Traumatic births are those resulting in feelings of distress that persist after the birth experience. Health care providers may play a role in these experiences through various forms of mistreatment. Analyses of global birth experiences have generated several domains of mistreatment. This study applies these evidence-based domains of mistreatment as an a priori coding scheme for analysis of 96 oral narratives of U.S.-based births to describe the nature of perceived mistreatment using participants' own descriptions of experiences.Ninety-six transcripts of oral birth stories from 61 participants were coded using the domains of mistreatment experiences described by the N = 131 individual experiences of perceived obstetric mistreatment were identified in 41 out of 96 narratives (42.7%). The most frequent types of experiences were Poor Rapport (90 incidences) and Failure to Meet Professional Standards of Care (29).Although most women in our study did not perceive any instances of obstetric mistreatment during their childbirth, over 40% of participants noted at least one event that fit one of the typologies we used as a framework for analysis. Visibility and review of the types of perceived mistreatment experiences that occur during birth enables health system leaders to implement prevention and accountability strategies. Most instances of perceived mistreatment during birth may be prevented through intentional implementation of individualized, respectful, supportive care during labor and birth. Women may experience a tramatic birth when they perceive they have not been respected, listened to, or treated kindly during the childbirth process. Procedures and protocols that are routine to nurses, midwives, and physicians are not always understood or desired by women giving birth. In this study, narratives of women who gave birth in the United States reveal more effort is needed to make sure all those who experience childbirth are treated with the respect they deserve. Obstetric mistreatment, dehumanizing treatment by medical personnel that results in an experience of maternal victimization via the loss of autonomy, is a factor contributing to traumatic birth experiences . The WorOne of the most robust assessments of domains of obstetric mistreatment was conducted by Giving Voice to Mothers project. In their sample of 2,138 U.S. births, 17.3% of participants self-reported experiencing some form of mistreatment in accordance with the original domains, suggesting the value of the domains as a framework for assessing mistreatment in U.S. births in other contexts and through other research approaches.Development of an evidence-based typology laid the groundwork for application of the domains in further research. One of the U.S.-based expansions is One limitation of survey-based applications of the domains as an assessment strategy is that this approach relies on participant identification of their experiences matching It was traumatic) and affective indicators  are used to interpret meaning from the participants' own descriptions and perceptions of their experiences during birth to determine whether Bohren et al.'s domain criteria are met.In our study, we extend on Participate in a research study on birth and infant feeding. If you are at least 18 years old and have experience giving birth, then we want you to interview for a study on your experience. Participants were not required to have experienced obstetric mistreatment to participate. Although birth, postpartum, and infant feeding experiences were collected for this sample, only birth narratives are analyzed in this study. Paper copies of the flyer were distributed to three pediatric offices, and other public spaces  within the New England region of the United States. Digital copies of the flyer were distributed via national maternal health professional ListServs, email contact lists for parenting and infant feeding groups, and via a local provider network contact list of approximately 300 clinical providers for distribution to their networks and patients, and for inclusion in their newsletters or social media pages. Recruitment was open from June 2018 through January 2020. This sample size is three times larger than the recommendation for thematic saturation . The survey intake collected additional information not used in the current study .in detail, as [they] experienced it, including any relevant circumstances leading up the birth that [they] consider important. Participants were instructed to include any memory that feels especially vivid or meaningful, including anything that [they] were thinking or feeling at the time. Participants with multiple birth experiences were invited to share their stories in any order that made the most sense to them.The interview protocol elicited narrative responses about participants' experiences with pregnancy, birth, and the postpartum period; there were no questions specific to mistreatment, victimization, or care quality. During the interview, participants were asked to share their birth story Consent was obtained from participants before completion of the preinterview online survey and at the beginning of their interview. All interviews were audio-recorded for later transcription. Participants were read a debriefing protocol at the end of their interview that summarized the research process, provided contact information for the research team, and offered local and national resources for any participant interested in support after recollecting negative experiences. The narratives were recorded and promptly transcribed with all identifying information  removed. Upon transcription, completion original audio files were deleted. All study materials and protocols were reviewed and approved by our Institutional Review Board.Audio recordings were initially transcribed using Transcribe  and checked for transcription accuracy by researchers. Transcripts were coded in NVivo 12  using thWe relied on participants' own description of their birth experiences as the primary unit of analysis; therefore, researchers did not correct or edit participant descriptions even when they were likely to contain misapplied or inaccurate medical terminology. Instead, to focus coding on the perceptual experiences of participants and mitigate potential effects of coder bias, incidents were only coded when 1) they met one of I had a panic attack. I was not really aware of certain aspects of the surgery... It was traumatic. In this example, I was not really aware of certain aspects of the surgery met the domain criteria for Poor Rapport (primary domain) via ineffective communication (second-order theme) according to the identifying criteria of poor communication (first-order theme criteria); it was traumatic is an evaluative statement reflecting the participants' assessment of their experience, and therefore meets the coding criteria. Similarly, Nobody responded and nobody did anything [cries] met the domain criteria for Poor Rapport, and the indicator of cries satisfies the paralinguistic criteria. In contrast, a participant stated, [The physician] just wasn't paying attention to us. But for the most part I was fine with that. [The physician] just wasn't paying any attention to us met the criteria for Poor Rapport, but the participants' own evaluation (I was fine with that) indicates no perceived mistreatment, and therefore this was not coded as Poor Rapport.For example, a participant said, SD = 4.9; Table Sixty-one participants contributed 96 oral birth narratives; some participants reported more than one birth experience. Average participant age was 34 years old (SD = 3.04) unique instances per narrative, totaling 131 unique instances from 37 unique participants in our sample. The most frequently identified domain was Poor Rapport , followed by Failure to Meet Professional Standards of Care (22.1%), Stigma and Discrimination (6.9%), Verbal Abuse (1.5%), and System Conditions (.8%); there were no instances of Physical and Sexual Abuse identified.Two coders reviewed narratives with 60% overlap across codes. Coders' interrater reliability was estimated using Cohen's Kappa and indicated strong agreement (κ = 0.801). Fifty-five narratives (57.3%) did not include any instances of mistreatment. The other 41 (42.7%) narratives had an average of 3.11 , other experiences were more explicit. One participant was told she had lost her right to refuse procedures: I said that I didn't want Pitocin and he told - he patted my hand and said, ‘Well you lost your right to refuse when you came [to the hospital]. Some participants noted that, upon reflection, they had had the right to limit procedures, but felt pressured to comply at the time. One participant commented, And I realized after I had every right [to decline] legally but I was presented like I had no options, like I couldn't. It was horrible [cries].Although some experiences of lack of informed consent processes were associated with perceived pressure or coercion to comply  and our results are limited in understanding of U.S. birth experiences of underrepresented minority groups. In the United States, the disproportionately high rate of maternal and infant mortality for Black mothers  and the Understanding perceptions of mistreatment in birth experiences supports development of evidence-based practices for nursing practice. Interactions with providers are reported to be common factors driving trauma after birth . This isI wish that people would have listened to me. Participants felt that simple changes in communication, like more communication in advance of procedures, may have prevented their distress. Nurses can facilitate clear, compassionate communication on shared decision-making as a useful tool for preventing perceived mistreatment within this domain. More robust interventions to address systemic change may consider evidence-based quality improvement protocols used in the context of identification, prevention, and response to perceived mistreatment experiences.Our findings are further evidence that U.S. births are at risk of including an experience of perceived obstetric mistreatment. Many of the instances of perceived mistreatment may be prevented with relatively simple mitigation strategies. Most of the codes for mistreatment were within the domain of Poor Rapport. Some participants indicated that feeling their concerns were heard or being given the opportunity to connect with their providers would have improved their experiences, with one summarizing, Our study contributes to the growing body of research on maternal perceptions of mistreatment during their birth experiences, as well as offers a framework for analyzing oral narratives as a valuable source of data. Research that centers the lived experiences of those who have labored and given birth is critical for ensuring that the future development of evidence-based best practices prioritizes the mitigation of potential harm and psychological distress from perceived mistreatment.This research was supported in part by grant R50180000038539 from the College of Fine Arts, Humanities and Social Sciences and the Office of the Vice Chancellor for Research and Innovation at the University of Massachusetts Lowell .Everyone who gives birth deserves respectful maternity care.What physicians, midwives, and nurses consider routine care and usual procedures may not be perceived as such by patients during labor and birth.Listening to women, hearing their concerns, acting on them, answering their questions fully, explaining procedures before they are done, and giving them options, are ways to promote respectful maternity care.Clinical education for physicians, midwives, and nurses, and health care facility education programs should emphasize that a lack of intent to cause harm is not sufficient to prevent maternal distress or trauma as the perception of mistreatment plays an essential role in patient experience.Care settings must cultivate an environment of accountability in which nurses are empowered to identify, interrupt, and report mistreatment without retaliation.Most mistreatment experiences may be prevented with relatively simple measures that center supportive care practices, individualized care, and communication with people in labor.Systematic or policy drivers of experiences of perceived mistreatment during birth should be reviewed and amended as a prevention measure .Vulnerability to mistreatment is not equally distributed; patients who are Black, Hispanic, uninsured, and others are at higher risk of mistreatment. Where disparities in outcomes are present, the role of mistreatment should be considered as an especially critical driver to be interrupted and corrected.


