difference in fetal blood pH, PaCO2 and oxygen content between fetuses who received endotoxin or those who received saline at the end of the study. Despite absence of hypoxemia or hypotension, fetuses exposed to endotoxin developed brain damage [Citation162].
Recently, in an animal model, dams housed in an environmental chamber containing 10.5% oxygen for 14 days (chronic hypoxemia model) without the presence of intra-amniotic infection were found to have an elevation of IL-6 and tumor-necrosis factor-α proteins in fetal serum and mRNA expression in the fetal lung, heart and brain [Citation145]. Moreover, the fetal brains of these animals showed an increase in protein expression of lactate/pyruvate ratios and a decrease in gluthathione/oxidized gluthathione ratios (consistent with pro-oxidant state), as well as an increase in mRNA expression of Bax/Bcl-2 ratio and TUNEL staining positive cells (evidence of programmed cell death or apoptosis [Citation145]). These observations led the authors to conclude that hypoxia is a cause of FIRS. However, these animals gained weight normally, labored and delivered at term, and the pups had a moderately reduced size. This animal model is consistent with mild-to-moderate IUGR in clinical settings, but not spontaneous preterm delivery.
In the current study, among patients presenting with PTL and intact membranes, there was no significant difference in the fetal pH, PaO2 or BE between fetuses with and without FIRS. Therefore, it is possible that chronic hypoxemia may lead to a change in the peripheral cytokine profile; however, this does not seem to be associated with PTL. In other words, hypoxia can lead to a cytokine profile similar to that described in FIRS, but there is no evidence that this would lead to PTL/delivery. Why is this the case? We propose that chronic hypoxemia can cause a degree of systemic inflammation and a cytokine profile which resembles that originally described in FIRS. However, this is typically associated with IUGR, preeclampsia and stillbirth. The onset of labor in the context of FIRS induced by infection is associated with an inflammatory process in the chorioamniotic membranes which is absent in cases of hypoxemia.
Thus, the mechanisms of PTL with intact or ruptured membranes depend not only on the presence or absence of fetal systemic inflammation, but on the adequate recruitment and activation of the other components of the terminal pathway of parturition. Without this, hypoxemia and acidemia would compromise fetal growth but not initiate labor. We have presented evidence in support of this hypothesis [Citation161]. Fetuses with Rh disease and anemia have elevated fetal plasma IL-6 concentrations, but they do not have PTL: the most likely explanation is that the elevation in fetal plasma IL-6 reflects systemic immune activation by the presence of antigens against the red blood cells. yet, the phenotype of Rh disease is ascites, pleural effusion, anemia and other features which characterize fetal red blood cell alloimmunization, but not PTL.
Strengths and limitations of the study
Since the prevalence of intrauterine infection is higher in fetuses who delivered earlier rather than later, the gestational age at cordocentesis was significantly lower in patients who delivered within 72 hours than those who delivered after 72 hours (as expected by the design of the study). The Δ values for the fetal blood pH and PaO2 were calculated to adjust for the changes that occur due to gestational age.
Conclusion
This is the first study of the fetal pH and blood gases in PTL. It is clear that fetal acidemia, fetal hypoxemia and metabolic acidosis were not more frequent in fetuses destined to deliver preterm than in those who delivered at term. Similarly, these abnormalities were not observed in fetuses with PTL with FIRS compared to those without FIRS, indicating that systemic inflammation associated with PTL is not accompanied with changes in the fetal acid–base state. Finally, we do not exclude the possibility that fetal hypoxemia may lead to changes in the cytokine profile in fetal blood that resemble those observed in cases of infection-induced systemic inflammation. Inflammation is a general mechanism of host response to tissue injury and multiple insults (i.e. release of damage-associated molecular patterns which can elicit systemic inflammation [Citation122,Citation163-164]). The role of fetal systemic inflammation in the pathophysiology of IUGR, preeclampsia and stillbirth requires further investigation; yet, it is clear that PTL is not associated with fetal hypoxemia or acidemia in humans.
Declaration of Interest: This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS.
References
- Romero R, Espinoza J, Kusanovic JP, Gotsch F, Hassan S, Erez O, Chaiworapongsa T, Mazor M. The preterm parturition syndrome. BJOG 2006;113 Suppl 3:17–42.
- Lettieri L, Vintzileos AM, Rodis JF, Albini SM, Salafia CM. Does “idiopathic” preterm labor resulting in preterm birth exist? Am J Obstet Gynecol 1993;168:1480–1485.
- Ananth CV, Vintzileos AM. Epidemiology of preterm birth and its clinical subtypes. J Matern Fetal Neonatal Med 2006;19:773–782.
- Romero R. Prenatal medicine: The child is the father of the man. 1996. J Matern Fetal Neonatal Med 2009;22:636–639.
- Di Renzo GC. The great obstetrical syndromes. J Matern Fetal Neonatal Med 2009;22:633–635.
- Kovo M, Schreiber L, Ben-Haroush A, Asalee L, Seadia S, Golan A, Bar J. The placental factor in spontaneous preterm labor with and without premature rupture of membranes. J Perinat Med 2011;39:423–429.
- Kilari AS, Mehendale SS, Dangat KD, Yadav HR, Gupta A, Taralekar VS, Joshi SR. Long chain polyunsaturated fatty acids in mothers of preterm babies. J Perinat Med 2010;38:659–664.
- Cooley SM, Donnelly JC, Collins C, Geary MP, Rodeck CH, Hindmarsh PC. The relationship between maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGFBP-3 to gestational age and preterm delivery. J Perinat Med 2010;38:255–259.
