Birth weight and related outcomes have profound influences on life cycle health, but the effect of maternal hemoglobin concentration during pregnancy on birth weight is still unclear. This study aims to reveal the associations between maternal hemoglobin concentrations in different trimesters of pregnancy and neonatal birth weight, LBW, and SGA. This was a prospective study based on a cluster-randomized controlled trial conducted from July 2015 to December 2019 in rural areas of Northwest China. Information on maternal socio-demographic status, health-related factors, antenatal visits, and neonatal birth outcomes were collected. A total of 3748 women and their babies were included in the final analysis. A total of 65.1% and 46.3% of the participants had anemia or hemoglobin ≥ 130 g/L during pregnancy. In the third trimester, maternal hemoglobin concentration was associated with birth weight in an inverted U-shaped curve and with the risks of LBW and SGA in extended U-shaped curves. The relatively higher birth weight and lower risks for LBW and SGA were observed when hemoglobin concentration was 100–110 g/L. When maternal hemoglobin was <70 g/L or >130 g/L, the neonatal birth weight was more than 100 g lower than that when the maternal hemoglobin was 100 g/L. In conclusion, both low and high hemoglobin concentrations in the third trimester could be adverse to fetal weight growth and increase the risks of LBW and SGA, respectively. In addition to severe anemia, maternal hemoglobin >130 g/L in the third trimester should be paid great attention to in the practice of maternal and child health care. Birth weight is critical for the evaluation of fetal growth and the prediction of neonatal mortality and morbidity . The pooMaternal nutrition during pregnancy critically determines fetal nutrition and has a significant contribution to fetal and neonatal health. Maternal intakes of micronutrients such as folic acid and iron are crucial for fetal growth and development . HemogloPregnant women have a high prevalence of anemia . Lots ofAccordingly, the relationships between maternal hemoglobin concentration and birth outcomes reported in previous studies are complicated and have been disputed. The inconsistencies of the findings were mainly attributed to the differences in research design, sample size, time of hemoglobin measurement, hemoglobin classification cut-offs, race, and region of investigation ,23. AddiThe data was from a cluster-randomized controlled trial  which was conducted from July 2015 to December 2019 in rural areas of Northwest China. The original trial aimed to evaluate the effect of micronutrient supplementation during pregnancy on congenital heart disease (primary outcome) and other birth outcomes. Detailed design and methods of this trial have been described elsewhere . A briefBased on the original trial, the present study was conducted to investigate the associations between maternal hemoglobin during pregnancy and birth weight, LBW, and SGA. A total of 4383 eligible pregnant women enrolled in the original trial from December 2016 to December 2019 were included in the present study. Women who were lost to follow-up (n 205), withdrew (n 29), had spontaneous/induced abortion (n 147), had a stillbirth (n 5) or twin births (n 36) were excluded. In addition, since we focused on the maternal hemoglobin during pregnancy according to the study objective, a total of 3748 women who had hemoglobin records in each of the gestational trimesters  were finally included in the study . Women iThe sample size was calculated based on the main outcome (birth weight) of the study. Estimating the mean and standard deviation of the neonatal birth weight of women with non-anemia during pregnancy was 3250 g and 440 g , assuminParticipants enrolment and follow-ups were conducted in the township-level health centers, and deliveries were completed in the county-level hospitals. Data collection was carried out by trained township maternal and child healthcare professionals and was supervised by investigators from Xi’an Jiaotong University Health Science Center. At enrolment, maternal socio-demographic characteristics , reproductive history, and date of last menstrual period were collected via face-to-face interviews. Baseline height and weight were measured using unified facilities. During follow-ups, after women attended the antenatal visits at county-level hospitals, the township maternal and child healthcare professionals collected their anthropometric and hematological records from their antenatal visits and accounted the number of antenatal visits at the end of the follow-ups. Maternal uses of interventional micronutrient supplements were investigated every two months during follow-ups, and other maternal micronutrient supplementations during pregnancy were collected within one week after delivery. Neonatal birth outcomes, including birth date, birth weight, gestational age, and gender, were obtained according to medical records. All information was entered into a web-based surveillance system by trained township maternal and child healthcare professionals, and routine data quality monitoring was carried out by researchers from Xi’an Jiaotong University Health Science Center.Maternal hemoglobin measurement was conducted during antenatal visits at the county-level hospitals by the clinical laboratory technician. Hemoglobin concentration in a unit of g/L was measured through routine blood tests which were completed using the automatic hematology analyzer with the venous blood samples of participants. The township maternal and child healthcare professionals recorded the hemoglobin concentration according to the test results after antenatal visits.The gestational age at antenatal visits was calculated according to the last menstrual period. The period of pregnancy was divided into trimesters according to the gestational age, which included the first trimester , the second trimester , and the third trimester . The present study only included women with at least one hemoglobin record in each trimester, and for women who had more than one hemoglobin record in a certain trimester, the lowest was used for analysis ,30.Maternal hemoglobin concentration < 110 g/L can be diagnosed as gestational anemia according to the WHO standard, and the severity of anemia was defined as follows: 100–109 g/L is mild anemia, 70–99 g/L is moderate anemia, and <70 g/L is severe anemia . MaternaThe primary outcome of this study was neonatal birth weight, and the secondary outcomes were LBW and SGA. Birth weight was measured to the nearest 10 g with a baby scale within one hour after delivery. Gender  was recorded after delivery. Gestational age at delivery was calculated according to the last menstrual period and was confirmed by ultrasound scans. LBW was defined as birth weight < 2500 g according to the WHO .2), the times of antenatal visits (≤5/>5), and micronutrient supplementations (folic acid/folic acid + iron/folic acid + vitamin B complex). Maternal age and gestational age at enrolment were respectively calculated according to birth date and the last menstrual period. Height was measured to the nearest 0.1 cm with a stadiometer, and weight was measured to the nearest 0.1 kg with an electronic scale. BMI at enrolment was calculated as weight at enrolment in kilograms divided by height in meters squared, and was classified according to the standards recommended in the “Guidelines for prevention and control of overweight and obesity in Chinese adults” [Based on the existing literature ,34, cova adults” . MicronuContinuous variables were expressed as mean ± SDs, and categorical variables were described as numbers (proportions). Since the sample of the present study was obtained based on a cluster-randomized controlled trial (the township is the unit of randomization), the data collected had a hierarchical structure. Accordingly, generalized estimating equation (GEE) models  were appp-value for the overall association was used to evaluate the overall association between maternal hemoglobin and birth outcomes, and the p-value for the nonlinear association was used to assess any nonlinear association between maternal hemoglobin and birth outcomes.Restricted cubic spline (RCS) function was further used to estimate the dose–response relationship between maternal hemoglobin concentration in different trimesters of pregnancy and the birth outcomes . AccordiBased on the above analyses, subgroup analyses according to maternal hemoglobin concentration and maternal characteristics  were further conducted to estimate the associations between maternal hemoglobin during pregnancy and neonatal birth weight in different subgroups.p < 0.05. SAS code for GEE models could be accessed in “SAS System Documentation” and referred to the GEE syntax under “The GENMOD Procedure”. The RCS curve fitting was realized by an SAS macro program written by Desquilbet [All analyses were performed using SAS version 9.4 . All statistical tests were two-tailed, and statistical significance was set as squilbet .As shown in The average neonatal birth weight was 3233.4 ± 418.3 g, and the average gestational age at delivery was 39.7 ± 1.3 weeks. The proportions of LBW and SGA infants were 2.6%, and 13.4%, respectively.Maternal hemoglobin concentrations in the first, second, and third trimesters of pregnancy were tested averagely at 10.2 (SD 2.0), 19.4 (SD 3.2), and 36.1 (SD 2.7) weeks of gestation. As displayed in RCS functions with four knots  were further applied to estimate the dose–response relationships between maternal hemoglobin in different trimesters of pregnancy and birth outcomes. In the first and second trimester, no dose–response relationship was found (data was not shown). In the third trimester, dose–response relationships were observed between maternal hemoglobin concentration and neonatal birth weight, LBW, and SGA .p-values for overall and non-linear association were <0.001). The relatively-higher neonatal birth weight was obtained among women with a hemoglobin concentration of close to 100 g/L. When maternal hemoglobin was <70 g/L, neonatal birth weight significantly increased with the increase of hemoglobin; when maternal hemoglobin was 70–100 g/L, birth weight still showed an increasing trend when maternal hemoglobin was rising; when maternal hemoglobin was >100 g/L, neonatal birth weight significantly decreased with the increase of maternal hemoglobin; when maternal hemoglobin was >130 g/L, neonatal birth weight was more than 100 g lower than that when the maternal hemoglobin was 100 g/L . Both the relatively lower risks for LBW and SGA were obtained among women with a hemoglobin concentration of 100–110 g/L. When maternal hemoglobin was <100 g/L, risks of both LBW and SGA were sharply increased with the decrease of hemoglobin; when maternal hemoglobin was >110 g/L, the risk of LBW was slightly increased with the rise of hemoglobin, and the risk of SGA was significantly increased with the increase of hemoglobin . Among women with hemoglobin ≥100 g/L, maternal hemoglobin was significantly