Neonates are highly susceptible to intestinal infections; this has been generally ascribed to the immaturity of the immune system, but other factors might contribute. The composition of the gut microbiota is a key factor, as the microbiota protects the host against colonization by pathogens. The neonatal gut microbiota is less diverse and lacks two taxa that are dominant in older intestines: members of the orders Clostridiales and Bacteroidales. Microorganisms are closely related to the body’s physiological activities and growth and development of the body, and participate in many physiological metabolic activities. Analysis of the structure and source of early colonizing bacteria in the intestinal tract of humans and rodents shows that early colonizing bacteria in the intestinal tract of mammals have solid maternal characteristics, and maternal microbes play an essential role in the formation of progeny intestinal flora.Microorganisms are closely related to the body’s physiological activities and growth and development of the body, and participate in many physiological metabolic activities. Analysis of the structure and source of early colonizing bacteria in the intestinal tract of humans and rodents shows that early colonizing bacteria in the intestinal tract of mammals have solid maternal characteristics, and maternal microbes play an essential role in the formation of progeny intestinal flora. The placental microbiome, maternal microbiome and breast milk microbiome are currently hot topics in the field of life science. This paper discusses the vertical transmission and endogenous sources of the mother-to-piglet microbiome through these three pathways, aiming to provide a new research idea for intervention in the intestinal microbiome in young piglets. In large-scale pig production, sows and piglets are the key links to determine the production level and economic benefits of pig farms. At the same time, the corresponding gestation period, lactation period and newborn period are the core stages of feeding management of sows and piglets in large-scale pig production.Intestinal microorganisms are closely related to the body’s physiological activities and growth and development of the body, and participate in many physiological metabolic activities. Existing studies have described the microorganisms in animals as independent physiological organs . IntestiAlthough the importance of intestinal flora and the rule of colonization have been revealed, the origin of early intestinal flora and the earliest time of colonization have not yet been determined. The traditional view is that the intestinal tract in piglets is in a sterile state before delivery, and microbial colonization begins gradually through contact with food, the external environment, the maternal birth canal and feces, then evolves . HoweverIntestinal microorganisms are involved in many physiological and metabolic processes in the host and may be involved in the maternal pregnancy process. Previous studies have shown that maternal gut microbes undergo drastic changes during pregnancy. Compared with early pregnancy, the intestinal flora in late pregnancy can promote host fat deposition and improve insulin tolerance, suggesting that intestinal microbes are involved in metabolic changes during maternal pregnancy . In addiMany microorganisms colonize the intestinal tract of mammals, which profoundly impact on host nutrient metabolism and immune function . The intGram-negative bacteria infections include the following: Brucellosis , EscheriVertical transmission refers to the transmission of genetic material and microorganisms, such as bacteria and viruses, from parents to their offspring. Vertical transmission of microorganisms between the mother and child is widespread in mammals . The migThe traditional view is that the uterus and animal embryos are sterile, and the intestinal flora of piglets is gradually formed through contact with the mother, the environment and the diet during and after birth. With the deepening of research, microorganisms have been found in cord blood, amniotic fluid and meconium of newborn babies in a healthy pregnancy, which proves that a healthy uterus is not a sterile environment ,31. The Some scholars studied the intestinal flora in the first, second and third trimesters of pregnancy and found that the maternal intestinal flora changed dramatically during pregnancy. The changes were similar to the intestinal flora structure of non-pregnant women suffering from metabolic syndrome. However, the intestinal flora structure associated with this “metabolic disease” was conducive to the development of pregnancy during pregnancy. It promotes the adaptive changes and regulation of maternal metabolism and immunity during pregnancy . In addiThe placenta is a unique organ that connects the mother and protects the fetus in utero during pregnancy. It is comprised of tissues such as an amniotic membrane, dense chorionic membrane and decidua basalis . The plaA blood or tissue DNA extraction kit was used to extract the DNA from the gastrointestinal tract and placenta tissue of Kunming pregnant mice at 12 to 13 days of pregnancy and 19 to 20 days of pregnancy, and high-throughput sequencing was conducted. The results showed that there were four dominant bacteria at the phylum level, Proteobacteria , Actinobacteria , Bacteroidetes  and Firmicutila . There were nine dominant bacteria families at the family level. Among them, Enterobacteriaceae , Shivaraceae  and Moraxella  were the leading families. However, the presence of microorganisms in the placenta remains controversial, although the vertical transmission of microorganisms between the mother and offspring during pregnancy has been consistently demonstrated. Lauder could not isolate bacterial DNA in the human placenta using a near-sterile approach .The birth canal is another important route for mother-to-child transmission. The intestinal flora structure in vaginal birth babies is similar to that of the mother’s birth canal microbes. Therefore, during the passage through the birth canal, the microbial symbiotic bacteria in the birth canal will be spread on the baby’s body surface. The microbial flora on the whole body of the baby is closely related to the way of delivery. While the babies delivered through C-section lack this process, their microbial colonization process is also affected ,43.During parturition, the microflora in the maternal birth canal may also be an important source of intestinal probiotics for piglets. The widely colonized organisms in the birth canal of mammals are called the birth canal microbiome. In human beings, the birth canal microbes have been considered as an important barrier involved in protecting the host from various bacteria, fungi and viruses. A healthy and stable birth canal microecology is very important for a smooth pregnancy and delivery and is also an important source of early intestinal flora for cisinatal infants . Some scInterestingly, this defect in Caesarean section appears to be partially offset by artificial inoculation after birth by applying gauze with birth canal microorganisms . The abuFurther studies found that there was no significant difference in the diversity and abundance of Lactobacillus in the birth canal during the early, middle and late trimesters of pregnancy. However, the number of Lactobacillus increased rapidly in the short term before delivery, which may be a necessary preparation for the acquisition of maternal beneficial bacteria from the offspring intestine during subsequent delivery . HoweverAnimal experiments have also shown that the birth mode affects the intestinal flora structure in newborn piglets, and that piglets born naturally have a higher Bacteroides-Prevotella abundance . It has Breast milk is a very complex biological fluid, considered the most natural and safe source of nutrition for infant growth. Breast milk  is rich in proteins, lipids, sugars, immune cells and bioactive molecules. It not only meets the nutrition needed for the rapid growth of infants, but also has anti-inflammatory and anti-infection functions. Milk provides up to 30% of the intestinal microbes for infants. It plays an important role in the colonizing and developing of neonatal intestinal flora . Microbi4–105, including Lactobacillus plantarum [A large number of studies have proved that healthy mammalian breast milk contains a high concentration of microbes, with a content as high as 10lantarum , Bifidoblantarum , Ruminoclantarum , and Esclantarum , Streptolantarum . This relantarum , supportlantarum ,63. Signlantarum , 65, 66.lantarum , while tlantarum . These mThe results of high-throughput sequencing of the human milk microbiome showed that the microbial diversity in milk exceeded the traditional hypothesis. The diversity changed gradually with the increase in lactation days. At the phylum level, Proteobacteria (41%), Firmicutes (35%) and Bacteroides (17%) dominated human milk at week 1, accounting for more than 93%. Firmicutes in human milk at week 3 showed the highest relative abundance (50%), and there were always more than 200 species in human milk at the genus level . Many stMatrilineal transmission of the intestinal flora in piglets refers to the transmission of commensal bacteria from parents to offspring, including transmission through germ cells, transmission through the placenta during pregnancy, transmission through the canal during delivery, perinatal transmission and postpartum transmission through milk. In addition, vertical transmission plays an important role as the initial transmission and influence mode of bacteria in the intestinal tract of piglets.Based on the microbial migration theory prevalent in mammals, the microbiome in every part of the sow’s body is likely to be transferred to the piglets . HoweverIn conclusion, the maternal microbiome may colonize the intestinal tract of piglets through the placenta, birth canal and milk, so that the intestinal microflora of the offspring has a robust maternal origin. At the same time, the maternal microflora in the progeny intestinal tract has strong characteristics of the maternal intestinal flora, so that nutritional measures based on maternal intestinal microflora can also affect the intestinal microflora structure of the piglets. However, in the field of livestock production, there are still few reports on the vertical transmission of the microbiome. Therefore, the vertical transmission of the microbiome between female piglets, the related nutritional intervention and the changes in the structure of the microbiome are worthy of researchers’ attention. Further research on the vertical transmission of the microbiome will provide theoretical guidance for the development of the pig industry.