- Romero R, Sepulveda W, Baumann P, Yoon B, Brandt F, Gomez R, Mazor M et al. The preterm labor syndrome: Biochemical, cytologic, immunologic, pathologic, microbiologic and clinical evidence that preterm labor is a heterogenous disease. Am J Obstet Gynecol 1993;168:288.
- Romero R, Mazor M, Munoz H, Gomez R, Galasso M, Sherer DM. The preterm labor syndrome. Ann N Y Acad Sci 1994;734:414–429.
- Romero R, Sirtori M, Oyarzun E, Avila C, Mazor M, Callahan R, Sabo V, et al. Infection and labor. V. Prevalence, microbiology, and clinical significance of intraamniotic infection in women with preterm labor and intact membranes. Am J Obstet Gynecol 1989;161:817–824.
- Romero R, Mazor M, Wu YK, Avila C, Oyarzun E, Mitchell MD. Bacterial endotoxin and tumor necrosis factor stimulate prostaglandin production by human decidua. Prostaglandins Leukot Essent Fatty Acids 1989;37:183–186.
- Gibbs RS, Romero R, Hillier SL, Eschenbach DA, Sweet RL. A review of premature birth and subclinical infection. Am J Obstet Gynecol 1992;166:1515–1528.
- Dudley DJ, Chen CL, Branch DW, Hammond E, Mitchell MD. A murine model of preterm labor: Inflammatory mediators regulate the production of prostaglandin E2 and interleukin-6 by murine decidua. Biol Reprod 1993;48:33–39.
- Goldenberg RL, Andrews WW, Hauth JC. Choriodecidual infection and preterm birth. Nutr Rev 2002;60:S19–S25.
- Romero R, Avila C, Brekus CA, Morotti R. The role of systemic and intrauterine infection in preterm parturition. Ann N Y Acad Sci 1991;622:355–375.
- Wenstrom KD, Andrews WW, Hauth JC, Goldenberg RL, DuBard MB, Cliver SP. Elevated second-trimester amniotic fluid interleukin-6 levels predict preterm delivery. Am J Obstet Gynecol 1998;178:546–550.
- Arntzen KJ, Kjøllesdal AM, Halgunset J, Vatten L, Austgulen R. TNF, IL-1, IL-6, IL-8 and soluble TNF receptors in relation to chorioamnionitis and premature labor. J Perinat Med 1998;26:17–26.
- Averbuch B, Mazor M, Shoham-Vardi I, Chaim W, Vardi H, Horowitz S, Shuster M. Intra-uterine infection in women with preterm premature rupture of membranes: Maternal and neonatal characteristics. Eur J Obstet Gynecol Reprod Biol 1995;62:25–29.
- Lee SE, Romero R, Jung H, Park CW, Park JS, Yoon BH. The intensity of the fetal inflammatory response in intraamniotic inflammation with and without microbial invasion of the amniotic cavity. Am J Obstet Gynecol 2007;197:294.e1–294.e6.
- Rodríguez N, Fernandez C, Zamora Y, Berdasquera D, Rivera JA. Detection of Ureaplasma urealyticum and Ureaplasma parvum in amniotic fluid: Association with pregnancy outcomes. J Matern Fetal Neonatal Med 2011;24:47–50.
- Berger A, Witt A, Haiden N, Kaider A, Klebermasz K, Fuiko R, Langgartner M, Pollak A. Intrauterine infection with Ureaplasma species is associated with adverse neuromotor outcome at 1 and 2 years adjusted age in preterm infants. J Perinat Med 2009;37:72–78.
- DiGiulio DB, Romero R, Amogan HP, Kusanovic JP, Bik EM, Gotsch F, Kim CJ, et al. Microbial prevalence, diversity and abundance in amniotic fluid during preterm labor: A molecular and culture-based investigation. PLoS ONE 2008;3:e3056.
- DiGiulio DB, Romero R, Kusanovic JP, Gómez R, Kim CJ, Seok KS, Gotsch F, et al. Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes. Am J Reprod Immunol 2010;64:38–57.
- Oh KJ, Lee KA, Sohn YK, Park CW, Hong JS, Romero R, Yoon BH. Intraamniotic infection with genital mycoplasmas exhibits a more intense inflammatory response than intraamniotic infection with other microorganisms in patients with preterm premature rupture of membranes. Am J Obstet Gynecol 2010;203:211.e1–211.e8.
- Romero R, Mazor M, Wu YK, Sirtori M, Oyarzun E, Mitchell MD, Hobbins JC. Infection in the pathogenesis of preterm labor. Semin Perinatol 1988;12:262–279.
- Romero R, Espinoza J, Gonçalves LF, Kusanovic JP, Friel L, Hassan S. The role of inflammation and infection in preterm birth. Semin Reprod Med 2007;25:21–39.
- Jacobsson B, Aaltonen R, Rantakokko-Jalava K, Morken NH, Alanen A. Quantification of Ureaplasma urealyticum DNA in the amniotic fluid from patients in PTL and pPROM and its relation to inflammatory cytokine levels. Acta Obstet Gynecol Scand 2009;88:63–70.
- Nace J, Fortunato SJ, Maul H, Menon R. The expression pattern of two novel cytokines (IL-24 and IL-29) in human fetal membranes. J Perinat Med 2010;38:665–670.
- Kasper DC, Mechtler TP, Böhm J, Petricevic L, Gleiss A, Spergser J, Witt A, et al. In utero exposure to Ureaplasma spp. is associated with increased rate of bronchopulmonary dysplasia and intraventricular hemorrhage in preterm infants. J Perinat Med 2011;39:331–336.
