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PubMed1995

Myometrial estradiol and progesterone receptor changes in preterm and term pregnancies.

OBJECTIVE: To determine if labor is associated with changes in myometrial estradiol (E2) and progesterone receptors. METHODS: Lower myometrial segments were obtained from women undergoing cesarean deliveries at term in labor (n = 10), term not in labor (n = 10), preterm in labor (n = 9), and preterm not in labor (n = 11). Western immunoblotting was used to determine the presence and molecular size of E2 and progesterone receptor proteins. Immunocytochemistry was used to determine E2 and progesterone receptor changes in preterm and term pregnancies. RESULTS: Myometrium from pregnant women contained 74-kilodalton (kDa) E2 receptor and 94- and 110-kDa progesterone receptor proteins. These receptors are present in both myometrial smooth muscle and myometrial blood vessels. The nuclei of myometrial smooth muscle cells primarily contain both receptors. The immunostaining for progesterone receptors was less in patients in labor compared with those not in labor in preterm and term pregnancies. In comparing patients not in labor, the immunostaining for progesterone receptors was less at term compared with preterm pregnancy. Unlike the differences in progesterone receptors, there are no obvious differences in E2 receptor immunostaining in myometrial samples from all four groups of women. CONCLUSION: A myometrial decrease in progesterone receptors, rather than an increase in E2 receptors, may play a role in the onset of labor in women with term or preterm pregnancies.

Adult↗

PubMed1996

Elevations of amniotic fluid macrophage inflammatory protein-1 alpha concentrations in women during term and preterm labor.

OBJECTIVE: To determine whether elevated concentrations of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in amniotic fluid (AF) are related to term and preterm labor. METHODS: Amniotic fluid was obtained from women from five different clinical situations: 1) term cesarean delivery, no labor (n = 29); 2) normal term labor, no infection (n = 36); 3) preterm labor, delivery more than 1 week from sampling, no infection (n = 19); 4) preterm labor, delivery within 1 week from sampling, no infection (n = 18); and 5) preterm chorioamnionitis (n = 8). Amniotic fluid was collected aseptically at the time of amniocentesis, amniotomy, or hysterotomy. Concentrations of MIP-1 alpha were determined by enzyme-linked immunosorbent assay. Statistical analysis was by Wilcoxon rank-sum test, Kruskal-Wallis test, and unpaired t test. RESULTS: Women in normal term labor had significant elevations of AF MIP-1 alpha concentrations when compared with women at term undergoing repeat cesarean delivery (P < .001). In women with term gestation, AF MIP-1 alpha correlated well with cervical dilation (r2 = 0.479, P < .001). In women with preterm labor who later delivered within 1 week of presentation, AF MIP-1 alpha concentrations were higher than those from women who did not deliver within 1 week. Women who presented with clinically evident chorioamnionitis had the highest concentrations of AF MIP-1 alpha (P = .001). CONCLUSION: Women in labor have significantly elevated AF concentrations of MIP-1 alpha, particularly if labor is associated with intrauterine infection. We suggest that MIP-1 alpha is involved in the physiology of normal labor and in the pathogenesis of infection-associated preterm labor.

Amniotic Fluid↗

PubMed1996

Prediction of spontaneous preterm birth by fetal fibronectin and uterine activity.

OBJECTIVE: To evaluate the usefulness of fetal fibronectin and home uterine contraction assessment in predicting preterm birth (before 34 weeks) in at-risk asymptomatic women. METHODS: One hundred fifty women were enrolled prospectively; five were lost to follow-up, leaving 145 women available for analysis. Because patients with preterm labor before 34 weeks' gestation most commonly develop this problem after 28 weeks, the period of 26-28 weeks' gestation was selected prospectively as the first window for prediction and study analysis. Eighty-five of 145 asymptomatic women at high risk for preterm birth had both home uterine contraction assessment of 2 hours per day and one or more cervical sampling(s) for fetal fibronectin measurement at 26-28 weeks. A positive home uterine contraction assessment was defined as contractions exceeding two per hour averaged over the 2-week study interval. Positive fetal fibronectin was defined as greater than 50 ng/mL. RESULTS: Fourteen of the 85 women (16.5%) delivered before 34 weeks. Home uterine contraction assessment alone had a sensitivity, specificity, positive predictive value, and negative predictive value for preterm birth of 64, 85, 45, and 92%, respectively; fetal fibronectin alone was associated with values of 43, 89, 43, and 89%, respectively. A positive home uterine contraction assessment was associated with a relative risk (RR) for preterm birth of 5.9% (95% confidence interval [CI] 2.4-14.2), whereas a positive fetal fibronectin demonstrated an RR of 3.8 (95% CI 1.5-9.4). When both assessments were positive, all patients delivered before 34 weeks and there was an RR of 27.0 (95% CI 8.7-84.1) compared with those with both tests being negative. Only two patients with both tests negative delivered before 34 weeks (negative predictive value 96%). CONCLUSION: Both the home uterine contraction assessment and fetal fibronectin accurately predicted preterm birth before 34 weeks. When both tests were combined, the predictive ability improved substantially.