Background: The effect of gestational age (GA) on comorbidity prevalence, healthcare resource utilization (HCRU), and all-cause costs is significant for extremely premature (EP) infants in the United States.Objectives: To characterize real-world patient characteristics, prevalence of comorbidities, rates of HCRU, and direct healthcare charges and societal costs among premature infants in US Medicaid programs, with respect to GA and the presence of respiratory comorbidities.Methods: Using International Classification of Diseases, Ninth/Tenth Revision, Clinical Modification codes, diagnosis and medical claims data from 6 state Medicaid databases (1997-2018) of infants born at less than 37 weeks of GA (wGA) were collected retrospectively. Data from the index date (birth) up to 2 years corrected age or death, stratified by GA , were compared using unadjusted and adjusted generalized linear models.Results: Among 25 573 premature infants , comorbidity prevalence, HCRU, and all-cause costs increased with decreasing GA and were highest for EP. Total healthcare charges, excluding index hospitalization and all-cause societal costs (US dollars), were 2 to 3 times higher for EP than for M-LP .Conclusions: Complications of preterm birth, including prevalence of comorbidities, HCRU, and costs, increased with decreasing GA and were highest among EP infants during the first 2 years in this US analysis. Globally, around 15 million births each year are preterm, occurring before 37 weeks gestation.The management of premature infants with complications incurs high utilization of healthcare resources and a high cost burden.Despite improved survival of EP infants in recent years, there remains a significant risk of developing short- and long-term complications.The high costs associated with preterm birth have been documented previously, including costs of initial hospitalizationsStudies report increased costs throughout early childhood for children delivered at less than 37 wGA, primarily due to increased resource use, including rehospitalizations and doctor visits. Through discharge to age 6 years, the odds ratio for hospitalization was 1.3-1.6 compared with children delivered at full term.A national cost estimate in Canada from 1996 found that although EP births accounted for only 6.7% of preterm births, they accounted for 21.0% of the total national cost of preterm births.There remains a clear unmet need for therapies and clinical practices that reduce the prevalence of complications of prematurity and their associated longer-term morbidity burden, especially in EP infants. Determination of the major drivers of costs and healthcare resource utilization (HCRU) associated with premature infants, in both the short and long term, will help inform practitioners and policy makers. This study aimed to characterize real-world patient characteristics, prevalence of comorbidities, rates of HCRU, and direct healthcare charges and societal costs among premature infants in US Medicaid programs with respect to GA and the presence of respiratory comorbidities.International Classification of Diseases, Ninth/Tenth Revision, Clinical Modification (ICD-9-CM/ICD-10-CM) codes (Supplementary Table S1). Inclusion criteria included premature infants (<37 wGA) who were born during the data availability period; infants admitted to the intensive care unit (ICU) or neonatal ICU (NICU) within 1 day after birth, where the first hospitalization with ICU/NICU admission is defined as the index (birth) hospitalization; and infants with continuous eligibility from birth to 2 years CA or before death, where CA was defined as:Premature infants were identified retrospectively from approximately 26.6 million Medicaid beneficiaries from 6 US state Medicaid databases that were available from 1997 to 2018  and followed for up to 2 years of corrected age (CA). Patients were identified by GA using the Infants were excluded if they died before reaching 36 weeks postmenstrual age, or if they were diagnosed with congenital heart disease, diaphragmatic hernia, or other major congenital malformations from birth to death, 1 year CA, or end of continuous eligibility, whichever occurred first.Supplementary Tables S2-S9. The first NICU/ICU admission was defined as the index hospitalization. Bronchopulmonary dysplasia was defined as at least 1 diagnosis code of BPD in the ICD-9-CM/ICD-10-CM, during the period from birth to death or end of continuous eligibility (Supplementary Table S7). Chronic lung disease, determined for the EP cohort only, was defined as infants with at least 1 of the following events in 2 consecutive quarters during 1 year CA, excluding the index hospitalization: use of home oxygen therapy or respiratory aids, use of respiratory medications, or presence of respiratory symptoms (cough and wheeze) (Supplementary Tables S5 and S6).The database contained data related to patient demographic characteristics, enrollment history, and complete medical and pharmaceutical claims from Medicaid records for all eligible patients (including Medicare/Medicaid crossovers), identified by codes listed in Overall HCRU, direct charges, and societal costs were calculated from claims records. Subsequently, the numbers of events per person-year (PPY) and counts and percentages of patients with any use in each utilization category were estimated. Healthcare charge adjustments were made by the health plan and were not part of this analysis. The charges given in the claims data were used and adjusted to 2018 USD using the US Medical Services Component of the Consumer Price Index.For direct charges, the majority of claims were capitation claims, which are fixed advance payments adjusted for each patient based on age and health status, paid monthly by the health plan directly to service providers irrespective of actual services received . Because the amount paid for a capitation claim does not reflect the costs of the actual services provided, healthcare charges were analyzed individually for each claim.Because this was a retrospective cohort analysis of existing de-identified patient data and did not involve experiments on humans or the use of human tissues/samples, patient consent and approval from an institutional review board were exempt, per Title 45 CFR § 46.101.Descriptive statistics, including counts and percentages for categorical variables, and mean and SD for continuous variables, were generated. Unadjusted and adjusted generalized linear models with a negative binomial distribution and a log link were used to compare the number of HCRU events and length of stay between GA cohorts up to 2 years CA or death, and models with a Tweedie distribution and a log link were used to compare charges and costs between cohorts. Unadjusted and adjusted logistic regression models were used to compare the presence of HCRU events between cohorts. Adjusted models comparing GA cohorts accounted for demographic characteristics  and comorbidities .Incidence rates of rehospitalizations, emergency department (ED) visits, and outpatient visits after the index hospitalization due to respiratory causes and all causes were calculated by GA up to 2 years CA or death.Societal costs were estimated for each individual patient by multiplying the average hourly wage  by the hours of work loss incurred for 1 parent: work loss was assumed to be 2 hours for each outpatient visit, 4 hours for each ED visit, and 8 hours for each day in the hospital.Data were reported by GA cohort: EP (≤28 wGA), very premature (VP) (28 to 32 wGA), and moderate to late premature (M-LP) (≥32 to 37 wGA) infants. Note that although the World Health Organization definition of “extremely preterm” denotes infants less than 28 wGA, infants born at 28 weeks cannot be separated out owing to a limitation of the ICD-9-CM code, specifically, the ICD-9-CM code 765.24, which includes infants born at 27 to 28 completed gestation weeks; thus, the definition of EP for this study includes infants born up to 28 weeks 6 days GA.From 1997 to 2018, a total of 25 573 premature infants  were included in the study; 4462 (17.4%) were EP (≤28 wGA), 2904 (11.4%) were VP, and 18 207 (71.2%) were M-LP . CharactThe prevalence of comorbidities during the birth hospitalization increased with decreasing GA . In the In the VP and M-LP cohorts, RDS was also the most prevalent comorbidity; however, a smaller percentage of infants were affected . In these cohorts, PDA was present in 19.1% and 4.5% of infants, BPD in 14.4% and 2.4%, IVH in 14.3% and 3.3%, ROP in 10.2% and 2.1%, and PVL in 1.8% and 0.2%, respectively.The proportions of infants with rehospitalizations, ED visits, and outpatient visits from index hospitalization to 2 years CA or death were higher among EP infants than infants born at more than 28 wGA. All-cause rehospitalizations (≥1 per infant) were reported for 2001 (44.8%) EP infants, 984 (33.9%) VP infants, and 4534 (24.9%) ML-P infants. All-cause ED visits were reported for 3391 (76.0%) EP infants, 2130 (73.3%) VP infants, and 12 882 (70.8%) M-LP infants. All-cause outpatient visits were reported for 4206 (94.3%) EP infants, 2723 (93.8%) VP infants, and 15 780 (86.7%) ML-P infants.Observed incidence rates of rehospitalizations were 0.50, 0.32, and 0.21 PPY for EP, VP, and M-LP infants, respectively; 1.54, 1.37, and 1.25 PPY for ED visits; and 10.37, 8.08, and 5.78 PPY for outpatient visits . Of the Length of stay for all rehospitalizations was higher for infants with lower GA. The mean ± SD LOS for rehospitalizations for any cause was 22.53 ± 46.36 days for EP infants, 14.90 ± 32.81 days for VP infants, and 12.44 ± 34.59 days for M-LP infants. The mean ± SD LOS for rehospitalizations for respiratory causes was 19.46 ± 42.46 days for EP infants, 12.23 ± 22.29 days for VP infants, and 10.48 ± 25.65 days for M-LP infants.Total healthcare charges were higher among EP infants compared with infants born at 28 wGA; total all-cause healthcare charges in USD, inflated to 2018 values, were $843 499, $379 581, and $158 430 for EP, VP, and M-LP infants, respectively . ExcludiCompared with the EP cohort, all-cost healthcare charges for the EP cohort were 5.4 and 2.3 times higher than for the M-LP and VP cohorts, respectively. Findings were similar for respiratory-related healthcare charges; unadjusted ratios of healthcare charges were 10.3 and 3.5 times higher, respectively. There were no differences between cohorts in healthcare charge cost ratios when demographic characteristics and comorbidities were considered (adjusted ratios of 1.2 for both comparisons); however, for respiratory-related healthcare charges, the adjusted ratios were 1.6 and 1.4 times higher than the EP cohort compared with the ML-P and VP cohorts, respectively.Societal costs showed a similar pattern as healthcare charges; all-cause total societal costs were USD $28 504, $21 723, and $15 892 for EP, VP, and M-LP infants, respectively . RespiraIn this study, we evaluated the effect of GA on the prevalence of comorbidities, HCRU, and direct healthcare charges and societal costs associated with preterm birth using birth claims and follow-up claims up to 2 years CA from a large public insurance system in the United States (Medicaid). We found considerable increases in the number of comorbidities, rehospitalizations, ED visits, outpatient visits, direct charges, and societal costs associated with EP infants vs those born at more than 28 wGA. Respiratory comorbidities were a significant driver of the cost increases.The underdeveloped respiratory system is a major contributor to morbidity and mortality in premature infants. The findings from our analysis underscore the costs associated with respiratory comorbidities such as BPD and the need for improvement in respiratory care to minimize the risk for development of these complications. Although protocols and standard of care vary between healthcare systems in the United States, some quality improvement networks  have developed more specific guidelines for respiratory support in the EP population. Standardizing care has long been shown to improve outcomes and therefore would be a valuable practice to start toward decreasing the incidence of BPD and its associated long-term consequences.From our analysis of 25 573 infants