- Oh KJ, Lee SE, Jung H, Kim G, Romero R, Yoon BH. Detection of ureaplasmas by the polymerase chain reaction in the amniotic fluid of patients with cervical insufficiency. J Perinat Med 2010;38:261–268.
- Kloeck FK, Jung H. In vitro release of prostaglandins from the human myometrium under the influence of stretching. Am J Obstet Gynecol 1973;115:1066–1069.
- Laudanski T, Rocki W. The effects on stretching and prostaglandin F2α on the contractile and bioelectric activity of the uterus in rat. Acta Physiol Pol 1975;26:385–393.
- Ou CW, Orsino A, Lye SJ. Expression of connexin-43 and connexin-26 in the rat myometrium during pregnancy and labor is differentially regulated by mechanical and hormonal signals. Endocrinology 1997;138:5398–5407.
- Phelan JP, Park YW, Ahn MO, Rutherford SE. Polyhydramnios and perinatal outcome. J Perinatol 1990;10:347–350.
- Romero R, Mazor M, Avila C, Quintero R, Munoet H. Uterine “allergy”: A novel mechanism for preterm labor. Am J Obstet Gynecol 1991;164:375.
- Bytautiene E, Romero R, Vedernikov YP, El-Zeky F, Saade GR, Garfield RE. Induction of premature labor and delivery by allergic reaction and prevention by histamine H1 receptor antagonist. Am J Obstet Gynecol 2004;191:1356–1361.
- Garfield RE, Bytautiene E, Vedernikov YP, Marshall JS, Romero R. Modulation of rat uterine contractility by mast cells and their mediators. Am J Obstet Gynecol 2000;183:118–125.
- Romero R, Kusanovic JP, Muñoz H, Gomez R, Lamont RF, Yeo L. Allergy-induced preterm labor after the ingestion of shellfish. J Matern Fetal Neonatal Med 2010;23:351–359.
- Romero R, Kusanovic JP, Gomez R, Lamont R, Bytautiene E, Garfield RE, Mittal P, et al. The clinical significance of eosinophils in the amniotic fluid in preterm labor. J Matern Fetal Neonatal Med 2010;23:320–329.
- Hassan SS, Romero R, Berry SM, Dang K, Blackwell SC, Treadwell MC, Wolfe HM. Patients with an ultrasonographic cervical length < or = 15 mm have nearly a 50% risk of early spontaneous preterm delivery. Am J Obstet Gynecol 2000;182:1458–1467.
- Iams JD, Johnson FF, Sonek J, Sachs L, Gebauer C, Samuels P. Cervical competence as a continuum: A study of ultrasonographic cervical length and obstetric performance. Am J Obstet Gynecol 1995;172:1097–103; discussion 1104.
- Ludmir J, Samuels P, Brooks S, Mennuti MT. Pregnancy outcome of patients with uncorrected uterine anomalies managed in a high-risk obstetric setting. Obstet Gynecol 1990;75:906–910.
- Berghella V, Roman A, Daskalakis C, Ness A, Baxter JK. Gestational age at cervical length measurement and incidence of preterm birth. Obstet Gynecol 2007;110:311–317.
- To MS, Skentou C, Liao AW, Cacho A, Nicolaides KH. Cervical length and funneling at 23 weeks of gestation in the prediction of spontaneous early preterm delivery. Ultrasound Obstet Gynecol 2001;18:200–203.
- Kim CJ, Romero R, Kusanovic JP, Yoo W, Dong Z, Topping V, Gotsch F, et al. The frequency, clinical significance, and pathological features of chronic chorioamnionitis: A lesion associated with spontaneous preterm birth. Mod Pathol 2010;23:1000–1011.
- Kim JS, Romero R, Kim MR, Kim YM, Friel L, Espinoza J, Kim CJ. Involvement of Hofbauer cells and maternal T cells in villitis of unknown aetiology. Histopathology 2008;52:457–464.
- Kim MJ, Romero R, Kim CJ, Tarca AL, Chhauy S, LaJeunesse C, Lee DC, et al. Villitis of unknown etiology is associated with a distinct pattern of chemokine up-regulation in the feto-maternal and placental compartments: Implications for conjoint maternal allograft rejection and maternal anti-fetal graft-versus-host disease. J Immunol 2009;182:3919–3927.
- Lee J, Romero R, Xu Y, Kim JS, Topping V, Yoo W, Kusanovic JP, et al. A signature of maternal anti-fetal rejection in spontaneous preterm birth: Chronic chorioamnionitis, anti-human leukocyte antigen antibodies, and C4d. PLoS ONE 2011;6:e16806.
- Oggé G, Romero R, Lee DC, Gotsch F, Than NG, Lee J, Chaiworapongsa T, et al. Chronic chorioamnionitis displays distinct alterations of the amniotic fluid proteome. J Pathol 2011;223:553–565.
- Check JH, Lee G, Epstein R, Vetter B. Increased rate of preterm deliveries in untreated women with luteal phase deficiencies. Preliminary report. Gynecol Obstet Invest 1992;33:183–184.
- Dudley DJ, Branch DW, Edwin SS, Mitchell MD. Induction of preterm birth in mice by RU486. Biol Reprod 1996;55:992–995.
- Keirse MJ. Progestogen administration in pregnancy may prevent preterm delivery. Br J Obstet Gynaecol 1990;97:149–154.
- Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, Spong CY, et al.; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 α-hydroxyprogesterone caproate. N Engl J Med 2003;348:2379–2385.
- Challis JR. CRH, a placental clock and preterm labour. Nat Med 1995;1:416.