Adult↗

PubMed1996

Elevated placental cytokine release, a process associated with preterm labor in the absence of intrauterine infection.

OBJECTIVE: To investigate the role of cytokines in normal term and preterm labor in the absence of intrauterine infection. METHODS: Cytokine (interleukin [IL]-1 beta, IL-6 and tumor necrosis factor-alpha [TNF-alpha]) release was estimated from placental and decidual cell cultures from 22 nonlaboring women at term with cesarean deliveries, 18 women with spontaneous labor at term, and 21 women with preterm labor (19-36 weeks gestation) who delivered vaginally or by cesarean, according to gestational age. Eight of 21 women delivering preterm had clinical evidence of intrauterine infection, and 13 were not infected. RESULTS: Placental cell cultures obtained from women with spontaneous term labor released significantly larger amounts of cytokines (median: IL-1 beta 6450 pg/mL, IL-6 1821 ng/mL, and TNF-alpha 13,506 pg/mL) compared with placental cell cultures from nonlaboring women at term (median: IL-1 beta 2602 pg/mL, IL-6 993 ng/mL, TNF-alpha 3475 pg/mL; P < .02). Placental cells from women delivering preterm with intrauterine infection did not produce significantly different amounts of cytokines (median: IL-1 beta 3929 pg/mL, IL-6 1084 ng/mL, TNF-alpha 2847 pg/mL) when compared with those of nonlaboring women at term, whereas placental cells from uninfected women delivering preterm produced significantly larger amounts of cytokines (median: IL-1 beta 22,903 pg/mL, IL-6 1899 ng/mL, TNF-alpha 15,005 pg/mL; P < .01) than cells from nonlaboring women at term. Cytokine release from decidual cell cultures was similar in all groups tested. CONCLUSION: In the absence of intrauterine infection, preterm labor was associated with elevated placental cytokine release.

Adult↗

PubMed1992

Amniotic fluid platelet-activating factor (PAF) is elevated in patients with tocolytic failure and preterm delivery.

Certain biological properties of PAF, including its ability to promote PGE2 synthesis and to induce myometrial contractions, support its potential role in parturition. The presence of PAF in amniotic fluid of human pregnancy appears to correlate with normal and pathologic labor. To further refine this relationship, we selected the clinical endpoints of preterm labor, tocolytic failure and preterm delivery, and evaluated amniotic fluid PAF within these groups of patients. We also measured acetylhydrolase (AH), PAF's primary degradative enzyme, to identify any correlation with the observed PAF levels. 39 specimens were collected by amniocentesis: 17 for karyotype, 6 to assess lung maturity at term and 16 in cases of preterm labor; 8 each with intact membranes and ruptured membranes at the time of sampling. PAF and AH were measured by a 3H-serotonin release bioassay and an in vitro enzyme assay using radiolabelled substrate, respectively. A 12-fold increase in PAF was found in the 3 preterm labor patients in whom tocolysis failed (delivery less than 48 hrs after treatment) compared to the 7 patients in whom labor was arrested (mean PAF = 35.0 vs 2.9 ng/ml, respectively; p = .017). Four of 8 patients with membrane rupture had preterm deliveries; their PAF levels were also elevated when compared to those that delivered at term (mean PAF = 19.7 vs 4.95 ng/ml). The 2 patients with positive amniotic fluid gram stains had the highest PAF levels in the entire cohort (30.5, 44.1 ng/ml), with low or undetectable AH. These data suggest that increased PAF production may be associated with preterm labor subsequent to tocolytic failure.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMedDate not supplied

Preterm birth prevention.