born prematurely in 6 US state Medicaid databases from 1997 to 2018, 17.4% were EP (28 wGA). Of note, the proportion of infants who were Black increased with lower GA, whereas the proportion of White infants increased with higher GA. The proportion of EP infants overall in our study was higher than the previous reported national estimate of 6%.Birth hospitalization LOS was found to approximately double with each 4-week decrease in GA in our study. This is in agreement with a 2006-2007 study of preterm birth in Canada, in which LOS was 83.1 days for infants born at less than 28 wGA, 42.6 days for infants 28 to 31 wGA, and 21.2 days for infants 32 to 33 wGA.In our study, RDS was the most common comorbidity across all GA cohorts, affecting 57.5% of infants; twice as many infants in the EP cohort were affected (91.5%) than in the M-LP cohort (45.3%). This is consistent with recent reviews on complications of prematurity that find respiratory complications among the most common comorbidity in preterm infants.Bronchopulmonary dysplasia, the next most frequently occurring comorbidity across all GA cohorts in the present study, affected 50.6% of EP infants; the prevalence was 3.5 times higher than in the VP cohort (14.4%) and more than 20 times higher in the EP cohort than in the M-LP cohort (2.4%). Invasive respiratory support is a major contributor to the development of BPDIn the present study, all-cause rehospitalizations were reported in just under half of EP infants (44.8%), compared with a quarter of ML-P infants. For EP infants with BPD, this percentage rose to 51.6%. These findings are higher overall than reported in previous studies, although the trends by GA are consistent. The rates of rehospitalization found by Reed et alOur study found that in the first 2 years of life, total healthcare charges for EP infants were significantly higher than for infants born at more than 28 wGA; total all-cause healthcare charges in USD, inflated to 2018 values, were 5.4 times higher in the EP cohort ($843 499) than in the M-LP cohort ($158 430), and 2.3 times higher than in the VP cohort ($379 581). Excluding birth hospitalization, charges associated with the treatment of respiratory comorbidities accounted for 52.7% of the all-cause costs for the EP cohort, vs 43.5% for the M-LP cohort. Healthcare charges have been found to increase with decreasing GA in numerous previous studies.We found that all-cause societal costs increased 1.8-fold for EP infants compared with those born M-LP. However, there is a paucity of reported data comparing societal costs of preterm birth by GA. The Neonatal Adequate Care for Quality of Life study of infants up to age 18 months compared very low birthweight infants without prematurity-related morbidities with full-term infants to assess productivity loss costs during the initial hospitalization.Although our findings are in line with previous studies on the health burden and healthcare costs of preterm birth, there are limitations to the current study, including limitations related to the nature of data collected from medical insurance claims. The use of ICD-9-CM and ICD-10-CM diagnosis codes for medical claims approximate actual diagnoses and may not capture all relevant medical diagnoses. Medical services obtained outside the Medicaid system are not captured. Interstate differences in the coding of Medicaid patient data require a non-uniform treatment of the study data. For example, dates of birth of infants from New Jersey and Missouri were not available, due to requirements for de-identification of data; in these instances, the date of birth was approximated using the date of the earliest claim in the birth year. For premature infants identified by ICD-9-CM and ICD-10-CM diagnosis codes, GA was conservatively approximated using the upper bound of the GA range. Because the Medicaid system is a public insurance with strict maximum income eligibility requirements, our results may not be representative of data from private insurers or a broader population.Limitations of our analytic methods include a variable follow-up period across infants, due to a small number of infants who died before 2 years CA. Additionally, there was a high prevalence of capitation claims throughout the dataset; thus, actual healthcare costs could not be estimated without strong assumptions. Estimates of work time lost (due to ED and outpatient visits) are reflective of the geographic regions analyzed, and could be considered comparatively low, resulting in underestimation of total societal costs. Lastly, premature infants included in this study were identified retrospectively from 1997 to 2018, and it is possible that clinical care changes over that period may have affected the results.This retrospective cohort analysis of US Medicaid data demonstrated that presence of comorbidities, HCRU, direct hospital charges, and societal costs from birth to 2 years CA were higher among EP infants than for premature infants born at more than 28 wGA and increased with decreasing GA. A significant portion of healthcare costs is associated with respiratory complications of preterm birth, which increase in prevalence with decreasing GA. Our findings highlight a need for strategies to improve clinical outcomes for EP infants to reduce the burden of comorbidities of prematurity on healthcare systems and families.M.E.M. and S.P.S. contributed to the conception and design, interpretation of data, and drafting/revising of the article critically for important intellectual content. W.G., H.S., P.Z., H.W., and R.A. contributed to the acquisition of data and analysis, interpretation of data, and drafting/revising of the article critically for important intellectual content. All authors approved the final manuscript.M.E.M. declares no competing interests. W.G., H.S., P.Z., H.W., and R.A. are employees of Analysis Group, Inc., which was contracted through Shire, a Takeda company, to perform this study. S.P.S. was an employee of Shire, a Takeda company, at the time of the study.The data that support the findings of this study are available from Medicaid records from individual states, but restrictions apply to the availability of these data due to applicable privacy laws and data use agreements. The data were used pursuant to data use agreements between Analysis Group, Inc. and the individual states. Requests for data access should be directed to Alexandra Miller, Data Governance, Analysis Group, Inc. . The data may be available with permission directly from individual states, subject to the state’s requirements for data access to Medicaid records.


Data reporting the number of births given by women resident in Vienna for each week between 1999 and 2019, and the duration (in weeks) of their pregnancies, were used to estimate the week of conception. When preliminary examinations detected cyclical patterns for births and conceptions, a series of Poisson regressions for births and conceptions were performed to assess whether these cycles could be associated with lunar or solar phases.To that end 2 sine-cosine functions, 1 with a wavelength of 1 year (365.25 days) and 1 with a wavelength of 29.529 days, the latter resembling the average length of a lunar cycle, were constructed. In addition, also average weekly temperatures were included in the models.Same week temperature was a strong non-linear predictor for both births and conceptions. Extreme temperatures, especially hot temperatures, increased the number of births while the numbers of successful conceptions were decreased by extreme temperatures. Regarding annual variation in conceptions, the lowest values were found in May and the highest in late autumn and early winter. Therefore, the highest numbers of births are observed in the summer. As per lunar variations, the highest numbers of conceptions occurred at the full moon and the highest numbers of births at the waxing crescent to first quarter moon.The latter results should be treated with caution, as they are not hypothesis driven. Furthermore, literature reports on this topic are conflicting. Nevertheless, these findings will be useful in further analyses examining air pollution effects. Folk wisdom wants us to believe that the moon phases affect birth numbers . ScientiAir pollution causes oxidative stress and systemic inflammation. We hypothesized that this would particularly affect early pregnancy shortly after conception . TherefoTime series analysis must control for time-varying confounding variables . TherefoExtreme temperatures cause bodily stress in humans , 10. VerConception rates are most probably affected by human behavior in relation to sexual intercourse. It is perceivable that after a very hot or a very cold day, sexual desires might be weakened. Even though most sexual intercourse will occur indoors where people are less affected by outdoor temperatures, stressful temperatures over the course of the day will likely reduce nighttime activities. Therefore, we would expect fewer conceptions at extreme temperatures. In the literature though, evidence is stronger for the effect of high temperature , 12.Annual variation in birth rates is well known –18. UsuaAlthough data were obtained in anonymous format, there is always concern about too detailed information due to data privacy considerations. Also, information about pregnancy duration is only provided as pregnancy weeks. Therefore, we only obtained the week and not the exact day of birth from the Austrian birth register. We received data on both live and stillborn births with information on live status and about twin births and gender of the child included in the obtained data. In this first examination of the data this additional information was neglected though. Pregnancy duration is reported as number of weeks since the last menstrual bleeding. Since conception occurs roughly 2 weeks after the last bleeding, we calculated conception date by subtracting the pregnancy duration minus 2 from the week of birth.We restricted our analysis to the 20 years 1999–2018 because from these years we were sure to have complete coverage both for birth and for conception dates, while in 2019 conception dates were necessarily incomplete.Originally, we obtained daily average temperatures at the meteorological station “Hohe Warte” from the Zentralanstalt für Meteorologie und Geodynamik (ZAMG) and averaged these over the 7 days of every week, Next, we calculated the square of that weekly temperature minus 11.7 °C  and finally, we also added longer term averages (2 or 3 weeks) of temperature  and weekSeasonality in the number of births and conceptions has first been explored preliminary using decompose and stl packages in R software  to perfoWhen, apart from a long-term increasing trend, we saw clear evidence of two cycles, one the length of a year and the other of about 4 weeks, we decided to examine these cycles in more detail. We assumed that the shorter cycle was linked to the moon phases. Therefore, we constructed 2 sine-cosine functions, 1 with the wavelength of 1 year (365.25 days) and 1 with a wavelength of 29.529 days. The duration of a lunar month varies by 1 or even 2 days due to the fact that both earth and moon move on ellipses, not circles. But over the whole observation period the duration of 29.529 days turned out to be the best approximation of the average.The sine-cosine functions were defined such that for the annual cycle the sine part of the function was closest to zero and the cosine part closest to 1 on each 31 December. For the lunar cycle the sine part was approximately −1 and the cosine part was zero at each full moon. At each new moon the sine part was approximately 1 and the cosine part was again zero. The cosine part reached its maximum (1) at the third quarter moon. The sine and cosine values of each Monday were used to represent the weekly values.Initially, we examined negative binomial regression models. But, when we saw that overdispersion was negligible, we reverted to Poisson regression models. We ran separate but similarly constructed Poisson regression models for weekly number of births and number of conceptions. The first model each contained a linear term (weeks since 1 January 1999) and the two sine-cosine functions as independent