- Copper RL, Goldenberg RL, Das A, Elder N, Swain M, Norman G, Ramsey R, et al. The preterm prediction study: Maternal stress is associated with spontaneous preterm birth at less than thirty-five weeks’ gestation. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol 1996;175:1286–1292.
- Hobel CJ, Dunkel-Schetter C, Roesch SC, Castro LC, Arora CP. Maternal plasma corticotropin-releasing hormone associated with stress at 20 weeks’ gestation in pregnancies ending in preterm delivery. Am J Obstet Gynecol 1999;180:S257–S263.
- Jones SA, Challis JR. Steroid, corticotrophin-releasing hormone, ACTH and prostaglandin interactions in the amnion and placenta of early pregnancy in man. J Endocrinol 1990;125:153–159.
- Liggins GC. Premature parturition after infusion of corticotrophin or cortisol into foetal lambs. J Endocrinol 1968;42:323–329.
- Arias F, Rodriquez L, Rayne SC, Kraus FT. Maternal placental vasculopathy and infection: Two distinct subgroups among patients with preterm labor and preterm ruptured membranes. Am J Obstet Gynecol 1993;168:585–591.
- Brar HS, Medearis AL, DeVore GR, Platt LD. Maternal and fetal blood flow velocity waveforms in patients with preterm labor: Prediction of successful tocolysis. Am J Obstet Gynecol 1988;159:947–950.
- Chaiworapongsa T, Romero R, Tarca A, Kusanovic JP, Mittal P, Kim SK, Gotsch F, et al. A subset of patients destined to develop spontaneous preterm labor has an abnormal angiogenic/anti-angiogenic profile in maternal plasma: Evidence in support of pathophysiologic heterogeneity of preterm labor derived from a longitudinal study. J Matern Fetal Neonatal Med 2009;22:1122–1139.
- Combs CA, Katz MA, Kitzmiller JL, Brescia RJ. Experimental preeclampsia produced by chronic constriction of the lower aorta: Validation with longitudinal blood pressure measurements in conscious rhesus monkeys. Am J Obstet Gynecol 1993;169:215–223.
- Fonseca E, Yu CK, Singh M, Papageorghiou AT, Nicolaides KH. Relationship between second-trimester uterine artery Doppler and spontaneous early preterm delivery. Ultrasound Obstet Gynecol 2006;27:301–305.
- Kim YM, Chaiworapongsa T, Gomez R, Bujold E, Yoon BH, Rotmensch S, Thaler HT, Romero R. Failure of physiologic transformation of the spiral arteries in the placental bed in preterm premature rupture of membranes. Am J Obstet Gynecol 2002;187:1137–1142.
- Kim YM, Bujold E, Chaiworapongsa T, Gomez R, Yoon BH, Thaler HT, Rotmensch S, Romero R. Failure of physiologic transformation of the spiral arteries in patients with preterm labor and intact membranes. Am J Obstet Gynecol 2003;189:1063–1069.
- Brosens I, Pijnenborg R, Vercruysse L, Romero R. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol 2011;204:193–201.
- Romero R, Kusanovic JP, Chaiworapongsa T, Hassan SS. Placental bed disorders in preterm labor, preterm PROM, spontaneous abortion and abruptio placentae. Best Pract Res Clin Obstet Gynaecol 2011;25:313–327.
- Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal inflammatory response syndrome. Am J Obstet Gynecol 1998;179:194–202.
- Romero R, Gomez R, Ghezzi F, Yoon BH, Mazor M, Edwin SS, Berry SM. A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. Am J Obstet Gynecol 1998;179:186–193.
- Gotsch F, Romero R, Kusanovic JP, Mazaki-Tovi S, Pineles BL, Erez O, Espinoza J, Hassan SS. The fetal inflammatory response syndrome. Clin Obstet Gynecol 2007;50:652–683.
- Yoon BH, Romero R, Kim CJ, Jun JK, Gomez R, Choi JH, Syn HC. Amniotic fluid interleukin-6: A sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal morbidity. Am J Obstet Gynecol 1995;172:960–970.
- Yoon BH, Romero R, Park JS, Kim M, Oh SY, Kim CJ, Jun JK. The relationship among inflammatory lesions of the umbilical cord (funisitis), umbilical cord plasma interleukin 6 concentration, amniotic fluid infection, and neonatal sepsis. Am J Obstet Gynecol 2000;183:1124–1129.
- Moon JB, Kim JC, Yoon BH, Romero R, Kim G, Oh SY, Kim M, Shim SS. Amniotic fluid matrix metalloproteinase-8 and the development of cerebral palsy. J Perinat Med 2002;30:301–306.
- Park JS, Romero R, Yoon BH, Moon JB, Oh SY, Han SY, Ko EM. The relationship between amniotic fluid matrix metalloproteinase-8 and funisitis. Am J Obstet Gynecol 2001;185:1156–1161.
- Park CW, Lee SM, Park JS, Jun JK, Romero R, Yoon BH. The antenatal identification of funisitis with a rapid MMP-8 bedside test. J Perinat Med 2008;36:497–502.
- Yoon BH, Romero R, Kim KS, Park JS, Ki SH, Kim BI, Jun JK. A systemic fetal inflammatory response and the development of bronchopulmonary dysplasia. Am J Obstet Gynecol 1999;181:773–779.
- Kramer BW. Antenatal inflammation and lung injury: Prenatal origin of neonatal disease. J Perinatol 2008;28 Suppl 1:S21–S27.
- Kramer BW, Kallapur S, Newnham J, Jobe AH. Prenatal inflammation and lung development. Semin Fetal Neonatal Med 2009;14:2–7.
- Yoon BH, Romero R, Yang SH, Jun JK, Kim IO, Choi JH, Syn HC. Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia. Am J Obstet Gynecol 1996;174:1433–1440.