The prevention of preterm birth may be the most important problem facing maternity care providers. Preterm birth occurs in 10% of all births in the United States and is associated with 83% of perinatal deaths not caused by congenital anomalies. This article reviews the anatomy and physiology of the uterus, the physiology of uterine contractions, the initiation of labor, the etiology of preterm labor, risk factors and risk scoring for preterm labor, and the diagnosis and management of preterm labor. The components of a preterm birth prevention program are described, and recommendations for clinical practice are made.

Bed Rest↗

PubMed1988

Identification of women at high risk for preterm-low-birthweight births.

Preterm-low-birthweight births comprise a subset of extremely high-risk low-birthweight infants. While numerous studies have evaluated risk factors to predict an individual's chance of a high-risk pregnancy, few have identified risk factors specifically related to preterm-low-birthweight births. Risk factors for preterm-low-birthweight births were analyzed in a sample of 11,623 women from northwest North Carolina enrolled in a low-birth-weight prevention program. Significant risk factors for preterm-low-birthweight births in this population were identified, and weights were assigned to each factor. Application of the weighting system to each patient's specific risk factors identifies women at high risk for a preterm-low-birthweight birth and assists in the determination of appropriate intervention. These data make use of all current information in the low-birthweight births prevention project. Prospective assessment of the scoring system as the project continues should improve the ability to identify and intervene with women at highest risk for a preterm-low-birthweight birth.

Adult↗

PubMed1992

A comparison of risk assessment models for term and preterm low birthweight.

BACKGROUND: Most epidemiological research dealing with the assessment of risk for low birthweight has focused on all low birthweight births. Studies that have attempted to distinguish between term and preterm low birthweights have tended to examine preterm low birthweight, since the risk of perinatal mortality and morbidity is greatest for this group of infants. METHOD: This study uses data from 25,408 singleton births in a 20-county region in North Carolina to identify and compare risk factors for term and preterm low birthweights, and also examines the usefulness of separate multivariate risk assessment systems for term and preterm low birthweights that could be used in the clinical setting. RESULTS: Risk factors that overlap as significant predictors of both types of low birthweight include race, no previous live births, smoking, weight under 100 lb, and previous preterm or low birthweight birth. Age also is a significant predictor of both types of low birthweight, but in opposite directions. Younger age is associated with reduced risk of term low birthweight and increased risk of pattern low birthweight. CONCLUSION: Comparison of all risk factors indicates that different multivariate models are needed to understand the epidemiology of preterm and term low birthweights. In terms of clinical value, a general risk assessment model that combines all low birthweight births is as effective as the separate models.

Adolescent↗

PubMed1993

Induction of lipid peroxidation of pulmonary surfactant by plasma of preterm babies.

Respiratory distress syndrome of the preterm baby is believed to be caused by a deficiency of pulmonary surfactant and leakage of plasma into the alveolar spaces. Since the two pathogenetic factors seem to be inter-related, we postulated that peroxidation of surfactant by plasma iron could be the linking mechanism. We obtained cord blood samples from 22 preterm babies (mean gestational age 32.2 [SD 2.7] weeks) and 24 term babies (40.1 [1.6] weeks), and venous blood samples from 18 healthy adults. No adult had detectable non-protein-bound iron in the plasma, but 10/21 (48%) preterm babies and 6/24 (25%) term babies had detectable concentrations (rate difference 23% [95% Cl -5 to 51%], p = 0.20). Transferrin and haptoglobin concentrations were higher and free haemoglobin concentrations lower in adults than in babies (p < 0.005). Only transferrin differed significantly between term and preterm babies. Plasma from all 18 adults and from 23 (96%) term babies inhibited iron-catalysed lipid peroxidation of pulmonary surfactant liposomes. By contrast, plasma from 11 (50%) preterm babies stimulated such peroxidation (difference in stimulation rate 46% [20-71%], p < 0.005 for preterm vs term babies); the ability to stimulate peroxidation was related to the presence of non-protein-bound iron (p < 0.001). Peroxidation decreased in the babies when apotransferrin was added to plasma and in all subjects when alpha-tocopherol was incorporated into the surfactant liposomes. Lipid peroxidation of surfactant may contribute to the pathogenesis of respiratory distress syndrome. Possible therapeutic approaches are increasing babies' iron-binding capacity by plasma transfusions and increasing the antioxidant capacity of commercial surfactant.

