•The balance between inflammation and progesterone activity determines timing of delivery.•Intrauterine infection is the cause of many early preterm births and adverse perinatal outcomes.•Sterile ...inflammation is a more common cause of preterm birth than infection-driven inflammation.•The maternal inflammatory burden is increased with gestational age and external stressors.•Inflammation is an attractive target for interventions to prevent and treat preterm labour.
The central role of inflammatory processes in labour and delivery is now well-recognised. However, the biomolecular, immunological and endocrine mechanisms involved in the labour process, and the clinical manifestations of inflammation in pregnancy, are complex, variable and modulated by factors such as aetiology, ethnicity and gestational age. In this review, evidence is presented of the pivotal relationship between progesterone and inflammation in pregnancy in terms of determining the timing of labour and delivery. The maternal inflammatory burden increases with advancing gestational age in response to endocrine, maturational, physical, metabolic and biochemical drivers, leading to functional progesterone withdrawal necessary for labour and delivery. Variability in the nature, timing and magnitude of these drivers influence the timing of delivery and the likelihood of preterm birth. Pathological inflammatory insults in pregnancy, such as infection, oxidative stress, senescence and maternal allograft rejection, can precipitate preterm birth, often involving common signalling pathways. Intrauterine infection is an important cause of early preterm birth, associated with delivery of the infants at greatest risk of death and disability; however, most preterm deliveries with intrauterine inflammatory activation are not infection-associated. This observation has important diagnostic and therapeutic implications and challenges. The key differences and similarities between infection-associated and sterile inflammation in this context are highlighted, and the clinical implications and significance of these processes and how they might be exploited are discussed.
The human microbiome includes trillions of bacteria, many of which play a vital role in host physiology. Numerous studies have now detected bacterial DNA in first-pass meconium and amniotic fluid ...samples, suggesting that the human microbiome may commence
. However, these data have remained contentious due to underlying contamination issues. Here, we have used a previously described method for reducing contamination in microbiome workflows to determine if there is a fetal bacterial microbiome beyond the level of background contamination. We recruited 50 women undergoing non-emergency cesarean section deliveries with no evidence of intra-uterine infection and collected first-pass meconium and amniotic fluid samples. Full-length 16S rRNA gene sequencing was performed using PacBio SMRT cell technology, to allow high resolution profiling of the fetal gut and amniotic fluid bacterial microbiomes. Levels of inflammatory cytokines were measured in amniotic fluid, and levels of immunomodulatory short chain fatty acids (SCFAs) were quantified in meconium. All meconium samples and most amniotic fluid samples (36/43) contained bacterial DNA. The meconium microbiome was dominated by reads that mapped to
. Aside from this species, the meconium microbiome was remarkably heterogeneous between patients. The amniotic fluid microbiome was more diverse and contained mainly reads that mapped to typical skin commensals, including
and
spp. All meconium samples contained acetate and propionate, at ratios similar to those previously reported in infants.
reads were inversely correlated with meconium propionate levels. Amniotic fluid cytokine levels were associated with the amniotic fluid microbiome. Our results demonstrate that bacterial DNA and SCFAs are present
, and have the potential to influence the developing fetal immune system.
It has long been assumed that establishment of the fetal microbiome commences with the birthing process. However, recent studies have found bacterial DNA in umbilical cord blood, placenta, amniotic ...fluid, meconium, and fetal membranes in healthy normal pregnancies, leading to suggestions that the seeding of the fetal microbiome may commence in utero long before delivery. The origins of the microbiota of the fetal gastrointestinal (GI) tract have not yet been conclusively determined, although bacterial translocation from the maternal circulation, or ascension from the vagina, are both likely to be contributing pathways. Mother-to-child efflux of bacteria during pregnancy has the potential to markedly influence postnatal health, as the composition of gut microbiota determines production of important metabolites which are absorbed systemically and which modify immune function and development. Hence, the importance of understanding the colonization of the fetal GI microbiome is becoming clear, although few studies have investigated the origins, dynamics, and timing of the fetal microbiome. This is the topic of this review. By gaining a deeper understanding of the mechanisms underpinning fetal microbiome seeding, strategies may be developed to optimize fetal immune development and reduce the risk of adverse health and developmental outcomes.
Prenatal testosterone may have a powerful masculinizing effect on postnatal physical characteristics. However, no study has directly tested this hypothesis. Here, we report a 20-year follow-up study ...that measured testosterone concentrations from the umbilical cord blood of 97 male and 86 female newborns, and procured three-dimensional facial images on these participants in adulthood (range: 21–24 years). Twenty-three Euclidean and geodesic distances were measured from the facial images and an algorithm identified a set of six distances that most effectively distinguished adult males from females. From these distances, a ‘gender score’ was calculated for each face, indicating the degree of masculinity or femininity. Higher cord testosterone levels were associated with masculinized facial features when males and females were analysed together (n = 183; r = −0.59), as well as when males (n = 86; r = −0.55) and females (n = 97; r = −0.48) were examined separately (p-values < 0.001). The relationships remained significant and substantial after adjusting for potentially confounding variables. Adult circulating testosterone concentrations were available for males but showed no statistically significant relationship with gendered facial morphology (n = 85, r = 0.01, p = 0.93). This study provides the first direct evidence of a link between prenatal testosterone exposure and human facial structure.