variables. In a second model we also included temperature at the date of interest (either birth or conception). Since from air pollution studies on mortality we are familiar with a U-shaped non-linear association with temperature, we modelled temperature by a quadratic polynomial. In a sensitivity analysis, we assessed also each of the variables  separately because we were concerned that the effect for example of temperature was a spurious one only due to smoothing out the misfit of the seasonal patterns. When we saw significant effects of temperature in the quadratic polynomial model, for visualization purposes we also performed a general additive model (GAM) using natural splines. We optimized the degrees of freedom for the temporal variation by minimizing the sum autocorrelation of the residuals . The temIn 1044 weeks there occurred on average 341.4 births  and 344.1 conceptions . Average weekly temperature was 11.7 °C . The number of births and conceptions increased over the years and within each year some seasonal variation was visible  and the linear trend accounted for most of the explained variation. Also, the sine and cosine parts of the annual cycle were highly significant. Birth numbers according to this smoothed model were lowest in January and February and highest in July and August. The number of conceptions were lowest in May and highest in November.Long-term trend, annual and lunar cycle, and same week temperature were all significantly associated with the numbers of birth and of conception Tables  and 2. Ap = 0.003) and negative, while the sine part was approximately zero, indicating the highest birth numbers to occur roughly between the new and the full moon (waxing crescent to first quarter moon). According to the Akaike information criterion [p = 0.038) and negative, while the cosine part was practically zero, indicating the highest number of conceptions occurring at the full moon.Adding a sine-cosine function for the lunar cycles did not add much explanatory value and the coefficients were small. Nevertheless, the cosine part was significant for birth numbers  at the time of birth and conception, respectively, had also a highly significant effect on birth and conception numbers, but neither increased the explained variance much nor substantially changed the effect estimates for the two cycles. A positive coefficient for the quadratic term in the model explaining birth numbers indicated a U-shaped association between temperature and births. With conceptions a negative coefficient of the quadratic term was found indicating lower conception numbers at extreme temperatures. Both findings were confirmed in a GAM with a natural spline Fig. . ChronicLong-term, seasonal trends and meteorological conditions (and day of the week in the case of daily data) must be controlled for in time series analyses of air pollution, because these factors strongly affect mortality risk , 30 and Since day of the year and temperature do not display a linear association with mortality, some non-linear smoothing functions (e.g. spline models or LOESS) must be applied. It is vital to ensure that smoothing is optimized in order to neither cause residual confounding nor overadjustment. Several methods have been proposed to find the optimal smoother , 30. In Controlling for temporal and meteorological factors reduced overdispersion even more with an alpha in negative binomial regression being around 0.001 in the full model. Generally, it is encouraging that these factors do not play an important role in birth and conception rates. This might render studies on air pollution effects less complicated. But still, to our surprise, some temporal and meteorological effects were found that warrant further discussion and closer examination.As theoretically expected, a positive effect estimate for temperature squared on births was found, indicating that both hot and cold temperatures in late pregnancy could induce labor. For a deeper understanding of this phenomenon, temperature effects on pregnancy duration and not just birth counts should be studied as well. Especially the issue of low temperature effects deserves further research as several studies did not find an effect , 35, whiWe expected fewer conceptions at extreme temperatures, which indeed was the case in our dataset. Although evidence from previous studies is stronger for the effect of high temperature , 12, temContrary to what we are told by numerous folk songs May is not the month of love. On the contrary, our data indicate that the least numbers of successful intercourse occur in that month, while late autumn and early winter months are most productive, leading to highest birth rates in summer. These findings are mostly in line with previous findings –18. It iWe had not expected any variations with a cycle length approximating a lunar month. Most studies do not find lunar influences on birth rates –4, 38–42We found the highest frequency of conceptions around the full moon. Because we estimated the conception data as 2 weeks after the last menstrual bleeding, that bleeding would then have occurred around the new moon. This finding is consistent with Law . A recen2 Study [p-values 0.58 for the sine part and 0.35 for the cosine part). If specificity is indeed a criterion for causality [Out of pure curiosity we also applied the sine-cosine cycle of 29.529 days to all-cause mortality data from Vienna 1970–2018 from our NO2 Study . In the ausality , this wop-values should be treated with caution. We examined birth and conception data over 20 years in a city with nearly 2 million inhabitants. That amount of data allowed for strong statistical power, enabling also the demonstration of small effects that need not have much biological relevance. We had no data on nighttime or daytime births nor on circumstances of birth like induced birth or cesarean section. And we only had weekly data. The latter might even have reduced statistical noise and the growing impact of the day of the week [This analysis was not driven by any a priori hypothesis. Therefore, the week , 39 rendWhile examining the temporal shape of weekly birth and conception data in preparation of a time series analysis on the effects of air pollution, we observed small quasi-monthly cycles. We tested the hypothesis applying a sine-cosine function with the average wavelength of the lunar cycle (29.529 days) and found that this function significantly predicted small-scale variations in birth and conception numbers. The variation explained is small and likely not biologically relevant. Nevertheless, given the controversy regarding lunar influences on human biology, we still find it noteworthy.


The gut microbiota has a central role in the programming of the host’s metabolism and immune function, with both immediate and long-term health consequences. Recent years have witnessed an accumulation of understanding of the process of the colonization and development of the gut microbiota in infants. The natural gut microbiota colonization during birth is frequently disrupted due to C-section birth or intrapartum or postpartum antibiotic exposure, and consequently aberrant gut microbiota development is common. On a positive note, research has shown that restoration of normal gut microbiota development is feasible. We discuss here the current understanding of the infant microbiota, provide an overview of the sources of disturbances, and critically evaluate the evidence on early life gut microbiota restoration for improved health outcomes by analyzing published data from infant gut microbiota restoration studies. A wealth of association studies have been reported of microbiota and health and disease, and in some cases studies using fecal microbiota transfer have provided quantum leap insight regarding causality.3–5One of the most exciting events that takes place in life is the birth of a child. As the human microbiota is known to play an important and determining role in health, it is of great interest to understand how, when and where the newborn is colonized. This notably holds for the intestinal microbiota that rapidly becomes the most dominant microbial part of our body. Early approaches two decades ago using 16S rRNA gene sequence-based molecular tools applied to the fecal microbiota already indicated the existence of succession events in early life, the impact of antibiotics on this process, and the differences between breastfed and formula-fed babies.6 The gut microbiota has a central role in the early-life programming of the host’s metabolism and immune function, with both immediate and long-term health consequences. In the first few years after birth, the overall gut microbiota development follows a biologically determined pattern, which is consistent across cultures and geographic areas.7 Due to the specific temporal features of this development, the host receives specific microbial signals at specific age windows. If these signals are altered or missing due to abnormal microbiota development, the host’s physiological development may be affected. Deviations from normal microbiota succession in infants and young children often occur without clear symptoms, but can increase the susceptibility to later health problems, such as allergic disease including asthma,8–10 autoimmune diseases such as type 1 diabetes,11 and overweight.12Microbial colonization, i.e. the permanent establishment of viable and hence multiplying microbial populations on and in the body of the host, is an important process that affects long-term health.13–17 the current evidence-based consensus is that healthy infants are normally colonized by microbes during and after birth, not in utero.19 The infant is exposed to maternal vaginal, fecal and skin microbes during and after birth, depending on the mode of birth. However, bacteria establish only in habitats that provide suitable conditions for them: while vaginal and skin microbes may be transiently detected in infant fecal samples, the infant gut is permanently colonized specifically by gut bacteria that are partly of maternal origin.20–25 The neonate gut provides a different environment compared to the maternal gut, and therefore only infant-adapted strains from the mother have the ability to establish permanent populations in the infant. The dominant mother-to-infant transmitted gut microbes include Bifidobacterium and Bacteroides strains,25 which have the capacity to utilize human milk oligosaccharides (HMOs) present abundantly in breastmilk.26 These bacteria have a poor ability to be transmitted horizontally via the environment due to their oxygen sensitivity and lack of spore formation,27 and they appear to have evolved to rely mostly on vertical transmission at birth, after which they persist indefinitely.24 If such bacteria are lost or fail to colonize at birth, it may take a long time to regain them, making them particularly vulnerable to disturbance.Although microbial DNA has been identified in placenta, amniotic fluid and meconium samples,28 The human milk oligosaccharides show great diversity within and between women, the composition varying temporally and according to diet and genotype. As HMOs constitute ca. 20% of all carbohydrates in breastmilk,28 and the majority of them are degraded by gut bacteria into short-chain fatty acids,29 HMO fermentation represents a significant energy source to the infant. Several species of Bifidobacterium and Bacteroides have the capacity to ferment human milk oligosaccharides (HMOs),26 which very likely explains their success in colonizing the infant gut. While several Bifidobacterium species are specialized in oligosaccharide utilization, Bacteroides species have the capacity to opportunistically use both diet-derived and host-derived glycans and they employ the same pathways for host mucin and HMO degradation.26 On the contrary, HMO-utilizing bifidobacteria do not degrade mucin efficiently and have an advantage in degrading non-mucin-like HMO structures.26 In addition to providing substrates for bacterial fermentation, breastmilk is immunologically active, containing immunoglobulins and anti-microbial compounds, which can guide the development of the infant gut microbiota. Consequently, the gut microbiota of exclusively breastfed