- Bashiri A, Burstein E, Mazor M. Cerebral palsy and fetal inflammatory response syndrome: A review. J Perinat Med 2006;34:5–12.
- Yoon BH, Park CW, Chaiworapongsa T. Intrauterine infection and the development of cerebral palsy. BJOG 2003;110 Suppl 20:124–127.
- Dammann O, Leviton A. Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant. Semin Pediatr Neurol 1998;5:190–201.
- Dammann O, Leviton A. Role of the fetus in perinatal infection and neonatal brain damage. Curr Opin Pediatr 2000;12:99–104.
- Dammann O, Kuban KC, Leviton A. Perinatal infection, fetal inflammatory response, white matter damage, and cognitive limitations in children born preterm. Ment Retard Dev Disabil Res Rev 2002;8:46–50.
- Leviton A. Preterm birth and cerebral palsy: Is tumor necrosis factor the missing link? Dev Med Child Neurol 1993;35:553–558.
- Leviton A, Paneth N, Reuss ML, Susser M, Allred EN, Dammann O, Kuban K, et al. Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants. Developmental Epidemiology Network Investigators. Pediatr Res 1999;46:566–575.
- Yoon BH, Jun JK, Romero R, Park KH, Gomez R, Choi JH, Kim IO. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1β, and tumor necrosis factor-α), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol 1997;177:19–26.
- Athayde N, Romero R, Maymon E, Gomez R, Pacora P, Yoon BH, Edwin SS. Interleukin 16 in pregnancy, parturition, rupture of fetal membranes, and microbial invasion of the amniotic cavity. Am J Obstet Gynecol 2000;182:135–141.
- Kusanovic JP, Romero R, Chaiworapongsa T, Mittal P, Mazaki-Tovi S, Vaisbuch E, Erez O, et al. Amniotic fluid sTREM-1 in normal pregnancy, spontaneous parturition at term and preterm, and intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med 2010;23:34–47.
- Massaro G, Scaravilli G, Simeone S, Capuano S, Pastore E, Forte A, Parisi P, et al. Interleukin-6 and Mycoplasma hominis as markers of preterm birth and related brain damage: Our experience. J Matern Fetal Neonatal Med 2009;22:1063–1067.
- Maymon E, Ghezzi F, Edwin SS, Mazor M, Yoon BH, Gomez R, Romero R. The tumor necrosis factor α and its soluble receptor profile in term and preterm parturition. Am J Obstet Gynecol 1999;181:1142–1148.
- Pacora P, Romero R, Maymon E, Gervasi MT, Gomez R, Edwin SS, Yoon BH. Participation of the novel cytokine interleukin 18 in the host response to intra-amniotic infection. Am J Obstet Gynecol 2000;183:1138–1143.
- Park JS, Park CW, Lockwood CJ, Norwitz ER. Role of cytokines in preterm labor and birth. Minerva Ginecol 2005;57:349–366.
- Romero R, Manogue KR, Mitchell MD, Wu YK, Oyarzun E, Hobbins JC, Cerami A. Infection and labor. IV. Cachectin-tumor necrosis factor in the amniotic fluid of women with intraamniotic infection and preterm labor. Am J Obstet Gynecol 1989;161:336–341.
- Romero R, Avila C, Santhanam U, Sehgal PB. Amniotic fluid interleukin 6 in preterm labor. Association with infection. J Clin Invest 1990;85:1392–1400.
- Romero R, Mazor M, Brandt F, Sepulveda W, Avila C, Cotton DB, Dinarello CA. Interleukin-1 α and interleukin-1 β in preterm and term human parturition. Am J Reprod Immunol 1992;27:117–123.
- Romero R, Gomez R, Galasso M, Mazor M, Berry SM, Quintero RA, Cotton DB. The natural interleukin-1 receptor antagonist in the fetal, maternal, and amniotic fluid compartments: The effect of gestational age, fetal gender, and intrauterine infection. Am J Obstet Gynecol 1994;171:912–921.
- Gotsch F, Romero R, Kusanovic JP, Erez O, Espinoza J, Kim CJ, Vaisbuch E, et al. The anti-inflammatory limb of the immune response in preterm labor, intra-amniotic infection/inflammation, and spontaneous parturition at term: A role for interleukin-10. J Matern Fetal Neonatal Med 2008;21:529–547.
- Gotsch F, Romero R, Chaiworapongsa T, Erez O, Vaisbuch E, Espinoza J, Kusanovic JP, et al. Evidence of the involvement of caspase-1 under physiologic and pathologic cellular stress during human pregnancy: A link between the inflammasome and parturition. J Matern Fetal Neonatal Med 2008;21:605–616.
- Chaiworapongsa T, Romero R, Espinoza J, Kim YM, Edwin S, Bujold E, Gomez R, Kuivaniemi H. Macrophage migration inhibitory factor in patients with preterm parturition and microbial invasion of the amniotic cavity. J Matern Fetal Neonatal Med 2005;18:405–416.
- Esplin MS, Romero R, Chaiworapongsa T, Kim YM, Edwin S, Gomez R, Mazor M, Adashi EY. Monocyte chemotactic protein-1 is increased in the amniotic fluid of women who deliver preterm in the presence or absence of intra-amniotic infection. J Matern Fetal Neonatal Med 2005;17:365–373.
- Hamill N, Romero R, Gotsch F, Kusanovic JP, Edwin S, Erez O, Than NG, et al. Exodus-1 (CCL20): Evidence for the participation of this chemokine in spontaneous labor at term, preterm labor, and intrauterine infection. J Perinat Med 2008;36:217–227.