negatively associated with neonatal birth weight . Similar associations were found in most of the subgroups according to maternal characteristics . In the third trimester, among women with hemoglobin <100 g/L, maternal hemoglobin was negatively associated with the risks of LBW/SGA . Among women with hemoglobin ≥100 g/L, maternal hemoglobin was positively associated with the risk of SGA . Similar associations were found in many subgroups according to maternal characteristics .In the present prospective study, about two-thirds of the participants had anemia during pregnancy, and about half of the participants had hemoglobin ≥ 130 during gestation. We found that maternal hemoglobin concentration in the third trimester had an inverted U-shaped association with neonatal birth weight, and had extended U-shaped associations with the risks of LBW and SGA. The relatively higher birth weight and lower risks for LBW and SGA were observed when hemoglobin concentration was 100–110 g/L. Maternal hemoglobin < 70 g/L or >130 g/L was strongly related to the decreased birth weight and increased risks of LBW and SGA.In our population from the rural areas of Northwest China, 65.1% of the participants had anemia during pregnancy. Our prevalence of gestational anemia was much higher than that of Western countries such as the United States (5.7%), Canada (11.5%), and Germany (12.3%), and it was also higher than that of Asian countries such as Japan (14.8%) and Singapore (23.8%) . AdditioIn the present study, we found that maternal hemoglobin concentration in the third trimester was associated with neonatal birth weight in an inverted U-shaped curve and was associated with the risks of LBW and SGA in extended U-shaped curves. Women with severe anemia or hemoglobin > 130 g/L in the third trimester had significantly decreased neonatal birth weight and increased risks of LBW and SGA. Compared with previous studies ,43, our Similar nonlinear associations between maternal hemoglobin concentration and birth weight-related outcomes were shown in several previous studies ,11,26,44The timing of maternal hemoglobin measurement varied in previous studies, which was one of the causes of inconsistent results. We measured maternal hemoglobin concentration in each trimester and the significant associations of maternal hemoglobin with risks of LBW and SGA were observed only in the third trimester, which was partially consistent with the results of Young et al.’s systematic review and meta-analysis in 2019 . This reThe possible mechanisms involved in the relationship between low or high hemoglobin concentrations and fetal weight growth are as follows. Severe anemia in the third trimester leads to a decline in the body’s oxygen supply capacity and poor placental development, which affects the maternal delivery of oxygen and nutrients to the fetus. These adverse effects further induce fetal chronic hypoxia and insufficient nutritional intake, which finally causes poor fetal weight growth and adverse birth outcomes such as LBW and SGA ,47. The The plasma volume expansion is also an explanation for our results that better birth weight-related outcomes were obtained when maternal hemoglobin concentration in the third trimester was 100–110 g/L. The slightly lower hemoglobin concentrations in the third trimester may reflect an adequate plasma volume expansion and thus achieve the optimal nutrient transport from mother to fetus, which consequently promotes fetal growth and development . AnotherTo the best of our knowledge, the present study was the first prospective study that revealed nonlinear relationships between maternal hemoglobin concentration in the third trimester and birth weight-related outcomes in the Chinese population. We disclosed that both low and high hemoglobin concentrations could be harmful to fetal weight growth and increase the risks of LBW and SGA, and maternal hemoglobin > 130 g/L in the third trimester could be highly focused on, in addition to severe anemia, in maternal and child health care. Nonetheless, several limitations of the present study should be addressed. Firstly, this study was conducted in the rural areas of Northwest China, and thus the results mainly reflected the association between maternal hemoglobin during pregnancy and birth outcomes in women with disadvantaged socio-demographic conditions, which may limit the generalizability of the findings to other populations. However, it is noteworthy that, compared with women with disadvantaged socio-demographic status, those with advantaged socio-demographic status are more likely to have relatively higher hemoglobin concentrations during pregnancy, suggesting that the adverse impact of high hemoglobin in the third trimester on fetal weight growth should be paid more attention to in such populations. Secondly, although we carried out the analysis by controlling for some potential confounders, including socio-demographic and health-related factors, there were still some unobserved or unknown confounders that we could not fully investigate. For example, excessive maternal gestational weight gain was related to reduced risks of LBW and SGA . UnfortuMaternal hemoglobin concentration in the third trimester had an inverted U-shaped association with neonatal birth weight, and had extended U-shaped associations with the risks of LBW and SGA. Both low and high hemoglobin concentrations in this period could be adverse to fetal weight growth and increase the risks of LBW and SGA, respectively. In addition to severe anemia, maternal hemoglobin > 130 g/L in the third trimester should be paid great attention to in the practice of maternal and child health care.


This article addresses the short-term impacts of the COVID-19 pandemic in Italy and hints at its potential long-term effects. Though many might want it to, birth does not stop during a pandemic. In emergency times, birth practices need to be adjusted to safeguard the health of birthing mothers, babies, birth providers, and the general population. In Bologna, Italy, one of the emergency measures employed by local hospitals in response to COVID-19 was to suspend women’s right to be accompanied by a person of their choice for the whole duration of labor and childbirth. In this work, we look at how this measure was disputed by the local activist birth community. Through the analysis of a social campaign empowered by Voci di Nascita—an association of parents, birth providers, and activists—we examine how social actors negotiated the balance between public health and reproductive rights in a time of crisis. We argue that this process unveils several structural issues that characterize maternity care at the local and national levels, including the (re)medicalization of birth, the discourse on risk and safety, the internal fragmentation of Italian midwifery, and the fragility of reproductive rights. The Covidian experience forced the reshaping of the birth carepath during the peak of the emergency. We suggest that it also offered an opportunity to rethink how birth is conceived, experienced, and accompanied in times of unprecedented global uncertainty—and beyond. The first case of an Italian contracting COVID-19 was documented on February 21, 2020. “Patient 1” is a 38-year-old man from a small town near Milan whose wife was pregnant. In the turmoil of the breaking news, this detail was often repeated. Our thoughts—as a medical anthropologist and an activist mother engaged in the field of birth—ran to this mother-to-be, who was abruptly separated from her husband when he was confined to intensive care. We felt frightened and powerless, thinking about the health risk to her and their baby. Very little was then known about SARS-CoV-2, let alone about its effects during pregnancy. At that time, we could not imagine that separation, isolation, and loneliness would become trademarks of how we give birth—and die—during a pandemic.This was also when the national hunt for the “culprit”  began. A“Patient 1” and his pregnant wife were the tip of an iceberg that would soon reveal its magnitude. At the end of February, a frightening scenario was emerging: thousands of people were exposed to the risk of being infected, including hundreds of women who were soon to become mothers. Hospitals—where 99.9% of births occur in Italy —were quiNew York Times was provocatively titled: “Even Mass Is Canceled” . All of our primary respondents had written at least once to the campaign’s official email address during the lockdown period (March-May). Additionally, parents had to have given birth during that time or immediately afterward. A secondary sample is composed of parents and midwives from outside of Bologna who had not been directly involved in the local campaign. Because of their efforts in reacting spontaneously to the survey, we decided to include their input in the broader context of our analysis.Both questionnaires were open from July 4 to August 4, 2020 on the web-based platform Qualtrics. The invitation to participate in the questionnaire for parents was sent by email from the dedicated address of the association Voci di Nascita to 62 parents. Afterwards, we published a post on the Facebook page of Voci di Nascita, thus introducing the work to a broader audience. Information on the campaign and the link to the survey then circulated among secondary recipients outside Bologna.We emailed the invitation to participate in the second questionnaire to 12 midwives, all of them active in the city of Bologna. The message included a request to forward the email to colleagues potentially interested in participating in the study. Another email was sent to the local College of Midwives and, a few days later, a post with the link to our survey appeared on their Facebook page. The announcement was reposted on Voci di Nascita’s Facebook page.The goal of the questionnaire dedicated to parents was to collect stories of those who gave birth during the lockdown in Bologna and how the emergency restrictions reshaped their experiences before, during, and after the birth. We focused our queries on the presence/absence of the partner or support person during labor and childbirth, as this was the issue we were most interested in exploring. Most inquiries were directed to birthing mothers; however, a final question was dedicated to the partners . We asked no personal details apart from the parents’ age, and whether it was the first birth. We set up the survey using the strictest anonymity settings, and no additional sensitive data was recorded.The mothers’ questionnaire received 49 complete or partially complete responses (more than 60% filled in). These 49 accounts constitute the sample taken for analysis. Of these responses, 29 concern the Bologna area, and 20 are from other parts of Italy. The average age of the respondents (mothers) was 35 for the Bologna area and 34.6 for the whole national area. The average age of the partners was 36.3 and 36.7, respectively. The percentage of primiparas in the Bologna area was 22% and 30% for the whole national area. 27 of the Bolognese births took place