Fear of birth (FOB) is becoming increasingly recognized as a mental health issue that may endanger maternal and infant health and affects women’s subsequent fertility desires. It has also been shown to be related to the choice of delivery mode. Given the differences in healthcare systems and policies between countries, and the gaps in the exploration of women’s experience of fear of birth and its association with the delivery mode in the Chinese cultural context, this study thus attempt to understand Chinese women’s experience with fear of birth and their preferences for delivery mode through a qualitative study.A descriptive qualitative research was performed among twenty pregnant women from the obstetric outpatient of a tertiary hospital in China. Colaizzi’s method was used to analyze the participants’ data.We proposed three themes and nine subthemes on the participants’ experience with fear of birth: (1) an invisible dilemma: trapped in lingering fear ; (2) an unexpected decision: choose to give birth naturally (initiative selection and passive acceptance); and (3) A strength to confront challenges head-on: move forward with fear .Fear of birth is a complex emotion, accompanied by feelings of loneliness and ambivalence in addition to fear. We found that women with fear of birth in this study prefer vaginal birth, and it was revealed to be the result of a combined action of intrinsic and extrinsic factors. Fear of birth (FOB) is becoming increasingly recognized as a mental health issue, which is manifested as nightmares, physical complaints, and difficulties in concentrating on work or on family activities . FOB is Given the harm caused by fear of birth, it is currently being explored in depth worldwide. Numerous qualitative studies have stated that fear of birth is multi-dimensional . In addiFear of birth has been shown to be associated with the choice of delivery mode. Many studies in Western countries identified fear of birth as a highlighted reason for unnecessary cesarean sections without medical indication . On the Given the dangers of childbirth fear to maternal and infant health, the differences in healthcare systems and policies between countries, and the gaps in the exploration of women’s experience of fear of birth and its association with the delivery mode in the Chinese cultural context, in this study, we thus attempt to understand pregnant women’s experience with fear of birth in the Chinese cultural context and their preferences for delivery mode through a qualitative study. This may contribute to identifying factors that can be intervened and developing antenatal interventions to reduce cesarean section rates. The research questions were:•What are the pregnant women’s experiences with fear of birth in Chinese cultural context?•What are the perceptions and preferences for delivery mode of Chinese pregnant women with fear of birth?A descriptive qualitative design with in-depth interviews was utilized, as it was deemed appropriate for exploring the real and comprehensive feelings, attitudes, perceptions, and behaviors in the context of where the action occurred .In this study, pregnant women who underwent routine outpatient obstetric check-ups at a tertiary hospital in Wuhan, Hubei province between March 2019 and October 2020 were selected as the study population using a purposive sampling method. Subjects of different ages, occupations, education levels, parity, and gestational weeks were selected to obtain a more representative and diverse sample. The sample size was determined based on the criterion that the data of the respondents were repeated and no new themes were presented at the time of data analysis (data saturation). Those under 18 or with serious pregnancy complications  were excluded. A total of 20 pregnant women were eventually enrolled in the study, 14 of whom were interviewed before the COVID-19 period and six were interviewed after the pandemic had been controlled.When pregnant women came to the target hospital for routine outpatient obstetric check-ups, the researchers communicated with them while they were waiting for the examinations to know their general condition. For pregnant women who met the inclusion criteria, the researchers would inform them of the purpose, method, content, time of the interview, and recording requirements of the study, and those who agreed would be invited by the researchers to participate in the study. After the participants have completed their obstetric check-ups, the researcher would bring them to the obstetric classroom task room of the maternity clinic, which was chosen to eliminate unfamiliarity. Consenting participants were required to sign an informed consent form detailing the purpose of the study, participants’ rights, and guarantees of confidentiality and anonymity. During the interview, the environment was kept quiet and comfortable, and no extraneous people were allowed in or out to ensure the privacy of the interview.The interviews were conducted by an experienced researcher who had received training in interviewing. An innovative method involving drawing was used during the interviews. It was considered a rich and insightful research method for exploring how people make sense of their world and was widely used on vulnerable and sensitive topics . All parThe process of the participant’s description of the drawing was combined with the interview process. That is, during the participants’ narration of the drawings, the researcher did not express subjective opinions, but asked questions at appropriate times in order to follow up and probe deeper into some issues in the scenario and facilitate the participants to express their true inner feelings. The researcher’s question was conducted in two ways: (1) the researcher asked questions based on some phenomena or issues mentioned in the participants’ narratives about the drawing; (2) the researcher asked questions at the right time based on open-ended questions prepared in advance see . The entIn this study, the data analysis method of Colaizzi  was usedTwo researchers simultaneously transcribed and organized the original data, independently coded, categorized, and refined the themes, and if they could not agree, the group discussed and reached a consensus to ensure the objectivity of the data analysis. Finally, the distilled themes were returned to the interviewees for validation.This study was approved by the Ethics Committee of local University. The principle of informed consent was followed and a detailed and clear explanation of the purpose and process of the study was given before the interview.A total of 20 participants, numbered P1 to P20, were included in this study. 14 participants were primiparous and 6 were multiparas, aged between 26 and 42 years (median = 30 years) and between 24 and 40 weeks of gestation (median = 29 weeks). Of these, 16 planned natural childbirth and 4 chose to have a cesarean section. The characteristics of the participants are shown in Careful analysis of the interview transcripts and reference to the interview outline led to the use of class analysis to summarize the following 3 themes: “An invisible dilemma: trapped in lingering fear,” “An unexpected decision: choose to give birth naturally” and A strength to confront challenges head-on: move forward with fear.”Pregnant women were full of worries and fears, but others couldn’t understand. This made them feel deeply lonely and often struggle with contradictions alone.The most common fear of birth described by participants was a concern for the health of the fetus, which they valued more than themselves.“My early pregnancy reaction was very heavy, so I often worried about something terrible would happen, like abortion, fetal arrest, or fetal malformation” (P5)Many women also mentioned concerns about the birth process. Notably, primiparas in this study mostly worried about their inability or loss of control during their childbirth. Multiparas were more afraid about childbirth pain. Additionally, some participants expressed their fears about obstetric interventions, or worried about the unfamiliar labor environment.“This was my first time having a baby, and although I had watched a lot of videos and read books related to childbirth, I was still scared about going into labor because I had no idea what was going to happen to me” (P11).“I have to go into the delivery room alone. I have no idea how I am going to get through that difficult time alone. It’s scary to think about” (P13).Changes after giving birth were also under some participants’ concern, such as losing their partner’s attention, or being criticized and blamed for being unable to care for the child. In addition, two pregnant women expressed their fears about losing jobs and family economic status.“I’m also worried that after childbirth I’m going to switch to my mother’s role and feel like I’m not mature enough to be a qualified mother” (P3).“I have resigned. I have no choice but to look for it again in the future. I lost a lot of things because of pregnancy” (P15).Participants also reported a sense of loneliness. It is due to lack of understanding, support, and effective communication with others, and also because pregnant women engage in self-isolation. Some participants reported that their fears of childbirth are not sufficiently understood and valued.“Sometimes I feel scared thinking about upcoming childbirth. Although my husband would reassure me that it was okay, I didn’t think he really understood how I felt about it” (P6).At the same time, some women engage in self-isolation and avoid discussing their fears about childbirth with others. Some participants did so because they felt that no one could help them and therefore preferred to remain silent. Two pregnant women felt it was inappropriate to fear childbirth as it should be a pleasant process traditionally.“What’s the point of talking about it [fear of birth]? You still have to give birth and no one else can help you” (P18).“It’s difficult to talk to my family about the fear of giving birth. Everyone is so pleased that I’m pregnant and I don’t want to break the good mood” (P7).Lack of understanding from others and self-isolation create a vicious cycle. Some pregnant women reported that when they tried to communicate, negative reactions from others, such as lack of understanding, neglect, and perfunctory treatment, also acted as barriers to their communication.“I think there’s no need to say anything. They can’t understand it. My fears were nothing to them. If you say too much, others think you’re very hypocritical” (P14).Participants were in a state of ambivalence toward childbirth. Some participants described their fear of childbirth grew stronger as the birth date approaches, accompanied by anxiety, insomnia and other physical and mental symptoms. They wish the delivery day would come slower, and they try to find ways to escape the fear of childbirth.“Now that I am getting closer to the expected delivery date. I sometimes cried when I thought about it. As much as I want to see my baby, I really wish time would pass more slowly” (P11).At the same time, they also wished the time would pass faster due to the expectation of the baby’s arrival and being free from the bondage of pregnancy. Some women described there was a powerful inner drive that helped them to actively face and overcome their fears.