- Mittal P, Romero R, Kusanovic JP, Edwin SS, Gotsch F, Mazaki-Tovi S, Espinoza J, et al. CXCL6 (granulocyte chemotactic protein-2): A novel chemokine involved in the innate immune response of the amniotic cavity. Am J Reprod Immunol 2008;60:246–257.
- Nhan-Chang CL, Romero R, Kusanovic JP, Gotsch F, Edwin SS, Erez O, Mittal P, et al. A role for CXCL13 (BCA-1) in pregnancy and intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med 2008;21:763–775.
- Romero R, Gomez R, Galasso M, Munoz H, Acosta L, Yoon BH, Svinarich D, Cotton DB. Macrophage inflammatory protein-1 α in term and preterm parturition: Effect of microbial invasion of the amniotic cavity. Am J Reprod Immunol 1994;32:108–113.
- Dudley DJ, Hunter C, Mitchell MD, Varner MW. Elevations of amniotic fluid macrophage inflammatory protein-1 α concentrations in women during term and preterm labor. Obstet Gynecol 1996;87:94–98.
- Helmig BR, Romero R, Espinoza J, Chaiworapongsa T, Bujold E, Gomez R, Ohlsson K, Uldbjerg N. Neutrophil elastase and secretory leukocyte protease inhibitor in prelabor rupture of membranes, parturition and intra-amniotic infection. J Matern Fetal Neonatal Med 2002;12:237–246.
- Pacora P, Romero R, Chaiworapongsa T, Kusanovic JP, Erez O, Vaisbuch E, Mazaki-Tovi S, et al. Amniotic fluid angiopoietin-2 in term and preterm parturition, and intra-amniotic infection/inflammation. J Perinat Med 2009;37:503–511.
- Kusanovic JP, Romero R, Mazaki-Tovi S, Chaiworapongsa T, Mittal P, Gotsch F, Erez O, et al. Resistin in amniotic fluid and its association with intra-amniotic infection and inflammation. J Matern Fetal Neonatal Med 2008;21:902–916.
- Mazaki-Tovi S, Romero R, Kusanovic JP, Erez O, Gotsch F, Mittal P, Than NG, et al. Visfatin/Pre-B cell colony-enhancing factor in amniotic fluid in normal pregnancy, spontaneous labor at term, preterm labor and prelabor rupture of membranes: An association with subclinical intrauterine infection in preterm parturition. J Perinat Med 2008;36:485–496.
- Mazaki-Tovi S, Romero R, Vaisbuch E, Kusanovic JP, Erez O, Mittal P, Gotsch F, et al. Adiponectin in amniotic fluid in normal pregnancy, spontaneous labor at term, and preterm labor: A novel association with intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med 2010;23:120–130.
- Vaisbuch E, Mazaki-Tovi S, Kusanovic JP, Erez O, Than NG, Kim SK, Dong Z, et al. Retinol binding protein 4: An adipokine associated with intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med 2010;23:111–119.
- Erez O, Romer R, Vaisbuch E, Chaiworapongsa T, Kusanovic JP, Mazaki-Tovi S, Gotsch F, et al. Changes in amniotic fluid concentration of thrombin-antithrombin III complexes in patients with preterm labor: Evidence of an increased thrombin generation. J Matern Fetal Neonatal Med 2009;22:971–982.
- Erez O, Romero R, Vaisbuch E, Kusanovic JP, Mazaki-Tovi S, Chaiworapongsa T, Gotsch F, et al. High tissue factor activity and low tissue factor pathway inhibitor concentrations in patients with preterm labor. J Matern Fetal Neonatal Med 2010;23:23–33.
- Soto E, Romero R, Richani K, Yoon BH, Chaiworapongsa T, Vaisbuch E, Mittal P, et al. Evidence for complement activation in the amniotic fluid of women with spontaneous preterm labor and intra-amniotic infection. J Matern Fetal Neonatal Med 2009;22:983–992.
- Vaisbuch E, Romero R, Erez O, Mazaki-Tovi S, Kusanovic JP, Pedro KJ, Soto E, et al. Fragment Bb in amniotic fluid: Evidence for complement activation by the alternative pathway in women with intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med 2009;22:905–916.
- Erez O, Romero R, Tarca AL, Chaiworapongsa T, Kim YM, Than NG, Vaisbuch E, et al. Differential expression pattern of genes encoding for anti-microbial peptides in the fetal membranes of patients with spontaneous preterm labor and intact membranes and those with preterm prelabor rupture of the membranes. J Matern Fetal Neonatal Med 2009;22:1103–1115.
- Espinoza J, Chaiworapongsa T, Romero R, Edwin S, Rathnasabapathy C, Gomez R, Bujold E, et al. Antimicrobial peptides in amniotic fluid: Defensins, calprotectin and bacterial/permeability-increasing protein in patients with microbial invasion of the amniotic cavity, intra-amniotic inflammation, preterm labor and premature rupture of membranes. J Matern Fetal Neonatal Med 2003;13:2–21.
- Soto E, Espinoza J, Nien JK, Kusanovic JP, Erez O, Richani K, Santolaya-Forgas J, Romero R. Human β-defensin-2: A natural antimicrobial peptide present in amniotic fluid participates in the host response to microbial invasion of the amniotic cavity. J Matern Fetal Neonatal Med 2007;20:15–22.
- Cruciani L, Romero R, Vaisbuch E, Kusanovic JP, Chaiworapongsa T, Mazaki-Tovi S, Mittal P, et al. Pentraxin 3 in amniotic fluid: A novel association with intra-amniotic infection and inflammation. J Perinat Med 2010;38:161–171.