in a hospital, 1 in a maternity home, and 1 at home. In the rest of the national territory, 15 births occurred in a hospital or clinic, three at home, and in 2 cases the place of birth was not declared. In Bologna, 2% of the respondents gave birth in a different place from the one planned and/or desired; this percentage rises to 6% in the rest of the country. Before the emergency, the desired labor companion(s) in Bologna was: the partner for 23 women, the partner and the parturient’s mother for 3, and the partner together with the midwife for 3. On the national scale, these numbers are 37, 6 and 6, respectively. In Bologna, 21% of women stated that they were left alone during labor and childbirth .The goal of the questionnaire dedicated to midwives was to gather their personal views on how obstetric practice and care changed in response to the pandemic and collect accounts of their direct experiences accompanying women and births in times of COVID-19. Particular focus in the midwives’ questionnaire was also on the temporary prohibition/limitation of partners in the birthing room; additionally, it addressed midwives’s needs during the crisis. Again no sensitive personal data was requested, aside from age and city. However, to better understand and contextualize the responses of our interlocutors, we asked midwives to describe their professional environment and experience, and to name the three words that they most associate with midwifery. Finally, we invited midwives to share their thoughts about the future of birth and maternity care.The questionnaire for midwives received 18 full responses, constituting the sample taken for analysis. Of these, eight concern the Bologna area and the other 10 the rest of Italy. The average age of the respondents in the Bologna area is 31.6 years; the total national average age is 36.6. In Bologna, four responding midwives work at a hospital, 1 in a family clinic, and 3 as freelance professionals. These numbers at the national level are 9, 2, and 7, respectively. The three words most frequently associated with midwifery by respondents were “listening,” “empathy,” and “compassion.”Voci di Nascita means “voices of birth” and was founded on International Women’s Day of 2017. The birth of the association is related to the personal experience of becoming a mother and a doula of the founder and president, co-author Daniela Canzini. For her, the direct encounter with motherhood suddenly revealed a personal lack of “birth culture,” which, she felt, demanded an active stance at the individual and social levels. From its beginning, the association’s fundamental aim was to create and promote “culture” around birth and parenthood through various forms of social activism and services to birthing families. Midwives were progressively identified as the strategic actors of their local birth communities. Together with women, Italian midwives are directly engaged in the biosocial process of birth and largely operate within the biomedical environment. In the association’s view, midwives’ voices—largely unheard—called for a dialogue with parents, institutions, and within midwifery as well.During the initial phase of the lockdown, dialogue appeared urgent yet almost impossible to achieve. This was the frantic time in which major emergency adjustments to the birth carepath were adopted, along with the broader reorganization of hospital spaces and services. Information on the new procedures for parents and staff appeared swiftly, increasing everyone’s anxiety and stress. Homemade signs popped up on the doors of maternity wards with vague communications such as “Due to the COVID-19 emergency, it is no longer possible to allow the accompaniment of women during the whole duration of labor.” In late March, a worried mother-to-be saw such an announcement during a prenatal visit at the hospital and sent a picture of it to Voci di Nascita to share her disorientation. Although other city hospitals had not employed the same restrictive measure (yet), the general feeling was that things could only worsen, and there was talk of the possibility of separating mother from child after the birth. Luckily, that did not happen. Eventually, on April 7, all three city hospitals adjusted to the strictest rule: the birth partner was not allowed during labor and was only to be admitted at the expulsion stage of birth. This left no choice to parents who, until then, could weigh their hospital options and decide to give birth where the partner or person of choice was still allowed to be with the mother and support her during labor as well.The association decided it was necessary to demand that parents’ and birth professionals’ voices be taken into consideration, despite—and, in virtue of—the current emergency. A few midwives had already shared their concerns and expressed their feelings of being impotent, voiceless, and stuck in a violent defensive mechanism with no clear direction. On April 17, Daniela Canzini signed and sent out a letter to the authorities in charge of local health and hospital services, social politics , and to the president of the Emilia-Romagna Region.The letter was successful in opening a dialogue and receiving formal feedback. Daniela was invited to be duly informed on the situation with the local health authorities. The most restrictive measures were corrected: starting from April 27, partners could be present from the beginning of active labor up until after the birth.Of course, the campaign’s immediate impact should also be read in light of the progressive decrease in the COVID-19 emergency and the consolidation of the scientific evidence. However, the social campaign did mark a turning point and created an important precedent. Moreover, the letter hinted at several structural issues that characterize the local culture of maternity care and birth, which the experience of COVID-19 unveiled. In the following sections, we will discuss these, combining the responses given by parents and midwives to our questionnaires with selected abstracts from the letter itself.principle of separation—have significantly shaped Western scientific thought, and that of biomedicine in particular. One of the side effects of its development has been a progressive medicalization process, which affects multiple aspects of society through forms of biopolitical control of bodily experiences .quid pro quo occurred: the terms “visitor,” “relative,” “support person,” and “parent” were suddenly mixed, with the result that partners were cut off just where their relationship with their newborns normally begins .The exclusion of partners was an absurdity experienced with anguish by women who sometimes turned towards alternatives in the wake of fear instead of awareness—a measure with absolutely no scientific basis: an action against human rights, a violence against parents and babies (Midwife #7).Another commented that:This midwife raises several crucial issues, including that birthing parents could end up changing their birthplace because of fear. A mother confirmed that she and her partner eventually changed hospitals because “she could not even think” of giving birth without her husband. Some parents in our study wrote that, during COVID-19, they felt out-of-hospital birth could be safer. However, no one planning a hospital birth actually shifted to homebirth. On the other hand, the women who gave birth at home (1 in Bologna and 3 nation-wide)—having previously decided to do so—said that their greatest fear was an emergency transfer to the hospital because they knew they might end up laboring alone.I spent the whole night outside the hospital on the phone with my wife to make her feel my presence and give her courage, even though I was afraid. I left my wife at 9 p.m., and I saw her again at 3 a.m., after labor. I was able to experience the emotion of childbirth during the pushing phase. Despite the restrictions, I was lucky to be there and see my daughter being born (Partner #20).22% of the birthing mothers in our survey declared that they were, in fact, left alone in the hospital during labor and birth. For example, one woman said that, although she had been assured that her partner could be there, he was only called into the room just after the birth. Partners usually remained outside the hospital premises, waiting to be called by the birthing mother herself or—more likely, given the circumstances—by the midwife on duty. A father said that this situation made him feel “powerless” and the typical scene is decribed by another man, who wrote:Most women have an attitude of acceptance of the restrictions. Some of us received official complaints from inpatients when they realized that we broke the rules when necessary. We endured continuous disputes with our superiors, and we feared being reported by other colleagues. Nowadays, it is more us than women who have been asking for more openness and urging them to stand up for themselves. Fear has been the master, lately (Midwife #11).Fear and luck are recurring expressions in both mothers’ and fathers’ accounts, and a midwife noted that:During the last few weeks of pregnancy, we feared that my partner could not be present at the birth. This made me really upset. Luckily, things changed shortly before the birth, and he was able to be there. Otherwise, I would have considered it as violence (Mother #25).This statement echoes the general feeling that most mothers expressed about their birthing experience: in the chaotic times of COVID-19, many women entered the hospital already “tired,” “stressed,” “fearful,” and “disillusioned.” Referring to the initial phase of the emergency, when protocols were not clear and could change from one day to the next, one mother said:In their accounts, almost all mothers expressed disappointment with regards to the prohibition. Some of them specifically pointed at the impossibility of reaching the necessary intimacy with partners during childbirth because they could only be there for the very final moments. And yet—while expressing frustration, sadness, and loneliness—most birthing mothers accepted the restrictive measure for the sake of “safety” and because they saw no feasible alternative. Some also pointed to the fact that they were “lucky” this was not their first birth, suggesting a diffused perception that the quality of assistance and care is ultimately a matter of luck , rather The “war” metaphor has been employed in mainstream media to describe the scenario generated by COVID-19, especially inside hospital wards. We chose to adopt this metaphor herein because it mirrors the words used by many midwives in our study when describing their experiences during the pandemic. Midwife respondents agreed that empathetic care is essential for birthing women. They were vocal in denouncing the risks connected to leaving mothers alone and depriving them of personalized midwifery care, which requires presence, empathy, and close contact. They also believe that such care is an essential safety factor, especially in critical times. Most midwives seemed to suggest that COVID-19 