“I know it’s painful to give birth, but I just think it’s right. The baby will make everything I’ve experienced worth it” (P13).Surrounded by fear, they made the unexpected choice to have a natural childbirth. Of the 20 participants, only four planned to have a cesarean section for physical reasons. The rest of the mothers all chose to have normal childbirth. This may be women’s initiative choice due to a strong belief in natural childbirth, or the result of passive acceptance.Participants believed that natural childbirth was the best way of birth, which was an important prerequisite for their preference for natural childbirth. Some women were passionate advocates of vaginal birth as they believed that childbirth should be a normal and natural process.“I want to give birth naturally as much as possible, because it’s good for me and my baby” (P1).Some women firmly chose to have natural childbirth due to a strong sense of responsibility to become good mothers. They thought it was conducive to the infants’ health.“I wanted to do even things that were only a little good for my baby. So, I tended to be more inclined to have a natural birth. This might be my psychological growth in the process of nine months of pregnancy” (P8).Encouragement and support from medical staff and family members will boost a woman’s belief and confidence in natural childbirth. And the medical staff provided enough information about the pros and cons of natural childbirth and cesarean section, and natural childbirth process which motivated pregnant women to eventually choose natural childbirth. In addition, their friends’ positive natural childbirth experience also helped women to establish a positive attitude and strengthen their belief toward natural childbirth.“I was not firm about spontaneous labor at first. My husband has always been by my side, encouraged me, believed me, so can I insist on it” (P17).“I heard from my friend that vaginal delivery only causes pain during childbirth and is very relaxed postpartum, unlike cesarean section” (P8).It is worth noting that among the four pregnant women who planned to have a cesarean section for physical reasons, two of them showed their expectation of natural childbirth, despite knowing that their condition required a cesarean section.“I actually want to ask if it’s possible to have a normal childbirth in my case [twin pregnancy] or not. I’ve read a lot of information before that it’s better to have a cesarean section, and the doctor also advised me to have a cesarean section, but I still want to have another consultation” (P4).Some women described that they chose natural childbirth were influenced by significant others, including medical staff and family members, even though they themselves did not have a particularly strong desire for it. Many women stated that their doctor’s advice had a strong influence on their choice of birth method. If their doctor suggested them to have a normal birth, they were inclined to accept his or her advice out of authority and trust in him or her.“The doctor said my condition was very suitable for vaginal birth and also gave me advice that vaginal birth was not traumatic to my body, so I accepted the doctor’s advice to have a trial vaginal childbirth” (P12).Many women also described that family members played an important role in choosing delivery mode. Family members’ expectations of natural childbirth affected women’s final choice of delivery mode.“My husband and mother-in-law wanted me to have a normal birth, even though I was scared. Maybe it’s the right choice” (P14).Besides, some planning to have another child also should have natural childbirth plan as the context of China’s two-child policy. Because the cesarean section meant that there would be a long waiting time for another childbirth and a high probability of cesarean section again.“If I can give birth naturally this time, I can have a child within one year. But if I have a cesarean section this time, I should wait at least three years to have a second child and might still have to have a cesarean section” (P20).Once the decision has been made to have a natural birth, awaken of maternal spirit, hope in bloom, obstetric analgesia, and tolerance helped them to relief and overcome their fears of childbirth.Many pregnant women described themselves realizing awaken of maternal spirit during pregnancy, which strengthened their belief in natural childbirth and gave them the courage to overcome their fears. The maternal spirit was mainly reflected in the strengthening of their role as mothers. With a deeper and closer tie established between them and their babies, they had a strong sense of responsibility to become good mothers. This made them change their mind from the initial desire for a cesarean section to a preference for a natural birth, as it was considered to be better for the baby’s health. Some women believed that their courage of motherhood would overcome fear of birth.“At first, I wanted to choose the cesarean section because of my fear of labor pain. But my doctor and friends all advised me to give birth naturally. I know natural childbirth is good for both myself and my children, and now painless childbirth, so I changed my mind” (P11).The participants described that they felt a sense of hope during their pregnancies. They shifted their fear of birth into the expectation of a better future after childbirth, which supported them in facing and overcoming the challenges of childbirth and fear. Besides, some of them regarded the baby as their hope and felt that the future deserved to look forward to.“After childbirth, I will live a very happy and joyful life, so this [Fear] could be overcome” (P8).“Although I still fear about the labor pain, I really look forward to having a baby. I believe that the courage to be a mother can overcome the feeling of fear. Therefore, if conditions permit, I will definitely choose natural childbirth, because it is good for the baby and mother” (P2).There are also some participants who choose to have a normal birth since they feel they should be tolerant of the labor pain for their baby’s health. Some women regarded enduring the p1ain of childbirth as one of the basic experiences that make a woman a good mother.“Natural childbirth seems to be regarded as a particularly brave and great thing in today’s society. People around me think I’m very powerful when they know I want to have a natural childbirth. For the sake of the baby, although I don’t know how much my own pain tolerance is, what I think is that even if it hurts again, I should bear it and insist on a natural birth” (P8).Many of the women in this study highlighted the importance of obstetric analgesia for their choice of natural childbirth, as this technique both eased their fears of labor pain and ensured a natural birth. They showed a strong willingness to use obstetric analgesia. One woman even described it as “light to humanity.”“I must give birth with labor analgesia. I would not have a cesarean section, or give birth without labor analgesia. Otherwise, I can’t complete the labor” (P19).“I was afraid of pain. After I knew that painless labor could be used, my mood was relieved” (P18).The fear of birth was shifted into concern about the uncertainty of using obstetric analgesia. One woman even decided to give birth in another city to make sure of using obstetric analgesia.“I have seen lots of cases on the Internet where women cannot use obstetric analgesia in hospitals due to a lack of doctors. I am really worried that this will happen to me, so even if this hospital is far from me, I will come here to give birth” (P20).Notably, no women in this study show any concerns about the side effects of obstetric analgesia.This study aimed to investigate Chinese women’s experience of childbirth fear and their preference for the delivery mode. The results showed that fear of birth was a synthesis of multiple complex emotions. In addition to the fear, women with the fear of birth also experienced a sense of loneliness and ambivalence. Also, we found that participants in this study preferred vaginal birth, actively choose or passively accept it. After women decided to have a normal birth, they overcame and eased their fears of childbirth through internal factors including awaken of maternal spirit, hope in bloom and Chinese tolerance culture, and external factors of obstetric analgesia.Participants with a fear of birth experienced complex feelings formed by three moods: fear, loneliness, and ambivalence. Previous research has mainly focused on fear , while tSurprisingly, we found that 16 out of 20 participants with the fear of birth in this study had vaginal birth plans. This is inconsistent with previous studies in which women with childbirth fear led to an increased rate of selective cesarean section. In this study, women’s choice to have a normal birth may be an active or passive choice. For women who actively chose vaginal childbirth in this study, their attitudes that natural birth was a better way to give birth are a fundamental premise for the choice of birth mode. This is in line with an Iran study, in which participants believe the superiority of vaginal delivery, due to its positive outcomes for both mother and infant . At the The impact of important others is not only in their support for pregnant women. Women who lack belief in natural childbirth may be forced to choose a normal birth because of their doctors’ advice or the family’s expectations. Previous studies have shown that women are vulnerable to family, peers, and other close people. Our results are consistent with these studies. In China, medical personnel often dominate and are regarded as an authority, so their suggestions have a great impact on women’s choice of delivery mode. In addition, influenced by Chinese traditional culture that stressed the concept of “more children, more blessings”, many families believed that two children would be more conducive to family harmony and children’s growth. Women are thus more inclined to have a second child in the context of the two-child policy, and thus choose natural childbirth to shorter the interval between two children and ensure the safety of the child . TherefoOnce women have decided to have a normal birth, they need to overcome their fear of birth. It has been shown that overcoming fear is a result of the combined action of intrinsic and extrinsic factors. Intrinsic motivation consists in the awakening of the maternal spirit, a sense of hope and tolerance. It is worth noting that there is a paucity of research on this topic. Many women described themselves as realizing that the awakening of the maternal spirit, the process of adapting to motherhood, and the closer mother-infant relationship supported them in overcoming their fear of birth. Our findings are supported by many other studies. Research evidence suggested that the transition to motherhood from early pregnancy to birth was an important factor in a mother’s ability to cope, overcome problems during the process, and adapt to the new environment . Also, aAmong the internal factors, the role of hope in choosing a delivery mode was also reported, which was unprecedented in previous