Adult↗

PubMed1982

Effects of cigarette smoking, alcohol, coffee and tea consumption on preterm delivery.

A case-control study of 175 mothers of singleton, preterm infants and 313 mothers of singleton, term infants was undertaken at Yale-New Haven Hospital during 1977 to explore possible risk factors of preterm delivery. Heavy alcohol consumption (an average of two or more drinks per day) during the pregnancy was associated with an approximately 3-fold risk of preterm delivery. Women who smoked 10 or more cigarettes per day were also at an increased risk of a preterm delivery, but the effect of cigarette smoking was less pronounced once confounding variables had been taken into account. No association was observed between coffee drinking and shortened gestations. Tea consumption, especially four or more cups of tea per day, was more frequent among women with a preterm as compared to a term infant, but no significant relation was evident between heavy tea consumption and preterm delivery after controlling for the effects of other risk factors.

Adolescent↗

PubMed1989

Follow-up of preterm children. I. Neurological assessment at 4 years of age.

In a long-term prospective study, 46 unselected infants born before 35 completed weeks of gestational age were compared with 26 full-term infants. At 4 years of age, 44 preterms and 25 full-terms were available to follow-up. Two preterm children manifested abnormal neurological development, slight spastic diplegia in one case, and psychomotor retardation in the other. Both these cases had already been identified at 18 months of age. Thorough neurological assessment revealed a number of differences between the two groups indicating both delayed neurological maturation and mild dysfunction in the preterms. We drew up a neurological profile to describe these minor neurological signs. The preterms had poorer muscle tone, more spontaneous movements, and were less skilled in certain gross motor functions. They also showed less developed balance reactions, had difficulties in some coordination tests, and asymmetry was more common in neurological functions. In the different subsystems of the neurological profile we also found a greater variation in the preterm group than in the full-term group. There were no significant correlations within the preterm group between the neurological findings at 4 years of age and gestational age, birthweight, and prenatal or perinatal factors.

Child, Preschool↗

PubMed1995

Maturation of the auditory brainstem in low risk-preterm infants: a comparison with age-matched full term infants up to 6 years.

Whether preterm birth has a significant effect on the maturation of the human brain remains an equivocal issue. Since experience plays a crucial role in the development of the brain, it is conceivable that extra-uterine preterm exposure could exert some effects on the maturation of the developing human brain. The present study compared the post-term maturation of the central components of brainstem auditory evoked response (BAER) in low risk preterm infants with that of age-matched full term infants up to 6 years. The preterm infants demonstrated similar maturational profiles to those of the term infants in both interpeak intervals and amplitude measures. No systematic, statistically significant differences were found between the preterm and term infants in any of the BAER variables although the I-V interval tended to be slightly shortened in the prematurely born infants. These results suggest that preterm birth or earlier exposure to sound environment extra utero is unlikely to lead to significant neurophysiological consequence in the developing auditory brainstem of low risk infants.

Aging↗

PubMed1996

Intrauterine growth and gestational age in preterm infants with cerebral palsy.

In a case-control study, gestational age and intrauterine growth of 191 preterm singleton infants 1971-82 with cerebral palsy were compared to all preterm live-born singletons in Denmark in 1982 (N = 2203). The distribution of gestational age among preterm cases was slightly bimodal with maximum values at 29 and 32 weeks. The risk for cerebral palsy was highest in the infants with gestational age 28-30 weeks (OR = 5.6 (4.0-7.8), 95% confidence interval). Birth weight deviation, in the 34-36 weeks infants, expressed as the number of standard deviations from the mean birth weight for gestational age, was more negative in cases than in controls (P < 0.001). The frequency of small for gestational age (SGA) was 13% in cases and 9% in controls (OR = 1.5 (0.96-2.3), 95% confidence interval). The odds for cerebral palsy being SGA, was lower in 28-30 weeks (OR = 0.22 (0.06-0.86), 95% confidence interval), the same in 31-33 weeks (OR = 0.83 (0.35-2.0), 95% confidence interval) and higher in 34-36 weeks (OR = 5.2 (2.9-9.5), 95% confidence interval). In conclusion, preterm infants with cerebral palsy are born earlier than other preterm infants. Small for gestational age is associated with cerebral palsy in preterm infants only above 33 weeks.