restrictions endangered a double right to quality midwifery care: for women to receive it, and for midwives to provide it, safely.During the lockdown in Italy, the first “battle” for midwives began with instructions to abide by emergency measures “without being asked what they thought about them”—as the letter by Voci di Nascita points out. One midwife in particular felt that, by adhering to the new rules, she was (re)producing violence against women—suggesting the urgent need to further analyze the forms of obstetric violence  that birMidwives’ second battle, shared with all other medical staff, was the initial lack or inappropriateness of personal protective equipment (PPE). This was particularly hard for freelance out-of-hospital midwives who had no direct access to PPE. Although facemasks were deemed necessary, midwives reported that these played a detrimental role in their relationships with women by disguising facial expressions; furthermore, recalling the experience of a birthing mother, a midwife commented that “birthing with a facemask was asphyxiating.”The third and most structural battle midwives have had to endure over the past few months is their intra-professional conflicts. Respondents testifed to the fact that not all midwives disagreed with the most restrictive measures and that, because of their own fear and exhaustion, some actually thought that it was better to exclude partners from the birthing room. Generational issues should also be factored in, as younger hospital midwives tend to be more enthusiastic about their jobs. Older, more experienced midwives who had already fought for decades for mothers’ rights were often tired and disillusioned by the fact that women themselves sometimes only care about not feeling pain or having a “souvenir” photo of their birth. Unfortunately, none of these midwives filled out our survey and therefore we cannot further elaborate on their perspectives. However, a young midwife wrote:The fact that there are no partners is seen by the majority as safer. For me, this emergency showed who loves their job, and who does it only for money. I am not saying that we should go out and die for midwifery, but neither that we have to carry out illogical and absurd procedures. For me it does not have to be like that: every mother is different, and we have to remember that we are not there to cure them but to accompany them. I think some of my colleagues are in burnout (Midwife #1).Anxiety and burnout are very likely to increase during emergency situations. Adequate psychological support for hospital staff is structurally lacking in regular times, let alone during the pandemic. Yet women’s needs for emotional support and reassurance grow during times of crisis, and midwives should be adequately prepared to respond , even thThe key to understanding this broader “cold war” is structural in nature and goes well beyond midwives’ experiences of COVID-19. It interrogates the very status of the midwifery profession in Italy, which has been defined a “semi-profession” due to a lack of collective identity and professional autonomy, and for its internal fragmentation . This “pMore broadly, when questioned about the future of birth and maternity care in post-Covidian times, midwives raised a number of issues. Some were afraid that fear might normalize the strictest rules and that the medicalization of birth might increase at the expense of midwifery care. Others worried about the quality of virtual antenatal and postnatal care and feared that women will end up being even more isolated. Some hope for the development of social policies to support out-of-hospital birth for normal physiologic pregnancies. One midwife summarized the feeling of most respondents: “An unfortunate scenario has opened up: the little importance given to being born as a form of relationship.”As elsewhere, as also demonstrated in other articles in this Special Issue, the experience of COVID-19 exposed pre-existing structural issues in Italian maternity care, especially within the hospital environment. Under the initial epidemiological pressure, emergency measures reshaped the birth carepath in ways that highlighted the delicate balance between safeguarding public health and guaranteeing reproductive rights . In thisWell past the first and hopefully last Covidian summer, a generalized feeling of uncertainty still characterizes the entire Italian scenario. There has not been a “second wave” of emergency and, therefore, no further lockdowns. The contagion at the national level seems relatively under control, particularly compared with other European countries . However, it is hard to make predictions for the upcoming weeks and months, and a serious threat remains. For this reason, at the Bolognese level, the “semi-restrictive” rules implemented in local hospitals after the campaign of Voci di Nascita still apply: women can be accompanied by a person of choice from the beginning of active labor only. According to informal testimonies we continue to receive, hospital staff seem to be more flexible than during emergency times, and their approaches—whether more or less medicalized—tend to resemble those in place before the pandemic. The situation could be rapidly shifting, and it is too early to confirm any stable changes in midwifery practice in the hospitals of Bologna, let alone at the broader national level.In our study, we could not analyze what happened outside of the hospital during the emergency, in private homes, family clinics, and birthing centers. Parents and midwives who participated in our survey raised several themes that also deserve further attention, such as the need to design supportive out-of-hospital birth policies at the local and national levels ; the rolOur work suggests that the pandemic has been a touchstone, or pivotal moment, for local in-hospital birthcare. It shows how easy it is to go back to over-medicalized birth practices that had been considered outdated and not evidence-based; how fragile is the awareness of parents of their reproductive rights; how paralyzing is the internal fragmentation of the midwifery profession. On the other hand, the social campaign empowered by Voci di Nascita represented a strong example of activist strategy during emergency times. It pronounced the needs for clear communication of the new rules and protocols, appropriateness of evidence-based emergency measures, recognition of professional roles and responsibilities among birth providers, and the guarantee of parents’ rights. Respectfully, yet firmly, the letter demanded that the voices of all actors involved in the birth process be taken into consideration during times of crisis. It also created an opportunity to reclaim engaged parenthood.The immediate achievement of the social campaign probably rests on the fact that it came from outside the hospital environment and that it was openly political. However, medium- and long-term effects of COVID-19 on maternity care practices and policies cannot be clearly foreseen and will be largely determined by the active and direct involvement of birth providers, health authorities, and parents in the aftermath of the emergency. In the words of one of the midwives in our study, it is a matter of whether the “message sent out by COVID-19 is understood, or not.” COVID-19 dramatically exposed structural issues that characterize the multilayered experience of giving birth and accompaning the births of babies and parents. Oddly enough, the virus forced an eye to the socio-cultural implications of the process of birth as rooted in—yet not limited to—the biological experience.Postscript (December 2020). At the time of submission for review of this article (October 2020), a second wave of COVID-19 had not yet hit Italy and we anticipated that no clear predictions could be made and that uncertainty and fear were still dominant. Indeed, a second wave did hit Europe and Italy did not escape it. The semi-restrictive rules described in our work are still in place, and no further significant progress has been made in the longed-for engagement towards an alliance of the actors involved for the safeguarding of appropriate and well-rounded practices in maternity care.


Neonatal morbidities as well as the neurodevelopmental outcome at 2 years of corrected age were analyzed. Six-hundred infants completed the study successfully. Of these, 38% experienced an NI episode. NIs were associated with an increased risk of neonatal complications, such as brain injury, bronchopulmonary dysplasia (BPD) and death, and were a significant risk factor for adverse motor development at 2 years of corrected age in our cohort of VLBWIs. The negative impact of NIs on neurodevelopmental outcomes was particularly associated with necrotizing enterocolitis (NEC), suspected NIs and Gram-positive NIs. This study demonstrated that NIs are a significant risk factor for both morbidity and mortality as well as adverse neurodevelopmental outcomes in VLBWIs.Nosocomial infections (NIs) are important conditions associated with mortality and morbidity in very low birth weight infants (VLBWIs). The aim of this study was to investigate the impact of NIs and the different subtypes on neurodevelopmental outcomes in a cohort of VLBWIs. VLBWIs born with a gestational age between 23  Improvements in obstetric and neonatal intensive care within the last decade have markedly increased the survival and lowered the border of viability of preterm infants. However, these improvements have not succeeded in reducing the rate of adverse neurodevelopmental outcome of extremely preterm infants ,2. Staphylococcus aureus, E. coli and other Gram-negative aerobes, as well as in rare cases fungi. In some cases, despite the presence of clinical and laboratory signs of infection, no causative pathogen can be identified. This might be attributed to technical issues, primarily the low blood volume available in these small patients. Although a blood volume of 0.5–1.0 mL has been considered sufficient for detecting blood stream infections in neonates and preterm infants, today, researchers presume that the incidence of low-level bacteremia in these patients is more common than previously reported [Nosocomial infections  are important conditions that are associated with mortality and morbidity as well as poor neurodevelopmental outcomes among infants hospitalized in the neonatal intensive care unit (NICU) . The morreported . InfectiThe aim of the present study was to investigate the impact of nosocomial infections and its different subtypes on neurodevelopmental outcomes at 2 years of corrected age in a cohort of VLBW infants. Although of multifactorial origin, cases of necrotizing enterocolitis (NEC) were also included in the analysis. This was performed in analogy to former studies on this topic ,8 and du0/7 and 31 6/7 weeks and birth weight <1500 g, born in our level III neonatal center between January 2009 and June 2016, who were admitted to the NICU. Infants with major congenital malformations/syndromes and congenital metabolic disorders were excluded from the study. This