studies. According to Hope Theory, Hope helps people articulate their goals and their ability to develop and implement specific strategies to achieve them . VariousIn this study, “Tolerance” of Chinese traditional culture was also used to cope with the fear of birth. It is an important and commonly prevalent psychosocial phenomenon that potentially influences Chinese people’s behavior. The thought of tolerance is a strategic self-repression and self-adjustment cognitive process closely related to the individual’s attitude towards the object to be tolerated. When women identify with and decide to have a natural birth, this personality trait helps them to proactively shift their attention and cognitive changes to overcome or suppress their inner fears and achieve their desired goal. However, it is important to note that endurance could bring an unpleasant emotional experience. Health professionals should help women to confront their emotions rationally, without prejudice, and consciously, rather than by ‘suppressing’ them.Research has shown that obstetric analgesia is a very important external factor in helping women overcome their fear of birth. In this study, obstetric analgesia, as a breakthrough between natural birth and fear of birth, played a very important role in the choice of delivery mode. Studies have shown that obstetric analgesia increases the incidence of spontaneous birth . HoweverSeveral limitations to our study should be considered. Firstly, this study was conducted only in a tertiary hospital located in central China, and the Chinese cultural context played an important role in participants’ experience and feelings, the transferability of the findings thus needs further validation. Secondly, we only interviewed each participant once and failed to capture their experiences over time. Therefore, more longitudinal studies are needed to fully understand women’s experiences of fear of birth in different regions and across different trimesters. Thirdly, for the six individuals interviewed after the pandemic, we did not fully consider the potential impact of the post-pandemic psychological consequences on their fear of childbirth.In conclusion, fear of birth is a complex emotion, accompanied by feelings of loneliness and ambivalence in addition to fear. We found that women with fear of birth in this study prefer vaginal birth, and it was revealed to be the result of a combined action of intrinsic and extrinsic factors. Healthcare providers should provide adequate professional support during antenatal care, and fully mobilize the social support system for pregnant women. So as to, on the one hand, eliminate their sense of loneliness, helplessness, and fear, and at the same time can stimulate intrinsic motivation, awaken the maternal strength, and increase their sense of hope, so that to face their fear of birth with courage. In addition, a more cautious attitude should be taken towards obstetric analgesia, improving the deficiencies of obstetric analgesia in China and strengthening health education interventions to avoid the adverse effects of blindly choosing obstetric analgesia.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, and Huazhong University of Science and technology. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.TZ: conceptualization, data curation, writing—review and editing, and supervision. MY: conceptualization, investigation, data curation, roles/writing—original draft, and formal analysis. MW: investigation, data curation, and writing — review and editing. YC: data curation and writing — review and editing. KZ: investigation and data curation. All authors contributed to the article and approved the submitted version.


Phenology refers to the seasonal timing patterns commonly exhibited by life on Earth, from blooming flowers to breeding birds to human agriculture. Climate change is altering abiotic seasonality  and in turn, phenological patterns contained within. However, how phenology should evolve is still an unsolved problem. This problem lies at the crux of predicting future phenological changes that will likely have substantial ecosystem consequences, and more fundamentally, of understanding an undeniably global phenomenon. Most studies have associated proximate environmental variables with phenological responses in case-specific ways, making it difficult to contextualize observations within a general evolutionary framework. We outline the complex but universal ways in which seasonal timing maps onto evolutionary fitness. We borrow lessons from life history theory and evolutionary demography that have benefited from a first principles-based theoretical scaffold. Lastly, we identify key questions for theorists and empiricists to help advance our general understanding of phenology. Phenology—the seasonal timing of biological events on scales ranging from individual life cycles to global cycles—is a universal feature across plants and animals, from ecosystems  to human systems  –3. PhenoPhenology—regardless of scale or system—describes cyclical patterns in the dimension of time . HistoriClimate change influences cyclical timing patterns in 2 main ways. The first is via overall warming , e.g., iPhenological shift: directional change in the timing or phase duration of life cycle schedules within the context of geophysically fixed annual oscillations in the environmentPhenophase: the duration of a categorically distinct phase of a life cycle, such as adolescence or reproductive periodProximate phenological causality: system-specific triggers that induce the expression of phenological traitsUltimate phenological causality: broad evolutionary forces that influence the seasonal timing of universal life history traits such as birth, growth, reproduction, and death, considering that the timing of each trait contributes to fitness and all are constrained by trade-offs with one another Life history evolution: the evolution of the holistic suite of life cycle traits in the context of the ecology of populations as well as predictable fluctuations in the environmentEvolutionary demography: selection dynamics that produce, as well as directly result from dynamics in the size and structure  of populationsEco-evolutionary dynamics: the concurrent and reciprocal dynamics of ecological and evolutionary processes where one shapes the context of the other, usually described as a feedbackPerhaps the most unresolved conundrum is that the same change in climatic growing seasons often induces very different phenological shifts between organisms occupying the same habitat in both direction (when) and magnitude (by how much). Discrepancies in shifts are observed among individuals , betweenIn summary: The rapidly growing body of top-down (observations first) studies of phenological change is brimming with contrasting effects and specific explanations, which makes it difficult to generalize the eco-evolutionary links between seasonality change and phenological change across systems ,46,47. WIn our first section, we argue that a first principles view of phenological evolution starts with the recognition of a simple truth in any system: the fitness consequences of some key phenological traits vary over time within a year. In other words, if any phenological manifestation confers an equivalent consequence for fitness, there would be no discernible phenological pattern around the planet. Drawing analogies from spatially oriented theory, we highlight that discretizing the dimension of time in bounded units enables quantitative conceptualization of how phenological variation maps to variation in fitness. Then, we outline how this variation in fitness produces selection pressures on phenological variation, first at the scale of individuals and populations, and then at the scale of multispecies communities. Our overarching goal is to introduce theorists to the unsolved puzzle of general selective forces acting on phenology around the world and invite empiricists to test those emerging hypotheses to advance cross-system understanding.Patterns, in any dimension, can only be quantified and systematically compared in the context of defined bounds and scales. Drawing analogies from the more familiar spatial dimension helps crystallize this point . EcologiFocusing on the temporal bounds that encompass annual patterns might be an important step for first principles theory development because bounds are one of few parameters that are universal. In other words, any system that exhibits cyclical phenological patterns has a beginning and an end to the seasons that constrain the sequence. The relationship between the size of the bounded domains in natural systems—whether in space (area) or time (duration)—and the biological patterns they contain is often complex, and thus inevitably requires mathematical modeling. For example, in space, the size of islands or habitat patches nonlinearly determines biodiversity, distribution, and coexistence patterns contained within that space ,10,49–52Arabidopsis show that phenological traits like flowering time are expressed in the laboratory even in the absence of climatic cues characteristic of the natural populations’ localities and can even be mapped to specific genes under selection [In theorizing the causality behind any change in temporal patterns, it is also important to keep in mind that cyclical phenological patterns are distinct from emergent “phenomenological cycles” that arise from internal systems dynamics  or Markovian transition processes . In contrast, phenological patterns are evolutionarily adaptable strategies that are repeatedly expressed within periods of geophysical environmental cycles  in time, from past to future. The anisotropic nature of temporal patterns makes causal influences stronger in time than in space since effects from multiple directions can be counteracted or obfuscated in space . In otheA collection of species that exhibits a repeatable phenological pattern year to year in the same space may consist of strikingly different generation times or activity schedules; hence, those species’ population dynamics actually operate on very different scales of time . AnnualTowards that goal, we ask a general guiding question: How do organisms that live in environments with periodic time windows evolve to utilize nonrandom portions of the windows? We break the question down to 2 key hierarchies: single-species phenological evolution and community interactions that influence multiple coexisting phenologies.Phenological timing is typically studied as a variable responding to seasonal transitions in the abiotic environment . Responses to seasonal environmental variables, often involving plastic expressions of traits ,72, consA sense of what constitutes “correct” timing, or the baseline null expectation of how phenological timing should change given some change in the environment, is currently not theoretically generalized. Expectations are often set by intuitions that can arise from system-specific knowledge, e.g., food availability for birds . HoweverLife history theory and evolutionary demography  have conSimilar to the phenotype-to-fitness mapping considered by life history and demography theorists, timing of occurrence or trait expression within seasonal windows is an axis that covaries with