Case-Control Studies↗

PubMed1995

Spontaneous otoacoustic emissions in preterm neonates: prevalence and gender effects.

A number of lines of evidence indicate that the human cochlea is fully functional as a mature sound transducer by 6 months of age. However, information about the development of the active cochlear mechanisms and notably the development of outer hair cell (OHC) activity is yet incomplete. Recording and analysis of otoacoustic emissions (OAEs), probably generated by the OHCs of the organ of Corti, have led to a better understanding, in humans, of how sounds are analysed in the cochlea by means of active mechanisms. Evoked OAEs (EOAEs) and spontaneous OAEs (SOAEs), when they can be recorded in full-term and preterm neonates, show different characteristics from those in adults, suggesting that maturation of the peripheral auditory system is incomplete at birth. To learn more about this maturation, using the best-established facts concerning SOAEs in adults, such as their greater prevalence in females and also in right ears, SOAEs were studied in more detail in 81 preterm neonates, from 30 to 40 weeks of conceptional age, all presenting bilateral EOAEs according to objective criteria. The first finding of this study was that SOAEs existed and could be recorded as of 30 weeks of conceptional age in humans. Some SOAE characteristics in preterm neonates, such as prevalence, peak number and acoustic frequencies, showed similarity with full-term neonates. Comparison of other criteria between the two populations, such as greater SOAE prevalence in right ears and higher SOAE peak number in females, suggested that these developmental factors emerge around term in humans. Comparison of SOAE characteristics between male and female preterms suggested that male preterms were less advanced in peripheral auditory development than were female preterms.

Acoustic Stimulation↗

PubMed2004

The effect of phosphoramidon on inflammation-mediated preterm delivery in a mouse model.

OBJECTIVE: Several metallopeptidases have been implicated in both term and preterm parturition. We hypothesize that endotoxin-induced preterm delivery can be prevented by the administration of a metallopeptidase inhibitor. STUDY DESIGN: We used an animal model of endotoxin-induced preterm delivery in timed pregnancy C57Bl/6 mice. Test animals received lipopolysaccharide followed by phosphoramidon, either every 1.5 or every 3 hours. Control mice received lipopolysaccharide followed by buffer injections at the same intervals. The primary outcome was a preterm delivery rate. RESULTS: The rate of preterm delivery for the control animals was 88.0% compared with the treatment groups of 45.5% for the mice that received phosphoramidon every 3 hours and 30.8% for the group that received it every 1.5 hours (P<.01). CONCLUSION: The administration of a metallopeptidase inhibitor resulted in a decreased rate of preterm delivery in this animal model.

Animals↗

PubMed2004

Necrotic cell injury in the preterm and near-term ovine fetal brain after intermittent umbilical cord occlusion.

OBJECTIVE: This study was undertaken to determine the extent of necrotic cell death as a measure of neurologic injury in the preterm and near-term ovine fetal brain in response to intermittent umbilical cord occlusion (UCO) with severe, but limited hypoxia and no cumulative acidosis to ensure longer-term survival. STUDY DESIGN: Fetal sheep (control and experimental groups at 0.75 and 0.90 of gestation) were studied over 4 days with UCOs performed in the experimental group animals by complete inflation of an occluder cuff for 90 seconds every 30 minutes for 3 to 5 hours each day. Animals were then euthanized and the fetal brain perfusion-fixed and prepared for subsequent histology and assessment of necrotic cell injury by using standard staining with hematoxylin and eosin (H&E), and with a novel fluorescent marker, Fluoro-Jade B, that targets degenerating neurons. RESULTS: In both preterm and near-term animal groups, UCO caused a large decline in arterial Po(2) (to approximately 7 mm Hg), a modest decline in pH (to approximately 7.30), and a modest rise in Pco(2) (to approximately 61 mm Hg) (all P<.01), but with a return to control values after the occluder release and no cumulative acidosis over each day of study. Overall, very low levels of H&E-stained necrotic-appearing cells and Fluoro-Jade B-stained positive cells were observed across all brain regions studied with values not significantly different from zero, excepting that for the gray matter of the preterm control (by H&E staining), preterm and near-term cord occlusion (by H&E and Fluoro-Jade B staining), and the thalamus of the near-term cord occlusion (by H&E staining) animals. Although there were no differences in the levels of H&E-stained necrotic-appearing cells and Fluoro-Jade B-stained positive cells between respective control and cord occlusion group animals for most of the brain regions studied, a significant increase in Fluoro-Jade B-stained positive cells was observed in the gray matter of both the preterm and near-term cord occlusion animals (P<.05). CONCLUSION: Intermittent cord occlusion insult with severe but limited fetal hypoxemia and no cumulative acidosis, was generally well tolerated in both the preterm and near-term animal groups as assessed by measures of necrotic cell injury throughout the brain with minimal evidence for such. However, compensatory mechanisms which are protective for the brain may become limited with repetitive hypoxia insult over time as suggested by the low level of Fluoro-Jade B-stained positive cells noted in the gray matter tissues for both occlusion groups.

