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Theories about fetal respiration began in antiquity. Aristotle characterized pneuma as warm air, but also as the enabler of vital functions and instrument of the soul. In Galen’s system of physiology, the vital spirit was carried by the umbilical arteries, the nutrients by the umbilical vein from the placenta to the fetus. In 1569 Aranzio postulated that the maternal and fetal vasculatures are distinct. From 1670 to 1690, a century before the discovery of oxygen, researchers understood that during respiration some form of exchange with the air must occur, naming the substance biolychnium , phlogiston , sal-nitro , or nitro-aerial particles . An analogy of placental and pulmonary gas exchange was described in 1674 by Mayow. In 1779, Lavoisier understood the discovery of oxygen, discarded the phlogiston theory, and based respiration physiology on gas exchange. With the invention of the spectroscope, it became possible to measure hemoglobin oxygenation, and in 1876 Zweifel proved fetal oxygen uptake. Major progress in understanding fetal gas exchange was achieved in the 20 th century by the physiologists Barcroft in Cambridge and Dawes in Oxford.

Mid-trimester preterm premature rupture of membranes (PPROM), defined as rupture of fetal membranes prior to 28 weeks of gestation, complicates approximately 0.4%–0.7% of all pregnancies. This condition is associated with a very high neonatal mortality rate as well as an increased risk of long- and short-term severe neonatal morbidity. The causes of the mid-trimester PPROM are multifactorial. Altered membrane morphology including marked swelling and disruption of the collagen network which is seen with PPROM can be triggered by bacterial products or/and pro-inflammatory cytokines. Activation of matrix metalloproteinases (MMP) have been implicated in the mechanism of PPROM. The propagation of bacteria is an important contributing factor not only in PPROM, but also in adverse neonatal and maternal outcomes after PPROM. Inflammatory mediators likely play a causative role in both disruption of fetal membrane integrity and activation of uterine contraction. The “classic PPROM” with oligo/an-hydramnion is associated with a short latency period and worse neonatal outcome compared to similar gestational aged neonates delivered without antecedent PPROM. The “high PPROM” syndrome is defined as a defect of the chorio-amniotic membranes, which is not located over the internal cervical os. It may be associated with either a normal or reduced amount of amniotic fluid. It may explain why sensitive biochemical tests such as the Amniosure (PAMG-1) or IGFBP-1/alpha fetoprotein test can have a positive result without other signs of overt ROM such as fluid leakage with Valsalva. The membrane defect following fetoscopy also fulfils the criteria for “high PPROM” syndrome. In some cases, the rupture of only one membrane – either the chorionic or amniotic membrane, resulting in “pre-PPROM” could precede “classic PPROM” or “high PPROM”. The diagnosis of PPROM is classically established by identification of nitrazine positive, fern positive watery leakage from the cervical canal observed during in specula investigation. Other more recent diagnostic tests include the vaginal swab assay for placental alpha macroglobulin-1 test or AFP and IGFBP1. In some rare cases amniocentesis and infusion of indigo carmine has been used to confirm the diagnosis of PPROM. The management of the PPROM requires balancing the potential neonatal benefits from prolongation of the pregnancy with the risk of intra-amniotic infection and its consequences for the mother and infant. Close monitoring for signs of chorioamnionitis (e.g. body temperature, CTG, CRP, leucocytes, IL-6, procalcitonine, amniotic fluid examinations) is necessary to minimize the risk of neonatal and maternal complications. In addition to delayed delivery, broad spectrum antibiotics of penicillin or cephalosporin group and/or macrolide and corticosteroids have been show to improve neonatal outcome [reducing risk of chorioamnionitis (average risk ratio (RR)=0.66), neonatal infections (RR=0.67) and abnormal ultrasound scan of neonatal brain (RR=0.67)]. The positive effect of continuous amnioinfusion through the subcutaneously implanted perinatal port system with amniotic fluid like hypo-osmotic solution in “classic PPROM” less than 28/0 weeks’ gestation shows promise but must be proved in future prospective randomized studies. Systemic antibiotics administration in “pre-PPROM” without infection and hospitalization are also of questionable benefit and needs to be further evaluated in well-designed randomized prospective studies to evaluate if it is associated with any neonatal benefit as well as the relationship to possible adverse effect of antibiotics on to fetal development and neurological outcome.

Objective: To determine whether a soft cervix identified by shear-wave elastography between 18 and 24 weeks of gestation is associated with increased frequency of spontaneous preterm delivery (sPTD). Materials and methods: This prospective cohort study included 628 consecutive women with a singleton pregnancy. Cervical length (mm) and softness [shear-wave speed: (SWS) meters per second (m/s)] of the internal cervical os were measured at 18–24 weeks of gestation. Frequency of sPTD <37 (sPTD<37) and <34 (sPTD<34) weeks of gestation was compared among women with and without a short (≤25 mm) and/or a soft cervix (SWS <25 th percentile). Results: There were 31/628 (4.9%) sPTD<37 and 12/628 (1.9%) sPTD<34 deliveries. The combination of a soft and a short cervix increased the risk of sPTD<37 by 18-fold [relative risk (RR) 18.0 (95% confidence interval [CI], 7.7–43.9); P<0.0001] and the risk of sPTD<34 by 120-fold [RR 120.0 (95% CI 12.3–1009.9); P<0.0001] compared to women with normal cervical length. A soft-only cervix increased the risk of sPTD<37 by 4.5-fold [RR 4.5 (95% CI 2.1–9.8); P=0.0002] and of sPTD<34 by 21-fold [RR 21.0 (95% CI 2.6–169.3); P=0.0003] compared to a non-soft cervix. Conclusions: A soft cervix at 18–24 weeks of gestation increases the risk of sPTD <37 and <34 weeks of gestation independently of cervical length.