infants differs from the non-exclusively breastfed in both composition and function.30Breastmilk contains > 10 g/l human milk oligosaccharides (HMOs) undigestible by human enzymes. There is a rich diversity of HMOs, with 2ʹfucosyllactose (2ʹFL) and trifucosyllacto-N-hexaose (TF-LNH) being usually the most abundant individual oligosaccharides at 2–3 g/l each in secretor mothers.20–25 The father’s role in microbial inheritance is currently not well understood, but a recent report suggests it increases in importance after the first year of life.24 Importantly, the inheritance of microbial genes differs from the inheritance of human genes in many ways. Although specific microbes are obtained from the mother during and after birth, other microbes are obtained from the environment, and the composition and abundance of the gut microbiota is not inherited, but affected mainly by environmental factors, such as diet. Nevertheless, the vertical transmission of gut microbes from mother to infant and the nourishing by breastmilk of these maternal microbes is a likely driving force preserving symbiotic relationships between host and microbiota. This would explain some observations on the impact of the host genotype on the microbiota.31 As gut microbes are strongly dependent on substrate availability, host genes that affect the glycan composition in the gut, such as those for lactase persistence and the fucosylation of mucin and HMOs, are particularly likely to influence gut microbiota composition.31–34 The utilization of HMOs by specific microbes is one example, where the genome of the mother determines the HMO structure of breastmilk and how the infant microbiota respond to breastfeeding.34 Another way in which the host genotype may influence the gut microbiota is through the immune system. We found a strong association between host innate immunity genotype, microbiota, and disease severity in pediatric patients with inflammatory bowel disease.35Genetic inheritance can essentially be divided into three categories: nuclear genes, which come from both parents, mitochondrial genes, which are inherited from the mother, and microbial genes, which are partly derived from the mother.36 Associations have been found between infant gut microbiota and maternal smoking,37 maternal BMI,38 maternal asthma,39 gestational diabetes,40 and maternal diet.41 Importantly, the casualties and mechanisms behind these prenatal associations have not been identified, but they suggest that infant physiology, affected by prenatal factors, may partly influence which microbes thrive in the gut. Overall, maternal effects through genetics, prenatal factors, transmission of microbes at birth, and breastfeeding have a strong influence on the early development of the infant gut microbiota.There is relatively little data on the effects of maternal diet and health during pregnancy on infant gut microbiota composition. Maternal stress during pregnancy is associated with reduced abundance of bifidobacteria and lactobacilli and increased abundance of Proteobacteria.Bacteroides and Bifidobacterium spp. and increased abundance of pathogens in C-section born infants.42–46 This can be explained by the fact that C-section eliminates the contact between maternal fecal microbes and the infant, inhibiting their colonization. The lack of the dominant infant gut microbes, that normally shape the gut environment though their metabolic activity, allows microbes from the hospital environment to colonize the infant.47While prenatal factors are associated with specific features of the infant gut microbiota, the most profound effect on the colonization and development of infant gut microbiota is caused by birth mode and perinatal exposure to antibiotics. Several large cohort studies of up to 1000 infants each have found consistent effects of birth mode, especially prominently the low abundance of the normally maternally derived 49 and increased abundance of pathogens.44 Many of these features are reminiscent of the aberrant microbiota development of C-section born infants.50 Importantly, it should be noted, that the main cause of microbiota disruption in C-section born infants is not the antibiotic associated with the surgical procedure but the absence of direct mother to infant contact, since only very few differences have been identified between C-section born infants exposed and not exposed to antibiotic during birth.51–53 Postponing the antibiotic administration to after cord clamping is therefore unlikely to help normalize the infant’s gut microbiota.It is becoming apparent that not all vaginal births result in the same degree of microbial transfer from mother. Little is still known on the effects of different birth interventions, procedures, and practices, with the exception of C-section and intrapartum antibiotic exposure. Maternal exposure to antibiotics during labor impacts the gut microbiota of vaginally born infants with reduced abundance of bifidobacteria48–50 Unfortunately, while the beneficial infant-adapted microbes are often highly sensitive to antibiotics and have a poor ability to colonize the infant postnatally, and thus need to be obtained at birth from the mother, many pathogens can be easily acquired from the environment and may be antibiotic resistant. Indeed, the low abundance of bifidobacteria caused by intrapartum antibiotic exposure can lead to increased, rather than decreased, abundance of streptococci in the infant gut.50 This is supported by the observation that bifidobacteria can inhibit the growth of streptococci in vitro.54Antibiotics are usually administered during vaginal birth due to maternal group B streptococcus positivity or suspected infection to prevent transmission of pathogenic microbes to infant. Perhaps not surprisingly, the antibiotic also acts to prevent the transmission of nonpathogenic microbes, resulting in a microbiota composition that resembles that of C-section born infants.56 In addition to this, postnatal antibiotic treatments and lack or short duration of breastfeeding are a common and significant disturbance to the infant gut microbiota development.58 Thus, natural microbiota colonization and development is becoming rare, the consequences of which on public health are not fully understood.Disrupted gut microbiota development is exceedingly and increasingly common globally. C-sections represent up to 50% of births in certain regions, with additional over 30% of infants exposed to antibiotics during vaginal birth in developed countries.59 and affect the development of the immune system toward heightened sensitivity. Indeed, signs of pain and distress in infants have been correlated with low abundance of bifidobacteria,61 symptoms of infant colic can in some cases be alleviated by supplementation with Lactobacillus reuteri,62 and both C-section born and vaginally born infants that were exposed to cephalosporin antibiotics at birth show increased signs of gastrointestinal discomfort during their first months.50Accumulating evidence indicates that altering the early-life gut microbiota has long-term health consequences . The inc63–65 and low abundance of Bifidobacterium spp. or high abundance of Proteobacteria66–70 in early life are associated with the development of chronic immune-related diseases and overweight. The long-term health effects of intrapartum antibiotic exposure have not been thoroughly studied. According to a recent meta-analysis and a large cohort study, intrapartum antibiotics increase the risk of childhood overweight.72 Prolonged exposure to intrapartum antibiotic has also been found to be associated with increased risk of atopic dermatitis.73 Similarly, repeated use of macrolide antibiotics in early life has been linked to increased BMI and risk of asthma in later childhood.74 While long duration of breastfeeding is protective against overweight due to the beneficial effects on the gut microbiota, even a single course of antibiotics during the breastfeeding period eliminates the protective effect, strongly indicating a causal role of the gut microbiota in metabolic development.58Numerous studies have shown that C-section birth75 Interestingly, the link between maternal BMI and infant gut microbiota appears to be eliminated by C-section birth.76 Therefore, one might be tempted to speculate that in some cases eliminating the effect of maternal gut microbiota by either C-section birth or intrapartum antibiotic treatment might be beneficial for the infant. However, C-section birth increases the risk of overweight in the infants of both normal weight and obese mothers, and maternal obesity and C-section birth appear to contribute additively to overweight risk.75 Vaginal birth is thus associated with reduced risk of offspring overweight in both normal weight and obese mothers. The overweight risk in infants born by C-section to obese mothers is therefore likely not mediated by transmission of maternal microbiota, but partly by the abnormal microbiota caused by C-section delivery and partly by genetic and environmental and life-style effects.Gut microbiota is emerging as a potential mediator of the intergenerational transmission of overweight.77 suggesting that the immature gut may not be able to sustain a normal microbiota prior to that. Because of this, birth mode has a less clear influence on the preterm infant gut microbiota.77 Various studies have shown the benefits of supplements of lactic acid bacteria or bifidobacteria in reducing the incidence of necrotizing enterocolitis and mortality in preterm infants, with multispecies products achieving the best outcomes.78 In addition, feeding breastmilk has long been known to reduce the incidence of necrotizing enterocolitis.79 Clearly, the gut microbiota is extremely important for the health and survival of prematurely born infants. However, restoration efforts should be specifically designed with their unique physiology and vulnerabilities in mind, accepting that term-like gut microbiota may not be biologically realistic or desirable. Because of this, we will focus the following analysis on microbiota restoration in term-born infants.Preterm infants represent a vulnerable group that are prone to intestinal infections among other complications and are often subject to microbiota-compromising treatments, such as C-section birth, antibiotics, and lack of maternal skin contact and breastfeeding. Their gut microbiota development differs from term-born infants, beginning the normal developmental pattern when they reach the gestational age of term birth,34 shows significant improvements in microbiota composition compared to formula feeding.80A few different microbiota-targeting treatments have been applied with the aim of improving the gut microbiota composition of C-section-born infants: supplementation with specific lactic acid bacteria marketed as probiotics, vaginal seeding, and maternal FMT. In addition to these, exclusive breastfeeding, especially by secretor mothers,Lactobacillus rhamnosus GG, L. rhamnosus LC705, Bifidobacterium breve Bb99, Cutibacterium freudenreichii ssp. shermanii with additional fructo-oligosaccharides (termed here Lactobacillus-Bifidobacterium-FOS supplement), was tested in a randomized placebo-controlled trial.81 This intervention was found to reduce the risk of IgE-associated allergy until the age of 5 years in the over 140 C-section delivered infants but not in the around 760 vaginally delivered ones.81 This is likely caused by correction of the microbiota, as the gut microbiota of the C-section born infants at 3 months of age was found to be partly normalized by the multispecies treatment.82 Among the vaginally born infants, allergy development was likely affected by factors other than the gut microbiota in infancy. These studies demonstrate that infant gut microbiota restoration can have long-term health benefits. In a smaller study with exclusively formula-fed infants, Lactobacillus reuteri supplementation modified the gut microbiota of C-section born infants toward the vaginally born composition.83 In a recent study, short-term supplementation of C-section born infants with B. breve and L. rhamnosus for the first two days of life caused a sustained increase in the abundance of lactobacilli, and a