Animals↗

PubMed2004

Racial and ethnic disparities in preterm birth: the role of stressful life events.

OBJECTIVE: The purpose of this study was to examine racial-ethnic disparities in stressful life events before and during pregnancy and to assess the relationship between stressful life events and racial-ethnic disparities in preterm birth. STUDY DESIGN: Using data from the Pregnancy Risk Assessment Monitoring System, we conducted a retrospective cohort analysis of a sample of 33,542 women from 19 states who were delivered of a live-born infant in 2000. Principal component analysis was used to group 13 stressful life events into 4 stress constructs: emotional, financial, partner-related, and traumatic. Racial-ethnic disparities in stressful life events were assessed with the use of bivariate and multivariate regression analyses. The contribution of stressful life events to racial-ethnic disparities in preterm birth was evaluated with the use of stepwise regression model and interaction terms. RESULTS: Black women and American Indian/Alaska Native women reported the highest number of stressful life events in the 12 months before delivery. Compared with non-Hispanic white women, black women were 24% more likely to report emotional stressors, 35% more likely to report financial stressors, 163% more likely to report partner-related stressors, and 83% more likely to report traumatic stressors. The addition of stress constructs to the stepwise regression model minimally affected the association between race-ethnicity and preterm birth, and none of the stress constructs were significantly associated with preterm birth. There were no significant interaction effects between race-ethnicity and stress on preterm birth, except for a modest effect between black race and traumatic stressors. CONCLUSION: There are significant racial-ethnic disparities in the experience of stressful life events before and during pregnancy. Stressful life events do not appear to contribute significantly to racial-ethnic disparities in preterm birth.

Adult↗

PubMed2004

Interleukins-1, -4, -6, -10, tumor necrosis factor, transforming growth factor-beta, FAS, and mannose-binding protein C gene polymorphisms in Australian women: Risk of preterm birth.

OBJECTIVE: The purpose of this study was to examine the relationship between preterm birth and 22 single nucleotide polymorphisms in genes that encode cytokines and mediators of apoptosis and host defense. STUDY DESIGN: Two hundred two white women with a spontaneous preterm birth of <35 weeks of gestation were compared with 185 white women with term births. Genotyping was performed with polymerase chain reaction and sequence specific primers. Multivariable analyses included demographic and genetic variables. RESULTS: Alcohol (multivariable odds ratio, 2.3; P = .001] and substance use (multivariable odds ratio, 3.7; P = .01) were associated with preterm birth at <35 weeks of gestation. Smoking (multivariable odds ratio, 2.3; P = .03), haplotypes IL10 -1082A/-819T/-592A (multivariable odds ratio, 2.1; P = .04), tumor necrosis factor ( TNF )+488A/-238G/-308G (multivariable odds ratio, 2.4; P = .04), and IL4 -509C/C (multivariable odds ratio, 3.4; P = .02), and the presence of MBL2 codon 54Asp (multivariable odds ratio, 2.3; P = .02) were associated independently with preterm birth at <29 weeks of gestation. Homozygosity for IL10 -1082G/-819C/-592C haplotype (multivariable odds ratio, 1.9; P = .02) was more common in women with preterm premature rupture of membranes. CONCLUSION: Polymorphisms in immunoregulatory genes may influence susceptibility to preterm birth or premature rupture of membranes.

Adolescent↗