fitness ,93,94. TAnalyzing phenological traits as independent response variables oversimplifies the manner in which life cycles are structured by trade-offs and contingencies between life history traits ,102 Fig. The expLife history optimization studies historically assumed constant environments, but theorists recognize that stochasticity in the environment can produce very different outcomes ,106–109.2 cycle [However, the manner in which life history timings are shaped by nonrandom cyclical temporal structures in the environment—such as those governed by Earth’s rotation around the sun which is geophysically locked—remains much less well understood theoretically . Specifi2 cycle ) and phe2 cycle .Above examples of studies that incorporated life history interdependencies and demographic structure into phenological analysis demonstrate that phenology is a highly eco-evolutionary process  and woulIn testing phenological evolution theory using the common types of phenological data, a nuanced conceptual gap that needs to be bridged is one between how “rate”  evolves and how “timing”  evolves. Rates are the parameters typically manipulated in demographic and life history models due to the time differential nature of dynamical systems modeling. Such models ask what happens over a fixed time step, whether that be a large step  or an infinitesimally small one . As a sPhenological evolution occurs in the context of ecological communities. The challenge is to understand how periodic interactions between coexisting species influence each species’ adaptive occupation of different portions of seasonal windows. Empirical evidence shows that different types of ecological interactions such as competition, invasion, or consumer-resource dynamics can alter the occurrence or trait expression timing of species in a community. Broadly, periodic interactions can favor overlap  or segresensu [The key ecological consequence of the differential expansions, contractions, and shifts among species’ phenologies is that the interaction potential between combinations of species can change within seasonal time windows ,123,124.sensu ) can forsensu  increasesensu . Among ssensu . Similarsensu , anuranssensu ,129, vassensu ,130,131,Within our framework of conceiving phenological phenomena as fitness-related distributions in time windows , we propTo what extent are parameters of abiotic environmental cycles  themselves agents of phenological selection? In other words, how do seasonal cycle parameter changes map to fitness landscape change? Does this perspective help explain phenological shifts in the context of global change, wherein parameters of environmental cycles are being altered?How do life history traits—which are intricately interdependent due to covariances and trade-offs—evolve upon a template of environmental cycles, which are themselves structured by temporal autocorrelation and lag effects? Recognizing connections among phenological traits, borrowing from life history theory, will advance our understanding of phenological shifts beyond correlative approaches that focus on single traits. We have highlighted that marrying concepts of timing and rate in models will be important.Temporal autocorrelation can occur at various resonances that may constructively or destructively interfere with seasonal cycles . How do multi-resonance regimes influence the evolution of seasonal phenology?Do phenologies of organisms with different numbers of generations per seasonal window evolve in fundamentally different ways, as the windows expand, contract, or become otherwise distorted ?How can we better integrate empirical approaches to enhance our general understanding of phenological evolution? As an example, can models that make predictions about optimal phenology  as a function of environmental cycle parameters  be tested by manipulating those parameters and measuring genetic and phenotypic frequency change simultaneously in experimental populations?How is the timing of a trait that is important from the perspective of the community  controlled simultaneously by life history optimization at the species level and periodic interactions with other species that favor co-occurrence or temporal segregation? Are there general rules regarding if and when single-species evolution or multispecies interaction is a stronger driver of phenological selection in nature?How do changes in seasonal time window parameters alter interaction potentials in ecological communities, create novel no-analog communities in different portions of the season, and affect phenological diversity?Phenology is ubiquitous. Species around the planet have evolved a panoply of physiological, genetic, behavioral, plastic, and neuronal mechanisms to strategically utilize seasonally available time windows ,132–135.While the sheer ubiquity of phenology itself warrants theoretical synthesis, global change makes it urgent. Perturbations to the cyclically occurring seasonal windows—analogous to spatial perturbations to habitats such as deforestation—are altering the familiar phenological patterns contained within those windows in perplexing ways ,126. CorUSA National Phenology Network and the Pan-European Phenology Database, and will make such interdisciplinary and comparative investigations possible.The microevolutionary process of phenological evolution will be another frontier of investigation. Population genetic processes such as recombination and drift are constrained by the seasonally fluctuating probabilities of encounter among individuals, which limit periodic opportunities for mating and gene exchange, and thus the inheritance of phenological traits. Studying how all of the above processes per species are simultaneously influenced by interactions between species in ecological communities will be the next challenge. We have strived to distill key questions for future investigators, particularly those interested in developing general theory . EmpiricFinally, the general concepts about time windows we discussed extend to a fundamental theme in ecology and evolution, beyond just the scale of seasons. While phenological research has focused on the seasonal scale, cycles in the physical environment in fact exist on many other temporal scales such as daily, tidal, and multiannual , with “phenological” scales to match . Geophy


Ischemic stroke (CIS) is characterized by a high incidence, disability, and mortality. Numerous studies have demonstrated that intracranial arterial stenosis is an important pathological basis of CIS, and its main cause is atherosclerosis. Dyslipidemia is an important risk factor for atherosclerosis. Lysophosphatidic acid (Lpa), apolipoprotein -A(APO-A), and apolipoprotein -B(APO-B) proved to be significantly correlated with the severity of coronary artery disease. This study retrospectively collected the case data of 186 patients with CIS treated from May 2020 to May 2022 and explored the correlation between Lpa, APO-A, APO-B, and middle cerebral artery (MCA) stenosis in CIS patients. Cerebral ischemic stroke (CIS) is the most common type of cerebrovascular disease, accounting for about 70% of all acute cerebrovascular diseases, with high morbidity, mortality, and recurrence rates . NeuroloThe case data of 186 CIS patients admitted to our hospital from May 2020 to May 2022 were retrospectively selected for research. According to the DSA evaluation results, they have been divided into 92 cases without MCA stenosis group and 94 cases in the MCA stenosis group, including 18 cases, 16 cases, and 60 cases of mild, moderate, and severe MCA stenosis.Inclusion criteria is as follows: (1) imaging examinations and clinical signs of all patients met the relevant diagnostic criteria of CIS ; (2) cliAccording to the purpose of this study, hospital professionals collected the age, gender, underlying diseases, smoking history, drinking history, systolic blood pressure (SBP), diastolic blood pressure (DBP), and the level of glycosylated hemoglobin (HbA1c), homocysteine (Hcy), uric acid level, and other data of the patient through the hospital medical record system. Wherein the underlying diseases include hyperlipidemia, type 2 diabetes mellitus, and coronary heart disease.All patients with CIS admitted to the hospital were evaluated for stenosis by digital subtraction angiography (DSA) using Aginnova digital subtraction X-ray angiography machine (model: Innova 3100-IQ) by the same group of physicians. Intracranial artery stenosis degree =  × 100%. Classification of cerebral artery stenosis: less than 50% stenosis is mild, 50% to 69% is moderate, and more than 70% is severe [Within 48 h after hospitalization, 2 ml venous blood was collected from the upper limbs in the fasting state in the morning. The levels of total cholesterol (CHOL), triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were measured by Mindray BS2000 automatic biochemical analyzer. The levels of Lpa, APO-A, and APO-B were detected by an immunoturbidimetric kit , and the ratio of APO-A/APO-B was calculated.S), and the differences between the two groups were compared by independent samples t-test. Differences between multiple groups were compared by one-way analysis of variance; measurement data that did not meet the normal distribution were expressed by M, and differences between groups were compared by Kruskal–Wallis test. The enumeration data were expressed by the number of cases and the rate, and the differences between groups were compared by the χ2 test. Logistic regression was used to analyze the independent risk factors of MCA stenosis. ROC was used to detect the diagnostic value of each index, and the Delong Test function was used to compare the AUC between the ROC curves. P < 0.05 indicates statistical significance.SPSS 22.0 statistical software was used for data analysis, and the measurement data that met the normal distribution were expressed as (±P > 0.05). The proportion of patients with hyperlipidemia, type 2 diabetes mellitus, and coronary heart disease in the MCA stenosis group was higher than that in the non-MCA stenosis group, and the HbA1c value was higher than that in the non-MCA stenosis group, and the differences were statistically significant (P < 0.05), as shown in There was no significant difference in gender, age, smoking, drinking, Hcy value, uric acid value, 24 hSBP value, and 24 hDBP value between the two groups (P > 0.05). The levels of Lpa and APO-B in the MCA stenosis group were higher than those in the non-MCA stenosis group, and the levels of APO-A, APO-A/APO-B were lower than those in the MCA stenosis group, and the differences were statistically significant (P < 0.05), as shown in There was no significant difference in the levels of CHOL, TG, HDL, and LDL between the two groups (P < 0.05), and high levels of APO-A and APO-A/APO-B were independent protective factors (P < 0.05), as shown in Logistic regression analysis was performed with variables with statistical differences in Tables P=0.014, 0.004, 0.003), as shown in The results of the ROC curve showed that the AUCs of Lpa, APO-A, and APO-B alone and in combination were 0.647, 0.660, 0.672, and 0.762, respectively, and the diagnostic value of combined detection was higher than that of each index alone (P < 0.05), as shown in There were significant