retrospective analysis included VLBW infants with a gestational age between 23 The basic patient characteristics and clinical data were collected from the medical records of the included infants: the maternal pregnancy history , 5-min APGAR score, gestational age at birth, birth weight, sex, single or multiple birth, early onset sepsis (EOS), duration and type of respiratory support, as well as the relevant complications associated with prematurity as defined below. The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the local ethics committee (EK-Nr. 1090/2018).A proven nosocomial infection (pNI) was defined as a positive result of one or more bacterial or fungal isolates obtained from a blood culture in an infant with clinical signs of infection  after day 3 of life treated with antibiotics for 5 or more days or until death. Based on the culture results , the infants were classified into three nosocomial infection subgroups. Pathogens that may represent contaminations (coagulase-negative staphylococci) were considered as proven sepsis only if clinical and laboratory signs of infection  were present and if antibiotics/antimycotics were administered for a minimum of 5 days or until death. Suspected nosocomial infection (sNI) was defined as an episode with clinical and/or laboratory signs of an infection in the absence of a positive bacterial or fungal culture in an infant who received treatment with antibiotics for a minimum of 5 days or until death.Cases of NEC Bell stage II or higher  with or Early-onset sepsis (EOS) was defined as culture-proven sepsis within the first 72 h of life.The uninfected group consisted of infants who had not developed pNI, sNI or NEC as defined above until discharge.Brain injury was defined as intraventricular hemorrhage grade 3 or higher, according to Deeg et al. , and/or Bronchopulmonary dysplasia (BPD) was defined as oxygen dependency at 36 weeks postmenstrual age .Neurodevelopmental examination was routinely performed by experienced pediatric developmental neurologists and developmental psychologists at 24 months of corrected age at the neonatal follow-up clinic of the department. Neurodevelopment was assessed using the Bayley Scales of Infant Development II (BSID-II) for those infants born between 1 January 2009 and 30 June 2012 . For tho® Statistics for Mac version 21.0. . The quantitative data are presented as the mean ± standard deviation (SD), while the qualitative data are shown as counts and percentages. The differences for continuous variables between the two groups (any type of NI vs. uninfected) were calculated using a t-test for independent samples, while differences in the descriptive characteristics for categorial variables were calculated using the chi-square test.Statistical analysis was performed using SPSSAn analysis of variance (ANOVA) was carried out to compare the means between the different NI groups, and a Tukey HSD test was used to calculate the specific differences between these groups. A multilinear regression model was performed to investigate the effect of the NI and its subtypes on the neurodevelopmental outcomes when correcting for important patient-specific and/or medical conditions . These conditions were chosen due to their high impact on neurodevelopmental outcomes according to the literature ,21,22,23During the observational period, 1046 infants met the inclusion criteria for the study and were included in the analysis . Ninety-p = 0.000*), a higher gestational age (p = 0.000*) and birth weight (p = 0.000*) and less complications associated with prematurity  compared to the infants who completed the study.The baseline characteristics of the infants who completed the study, those lost to follow-up and those who died during birth hospitalization are provided in p = 0.019*) and NEC (p = 0.002*) episodes and a significantly lower gestation age (p = 0.000*) and birth weight (p = 0.000*), as well as more complications associated with prematurity .Infants who died during birth hospitalization had a higher number of Gram-negative NI (p = 0.001*), had a higher birth weight (p = 0.000*) and gestational age (p = 0.000*), were more frequently multiples (p = 0.023*) and had less complications associates with prematurity . The baseline characteristics of the NI subtypes are given in Of the infants who completed the study, 230 (38%) infants experienced an NI episode, while 370 (62%) infants remained uninfected. The baseline characteristics of these infants are given in p = 0.000*) and motor score (90 (SD ± 15) versus 83 (SD ± 18); p = 0.000*) were significantly higher in uninfected infants versus infants with NI in an unadjusted analysis, revealing mild motor and mental impairment in the infants who experienced infectious episodes.The neurodevelopmental outcome assessments were performed at 2 years of corrected age. Both mental score (87 (SD ± 19) versus 80 (SD ± 21); p = 0.004*) but not mental outcome (p = 0.062) , NIs were still significantly associated with an adverse motor (= 0.062) .In an unadjusted analysis, infants with sNI and infants with episodes of NEC showed a significant, mild impairment in both motor and mental development compared to uninfected infants at 2 years of age. A mild significant impairment in motor development was detected also in infants with a Gram-positive NI .p = 0.031 */p = 0.025 *; In a regression model, episodes of NEC adversely influenced both the mental and motor development of VLBWIs at 2 years of age (As the pathophysiological mechanisms of NEC appear to be more complex than in other nosocomial infections, the regression model was also calculated excluding cases of NEC with comparable results . Nosocomial infections are an important morbidity in very low birth weight infants. In line with other studies ,21, our Our results are in line with the current data ,24 but dThe large cohort study by Stoll et al.  proposedThus, from the published data, it is reasonable to speculate that the influence of nosocomial infection on the neurodevelopmental outcome of very low and extremely low birth weight infants has declined over the last two decades, while other neonatal morbidities, such as BPD, ROP and brain injury, have gained more importance. This might be explained by improvements in neonatal care during these years, favoring less invasive treatment strategies, above all less invasive surfactant administration, the avoidance of mechanical ventilation and a strong focus on family centered care as well as advanced antibiotic stewardship . These iIn our study, infants with suspected nosocomial infection and infants with NEC showed a mild motor and mental delay at corrected 2 years of corrected age. Infants with Gram-positive nosocomial infections displayed a mild motor delay. In the regression model, NEC adversely influenced both the mental and motor development at 2 years of age. Reports on the influence of different types of nosocomial infections on the neurodevelopmental outcomes of preterm infants are sparse and report differing results. One study detected a significant influence of all types of nosocomial infections on neurodevelopmental outcomes , while aThe strength of our study is the fact that our study group reflects a representative NICU patient population. These outcomes may change as the children become older, i.e., some may improve, some may remain unchanged and some may worsen , and it In summary, the current study demonstrates that nosocomial infections are a significant risk factor for adverse motor development at 2 years of corrected age in very low birth weight infants as well as a risk factor for neonatal complications, such as brain injury, BPD and death in these infants. The negative impact of nosocomial infections on neurodevelopmental outcomes was particularly associated with NEC, suspected nosocomial infections and Gram-positive nosocomial infections in our study cohort.


People who were born prematurely have high risks of many individual diseases and conditions in the early part of the life course. However, our knowledge of the burden of multiple diseases (multimorbidity) among prematurely born individuals is limited. We aimed to investigate the risk and patterns of chronic disease multimorbidity in adolescence and early adulthood among individuals born across the spectrum of gestational ages, comparing preterm and full-term born individuals.st January 1987 and 31st December 2006, inclusive. All individuals were followed from age 10 years to the onset of multimorbidity, emigration, death, or 31 December 2016 (up to age 30 years). We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for multimorbidity using flexible parametric survival models. During 6,417,903 person-years at risk (median follow-up: 7.9 years), 11,919 individuals (1.3%) had multimorbidity in adolescence . During 3,967,419 person-years at risk (median follow-up: 6.2 years), 15,664 individuals (1.7%) had multimorbidity in early adulthood . Adjusted HRs for adolescent multimorbidity, comparing preterm to full-term born individuals, were 1.29 (95% CI: 1.22 to 1.36) and 1.26 (95% CI: 1.18 to 1.35) in females and males, respectively. The associations of preterm birth with early adult multimorbidity were less marked, with the adjusted HRs indicating 1.18-fold risk in females (95% CI: 1.12 to 1.24) and 1.10-fold risk in males (95% CI: 1.04 to 1.17). We observed a consistent dose-response relationship between earlier gestational age at birth and increasing risks of both multimorbidity outcomes. Compared to full-term born males, those born at 37–38 weeks (early term) had a 1.06-fold risk of multimorbidity in adolescence (95% CI: 0.98 to 1.14) and this risk increased in a graded manner up to 6.85-fold (95% CI: 5.39 to 8.71) in those born at 23–27 weeks (extremely premature), independently of covariates. Among females, the same risks ranged from 1.16-fold (95% CI: 1.09 to 1.23) among those born at 37–38 weeks to 5.65-fold (95% CI: 4.45 to 7.18) among those born at 23–27 weeks. The corresponding risks of early adult multimorbidity were similar in direction but less marked in magnitude, with little difference in risks between males and females born at 36–37 weeks but up to 3-fold risks observed among those born at 23–27 weeks.We used individual-level data from linked nationwide registers to examine the associations of gestational age at birth with specialised healthcare records of ≥2 chronic diseases (multimorbidity) in adolescence (age 10–17 years) and early adulthood (age 18–30 years). Our study population comprised 951,116 individuals  born alive in Finland between 1Our findings indicate that an earlier gestational age at birth is associated with increased risks of chronic disease multimorbidity in the early part of the life course. There are currently no clinical guidelines for follow-up of prematurely born individuals beyond childhood, but these observations suggest that information on gestational age would be a useful characteristic to include in a medical history when assessing the risk of multiple chronic diseases in adolescent and young adult