- Bianchi ME. DAMPs, PAMPs and alarmins: All we need to know about danger. J Leukoc Biol 2007;81:1–5.
- Chaiworapongsa T, Erez O, Kusanovic JP, Vaisbuch E, Mazaki-Tovi S, Gotsch F, Than NG, et al. Amniotic fluid heat shock protein 70 concentration in histologic chorioamnionitis, term and preterm parturition. J Matern Fetal Neonatal Med 2008;21:449–461.
- Friel LA, Romero R, Edwin S, Nien JK, Gomez R, Chaiworapongsa T, Kusanovic JP, et al. The calcium binding protein, S100B, is increased in the amniotic fluid of women with intra-amniotic infection/inflammation and preterm labor with intact or ruptured membranes. J Perinat Med 2007;35:385–393.
- Romero R, Chaiworapongsa T, Alpay S, Madan I, Dong Z, Kusanovic J, Kim C et al. HMGB1, a late mediator of sepsis and death, is involved in the host response to intra-amniotic infection/inflammation in preterm gestation. Reprod Sci 2011;18:245A.
- Romero R, Espinoza J, Hassan S, Gotsch F, Kusanovic JP, Avila C, Erez O, et al. Soluble receptor for advanced glycation end products (sRAGE) and endogenous secretory RAGE (esRAGE) in amniotic fluid: Modulation by infection and inflammation. J Perinat Med 2008;36:388–398.
- Fortunato SJ, Menon R, Lombardi SJ. MMP/TIMP imbalance in amniotic fluid during PROM: An indirect support for endogenous pathway to membrane rupture. J Perinat Med 1999;27:362–368.
- Fortunato SJ, Menon R. Distinct molecular events suggest different pathways for preterm labor and premature rupture of membranes. Am J Obstet Gynecol 2001;184:1399–405; discussion 1405.
- Maymon E, Romero R, Pacora P, Gervasi MT, Gomez R, Edwin SS, Yoon BH. Evidence of in vivo differential bioavailability of the active forms of matrix metalloproteinases 9 and 2 in parturition, spontaneous rupture of membranes, and intra-amniotic infection. Am J Obstet Gynecol 2000;183:887–894.
- Maymon E, Romero R, Pacora P, Gervasi MT, Bianco K, Ghezzi F, Yoon BH. Evidence for the participation of interstitial collagenase (matrix metalloproteinase 1) in preterm premature rupture of membranes. Am J Obstet Gynecol 2000;183:914–920.
- Maymon E, Romero R, Pacora P, Gervasi MT, Edwin SS, Gomez R, Seubert DE. Matrilysin (matrix metalloproteinase 7) in parturition, premature rupture of membranes, and intrauterine infection. Am J Obstet Gynecol 2000;182:1545–1553.
- Maymon E, Romero R, Pacora P, Gomez R, Athayde N, Edwin S, Yoon BH. Human neutrophil collagenase (matrix metalloproteinase 8) in parturition, premature rupture of the membranes, and intrauterine infection. Am J Obstet Gynecol 2000;183:94–99.
- Maymon E, Romero R, Pacora P, Gomez R, Mazor M, Edwin S, Chaiworapongsa T, et al. A role for the 72 kDa gelatinase (MMP-2) and its inhibitor (TIMP-2) in human parturition, premature rupture of membranes and intraamniotic infection. J Perinat Med 2001;29:308–316.
- Maymon E, Romero R, Chaiworapongsa T, Kim JC, Berman S, Gomez R, Edwin S. Value of amniotic fluid neutrophil collagenase concentrations in preterm premature rupture of membranes. Am J Obstet Gynecol 2001;185:1143–1148.
- Park KH, Chaiworapongsa T, Kim YM, Espinoza J, Yoshimatsu J, Edwin S, Gomez R, et al. Matrix metalloproteinase 3 in parturition, premature rupture of the membranes, and microbial invasion of the amniotic cavity. J Perinat Med 2003;31:12–22.
- Romero R, Chaiworapongsa T, Espinoza J, Gomez R, Yoon BH, Edwin S, Mazor M, et al. Fetal plasma MMP-9 concentrations are elevated in preterm premature rupture of the membranes. Am J Obstet Gynecol 2002;187:1125–1130.
- Mazor M, Wiznitzer A, Maymon E, Leiberman JR, Cohen A. Changes in amniotic fluid concentrations of prostaglandins E2 and F2 α in women with preterm labor. Isr J Med Sci 1990;26:425–428.
- Romero R, Wu YK, Sirtori M, Oyarzun E, Mazor M, Hobbins JC, Mitchell MD. Amniotic fluid concentrations of prostaglandin F2 α, 13,14-dihydro-15-keto-prostaglandin F2 α (PGFM) and 11-deoxy-13,14-dihydro-15-keto-11, 16-cyclo-prostaglandin E2 (PGEM-LL) in preterm labor. Prostaglandins 1989;37:149–161.
- Romero R, Quintero R, Emamian M, Wan M, Grzyboski C, Hobbins JC, Mitchell MD. Arachidonate lipoxygenase metabolites in amniotic fluid of women with intra-amniotic infection and preterm labor. Am J Obstet Gynecol 1987;157:1454–1460.
- Romero R, Emamian M, Wan M, Quintero R, Hobbins JC, Mitchell MD. Prostaglandin concentrations in amniotic fluid of women with intra-amniotic infection and preterm labor. Am J Obstet Gynecol 1987;157:1461–1467.
- Botet F, Figueras J, Carbonell-Estrany X, Narbona E. The impact of clinical maternal chorioamnionitis on neurological and psychological sequelae in very-low-birth weight infants: A case-control study. J Perinat Med 2011;39:203–208.