differences in the levels of Lpa, APO-A, and APO-B in CIS patients with different degrees of MCA stenosis . APO-A level was negatively correlated with the degree of MCA stenosis . The distribution of Lpa, APO-A, and APO-B levels in CIS patients with different degrees of MCA stenosis is shown in The results of Spearman correlation analysis showed that the levels of Lpa and APO-B in the peripheral blood of CIS patients were positively correlated with the degree of MCA stenosis . A number of studies have shown that hyperlipidemia and coronary heart disease are independent risk factors for MCA stenosis [In this study, Logistic regression analysis showed that hyperlipidemia and coronary heart disease were independent risk factors for MCA stenosis in CIS patients . Lpa, APO-A, and APO-B are closely related to MCA stenosis. Lpa is a bioactive phospholipid mediator that can induce cell proliferation and morphological changes, promote platelet aggregation, and form thrombosis [This study showed that the levels of Lpa and APO-B in the MCA stenosis group were higher than those in the nonstenosis group, and the levels of APO-A and APO-A/APO-B were lower than those in the stenosis group (rombosis . The sturombosis  reportedrombosis  found inrombosis . Li et arombosis  studied rombosis  found thrombosis  found thThe ROC curve results for the Lpa, APO-A, and APO-B indices in this study showed AUC values of 0.647, 0.660, 0.672, and 0.762, respectively, both individually and in combination. The diagnostic value of the combined detection was higher than that of single indicators. These results indicated that each index had a certain diagnostic value for MCA stenosis in CIS patients, and the combined detection of the three indexes has a higher diagnostic value. The relationship between Lpa, APO-A, APO-B, and MCA stenosis was further analyzed using the Spearman correlation. The results showed that the levels of Lpa and APO-B in CIS patients were positively correlated with the degree of MCA stenosis, and the APO-A level was negatively correlated with the degree of MCA stenosis. It has been reported by Shui et al.  that theIn conclusion, the levels of Lpa, APO-A, and APO-B in the peripheral blood of CIS patients have a certain correlation with the degree of MCA stenosis. When the levels of Lpa and APO-B increase and the level of APO-A decreases, the risk of MCA stenosis occurs. However, there are still some deficiencies in this study. If it is a retrospective study, there may be some data bias, and the specific mechanism of action of each index has not been clarified. In the later stage, further in-vitro animal experiments are still needed for in-depth research.


To understand the incidence and related risk factors of extrauterine growth retardation (EUGR) in preterm infants.The clinical data of 132 premature infants hospitalized in the neonatal ward of Maternity and Child Health Care of Zaozhuang from July 2019 to June 2020 were collected. Children were divided into groups according to their birth gestational age  and birth weight . Treatment during hospitalization and follow-up after discharge were investigated by retrospective analysis. Incidence of EUGR in premature infants at discharge and the related risk factors leading to this complication, demonstrated by logistic multivariate regression analysis, were summarized.When evaluated according to weight, length and head circumference, incidence of EUGR at discharge in premature infants were 36.36%, 41.67% and 21.97% respectively. Smaller gestational age and lower birth weight significantly correlated with higher incidence of EUGR at discharge (P<0.05). Logistic regression analysis showed that small gestational age, low birth weight, intrauterine growth retardation, late first intestinal feeding, digestive system complications and respiratory system complications were independent risk factors for EUGR in premature infants discharged from hospital (P<0.05).The incidence of EUGR in premature infants at discharge is relatively high. Strengthening perinatal health care for pregnant women, reducing the incidence of intrauterine growth retardation and preterm birth, giving intestinal feeding as soon as possible after birth, and actively participating in preventing and treating postnatal complications are effective ways to reduce the incidence of EUGR at discharge. With the continuous improvement of medical technology, the survival rate of very low birth weight infants and preterm infants has significantly improved in recent years.At present, EUGR has become a common complication in preterm infants. Studies, evaluating weight, head circumference, body length and other related growth parameters of these children show that they fail to reach the 10th percentile of newborns of the same gestational age.6Some animal studies show that the early occurrence of EUGR can seriously affect the development of pulmonary vessels in preterm infants. This may cause pulmonary hypertension and bronchopulmonary dysplasia, significantly reduce the cure rate of preterm infants, significantly increase the risk of related respiratory diseases after discharge, and the later quality of life.Clinical data and follow-up data of 132 premature infants treated in the neonatal ward Maternity and Child Health Care of Zaozhuang from January 2019 to June 2020 were collected and retrospectively analyzed. The ethics committee of Maternity and Child Health Care of Zaozhuang approved this study .Gestational age do not exceed 37 weeks; entry into the neonatal department for treatment within 24 hours after birth, and length of hospital stay not less than seven days; satisfactory relevant clinical data during hospitalization; telephone follow-up done after discharge, with the satisfactory follow-up data.Death in hospital or after discharge; serious condition at discharge: genetic metabolic diseases and congenital malformations that have a significant impact on normal growth and development. Patients were divided into groups according to relevant data during hospitalization and follow-up data after discharge.The data collected included the general information , postnatal nutritional support, clinical diagnosis and treatment, IUGR occurrence. Relevant information (mainly the feeding status and body mass growth of the children) and data were extracted from weekly telephone follow-up post-discharge up until 44 weeks of corrected gestational age. The main factors related to the occurrence of EUGR were then analyzed.All children were given formula milk for preterm infants after birth with the volume of milk gradually increased according to the actual condition of infant. Briefly, according to the doctor’s advice, 12ml/kg per day was taken as the initial milk volume. Infants were fed once/every two hours, and the milk volume was gradually increased to 24ml/(kg·d) by the 10th day after birth. From the 11th day after birth, the feeding rate increased from 15~20ml/(kg·d) to 140~160ml/(kg·d). For infants whose growth and development cannot be well met by oral gastrointestinal feeding, parenteral nutrition was given daily according to their required heat card.Fenton growth curve for preterm infants was used as the evaluation criteria of IUGR and EUGR at discharge. Neonates were classified as IUGR if their birth weight was below the 10th percentile Compared with newborns of the same gestational age, the body mass at discharge, corrected gestational(P10). EUGR was defined in a static way (weight at discharge below P10 Fenton) and dynamically . The percentile reference values of body length, weight, and head circumference of newborns of the same gestational age in 15 cities of China were used as the reference standard. Catch-up growth refers to a phenomenon of accelerated growth of children with growth retardation caused by disease status after removing disease factors.9By analyzing the data, children were divided into groups according to their birth gestational age: gestational age <32 weeks, 32~35 weeks and >35 weeks and weight . The incidence of EUGR at discharge was compared and analyzed, and multivariate logistic regression analysis was performed.2 inspection. The risk factors were analyzed by logistic regression analysis. When p<0.05, the difference was considered statistically significant.Statistical analysis was performed by SPSS 22.0 software. All measurement data are expressed in (± s) and for t-test; The counting data is expressed as a percentage “n (%)” and analyzed ΧA total of 132 preterm infants  were included in the study. The average gestational age of the infants was (33.10±2.10) weeks, average birth weight was (2.10±0.35) kg, average length of hospital stay was (18.89±2.10) days, and the average corrected gestational age at discharge was (36.65±1.06) weeks.P<0.05).The analysis of data showed 43 children with gestational age <32 weeks, 61 children with gestational age of 32~35 weeks and 28 children with gestational age >35 weeks. According to weight, length and head circumference, EUGR was diagnosed in 48 (36.36%) preterm infants in the <32 weeks group, 55 (41.67%) infants in the 32~35 weeks group, and 29 (21.97%) infants in the >35 weeks group . As summP<0.05) as shown in Among 132 infants in the study, 16 children had birth weight <1500 g, 93 children were with birth weight between 1500~2500 g and 23 children- with birth weight >2500 g. There was a significant association between EUGR and weight, body length and head circumference of infants with different birth weight (Infants were then divided into EUGR group (n=48) and non-EUGR (n=84) groups according to their weight, and gestational age, length of hospital stay and related complications between the two groups were compared. As shown in Logistic regression analysis was next performed with EUGR at discharge as the dependent variable and birth gestational age, birth weight, IUGR, time of first intestinal feeding, complications of digestive system and respiratory system as independent variables. As shown in EUGR not only affects the short-term physical development and incidence of related complications of newborns, but also have a serious impact on their long-term growth and development, especially the development of nervous system.16The results of this study show a significant correlation between the low gestational age and birth weight and the risk of EUGR. Carducci B et al.18There are many reasons for the occurrence of EUGR after discharge of preterm infants. Darmun D et al.The main limitation of this study is that all data was acquired from a single center retrospectively and relied on accurate, detailed and available preterm data. Further large-scale and multi-center studies are needed to confirm our observations.The risk of EUGR in preterm infants is high. The independent risk factors leading to this complication are small gestational age, low weight, intrauterine growth retardation, late first enteral feeding, digestive system diseases and respiratory diseases. This study may provide reference for the prevention of EUGR in preterm infants.MS: Conceived and designed the study. JL, MS, YZ, QZ & CL: Collected the data and performed the analysis. MS: Was involved in the writing of the manuscript and is responsible for the integrity of the study. All authors have read and approved the final manuscript.