patients. Multimorbidity, the co-occurrence of two or more chronic, non-communicable diseases in one individual, is a growing health concern worldwide –5. MultiPreterm birth constitutes approximately 6% of all births in Finland and the Nordic countries, and 11% of births worldwide , 15, 16.The primary aim of our study was to investigate the risks of chronic disease multimorbidity in adolescence (age 10–17 years) and young adults (age 18–30 years) across the spectrum of gestational ages, comparing preterm-born individuals and those born at full-term. The secondary aim was to examine the overlap of chronic disease multimorbidity in adolescence and early adulthood with intellectual disabilities and developmental disorders, comparing preterm and full-term born individuals.st January 1987 and 31st December 2016).Data on gestational age at birth, sex, date of birth, birth weight, multiple pregnancy and mother’s characteristics  were ascertained from the Medical Birth Register. Congenital anomalies were ascertained from Register of Congenital Malformations and mother’s diabetes or hypertensive disorder from a combination of data from the Medical Birth Register and Care Register for Health Care. Chronic disease multimorbidity in adolescence and early adulthood, as well as intellectual disabilities and disorders of psychological development, behaviour or personality, were ascertained from the Care Register for Health Care. Information on dates of death and emigration from Finland was obtained from the nationwide Population Information System. All these data sources cover the whole population of Finland for the study period  and the relevant register authorities. All register data were pseudonymised and linked prior to analysis by Statistics Finland and Information Services, Finnish Institute for Health and Welfare, and the researchers only had access to pseudonymised data.Our investigation was based on analysis of existing register data and no patients or members of the public were involved in the design, conduct or interpretation of the study. Due to data security and privacy constraints, it was not possible to involve members of the public in the investigation.st January 1987 and 31st December 2006 (inclusive) and who remained alive and living in Finland at the age 10 years . Individuals were followed up from age 10 years to the onset of multimorbidity , death, emigration or 31st December 2016. We excluded individuals with a gestational age earlier than 23 weeks (n = 411), those with implausible data on birth weight alone or birth weight in combination with gestational age . Further excluded were individuals of undetermined sex (n = 26) and individuals with incomplete data on birth weight and/or gestational age .The study population comprised all individuals who were born alive in Finland between 1Gestational age in completed weeks was analysed as a categorical variable as follows: 23–27 weeks (extremely preterm), 28–31 weeks (very preterm), 32–33 weeks (moderately preterm), 34–36 weeks (late preterm), 37–38 weeks (early term), 39–41 weeks  and > = 42 weeks , 33, 34.Chronic disease multimorbidity was defined as one individual having records of two or more non-communicable chronic diseases (psychiatric or somatic) during the same or subsequent secondary care episode(s). The diseases constituting multimorbidity were selected based on evidence on commonly occurring diseases among preterm and term born adolescents and young adults , 36–44. Intellectual disabilities and disorders of psychological development, behaviour or personality  were identified using diagnostic codes provided in S2 Table in ow: manual workers, pensioners, students and long-term unemployed; intermediate: non-manual workers; high: executive employees; self-employed and unknown), mother’s diabetes during pregnancy (yes vs. no), mother’s hypertensive disorder during pregnancy (yes vs. no), and year of birth (categories). Mother’s occupation during pregnancy was unknown for 309,882 mothers (32.9%), who were likely to be stay-at-home mothers or students [We adjusted the analyses for factors that previous research has shown to be associated with preterm birth –50 and wstudents ; rather st December 2016). Adolescent multimorbidity was modelled conditional on survival to age 10 and early adult multimorbidity conditional on survival to age 18. The analyses were conducted separately for females and males, and for those with intellectual disabilities or disorders of psychological development, behaviour or personality. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for both multimorbidity outcomes, across categories of gestational age, using flexible parametric survival models on the cumulative hazard scale, utilising Stata command stpm2 [Time at risk of adolescent multimorbidity was defined as time from age 10 to 17 years and time at risk of early adult multimorbidity as time from age 18 to 30 years, up to the first of the following: time of onset of multimorbidity, date of death, date of emigration or the end of follow-up  and 1.26 (95% CI: 1.18 to 1.35). The associations of preterm birth with early adult multimorbidity were less marked, with multivariable-adjusted HRs indicating 1.18-fold risk in females (95% CI: 1.12 to 1.24) and 1.10-fold risk in males (95% CI: 1.04 to 1.17).The associations of categories of gestational age (degrees of prematurity) with chronic disease multimorbidity in adolescence and early adulthood are shown in Tables To examine combinations of chronic diseases that typically comprised multimorbidity in our study population, we examined the co-occurrence of individual chronic diseases and their associations with preterm birth  [in utero exposures include mother’s diabetes or hypertensive disorder during pregnancy, which can influence glucose metabolism and insulin sensitivity in the prematurely born individual through shared genetic susceptibility or developmental programming. Perinatal events, e.g. prolonged ventilation, can cause injury and result in inflammation and potentially dysfunctional repair processes, leading to respiratory system disease later in life [One possible explanation for the increased risk of multimorbidity across the spectrum of premature gestational ages is that preterm born individuals are exposed to isation) . Example in life .Other possibilities include some characteristics of preterm born individuals influencing their risk of multimorbidity. Longitudinal studies of people born very prematurely have reported on a “preterm behavioural phenotype”, characterised by symptoms and disorders associated with inattention, anxiety and social difficulties, as well as low cognitive abilities , 55. ManAn important strength of our analyses is that we used a large set of nationwide register data, with up to 20 years’ follow-up. These whole-population data captured near-complete information on all births and specialised health care episodes in Finland during the study period, thus minimising the risks of sample selection or loss to follow-up introducing bias to our findings. Furthermore, a dataset of over 950,000 individuals and over 15,000 cases of chronic disease multimorbidity provided sufficient statistical power to precisely estimate the risks of multimorbidity across a wide spectrum of gestational ages, including among extremely prematurely born individuals, who are often under-represented in other types of observational studies.Limitations of our study derive from using routinely collected register data. The multimorbidity outcomes were ascertained from the nationwide Care Register for Healthcare, which overall has good coverage, with over 95% of individuals and care episodes identifiable by unique personal identity numbers . ValidatOur findings highlight the long-term health implications of preterm birth. Advances in perinatal care in the past decades mean that increasing proportions of even the smallest prematurely born babies now survive, and as a consequence, increasing numbers of people in paediatric, school, student and occupational health care settings have a preterm-born background. There are currently no clinical guidelines for follow-up of prematurely born individuals beyond childhood. Whilst our observations on their own cannot provide a basis for clinical practice recommendations, they suggest that information on gestational age at birth would be a useful characteristic to include in a medical history when assessing the risk of chronic diseases in adolescent and adult patients. Preterm birth could be one early life exposure that could be used to inform targeted screening or preventive strategies.Our findings indicate that earlier gestational age at birth is associated with an increased risk of chronic disease multimorbidity in adolescence and early adulthood. These findings suggest that information on gestational age would be a useful characteristic to include in a medical history when assessing the risk of chronic diseases in adolescent and adult patients.S1 File(PDF)Click here for additional data file.S1 Checklist(PDF)Click here for additional data file.


Bacteroides dorei and Prevotella species with versatile enzymatic potential likely allowing them to serve as primary degraders of cRG-I. These Bacteroidetes members are able to produce succinate, explaining the consistent increase of an OTU related to the succinate-converting Phascolarctobacterium faecium (+0.47 log10(cells/mL)). While the Bifidobacteriaceae family remained unaffected, a specific OTU related to Bifidobacterium longum increased significantly upon cRG-I treatment (+1.32 log10(cells/mL)). Additional monoculture experiments suggested that Bifidobacterium species are unable to ferment cRG-I structures as such and that B. longum probably feeds on arabinan and galactan side chains of cRG-I, released by aforementioned Bacteroidetes members. Overall, this study confirms the prebiotic potential of cRG-I and additionally highlights the marked consistency of the microbial changes observed across simulated subjects, suggesting the involvement of a specialized consortium in cRG-I fermentation by the human gut microbiome.The human gut microbiome is currently recognized to play a vital role in human biology and development, with diet as a major modulator. Therefore, novel indigestible polysaccharides that confer a health benefit upon their fermentation by the microbiome are under investigation. Based on the recently demonstrated prebiotic potential of a carrot-derived pectin extract enriched for rhamnogalacturonan I (cRG-I), the current study aimed to assess the impact of cRG-I upon repeated administration using the M-SHIME technology (3 weeks at 3g cRG-I/d). Consistent effects across four simulated adult donors included enhanced levels of acetate (+21.1 mM), propionate (+17.6 mM), and to a lesser extent butyrate (+4.1 mM), coinciding with a marked increase of OTUs related to  Bacteroides species display diverse and versatile glycan metabolising capabilities, allowing them to ferment extremely complex glycans [Bifidobacterium species growing on the polysaccharide degradation products