non-significant trend of increased bifidobacteria at 1 month.84 This suggests that even short-term interventions at the birth hospital may have some benefits.Surprisingly few interventions with live bacteria have been reported in term-delivered C-section-born infants. In a large study with over 1000 infants from mothers with a high risk of atopy, a multispecies mixture consisting of 85 Three studies have investigated the efficacy of microbiota restoration by inoculating term C-section born infants with maternal vaginal microbes either by swabbing the neonate with vaginal fluids87 or giving the infant vaginal bacteria orally.85 None of the studies have demonstrated a restoration of the normal gut microbiota composition, although one study showed effective seeding of some fecal bacteria.87 Interestingly, the study showed evidence indicating long-term effects of vaginal seeding on skin microbiota,87 suggesting that vaginal seeding may have benefits outside the gut.Lack of exposure to vaginal microbes clearly differentiates C-section born infants from the vaginally born. For this reason, it is easy to speculate that reconstituting the vaginal microbial exposure would restore normal gut microbiota. However, a closer inspection reveals that vaginal microbes are adapted to the vaginal environment, and usually do not find a suitable niche in the infant gut.24 maternal fecal microbiota transfer appears to be the optimal method of neonate gut microbiota restoration. We tested this idea in a pilot study and demonstrated that maternal FMT fully corrected the gut microbiota of C-section – born infants with sustained effects of a single oral administration at birth for at least 3 months.4 With carefully screened mothers not carrying known pathogens, the procedure caused no adverse effects on the infants apart from a transient increase in CRP in one infant. Of note, since this study did not alter the mothers’ microbiota or their breastmilk composition, it did not support the hypothesis that the deviating breast milk microbiota in mothers of C-section born infants was involved in the aberrant microbiota development.88 In contrast, the study provided further support for the concept that fecal-oral microbiota transfer is the normal way of vertical microbiota transmission.Because the normal inhabitants of the infant gut are fecal microbes obtained from the mother’s gut at birth,4 vaginal seeding from the infant’s mother,86 and two different types of treatments with live bacteria marketed as probiotics: Lactobacillus spp. only50 (Lactobacillus reuteri or Lactobacillus rhamnosus GG given regularly since before week 3) or the Lactobacillus–Bifidobacterium-FOS supplement that was given daily since birth.82 In total, this survey included 132 fecal samples collected at 1 month of age, and 249 fecal samples collected at 3 months (See Supplementary Table S1).Principal Coordinates Analysis of the fecal microbiota  of samples taken at 1 month and 3 months revealed that at both time points, birth mode divided the samples along the first principal component, indicating that it was the most significant source of variation in microbiota composition , including all available data from studies comparing the gut microbiota of untreated term C-section born infants to those subjected to a microbiota-targeting treatment. Unfortunately, data were not available for all of the above-mentioned studies. Hence, we compared the efficacy of maternal FMT,position . Vaginalposition .Figure Lactobacillus supplementation shifted the microbiota further away from the C-section cluster, but failed to do so in the antibiotic exposed infants .Inspecting the taxonomic differences between the birth groups revealed that the two most abundant bacterial families in vaginally born infants,  infants . The diffants .Of all the microbiota-targeting treatments in the CS-born infants, maternal FMT resulted in microbiota composition most closely resembling that of vaginally born infants, while vaginal seeding did not greatly alter the overall composition . Lactoba infants . Based oBifidobacterium-Lactobacillus-FOS treatment in C-section born infants was dependent on breastfeeding.82 While breastfeeding alone is insufficient in most cases to restore normal gut microbiota to C-section born infants,34 breastfeeding should be considered an essential part of any infant gut microbiota restoration effort. Breastmilk likely plays only a minor role as a source of bacteria to the infant gut, since the composition of breastmilk varies greatly between mothers and often does not include dominant gut microbes.88 Through its complex composition, mother’s milk provides both the baby and the existing gut microbiota with the right nutrients to support their growth, development, and symbiosis.Most of the infants in the analysis were breastfed: 91% at 1 month and 95% at 3 months. Our earlier analysis showed that the beneficial effect of the This review focused solely on infant gut microbiota, but the skin and respiratory tract microbiota may play an important role in infant health, as well. Specific gut-targeting treatments are unlikely to be effective in restoring microbial diversity at other body sites. Given that vaginal seeding and maternal FMT will provide the C-section born infant with different types of bacteria, and that naturally infants are exposed to both maternal vaginal and fecal microbes during birth, it will be interesting to see the outcome of an ongoing trial with both vaginal seeding and maternal FMT on infant microbiota and immune health (see NCT03928431).91 Our recent analysis of early life development based on absolute rather than relative numbers of microbes highlights the need to do so.50Current results provide promising evidence that gut microbiota restoration of term C-section born infants is feasible and likely has long-term health benefits. However, only a few fairly crude restoration methods have been studied. These should be followed up by studies aimed to identify optimal practices of infant gut microbiota restoration. Generally, to take the field from description to clinically relevant solutions, hence from correlation to causality, hypothesis-driven experimental research in humans is needed. Interventions should be based on clear hypotheses of the biological mechanism that is being tested. Careful research design, longitudinal sample and host data collection, sufficient sample sizes that allow for patient stratification due to individual differences in baseline microbiota, host genetics, or other characteristics, and the utilization of diverse data sources will help to uncover which methods improve the gut microbiota and health in which patient groups. The ecological differences between disrupted microbiota compared to healthy microbiota and the physiological and ecological properties of the key organisms to be restored should inform future restoration studies. For a mechanistic understanding, the gut microbiota should be viewed as an ecosystem consisting of interacting organisms with their unique requirements and characteristics. Importantly, it is not only the relative but also the absolute abundance of microbes that contributes to functional output, and the field would benefit from determining the real amount of gut microbes rather than relying solely on relative abundances.Evidence of the negative health effects of early-life gut microbiota disruption is strong enough to warrant action, especially when weighed against the demonstrated safety of the various microbiota restoration efforts. While the most effective, practical and widely applicable solution for infant microbiota restoration remains to be identified, promising results have been obtained with bacterial products marketed as probiotics and maternal FMT. Considering the scale of the issue – in many regions more than half of infants are exposed at birth to treatments that disrupt natural microbiota colonization – and the potential health consequences, we believe that infant medical care should benefit from addressing the early life gut microbiota and from exploring avenues to preserve and restore the natural biodiversity that is important for a healthy life.Click here for additional data file.


Using intrauterine ultrasonography here is increasing evidence of detection of structural abnormalities that influence prenatal treatment and prognosis.The role of prenatal ultrasonography in the fetal neck mass is to observe the size and position change of the mass through continous echogenicity and to plan the treatment protocol of delivery timing and method by a thorough inspection of the adjacent trachea, esophagus and larger vessels.We report a huge thyroid cyst in a fetus diagnosed by prenatal ultrasonography at 31st pregnant week. He suffered from postnatal apnea and a feeding disturbance which an operation on the 15th day after birth. Histopathology showed a cystic mass with a capsule that is composed of squamous epithelial cells, which is adherent to the postero-superior portion of thyroid. Herein we report the first known case of a thyroid cyst originated from the ultimobranchial body.A 35-year-old second gravida female at 31 weeks 6 days of gestation was transferred to our institution presenting a 3.6 cm × 1.8 cm fetal cystic neck mass diagnosed by fetal ultrasonography at an obstetric clinic. She had a history of endometriosis in 2001 and delivered her first baby through cesarean section in March 2003. The patient was not on any medication. Systemic examination was normal. Ultrasound examination revealed a 4.54 cm × 1.39 cm cyst of the fetal neck with normal amniotic fluid and normal fetal development. The mass was found behind the left trachea, showing no difference in size and shape on two occasions of follow-up ultrasonography, each done three weeks apart. At thirty-nine weeks of gestation, the patient was posted for cesarean section, and delivered a healthy male baby of 3240 g (50–75 percentile). The APGAR score was 9 point at 1 min and 10 points at 5 min. There were no gross external deformities or anomalies in the neonate.We suspected a tracheo-esophageal fistula. An esophagogram using gastrograffin was performed at two days after birth, which showed no evidence of fistula and normal esophageal passage. On the 3rd day after birth, the infant showed decreased feeding with crying. On the 4th day, several episodes of intermittent airway obstruction without cyanosis were observed. Arterial blood gas analysis was normal and the infant was fed by nasogastric tube. On the same day, a 2.3 cm × 1.3 cm cystic mass was observed in a neck ultrasonogram, which was positioned lateral to the left thyroid and protruding to the left carotid artery and internal jugular vein . The iniDuring examination in the operation room, there was found a soft mass with a diffuse swelling on the left anterior neck . After aA congenital lateral neck mass can originate from the obliteration failure of embryologic remnant. The second type of branchial cleft anomaly is the most common one. In 1983, Burge and Middleton proposed to term it as “a pyriform sinus cyst”, in that most congenital lateral neck mass is the fourth branchial cleft cysts.Ultimobranchial body (UBB) stems from the 4th and 5th branchial pouch and is the origin of parafollicular C cell. Parafollicular C cell produces calcitonin in the thyroid and lowers the calcium level of serum.Further evidence this cyst is a UBB remnant is the histopathology. The incidence of UBB remnant is 87.5% It is rare that a cystic thyroid lesion occurs the pediatric age group and very exceptional that it is detected as lateral neck mass by prenatal ultrasonography. This is due to universal ultrasonography, allowing for the regular observation of fetal development and screening of the structural abnormality. Fetal neck masses can cause many problems like asphyxia after birth, dystocia and hemorrhage due to hydroamniosis. Prenatal ultrasonography is essential to evaluate neck masses and to plan the delivery timing and approach.This report is meaningful in that the congenital neck cyst was early detected by early perinatal ultrasonography. Histologically, the origin of the cyst is the UBB remnant, which is rarely reported.The authors declare no conflicts of interest.