Aim: Ureaplasma parvum, Ureaplasma urealyticum and Mycoplasma hominis are also known as genital mycoplasmas. Acute chorioamnionitis is an inflammation of the placenta associated with miscarriage. We retrospectively evaluated a possible association between genital mycoplasmas detection, acute chorioamnionitis and fetal pneumonia from second and third trimester spontaneous abortions. Methods: One hundred and thirty placenta and fetal lung samples were evaluated for histological examination. The placenta samples, along with corresponding fetal tracheo-bronchial aspirates, also underwent bacterial and fungal culture and real-time polymerase chain reaction (PCR) assay for the detection of genital mycoplasmas. Results: Acute chorioamnionitis and pneumonia were diagnosed in 80/130 (61.5%) and 22/130 (16.9%) samples, respectively. Among samples positive for acute chorioamnionitis, the proportion of samples positive by real-time PCR and/or culture, was significantly higher than that of negative controls [54/80 (67.5%) vs. 26/80 (32.5%); P<0.001]. Ureaplasma parvum detection was significantly associated with acute chorioamnionitis compared to controls [9/11 (81.8%) vs. 2/11 (18.2%); P=0.019], as well as U. urealyticum [6/7 (85.7%) vs. 1/7 (14.3%); P=0.039]. Among tracheo-bronchial aspirates from abortions with pneumonia, the proportion of real-time PCR and/or culture positive samples was significantly higher than that of controls [13/22 (59.1%) vs. 9/22 (40.9%); P=0.029]. Conclusions: A strong association was found between acute histologic chorioamnionitis and microbial invasion with U. parvum and/or U. urealyticum .

Background: Recent studies have shown that epigenetic differences can increase the risk of spontaneous preterm birth (PTB). However, little is known about heterogeneity underlying such epigenetic differences, which could lead to hypotheses for biological pathways in specific patient subgroups, and corresponding targeted interventions critical for precision medicine. Using bipartite network analysis of fetal DNA methylation data we demonstrate a novel method for classification of PTB. Methods: The data consisted of DNA methylation across the genome (HumanMethylation450 BeadChip) in cord blood from 50 African-American subjects consisting of 22 cases of early spontaneous PTB (24–34 weeks of gestation) and 28 controls (>39 weeks of gestation). These data were analyzed using a combination of (1) a supervised method to select the top 10 significant methylation sites, (2) unsupervised “subject-variable” bipartite networks to visualize and quantitatively analyze how those 10 methylation sites co-occurred across all the subjects, and across only the cases with the goal of analyzing subgroups and their underlying pathways, and (3) a simple linear regression to test whether there was an association between the total methylation in the cases, and gestational age. Results: The bipartite network analysis of all subjects and significant methylation sites revealed statistically significant clustering consisting of an inverse symmetrical relationship in the methylation profiles between a case-enriched subgroup and a control-enriched subgroup: the former was predominantly hypermethylated across seven methylation sites, and hypomethylated across three methylation sites, whereas the latter was predominantly hypomethylated across the above seven methylation sites and hypermethylated across the three methylation sites. Furthermore, the analysis of only cases revealed one subgroup that was predominantly hypomethylated across seven methylation sites, and another subgroup that was hypomethylated across all methylation sites suggesting the presence of heterogeneity in PTB pathophysiology. Finally, the analysis found a strong inverse linear relationship between total methylation and gestational age suggesting that methylation differences could be used as predictive markers for gestational length. Conclusions: The results demonstrate that unsupervised bipartite networks helped to identify a complex but comprehensible data-driven hypotheses related to patient subgroups and inferences about their underlying pathways, and therefore were an effective complement to supervised approaches currently used.

Aim: Preterm birth is the world’s leading cause of neonatal death. Unfortunately, the pathophysiology of preterm birth remains poorly understood. Sjögren-Larsson syndrome is a rare, neurometabolic disorder caused by a fatty aldehyde dehydrogenase deficiency. A majority of patients with Sjögren-Larsson syndrome is born preterm. Methods: Data of all known Dutch patients with Sjögren-Larsson syndrome and all cases reported in literature were analyzed to learn from preterm birth in context of this rare disease. Results: Exact gestational age was known in 33 Dutch patients; 24 (73%) of them were born preterm, with a median gestational age of 36 weeks. The literature search confirmed our findings: 13 (59%) of 22 cases was born preterm. Conclusions: Preterm birth is a hallmark of Sjögren-Larsson syndrome, presumably caused by the abnormal lipid metabolism of the fetus. At least five additional rare genetic disorders (namely Ehlers-Danlos syndrome, ichthyosis prematurity syndrome, congenital analbuminemia, osteogenesis imperfecta type II and restrictive dermopathy) were found in literature that lead to preterm birth of the affected fetus. These disorders are in fact “experiments of nature” and as such they shed new lights on the mechanisms causing preterm birth.