and metabolites [Over the past decades, it became clear that the human gut microbiome constitutes an overlooked system that makes a significant contribution to human biology and development . Observa glycans ,12,13,14abolites . In contabolites . Due to Besides probiotics and polyphenols, prebiotic carbohydrates that are defined as substrates that are selectively utilized by beneficial host microorganisms  are wideThe lack of access to the in vivo site of activity combined with SCFA being rapidly absorbed  makes itThis study aimed to investigate the impact of repeated administration of cRG-I on the luminal and mucosal gut microbiota, while addressing potential interindividual differences among subjects. This complements the data of an earlier study where cRG-I treatment was evaluated over 2 days in batch fermentations . cRG-I hAll chemicals were obtained from Sigma  unless otherwise stated. cRG-I (same substrate as tested in ) was sup® technology  was used to conduct the current study. In terms of reactor design, the classical M-SHIME® setup was modified to allow parallel comparison of fermentation by four fecal samples, leading to a quad-M-SHIME setting, i.e., four parallel units, each comprising three sequential reactors  of one of the four donors under investigation , 2 , 3 , or 4 ), prepared according to Moens et al. [® was operated according to its standard parameters during the stabilization and control period (Day −14 to 0 and Day 0 to 14), cRG-I was added at 7.14 g/L in the nutritional medium between Days 14 to 35. Upon repeated administration (three times per day) and upon dilution with bile/pancreatic juice during each feeding cycle (140/200 ratio), this would thus result in a theoretical maximal concentration of 5 g/L in the PC and DC region.The experiment consisted of a stabilization (Day −14 to 0), control (Day 0 to 14), and cRG-I treatment period (Day 14 to 35) B. At days et al. . All donTo ensure proper operation of the SHIME model and avoid potential issues with stability over time, quality control was performed according to in-house procedures. Briefly, this involved a weekly verification of the accuracy of pumped volumes via a mock feeding cycle  together with a weekly check of the pH value inside the reactors via an external pH probe .The SHIME software  allowed for the online monitoring of base (0.5M NaOH) and acid (0.5 M HCl) consumption that was required to control the pH within the desired interval (5.7–5.9 for PC and 6.6–6.9 for DC). Therefore, a first indication on microbial activity was obtained via calculating the ‘base–acid consumption’ (mL/day). Short-chain fatty acid  and branched-chain fatty acids levels  were measured using the GC-FID method described by De Weirdt et al. . This meDNA was extracted from pelleted bacterial cells derived from a 1 mL sample as described by Boon et al.  with modBifidobacterium strains on cRG-I (w/v) instead of glucose (n = 2). Per plate, 2 × 50 µL of cell suspension was inoculated. Inocula were prepared by suspending cells from 48 h old cultures from the second or third generation on LMG medium 144 in saline (0.85% w/v). Results were read after 72 h of incubation at 37 °C under anaerobic conditions. Growth on cRG-I was scored after visual comparison to the positive and negative controls by one and the same researcher.An additional experiment was performed to assess the potential growth of 20 on cRG-I . For thiBifidobacteriaceae, Bacteroidaceae, Prevotellaceae, Acidaminococcaceae, Lachnospiraceae, Ruminococcaceae, Veillonellaceae, Desulfovibrionaceae, Synergistaceae, and Akkermansiaceae) via the online tool http://biit.cs.ut.ee/clustvis/ (accession date: 06/05/2021) [For exploratory data analysis, principal component analysis (PCA) was performed for both metabolic  and compositional data  . The ave05/2021) . All calTo gain insight into overall changes of microbial activity upon cRG-I treatment, the data were presented in two ways: (i) PCAs  and (ii)First, the PCAs based on the metabolic data explained a great part of the overall variation, i.e., 95.6% and 89.3% for the PC and DC, respectively. This observation stressed that both PCAs provide optimal insight in the factors underlying variation. A first factor included the interindividual differences among the four donors tested. Already at baseline, the samples of donors 1/2 and donors 3/4 located together, due to the higher butyrate production by the microbiota of donors 1/2, as opposed to higher propionate production by the microbiota of donors 3/4 .A second key factor driving differences in the dataset was cRG-I treatment. While in both PCAs, samples of the two control weeks (C1/C2) positioned together, cRG-I treatment induced a marked shift along the PC2 axis A and aloActinobacteria, e.g., increased in absolute numbers in the PC of Donor 1, the proportion of Actinobacteria in this environment decreased. Therefore, analysis of the luminal microbiota at lower taxonomic levels (family and OTU) was performed based on absolute data. In contrast, mucosal microbiota analysis was performed based on proportional data  and Lachnospiraceae (~25%), while samples of donors 3/4 clustered together given the high proportion of Veilonellaceae (~60%)  .Bifidobacteriaceae levels were not impacted, cRG-I strongly increased a specific OTU10 related to B. longum, seemingly at the expense of OTU8 related to B. bifidum. Further, there was a significant increase of Bacteroidetes upon cRG-I treatment, which was mainly driven by the marked increase of Bacteroidaceae and Prevotellaceae both in the PC and DC. At the OTU level, this could be explained by the significant increase of an OTU2 related to Prevotella sp. and an OTU6 related to Bacteroides dorei. In contrast, the levels of an OTU17 related to Bacteroides massiliensis decreased in the DC. Within the Firmicutes phylum, cRG-I significantly increased proximal levels of Acidaminococcaceae (~OTU11 related to Phascolarctobacterium faecium), Lachnospiraceae (~OTU9 related to Lachnoclostridium sp.), and Ruminococcaceae, while also increasing distal levels of Erysipelotrichaceae and Lachnospiraceae (~OTU5 related to Clostridium clostridioforme/bolteae). Finally, in the DC, cRG-I significantly increased Xanthomonadaceae, while decreasing Ruminococcaceae and Synergistaceae.A key factor driving differences in microbial composition was cRG-I treatment. Upon initiation of cRG-I treatment, a marked shift along PC2 was observed for the luminal samples, in both PC and DC, indicating a consistent treatment effect of cRG-I on the luminal microbiota in the PC and DC regions A. The trB. longum and OTU2 related to Prevotella sp. both in the PC and DC. This was at the expense of OTU8 (related to B. bifidum) in both simulated colon regions and at the expense of OTU5 (related to Clostridium clostridioforme/bolteae) in the PC. In contrast to the lumen, treatment effects on the mucosal microbiota were less pronounced B. NevertBifidobacterium sp. to cRG-I fermentation, a growth experiment on solid medium was performed with single strains  amongst other members of a mixed microbiota [Bacteroides and Prevotella are indeed known as primary pectin degraders, possessing carbohydrate-active enzymes (CAZymes) within their polysaccharide utilization loci (PUL) [Bacteroides thetaiotaomicron has been demonstrated to ferment RG-I via several PULs, releasing polysaccharide breakdown products in the culture medium, making them available for other microbes [Bacteroides species might be capable of fermenting cRG-I, B. dorei seems the most capable species in the presence of a competitive background microbiota. This is supported by the genetic potential of B. dorei containing over 50 predicted enzymes related to pectin degradation [Bacteroides sp. are major producers of acetate and propionate [Bacteroides sp. Besides the well-described health benefits of both SCFA as reviewed by Rivière et al. [B. dorei as such could contribute to other health benefits. Inhibition of atherosclerotic lesion formation, lower endotoxemia, and suppression of proinflammatory responses have been observed in atherosclerosis-prone mice upon co-administration of live B. vulgatus and B. dorei to mice [First, cRG-I consistently and strongly stimulated OTUs related to compound . Interescrobiota . The genci (PUL) ,56. Specmicrobes . While sradation . At metaopionate , the mare et al. , the pre to mice .Bifidobacterium longum of which a related OTU strongly increased upon cRG-I treatment (+1.32 log10(cells/mL)). Even though the overall Bifidobacteriaceae family did not increase in this experiment, there was a clear stimulation of B. longum as previously observed in batch fermentations with cRG-I [Bifidobacterium species are unable to grow on cRG-I as a sole carbon source but are part of the bacterial consortium needed to ferment the complex cRG-I structure. This is in line with Chung et al., who did not identify any predicted enzymes concerned with pectin degradation in Bifidobacteriaceae sp. [Bifidobacteriaceae, rendering them dependent on the initial degradation of these large polymers by Bacteroides sp. [Bifidobacteriaceae that indeed are capable of fermenting arabinans and galactans [Bifidobacteriaceae species in this or preceding studies [Upon cRG-I fermentation by primary degraders, polysaccharide breakdown products likely become available for other microbial species. Microbial members benefiting from such polysaccharide breakdown products included th cRG-I . Additioceae sp. . Moreoveides sp. . The relalactans ,61, bothalactans . While l studies , along w studies , supportPhascolarctobacterium faecium as an OTU related to this species increased consistently over the four donors tested (+0.47 log10(cells/mL)). The stimulation of this species likely followed from the succinate production of aforementioned Prevotella sp. [Bacteroides sp. [Phascolarctobacterium faecium, an abundant colonizer [Phascolarctobacterium faecium has for instance also been linked to a positive mood [Another microbial member that is likely part of the cRG-I fermenting consortium is ella sp.  or Bacteides sp. , thus boolonizer  that is olonizer . Besidesive mood , furtherErysipelotrichaceae (DC), Lachnospiraceae (PC and DC), and Ruminococcaceae (PC). These changes correlated with the modest increases in butyrate levels that were observed upon cRG-I treatment, butyrate being indeed produced by members belonging to these families [Other microbial families that consistently increased across the four donors tested included families . OverallBacteroides dorei, Prevotella sp., and Bifidobacterium longum-related OTUs. Both studies also indicated the involvement of succinate scavengers, i.e., Phasolarctobacterium faecium (quad-M-SHIME) and Dialister succinatiphilus (batch incubation). A difference between both models was that the batch incubation strategy allowed the observation of effects of cRG-I treatment on a broader range of microbes. It was shown that cRG-I also stimulated other Bacteroides sp. beyond B. dorei, i.e., B. ovatus, B. plebeius, and B. xylanisolvens, while also boosting two