This study aims to investigate whether women with cervical dysplasia after LEEP have an increased risk of pregnancy/childbirth complications or recurrence of dysplasia in an upcoming pregnancy.Data from 240 women after LEEP were analysed retrospectively. The reference group consisted of 956 singleton births. Fisher’s and Wilcoxon rank tests were used to detect differences between groups. Using logistic regressions, we analysed the effect of surgery-specific aspects of LEEP on pregnancy/childbirth complications and the frequency of CIN recurrences.We found that tissue-preserving LEEP did not lead to premature birth or miscarriage and did not increase the likelihood of CIN recurrence.p < 0.28) < 34 (p < 0.31), < 32 weeks of gestation (p < 0.11)] or birth weight (< 2500 g (p < 0.54), < 2000 g (p < 0.77) between groups. However, women after LEEP exhibit a higher risk of premature rupture of membranes (PROM) at term (p < 0.009) and vaginal infections (p < 0.06). Neither volume nor depth of the removed tissue nor an additional endocervical resection seems to influence the likelihood of premature birth or early miscarriage. Performing an endocervical resection protects against CIN recurrence .We did not observe differences regarding preterm birth [< 37 (After tissue-preserving LEEP, there is an increased risk of vaginal infections and PROM at term in consecutive pregnancy. LEEP does not affect prematurity or miscarriage. The removal of additional endocervical tissue appears to be a protective factor against recurrence of CIN. Human papillomavirus (HPV) infection is one of the most common sexually transmitted viral diseases. Almost 80% of all sexually active people become infected with HPV during lifetime. Most people clear infection. Only in cases with persistent infection with one of the high-risk HPV subtypes, cervical intraepithelial neoplasia (CIN) or/and carcinoma of the uterine cervix may develop. If advanced dysplasia (CIN3) is detected by cervical biopsy, Pap smear, and/or colposcopy, surgical treatment is recommended according to the German guidelines to prevent the development of cervical carcinoma . The mosIn the literature, LEEP has been shown to be associated with an increased risk of complications during pregnancy and birth. Most notably, preterm delivery by inducing preterm labour and preterm rupture of membranes (PROM) with consecutively low birth weight < 2500 g) are often associated with this procedure 500 g are. Surgica2-laser-vaporized. To prove the endocervical in sano resection histologically, an additional, small endocervical resection with a Mini-LOOP (0.5 cm) is performed in most cases. Finally, the wound will be CO2-laser-vaporized for complete haemostasis.To minimize these pregnancy- and birth-related risks, LEEP at the dysplasia unit at University Hospital of Düsseldorf (UKD) is performed in the child-bearing age group in a minimally invasive manner under colposcopic guidance to minimize the excised volume and damage to the cervix. Using this technique, only the colposcopically visible major change lesion is excised (with a LOOP) and the surrounding minor change ectocervical lesions are COThis tissue-preserving method, however, may influence the effectiveness of LEEP in treating high-grade CIN: a sufficient resection of dysplastic tissue is crucial to stop the dysplastic change from progressing and even prevent the development of cervical cancer and minimize the rate of recurrence.The aim of this study is to investigate whether tissue-sparing LEEP increases the risk of premature birth, low birth weight, miscarriage, or recurrence of cervical dysplasia in a single-centre study of women treated in a large dysplasia unit in Germany.LEEP was performed in a total of 1177 women treated at the dysplasia unit at UKD from 2009 to 2014 . 73% of women were between 18 and 40 years old, considered to be in child-bearing age. We sent out a survey to these former patients with specific questions concerning potential pregnancies and birth-associated complications, miscarriages, or recurrence of CIN. Moreover, the questionnaire included questions related to information about numerous other variables which might be relevant to control for in a statistical analysis, such as health conditions, previous pregnancies, and previous preterm deliveries (amongst others). The institutional ethic board of the hospital approved all studies linked to the study and patients agreed to the analyses of their data being informed consent.Among the women who responded to the questionnaire, 91 women gave birth to a singleton after undergoing tissue-sparing LEEP at UKD. We used a sample of 956 (non-LEEP) singleton births, documented at UKD from January to June 2016 as a reference group. Information about individuals in our reference group included a list of possibly relevant covariates which we used in the regression analysis.Based on these data, we analysed two questions.Are there differences regarding important outcome variables between patients that underwent (tissue-preserving) LEEP and those who did not?(i) Next to simple descriptives, Fisher’s exact test and the Wilcoxon signed-rank tests were used to examine whether there were differences between the study and reference group. Furthermore, we performed several logistic regression analyses to quantify the effect of (tissue-preserving) LEEP on important outcome variables. In all regression analyses, LEEP was included as a categorical regressor variable , and the set of covariates observed for both groups were included as controls.What are the effects of surgery-specific aspects of LEEP  on pregnancy or birth complications as well as on the recurrence rate of CIN?(ii) P values are reported for regression coefficients as well as for all conducted tests. The program ‘R’ was used for statistical analyses.We used logistic regressions to estimate quantitative effects. The regression analysis was based on the data for the treatment group only. For that group, a large set of possibly relevant control variables was collected through the survey. Including all variables as regressors would increase the degrees of freedom drastically relative to the number of observations, which in turn would result in imprecise estimation and inference. This forces us to explicitly consider model selection to select only those controls that are “most relevant”. For every regression, we used the post-double model selection procedure as proposed in Belloni and Chernozhukov . The resGestational age and birth weight The mean gestational age in our treatment group (n = 91) women with singleton birth after LEEP) was 38.96 weeks of gestation . The rate of premature births was 9.89%. 2.2% of the pregnancies ended before 34 weeks of gestation. The mean birth weight at delivery in our treatment group was 3370.22 g .n = 956), women delivered her baby on average at 38.19 weeks of gestation . The rate of premature births was 14.12%. 4.81% of pregnancies ended before 34 weeks of gestation. The mean birth weight in the reference group was 3275.63 g  (see Table In our reference group (p < 0.28), < 34 (p < 0.31), < 32 weeks of gestation (p < 0.11)] and low birth weight  between the treatment group and reference group , p < 0.3] of the removed cervical tissue, nor by the excision of additional endocervical tissue  , 2.72, p < Pregnancy-associated complications: Based on Fisher’s exact test, we found a significant difference between LEEP patients and the reference group regarding premature rupture of membranes (PROM) (p < 0.009) at term and vaginal infections in subsequent pregnancies (p < 0.06)  also significantly increases after undergoing LEEP , nor the volume  of the removed tissue, nor an additional endocervical resection  affected the likelihood of miscarriage , p < 0.59] nor the volume  of the removed cervical tissue affected the need for further cervical surgeries. Neither the severity of CIN , nor the histological status of the ectocervical margins (p < 0.87), nor the histology of endocervical margin (p = 0.99) increased the need of further surgeries. Removing additional endocervical tissue appears to protect against the recurrence of CIN    . Similar< 0.001) .In our analysis, we did not find a connection between the extent of the excision of cervical tissue and the gestational age. This may be due to the  tissue-sparing manner in which LEEP is performed in our dysplasia unit, where only the excision of the major change lesion is performed with a size-adapted loop and the surrounding minor change lesion is removed with laser vaporization.p < 0.001]  . Armarni 0.0001) . This meThe risk of vaginal infections may be higher following LEEP, since the micro-environment of the uterine cervix is altered by the surgical intervention. The mucus composition and vaginal microbiome  may change after conization, since a portion of the glands has been surgically damaged or removed. In addition, scar tissue can form after surgical intervention –17. All The birth mode can also be affected: after performing LEEP, the uterine cervix could become scarred and the structural changes could result in loss of elasticity of the cervix. Both factors may make a natural birth more difficult. In our study, however, we did not find evidence that LEEP patients are more likely to require a caesarean section compared to our reference group -term effects. The operations were performed between 2009 and 2014, and the patients were contacted in December 2015/January 2016. Thus, our results concerning recurrence of CIN cover a period of up to 7 years post-surgery.Our finding that the removal of additional endocervical tissue significantly lowers the risk of recurrence of CIN is noteworthy. We also investigated whether the removal of additional endocervical tissue increases the risk of a premature birth. To our knowledge, this aspect has not yet been considered in the literature. We found that the removal of additional endocervical tissue does not increase the occurrence of prematurity. Nevertheless, endocervical resection may not be necessary in every case, especially if the major change lesion is easily visible and (only) located ectocervically, but rather indicated when an endocervical part of a major change lesion is suspected. This aspect serves to avoid unnecessary removal of healthy tissue.We did not find evidence that colposcopically guided tissue-preserving LEEP affects prematurity or miscarriage. There is an increased risk of vaginal infections and (preterm) premature rupture of membranes. Despite the tissue-sparing implementation of LEEP in our dysplasia unit in women in the child-bearing age, the risk of CIN recurrence proves to be very low. The removal of additional endocervical tissue appears to constitute a protective factor against recurrence.