BackgroundTransient tachypnea of the newborn (TTN) is a self-limiting, benign condition leading to respiratory distress shortly after birth. It is among the leading cause of respiratory distress in term and late preterm neonates. The disease is transient and resolves by three to four days in most neonates.ObjectiveThe objective of this study was to study the incidence of TTN, its clinical features, predictors of outcomes and duration of hospital stay in these neonates suffering from it.MethodsThis was a prospective study done at a tertiary care center carried out between August 2019 to July 2021. The study subjects were late pre-term (34 to 36 weeks of gestation) and term neonates with respiratory distress who were admitted to the neonatal intensive care unit (NICU). The diagnosis was based on clinical features, radiological features, and clinical course in NICU.ResultsThe total number of cases with TTN was 74. The incidence of TTN was 16 per 1000 live births. 63.5% were male, 75.7% were term births, 70.3% were born via lower section cesarean section (LSCS), and 66.2% were normal birth weight (≥2.5 kg) infants. A high incidence of TTN was found in late pre-term babies, babies born via LSCS, and male sex. None of the neonates required ventilatory support, either noninvasive or invasive.ConclusionDelivery by LSCS and male sex were risk factors for the development of TTN. The distress in TTN is usually mild to moderate, and in most cases, oxygen supplementation suffices. Higher Downes’ score at presentation, low birth weight, preterm, and delivery by LSCS were found to be predictors for a longer duration of distress and thus the longer duration of NICU stay. Although severe complications for TTN have been reported in the literature, they are rare. Careful observation can decrease not only a lot of unnecessary investigations but also allow clinicians at secondary and primary centers to better care for neonates with TTN.  Transient tachypnea of the newborn (TTN) is usually a self-limited benign condition seen commonly in term and late preterm babies and most recover by 72 hours after birth. It is due to delayed clearance of fluids from the lungs after birth. The incidence ranges from 4.0-5.7 per 1000 live births in high-income countries to 13 per 1000 live birth in India.Management is supportive and most neonates require supplemental oxygen with fraction of inspired oxygen FiO2) no more than 0.40, if a higher oxygen concentration (>60%) is needed ventilatory support (continuous positive airway pressure [CPAP]) should be given . Though  no more This was a prospective, cross-sectional observational study carried out between August 2019 and July 2021. Due approval was taken from the Institutional Ethics Sub-committee at Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pune . All the newborns who were delivered at this hospital and admitted to our NICU for respiratory distress were followed up. Neonates with delayed transition were excluded. Delayed transition is transient respiratory distress that resolves within a few hours (six hours) of birth ,5.Oxygen supplementation was given via hood or nasal prongs. The oxygen saturation of the neonates was constantly monitored and the response to oxygen supplementation was evaluated. Invasive and non-invasive continuous positive airway pressure (CPAP) support were reserved for those neonates who had severe distress, or those who required higher concentrations of oxygen (>60%) to maintain their saturation. Oral feeds were started by spoon or paladai for babies with mild respiratory distress (respiratory rate 60-80/minute). Oral feeds were avoided in those with moderate to severe distress or those who had a significant increase in the work of breathing. These neonates were administered gavage feeding along with intravenous fluids which included 10% dextrose, electrolytes, and multivitamins. As tachypnea improved (respiratory rate: <80/min), babies were gradually weaned off oxygen and oral feeds were started. The neonates were discharged from NICU 12 hours after their tachypnea had resolved. Other causes of distress were actively evaluated if there was no improvement in symptoms on oxygen supplementation, if they required a very high concentration of oxygen, if the distress did not resolve beyond 72 hours, or if the X-ray did not improve after 48 hours. The data was recorded in MS Office Excel tables  and analyzed using IBM SPSS 28.0.0 statistical software suite . Groups were evaluated using Student’s T-test, Man-Whitney U tests, Kruskal-Wallis test, and Rank sum test. The Chi-Square test was used for the comparison of proportions. Bivariate analysis was used to compare two numerical parameters. Statistical significance was determined as p < 0.05.The total number of live births at our institution was 4562. There were 1289 NICU admissions during this period. Of these, 987 neonates were ≥34 weeks of gestation. A total of 189 neonates with respiratory distress fulfilled the inclusion criteria, these cases were followed. Out of 189 cases, 74 cases were of TTN, 70 cases of meconium aspiration syndrome (MAS), 15 cases of persistent pulmonary hypertension (PPHN), and 30 cases of respiratory distress syndrome (RDS). TTN cases were further analyzed. The demographic data of the neonates diagnosed with TTN is summarized in Table The incidence of TTN was found to be 16 per 1000 live births. 5.7% of all patients admitted to the NICU were TTN. Seventy percent n=52) of newborns were delivered via LSCS, while 30% (n=22) were delivered by vaginal delivery. No difference was observed between both groups regarding gestational age, maturity, or birth weight. A significantly longer duration of distress was seen in neonates born via LSCS as compared to those born via vaginal delivery. 93.2% (69/74) mothers had no comorbidities, while two suffered from preeclampsia, two from gestational diabetes mellitus, and one from hypothyroidism. All the mothers with comorbidities had delivered via LSCS. No significant difference was observed among them concerning the duration of tachypnea. In this study, 33.8% of the neonates were LBW (<2.5 Kg). The rest of the neonates were normal birth weight (NBW). None of the neonate had macrosomia (> 4 Kg). The tachypnea had resolved in a more than half (55.4%) of the patients by 24 hours, and all the patients had successfully recovered by 72 hours. Birth weight and gestational age were independently correlated with the duration of tachypnea/distress. Duration of distress was inversely proportional to both birth weight (p<0.01) and gestational age (p=0.01).Duration of tachypnea was significantly longer in preterms, low birth weight newborns (LBW), and whose Downes' score was 5-6  on presentation had more chances of recovering within 24 hours Table .In our study, the incidence of TTN was 16 per 1000 live births. TTN accounted for 5.3% of all the cases admitted to our NICU. It was a leading cause of respiratory distress accounting for 39% of respiratory distress in term and late preterm infants. This was closer to reported incidences of TTN in India: 13 per 1000 live births in Northern India by Thomas et al. 1981) and 28 per 1000 live births in Southern India by Kumar and Bhat (1996) . A revie1 and 28 Kweon et al. had suggested that the duration of tachypnea lasted longer in low birth weight infants . Our finThe strength of this study includes a large sample size, and there was a thorough and meticulous evaluation of all cases of neonatal respiratory distress and their follow-up till discharge.A limitation of this study is the low number of patients with maternal comorbidities, so their impact on outcomes of TTN is not reflected in the findings. Also, being a tertiary care center that handles high-risk deliveries majority of which undergo LSCS, the incidence thus is high. This incidence may not reflect the true incidence in the community.TTN is the most common cause of respiratory distress among late preterm and term newborns. Oxygen supplementation and supportive therapy were mainstays of management, and no complications were seen. Delivery by LSCS and male sex are major risk factors for the development of TTN. Our study demonstrates that most patients will improve within the first 48 hours. Higher Downes' scores on presentation, cesarean delivery, low birth weight, and prematurity are predictors of a longer duration of hospital stay. Larger study samples are required to establish the complications of TTN  and factors that might predict them.


This is a correction to: Perumal et al. Impact of scaling up prenatal nutrition interventions on human capital outcomes in low- and middle-income countries: a modeling analysis. Am J Clin Nutr 2021;114:1708–18.In the originally published version of this manuscript, the 2015 fertility data from the World Population Prospectus 2019 were used for the number of birth, which presents birth cohort data in five-year intervals. This may not have been clear to some readers. Therefore, “5-year” has been added to the text to clarify the birth cohort size in the abstract, table/figure titles, and methods. These changes have been made online. The authors apologize for any confusion.