F. prausnitzii OTUs and an OTU related to R. hominis that profoundly increased in mucus from 9.8% in the blank up to 64.3% upon cRG-I treatment (27). That the batch incubation strategy allowed to observe effects on a broader range of microbes is likely explained by the fact that in batch fermentations, in vivo-derived fecal microbiota in its maximal diversity is used as direct inoculum, an approach of which the biorelevance is supported by the minor spatial differences along the colon according to recent in vivo studies [Clostridium cluster IV and XIVa members (including F. prausnitzii and R. hominis) [F. prausnitzii and R. hominis observed in batch fermentations were not recapitulated in the quad-M-SHIME. While Clostridium cluster IV and XIVa members can be more optimally maintained in in vitro gut models by including a simulation of the mucosal environment, as was shown during 3-day experiments [R. hominis were detected in any of the donors at the start of the treatment (after 4 weeks of pre-growth), impairing the observation of treatment effects on such mucosal microbes. The washout of true mucosal microbes upon long pre-growth periods could potentially also explain why treatment effects on lumen and mucus were relatively similar during the current study. Despite such differences between both in vitro models, many findings were consistent and provided confidence in the robustness of (i) the observed impact of cRG-I on the human gut microbiota and (ii) the use of both types of in vitro gut models in gut microbiome research. While the added value of in vitro gastro-intestinal models is currently well-recognized [As mentioned above, the first cRG-I fecal fermentation experiment was conducted in a 2-day batch incubation model . Interes studies . In conthominis) . This lieriments , frequeneriments , likely cognized , it is aFinally, a critical remark on the limitation of the applied experimental design is that the reference to which treatment effects were compared consisted of a preceding control period. Such longitudinal control is common in a SHIME setup ,70,71, aBacteroides dorei, Prevotella sp., and Bifidobacterium longum. Due to its structural complexity, cRG-I corresponds to a unique polysaccharide demonstrating prebiotic properties supported by a concomitant effect on the host microbiota and immune system (26). As a next step, it will be necessary to link the changes in microbiota composition and metabolite production to a discrete health benefit in well-designed human trials and altogether verify the predictivity of the data generated in vitro in the described study.Overall, this study confirms the potential of cRG-I to beneficially modulate the human gut microbiome with a marked consistency in SCFA production and microbial modulation across simulated human subjects displaying individual variability at baseline. High amounts of acetate and propionate were produced due to the involvement of a specialized consortium consisting of, amongst others, strains belonging to


Twin birth weight percentiles are less popular in clinical management among twin pregnancies compared with singleton ones in China. This study aimed to compare the incidence and neonatal outcomes of small for gestational age (SGA) twins between the use of singleton and twin birth weight percentiles.This was a retrospective cohort study of 3,027 pregnancies with liveborn twin pairs at gestational age of > 28 weeks. The newborns were categorized as SGA when a birthweight was less than the 10th percentile based on the singleton and twin references derived from Chinese population. Logistic regression models with generalized estimated equation (GEE) were utilized to evaluate the association between SGA twins and neonatal outcomes including neonatal unit admission, neonatal jaundice, neonatal respiratory distress (NRDS), neonatal asphyxia, ventilator support, hypoxic ischemic encephalopathy (HIE), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), intracranial hemorrhage (ICH), culture-proven sepsis, neonatal death within 28 days after birth as well as the composite outcome.The incidence of SGA was 33.1 % based on the singleton reference and 7.3 % based on the twin reference. Both of SGA newborns defined by the singleton and twin references were associated with increases in neonatal unit admission, neonatal jaundice and ventilator support. In addition, SGA newborns defined by the twin reference were associated with increased rates of BPD  as well as the severe composite outcome .The use of singleton birth weight percentiles may result in misdiagnosed SGA newborns in twin gestations and the twin birth weight percentiles would be more useful to identify those who are at risk of adverse outcomes.The online version contains supplementary material available at 10.1186/s12884-021-03907-1. Birth weight and fetal weight are common indicators of fetal growth. However, the terminology for newborns with abnormal growth is inconsistent. In the updated American College of Obstetricians and Gynecologist (ACOG) Practice Bulletin, fetal growth restriction (FGR) is defined based on a sonographic estimated fetal weight (EFW) less than 10th percentile for gestational age while small for gestational age (SGA) is defined based on a birth weight less than 10th percentile for gestational age –4. FurthOver the last decades, the incidence of twin pregnancies has been rising mainly due to the significantly increased use of assisted reproductive technology (ART) and the delayed childbearing age –11. CompIn this study, we compared the prevalence of SGA twins defined by the singleton-based and the twin-based birth weight percentiles and their associations with neonatal morbidity and mortality.The retrospective cohort study included twin deliveries at a tertiary hospital in Foshan, China, from January 2012 to December 2020. This study was approved by the ethics committee of Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan  and the ethics committee endorsed this research to waive the informed consent of the patients due to the retrospective design.The inclusion criteria for current study were pregnancies with both living born fetuses at gestational age beyond 28 weeks. Pregnancies with congenital anomalies, twin-to-twin transfusion (TTTS), monoamniotic twins, unknown chorionicity, intrauterine death and gestational age at delivery < 28 weeks were excluded for analysis.All electric medical records of eligible pregnancies were systematically reviewed to obtain maternal and neonatal Information. Data on maternal age, parity, use of assisted reproductive technology, chorionicity, fetal gender, gestational complications , maternal infections (syphilis and hepatitis B) and pre-existing hypertension and diabetes mellitus was collected. In the present study, the chorionicity was determined by sonographic examination and was confirmed by placental pathologic findings after birth, if available. The gestational age was calculated from the date of embryo transfer for IVF/ICSI pregnancies (+ 14 days) and based on the last menstrual period for spontaneous pregnancies and was confirmed by sonography in the first trimester. HDPs included gestational hypertension and preeclampsia (PE), which were diagnosed based on the criteria developed by ACOG . A diagnThe primary outcome was neonatal unit admission. The secondary outcomes included neonatal jaundice, neonatal respiratory distress (NRDS), neonatal asphyxia, ventilator support, hypoxic ischemic encephalopathy (HIE), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), intracranial hemorrhage (ICH), culture-proven sepsis and neonatal death within 28 days after birth. We also defined a composite outcome as any occurrence of HIE, NEC, ICH, BPD, sepsis as well as neonatal death.P-values < 0.05 were considered statistical significance. The statistical analyses were performed using Stata, version 15.1.The baseline characteristics of the included pregnancies were reported as mean ± standard deviation (SD) or frequency with its percentage, where appropriate. When analyzing the neonatal outcomes, the unit of analysis was the newborn. In this regard, logistic regression analyses were performed using a generalized estimating equation (GEE) approach to address the intertwin correlation. The adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated by performing multivariable models controlled for gestational age at delivery, nulliparity, maternal age, chorionicity, use of ART, GDM and pre-eclampsia. We also performed sensitivity analysis after excluding women with complications during pregnancy , pre-existing hypertension or diabetes mellitus and maternal infection (syphilis and hepatitis B). All two tailed The baseline characteristics of the included pregnancies were shown in Table In the multivariable analyses, as shown in Table Based on the twin standards, similarly, SGA newborns were associated with neonatal unit admission , neonatal jaundice  and ventilator support . In addition, they were associated with increased odds ratios of BPD  as well as the severe composite outcome  , pre-existing hypertension or diabetes mellitus or maternal infections, SGA newborns, irrespective of birth weight percentiles, were associated with increased incidences of neonatal unit admission, neonatal jaundice and ventilator support. However, the SGA newborns did not have significantly increased incidences of severe morbidities and mortality. The results were supplemented in Table Our analysis of retrospective data found that the use of singleton birth weight percentiles resulted in a higher prevalence of SGA twins compared with the use of twin birth weight percentiles. Both of SGA twins defined by singleton and twin birth weight standards were associated with common morbidities such as neonatal unit admission, neonatal jaundice and ventilator support. In addition, SGA twins defined by twin standards were associated with BPD and the severe composite outcome whereas those defined by singleton standards were not.The decision-making of clinical management on twin gestations depends on the chorionicity and the fetal growth –29. SomeDespite several birth weight standards for twin gestations has been published in recent years in China , 33, 38,While the strengths in current study were large size of study population, several limitations should be acknowledged in the interpretation of the current results. First, some potential for bias could not be avoided due to the retrospective nature. Data regarding some potential confounders or neonatal outcomes  was unavailable or incomplete. Second, the chosen birth weight standards derived from Chinese population and therefore the conclusion might not be applicable to populations in other countries . Third, The use of singleton birth weight percentiles among twins contributes to higher prevalence of SGA newborns. The twin standards are more applicable for the prediction of adverse neonatal outcomes among twins. The use of the twin birth weight references in twin gestations should be proposed and promoted in clinical practice.Additional file 1.