Introduction: The aim of this study was to evaluate the safety and efficacy of the combined treatment of cervical pessary and endovaginal progesterone for the prevention of spontaneous preterm birth (SPB) in women with a short cervical length (CL) between 20 and 24 weeks of gestation. Materials and methods: This is a prospective study of women with a singleton pregnancy and a sonographically detected mid-trimester CL ≤25 mm. The primary outcome measure was spontaneous delivery before 34 weeks (238 days) of gestation. Results: The study sample consisted of 90 women with a mean CL of 14.2 mm (SD=6.5 mm). Of the women, 34.4% had at least one risk factor for SPB; 7.8% delivered preterm before 34 weeks of gestation, and 25.6%, before 37 weeks. Neonatal death occurred in two (2.2%) cases due to respiratory distress syndrome. Lower body mass index values, history of preterm delivery and number of second trimester miscarriages were independently associated with delivery before 34 weeks. Conclusion: The combination of vaginal progesterone and cervical pessary for the prevention of SPB in women with a short cervix is safe and well tolerated. This therapy was associated with pregnancy prolongation, reduced prematurity rate and a low rate of perinatal complications.

We examined the risk of preterm birth (PTB, <37 weeks’ gestation) in a second pregnancy and analyzed the extent to which this risk varies by maternal age and race/ethnicity. The sample included nulligravida mothers in California who delivered two singletons between 2005 and 2011. Logistic regression was used to calculate the odds of PTB in the second pregnancy. Within each race/ethnicity stratum, women delivering term infants in their first pregnancy and between 25 and 34 years old for both pregnancies served as the referent group. There were 2,90,834 women included in the study. Among women who delivered their first infant at term, the odds of delivering their second infant early differed by race and age. Hispanic, Black and Asian non-Hispanic women who were <18 years for both pregnancies were at higher odds of having a PTB in their second pregnancy (adjusted odds ratios 1.7, 3.3 and 2.9, respectively). Asian non-Hispanic women who were <18 years for their first delivery at term and between 18 and 24 years for their second delivery, or were >34 years for both, were also at higher odds of delivering their second baby prematurely (adjusted odds ratios 1.9 and 1.3, respectively). Women who deliver their first infant at <37 weeks of gestation are at 3 to 7 times higher odds of delivering their second infant preterm. Providers should consider including information about these risks in counseling their patients.

Objective: To explore the associations between birth weight for gestational age (GA) and infant mortality as well as causes of infant death. Study design: A population-based observational study conducted between 2002 and 2012 included 203,620 non-malformed singleton live births from Slovenia. Poisson regression analyses were performed to estimate the crude relative risk (RR) and adjusted RR (aRR) for infant mortality by birth weight percentiles stratified by the GA subgroups term, moderate-to-late preterm, very preterm and extremely preterm. Results: Compared with appropriate for GA (AGA) term infants (referent-AGA), infant mortality was significantly higher in small for GA (SGA) term infants [aRR=2.79 (1.41–5.50)], with significant cause-specific infant mortality risk for neuromuscular disorders [RR=10.48 (2.62–41.91)]. The differences in infant mortality and cause-specific infant mortality in preterm subgroups between referent-AGA and SGA were insignificant. Conclusions: In the Slovenian population, birth weight for GA is significantly associated with infant mortality only in infants born at term.

Objective: A current descriptive assessment of perinatal outcomes in pregnancies complicated by previable preterm premature rupture of membranes (pPPROM) at <24 weeks of gestation, after expectant treatment. Study design: Maternal and short-term neonatal data were collected for patients with pPPROM. Results: Seventy-three patients with 93 fetuses were hospitalized with pPPROM at 15–24 weeks’ gestation. Among these patients, 27.4% (n=20) chose pregnancy termination, 27.4% (n=20) miscarried and 45.2% (n=33) proceeded to live births. After a median latency period of 38 days, ranging from 1 to 126 days, 24 singletons and 20 multiples were live-born, of whom 79.5% (n=35) survived the perinatal period. The main neonatal sequelae were pulmonary hypoplasia (29.5%; n=13), connatal infection (56.8%; n=25), intraventricular hemorrhage (25%; n=11; resulting in five neonatal deaths) and Potter’s syndrome (15.9%; n=7). Nine newborns died, within an average of 2.8 days (range, 1–10 days). The overall neonatal survival rate was 51.5% – including miscarriages but not elective terminations. The intact survival rate was 45.5% of all live-born neonates. Conclusions: Even with limited treatment options, overall neonatal survival is increasing. However, neonatal mortality and morbidity rates remain high. The gestational age at membrane rupture does not predict neonatal outcome.