Per- and polyfluoroalkyl substances (PFAS) are widespread chemicals. Legacy PFAS have been phased out of production in most developed countries and emerging PFAS (short-chain PFAS and polyfluorinated compounds) are used as legacy PFAS alternatives. The effect of legacy and emerging PFAS on cytokine homeostasis in human remains poorly understood. This study aimed to evaluate the associations between legacy and emerging PFAS and cytokine profiles, and identify the main contributors to the disturbance of cytokine homeostasis. We quantified 21 PFAS in 198 Chinese women of childbearing age from 2015 to 2016. 13 cytokines were measured using the Meso Scale Discovery U-PLEX and V-PLEX platforms. The associations between PFAS exposure and cytokine levels were assessed using multiple linear regression (single-exposure), and Bayesian kernel machine regression (BKMR) models (PFAS mixture exposure). In single PFAS models, legacy and alternative PFAS were positively associated with Th1 and Treg cytokines, and negatively associated with Th2 and Th17 cytokines. For instance, each ln-unit increase in 6:2 chlorinated perfluoroalkyl ether sulfonic acid (6:2 Cl-PFESA), perfluorooctanoic acid (PFOA), and perfluorooctane sulfonate (PFOS) was associated with a decrease in IL-10 by − 0.228 , − 0.153 , and − 0.174 , respectively. The BKMR model showed a significantly positive association of PFAS mixture with TGF-β and a negative association with IL-10. Overall, these results indicate that both legacy and emerging PFAS may affect the homeostasis of cytokines. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are two of the most studied long-chain PFAS, and are reported to induce adverse effects on human, including immunotoxicity2, carcinogenicity3, and reproductive and developmental toxicity4. Due to their persistence in the environment and potential health implications in humans, PFOS and PFOA production and applications have been restricted in Europe and North America6. Consequently, PFAS alternatives with either a short chain (perfluorosulfonic acid with carbon number < 6 and perfluorocarboxylic acid with carbon number < 81) or a slightly modified structure have emerged to meet market demand7. These alternatives are increasingly found in environmental and human samples at relatively high concentration due to the unrestricted use. For example, 6:2 chlorinated perfluoroalkyl ether sulfonic acid (6:2 Cl-PFESA) concentrations were as high as 2.13 ng/mL in Shenyang population, China8, and have become one of the main PFAS in Chinese local surface waters9. And PFAS alternatives showed comparable or even greater toxicities in both epidemiological and toxicological studies11. However, literature on immunotoxicity of PFAS alternatives is still scarce and inconsistent.Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic compounds that have been used in many industrial and consumer applications for over 70 years because of their high thermal and chemical stability12. The balance between pro- and anti-inflammatory cytokines in female immune system is essential for embryo implantation and pregnancy maintenance. T-helper 1 (Th1) and Th2 cells are the major subsets of Th cells with different patterns of cytokine production and different roles in immune responses13. In female, the deviation of the immune system from Th2 toward Th1 has been implicated in pregnancy complications, such as recurrent miscarriage14, preeclampsia15 and fetal growth restriction16. Th1 cells secrete pro-inflammatory cytokines such as interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), IL-8, and IL-12p70, that can activate macrophages and cell-mediated reactions that play critical roles in resistance to infection by intracellular pathogens and in cytotoxic and rejection reactions. Th2 cells secrete IL-4, IL-6, IL-10, and IL-13, which induce antibody production and are associated with strong humoral immunity17. IL-17 and IL-22 are the main Th17 effector cytokines, which are related to protective immunity against extracellular microbes during pregnancy18. Transforming growth factor-β (TGF-β) is secreted by regulatory T (Treg) cells and has the function of local inflammatory immune responses, potentially detrimental to the fetus13. Epidemiological findings regarding the possible relationship of PFAS and immune cytokines are limited and inconsistent. A recent study in 87 middle-aged women found that PFHpS was positively associated with Th1 cytokine (IL-8)19. But the C8 Health Project found that PFHxS, PFOA, and PFOS were inversely associated with TNF-α in 200 women aged 40–70 years. Similarly, PFOS and PFNA were negatively associated with IL-820. The inconsistency of previous findings warrants further research. We speculated that PFAS might affect pregnancy by disrupting immune balance19.The immune system plays a critical role in human reproductionWe conducted a cross-sectional study to examine the association between legacy and emerging PFAS exposure and cytokine levels and their balances.A total of 198 women were included in our study. Table Table Table P for trend < 0.001).Tables Figure In the PFAS mixture analysis, Th1 cytokines have inconsistent trends Fig. a–d, and Our study found that both legacy and emerging PFAS alternatives were associated with cytokine levels in women of childbearing age. Certain PFAS alternatives and isomers were positively associated with Th1 and Treg cytokines and negatively associated with Th2 and Th17 cytokines.21 in the general population and 1.54 ng/mL by Chen et al.22 in pregnant women in China. Moreover, 6:2 Cl-PFESA, 8:2 Cl-PFESA and HFPO-DA were detected in more than 95% of our population, suggesting that humans are also widely exposed to the PFAS alternatives.Consistent with our study, previous studies also reported high concentrations of PFAS alternatives. For example, the plasma concentration of 6:2 Cl-PFESA concentration was 1.4 ng/mL in our study, which is comparable to 1.75 ng/mL reported by Yu et al.14, preeclampsia15, and fetal growth restriction16. In addition, this study found a positive association between PFAS and TGF-β. As the principal function of TGF-β is to regulate cellular functions including cell adhesion, invasion and angiogenesis, which is essential for endometriosis development23, elevated TGF-β may have effects on endometriosis.Our results reported that PFAS were positively associated with Th1 cytokines and negatively with Th2 cytokines. Th1 cytokines tend to induce proinflammatory responses while Th2 cells produce anti-inflammatory cytokines. Th1/Th2 balance is beneficial to the maternal–fetal immune tolerance and maintenance of pregnancy. A shift in the Th1/Th2 balance toward Th1 dominance may cause miscarriages24. A significantly inverse association with PFOA was also found for IL-10 (β = − 0.22) among 101 healthy 1-year-old children25. Additionally, prenatal PFOS and PFNA in children aged 8 years were inversely related to Th2 cytokines (IL-4 and IL-13) in children from 1,101 mothers-child pairs in the Human Early Life Exposome project (HELIX)26. These evidences seem to suggest that PFAS may induce the production of pro-inflammatory cytokines. However, Zhu et al.27 showed that serum PFAS were positively associated with Th2 cytokines (IL-4 and IL-5) and negatively associated with Th1 cytokines (IFN-γ and IL-2) among male asthmatics. Positive associations were also observed for PFAS and Th2 cytokine (IL-6)  in 103 overweight or obese pregnant women in the U.S.28. Thus, evidence so far has been inconsistent.A recent study found that PFHpS was positively associated with IL-8  in 87 middle-aged women35. Dong et al. (2013) reported positive associations between PFOA, PFOS, PFBS, PFDA, PFDoA, PFHxS as well as PFNA exposure and asthma among 231 Taiwanese Children (10–15 years old). They also showed that PFAS were positively associated with serum IgE concentrations, absolute eosinophil counts (AEC), eosinophilic cationic protein (ECP) concentrations, and asthma severity scores among asthmatics31. However, PFAS were not statistically associated with the asthma diagnosis, or eosinophil count in 118 World Trade Center (WTC) participants33. As for immune globulin, no association between PFOS, PFOA and immunoglobulins IgA-IgG-IgM was found among 53 American male workers in PFOA production department29. No significant relationships between serum PFOA and white cell blood counts was discovered in 371 American residents30.A number of epidemiological studies in humans focused on the associations between legacy PFAS and immune outcomes such as asthma, allergies, and propensity to infections32. Moreover, a longitudinal study found that the PFAS concentrations in 5-year-old children were associated with higher basophil counts , but no significant relationship for neutrophils, eosinophils, lymphocytes, monocytes, and white cell counts. Furthermore, no association was found between PFAS from mothers as well as children at 18 months with aforementioned cell counts34.Knudsen et al. (2018) reported significant negative associations between PFAS and lymphocyte , neutrophil , monocyte , and white cell counts  in 192 Greenlandic pregnant women37. For example, 10 mg/kg PFOS exposure was positively associated with the expression levels of IL-1β and TNF-α in rats after 14-day exposure36. PFAS can also induce a markable