Numerous studies suggest that infants delivered by cesarean section are at a greater risk of non-communicable diseases than their vaginal counterparts. In particular, epidemiological studies have ...linked Cesarean delivery with increased rates of asthma, allergies, autoimmune disorders, and obesity. Mode of delivery has also been associated with differences in the infant microbiome. It has been suggested that these differences are attributable to the "bacterial baptism" of vaginal birth, which is bypassed in cesarean deliveries, and that the abnormal establishment of the early-life microbiome is the mediator of later-life adverse outcomes observed in cesarean delivered infants. This has led to the increasingly popular practice of "vaginal seeding": the iatrogenic transfer of vaginal microbiota to the neonate to promote establishment of a "normal" infant microbiome. In this review, we summarize and critically appraise the current evidence for a causal association between Cesarean delivery and neonatal dysbiosis. We suggest that, while Cesarean delivery is certainly associated with alterations in the infant microbiome, the lack of exposure to vaginal microbiota is unlikely to be a major contributing factor. Instead, it is likely that indication for Cesarean delivery, intrapartum antibiotic administration, absence of labor, differences in breastfeeding behaviors, maternal obesity, and gestational age are major drivers of the Cesarean delivery microbial phenotype. We, therefore, call into question the rationale for "vaginal seeding" and support calls for the halting of this practice until robust evidence of need, efficacy, and safety is available.
The establishment of human gut microbiota commences initially
. Meconium-the first fecal material passed after birth-can be used to study fetal gut contents; however, processing meconium samples for ...microbiome studies presents significant technical challenges. Meconium hosts a low biomass microbiome, is tar-like in texture and contains high concentrations of PCR inhibitors. This study aimed to evaluate four different DNA extraction methods to elucidate the most effective method for bacterial DNA recovery and sequencing analysis from first-pass meconium. Samples from five infants were collected and processed using the following extraction kits: (1) Qiagen QIAamp DNA Stool Mini (QS); (2) Qiagen QIAamp DNA Microbiome (QM); (3) MoBio PowerSoil (PS); (4) MoBio MagAttract PowerMicrobiome (PM). Additionally, Kit PM was employed with a double inhibitor removal treatment (IRT) step (PM2). Bacterial DNA recovery was assessed by qPCR. Any PCR inhibition in samples was measured by spiking DNA eluates with 0.1 ng of pure
(GBS) DNA followed by qPCR quantitation. Kit PM yielded the highest average total DNA yield (79.3 ng per gram of meconium). Samples extracted with kit PS had the highest detectable levels of 16S rRNA gene by qPCR. The ability of each kit to overcome PCR inhibition varied, with qPCR on GBS-spiked DNA from kits QS, QM, PS, and PM recovering 87.1, 91.0, 88.8, and 37.9% GBS DNA, respectively. Double IRT improved the performance of kit PM, increasing GBS recovery to 56.5%. However, once DNA yield was normalized to the level recovered with the other kits 100% of GBS DNA was detected, suggesting that levels of PCR inhibitors are related to DNA yield from kit PM. Ion Torrent 16S rRNA gene sequencing revealed a high level of inter-kit variation in meconium microbiome structure. In particular, kit QM showed a bias toward extracting Firmicute DNA, while the other kits extracted primarily Proteobacterial DNA. Choice of extraction kit greatly impacts on the ability to extract and detect bacterial DNA in meconium and on the microbiome community structure generated from these samples.
During the past decade there has been an explosion in the number of nanoparticulate drugs or drug delivery systems being explored, developed and marketed for the treatment and prevention of human ...diseases. While the potential dangers of drug administration in pregnancy are well known, there are circumstances where the benefits of maternal drug administration are perceived to outweigh the risks to the fetus. Hence, the administration of potentially harmful drugs in pregnancy is surprisingly common. Nanoparticulate delivery systems offer a potential avenue for delivering therapeutics to maternal tissues with minimal risk of incidental fetal exposure, depending on the ability of the nanoparticle in question to cross the placenta. As the conduit to the fetus, the placenta is both a drug target and a drug barrier, as well as a potential target of any toxicity. Limited studies on this topic show considerable uncertainty regarding the transplacental passage of nanoparticles, and our understanding of the criteria that determine transferability is poor. Despite the fact that the toxicity caused by environmental and man-made nanoparticulates has been widely studied in various organ systems, data on the effects of maternal nanoparticle exposure on human fetal tissues are lacking, although studies in rodents indicate that caution is justified. In this review, we examine the evidence relating to the potential toxicity of nanoparticles in pregnancy, the ability of the placenta to take up and transfer nanoparticles to the fetus, and the theoretical benefits and risks of administration of nanoparticle-based therapeutics in pregnancy.
Preterm birth (PTB) at less than 37 weeks of gestation is the leading cause of neonatal morbidity and mortality. Intrauterine infection (IUI) due to microbial invasion of the amniotic cavity is the ...leading cause of early PTB (<32 weeks). Commensal genital tract Ureaplasma and Mycoplasma species, as well as Gram-positive and Gram-negative bacteria, have been associated with IUI-induced PTB. Bacterial activation of Toll-like receptors and other pattern recognition receptors initiates a cascade of inflammatory signaling via the NF-κB and p38 mitogen-activated protein kinase (MAPK) signaling pathways, prematurely activating parturition. Antenatal antibiotic treatment has had limited success in preventing PTB or fetal inflammation. Administration of anti-inflammatory drugs with antibiotics could be a viable therapeutic option to prevent PTB and fetal complications in women at risk of IUI and inflammation. In this mini-review, we will discuss the potential for anti-inflammatory drugs in obstetric care, focusing on the class of drugs termed "cytokine suppressive anti-inflammatory drugs" or CSAIDs. These inhibitors work by specifically targeting the NF-κB and p38 MAPK inflammatory signaling pathways. Several CSAIDs are discussed, together with clinical and toxicological considerations associated with the administration of anti-inflammatory agents in pregnancy.
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