- Botet F, Figueras J, Carbonell-Estrany X, Arca G, The Castrillo Study Group. Effect of maternal clinical chorioamnionitis on neonatal morbidity in very-low birthweight infants: A case-control study. J Perinat Med 2010;38:269–273.
- Yoon BH, Romero R, Moon JB, Shim SS, Kim M, Kim G, Jun JK. Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Obstet Gynecol 2001;185:1130–1136.
- Kim SK, Romero R, Chaiworapongsa T, Kusanovic JP, Mazaki-Tovi S, Mittal P, Erez O, et al. Evidence of changes in the immunophenotype and metabolic characteristics (intracellular reactive oxygen radicals) of fetal, but not maternal, monocytes and granulocytes in the fetal inflammatory response syndrome. J Perinat Med 2009;37:543–552.
- Yafeng D, Weijian H, Jiaxue W, Weiner CP. Chronic hypoxemia absent bacterial infection is one cause of the fetal inflammatory response syndrome (FIRS). Reprod Sci 2009;16:650–656.
- Nicolaides KH, Economides DL, Soothill PW. Blood gases, pH, and lactate in appropriate- and small-for-gestational-age fetuses. Am J Obstet Gynecol 1989;161:996–1001.
- Nicolaides KH, Soothill PW, Rodeck CH, Campbell S. Ultrasound-guided sampling of umbilical cord and placental blood to assess fetal wellbeing. Lancet 1986;1:1065–1067.
- Soothill PW, Nicolaides KH, Rodeck CH, Campbell S. Effect of gestational age on fetal and intervillous blood gas and acid-base values in human pregnancy. Fetal Ther 1986;1:168–175.
- Weiner CP, Sipes SL, Wenstrom K. The effect of fetal age upon normal fetal laboratory values and venous pressure. Obstet Gynecol 1992;79:713–718.
- Nava S, Bocconi L, Zuliani G, Kustermann A, Nicolini U. Aspects of fetal physiology from 18 to 37 weeks’ gestation as assessed by blood sampling. Obstet Gynecol 1996;87:975–980.
- Economides DL, Nicolaides KH, Gahl WA, Bernardini I, Bottoms S, Evans M. Cordocentesis in the diagnosis of intrauterine starvation. Am J Obstet Gynecol 1989;161:1004–1008.
- Pardi G, Cetin I, Marconi AM, Lanfranchi A, Bozzetti P, Ferrazzi E, Buscaglia M, Battaglia FC. Diagnostic value of blood sampling in fetuses with growth retardation. N Engl J Med 1993;328:692–696.
- Cox WL, Daffos F, Forestier F, Descombey D, Aufrant C, Auger MC, Gaschard JC. Physiology and management of intrauterine growth retardation: A biologic approach with fetal blood sampling. Am J Obstet Gynecol 1988;159:36–41.
- Carroll SG, Papaioannou S, Nicolaides KH. Doppler studies of the placental and fetal circulation in pregnancies with preterm prelabor amniorrhexis. Ultrasound Obstet Gynecol 1995;5:184–188.
- Hankins GD, Snyder RR, Yeomans ER. Umbilical arterial and venous acid-base and blood gas values and the effect of chorioamnionitis on those values in a cohort of preterm infants. Am J Obstet Gynecol 1991;164:1261–1264.
- Moore LG, Rounds SS, Jahnigen D, Grover RF, Reeves JT. Infant birth weight is related to maternal arterial oxygenation at high altitude. J Appl Physiol 1982;52:695–699.
- Yangzom Y, Qian L, Shan M, La Y, Meiduo D, Hu X, Da Q, et al. Outcome of hospital deliveries of women living at high altitude: A study from Lhasa in Tibet. Acta Paediatr 2008;97:317–321.
- Ducsay CA. Fetal and maternal adaptations to chronic hypoxia: Prevention of premature labor in response to chronic stress. Comp Biochem Physiol, Part A Mol Integr Physiol 1998;119:675–681.
- Rhee JW, Longo LD, Pearce WJ, Bae NH, Valenzuela GJ, Ducsay CA. Effect of chronic hypoxia on myometrial responsiveness in the pregnant rat. Am J Physiol 1996;270:E477–E482.
- Nyström PO. The systemic inflammatory response syndrome: Definitions and aetiology. J Antimicrob Chemother 1998;41 Suppl A:1–7.
- Vaisbuch E, Romero R, Gomez R, Kusanovic JP, Mazaki-Tovi S, Chaiworapongsa T, Hassan SS. An elevated fetal interleukin-6 concentration can be observed in fetuses with anemia due to Rh alloimmunization: Implications for the understanding of the fetal inflammatory response syndrome. J Matern Fetal Neonatal Med 2011;24:391–396.
- Duncan JR, Cock ML, Suzuki K, Scheerlinck JP, Harding R, Rees SM. Chronic endotoxin exposure causes brain injury in the ovine fetus in the absence of hypoxemia. J Soc Gynecol Investig 2006;13:87–96.
- Lotze MT, Deisseroth A, Rubartelli A. Damage associated molecular pattern molecules. Clin Immunol 2007;124:1–4.
- Romero R, Chaiworapongsa T, Alpay SZ, Xu Y, Hussein Y, Dong Z, Kusanovic JP, Kim CJ, Hassan SS. Damage-associated molecular patterns (DAMPs) in preterm labor with intact membranes and preterm PROM: a study of the alarmin HMGB1. J Matern Fetal Neonatal Med 2011; Sept 29 [e-pub ahead of print].