upregulation of proinflammatory cytokines TNF-α expression in the jejunum of the PFOS 1 mg/kg and 10 mg/kg groups compared with the control in rats37. Collectively, these results indicated that PFOS exposure induces an upregulated pro-inflammatory infiltration. But inconsistent results also reported that PFOS exposure decreased TNF-α and increased IL-10 in the mice colon tissues38. Similarly, another study found that exposure to PFOS and F-53B significantly downregulated the expression of pro-inflammatory cytokine genes, including IL-8 and TNF-α, in the liver of adult zebrafish11.Many in vivo and in vitro experiments have demonstrated that dysregulation of cytokine caused by environmental pollutants induces the inflammatory responseThe main strength of our study is that we measured various types of PFAS, including PFAS alternatives and isomers. We also measured an array of cytokines including Th1, Th2, Th17, and Treg cytokines. We further used more advanced statistical methods to take into account of PFAS mixture exposure. Thus, our study has given a comprehensive and robust assessment of the association between PFAS, especially the emerging alternatives, and cytokine homeostasis in humans.39. It remains to be tested whether our finding is due to such unmeasured confounding.Our study also has several limitations. Firstly, the cross-sectional study design does not allow us to draw causal conclusions. Secondly, previous studies showed that other persistent chemicals like polybrominated diphenyl ethers (PBDEs), organochlorine pesticides (OCPs) and bisphenols are also associated with cytokinesIn conclusion, our study suggests that both legacy PFAS and emerging alternatives may affect the homeostasis of cytokines in humans.A total of 198 healthy females were recruited in the Center for Reproductive Medicine of Shandong University, China, between 2015 and 2016. Non-pregnant women who had no chronic diseases, endocrine disorders, autoimmune diseases, or active infection were eligible. Blood specimens were collected at the recruitment and centrifuged at 1500 rpm for 20 min to collect serum and plasma, and subsequently stored at − 80 °C until analysis. The study was performed in accordance with the Declaration of Helsinki, the ethics committee of Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine granted ethical clearance for this study (XHEC-C-2015-046), and all participants provided a written informed consent.A total of 21 PFAS analytes were detected in 0.1 mL of plasma by ultra-performance liquid chromatography Agilent 1290 Infinity II coupled with an Agilent 6495C triple-quadrupole tandem mass spectrometry  in the negative electrospray ionization (ESI-) mode in all subjects. They included PFOA, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorododecanoic acid (PFUdA), perfluorododecanoic acid (PFDoA), perfluorohexane sulfonate (PFHpS), 6:2 Cl-PFESA, 8:2 chlorinated perfluoroalkyl ether sulfonic acid (8:2 Cl-PFESA), hexafluoropropylene oxide dimer acid (HFPO-DA)], perfluorobutane sulfonate (PFBS), perfluorobutanoic acid (PFBA), perfluoroheptanoic acid (PFHpA), perfluorohexanoic acid (PFHxA), linear perfluorohexane sulfonate (n-PFHxS), br-PFHxS, linear PFOS (n-PFOS), 1 m-PFOS, 3 m-PFOS, 4 m-PFOS, 5 m-PFOS and 6 m-PFOS. In addition, ∑3,4,5 m-PFOS was calculated as the sum of 3 m-PFOS, 4 m-PFOS, and 5 m-PFOS due to limited separation capacity. Br-PFOS was computed as the sum of 1 m-PFOS, ∑3,4,5 m-PFOS and 6 m-PFOS, and total PFOS (PFOS) was the sum of n-PFOS and br-PFOS. Similarly, total PFHxS (PFHxS) was the sum of n-PFHxS and br-PFHxS. Internal quality control samples and procedure blanks were included along with each batch of samples for quality assurance throughout the project.40 and Benskin et al.41. Briefly, the Oasis HLB extraction cartridges (3 cc)  were pretreated with 1 mL methanol and 1 mL formic acid (0.1 M). 100 μL plasma samples were spiked with 2 ng of mass-labelled standard, and 1 mL formic acid (0.1 M). After shaking, the sample was loaded onto the cartridge. Then the cartridge was washed with 1 mL 0.1 M formic acid, 3 mL of 50% 0.1 M formic acid/50% methanol, and 0.5 mL of 1% ammonium hydroxide in succession. The PFAS were eluted with 1.8 mL of 1% ammonium hydroxide in acetonitrile (ACN). The eluate was evaporated and reconstituted to 0.1 mL in a mixture of methanol and 10 mM ammonium acetate. Finally, the mixture was transferred to UPLC-MS/MS for analysis. The limit of detection (LOD) was from 0.002 to 0.0083 ng/mL for all PFAS examined. More detailed information on LOD and limits of quantification (LOQ) can be found in Supplementary Table 42.Extraction methods were modified by Kuklenyik et al.43. Briefly, cytokines including Th1 cytokines , Th2 cytokines , and Th17 cytokines (IL-17 and IL-22) were quantified by a multiplex assay U-PLEX platform with electrochemiluminescent enzyme-linked immunosorbent assays . And Treg cytokines (TGF-β) were measured by a single-plex assay V-PLEX assay platform following the manufacturer’s instructions. MESO QuickPlex SQ 120 plate reader  was used to determine the analyte concentration.The method for measuring cytokines in serum has been detailed in a previous study2, continuous), and education .Potential confounding factors included age , age at menarche , body mass index  or number (percentage) for general characteristics among the participants. The plasma PFAS concentrations and serum cytokines were presented as median (interquartile range) and mean (SD). PFAS and cytokines concentrations were natural log transformed to reduce skewness in further analyses. Spearman’s rank correlation was used to assess correlations between different plasma PFAS.Multiple linear regression models were used to assess the associations between plasma PFAS concentrations and cytokines. In adjusted single-PFAS models, age, age at menarche, BMI, and education were used as covariates. Subsequently, PFAS levels were categorized into quartiles and the β coefficients (95% CI) of cytokine were estimated using the first quartile as the reference.44. Individual exposure-outcome relationships in the mixture can be inconsistent, and this method produces unbiased estimates of overall mixture effects in small sample sizes with an acceptable CI coverage44. It has the advantage to allow chemicals to interact with the outcome in either a positive or negative direction and is performed in the following three steps. First, all PFAS were categorized into quantiles. Second, PFAS, covariates, and cytokines were fit in a linear model. Finally, an index weight was calculated between 0 and 1 for each exposure, corresponding to the contributing individual component of the mixture effect on the outcome. The overall mixture effect can be considered as the change in outcome per one quantile of change in all PFAS exposures after adjusting for covariates.Quantile g-computation (gqcomp) is an improved modeling method based on weighted quantile sum (WQS) regression that can assess the joint effect of all mixture exposures by one quartile at a time45 was conducted as a semi-parametric machine learning method to investigate non-linear dose–response associations, interactions among PFAS, and overall cumulative effects of the PFAS mixture. In this study, the BKMR models were applied as Yi = h (PFAS) + ßT Zi + ei, where Yi is the change of cytokines; h  is an exposure–response kernel function; Zi contains a set of potential confounders; β is the regression coefficient; and ei represents residuals. We identified the most important PFAS contributing to cytokine changes within the mixture using the hierarchical variable selection and presented the posterior inclusion probability (PIP) for each PFAS.Bayesian kernel machine regression (BKMR)P-values were two-tailed, and statistical significance was defined as p value less than 0.05.Most statistical analyses were performed using the survey analysis procedures in SAS . In addition, we used R software  with “qgcomp” and “bkmr” packages to conduct PFAS mixture analyses. All the Supplementary Information.


We read with great interest the recent article by Bastos et al :” ChalleIn this study, the authors reported their experiences using both 3D intraoperative ultrasound(iUS) and intraoperative MRI (iMRI) in 23 glioma surgeries. In 65% of patients, the tumors are located near the eloquent areas. 43% were recurrent cases. Three 3D iUS scans were routinely performed before and after dural opening and before the iMRI scan. More 3D iUS scans might be added if necessary. After tumor resection, one or two iMRI scans were performed to confirm the residual tumor. Multimodule neuro-navigation and electrophysiological monitoring techniques were also utilized during surgery. After surgery, 53% of patients achieved gross total resection. 21% of patients had temporary neurological deficits. None of them were permanent. In 82% of patients, the results of iUS were consistent with iMRI findings. While in the other four recurrent cases, the image quality of iUS was poor for the authors to decide.Three cases were presented in the paper. Case one was a small tumor located just before the precentral gyrus. IUS showed an apparent brain shift just after the dural opening. This information helped the surgeon choose the right site without causing injuries to the precentral gyrus. Case two was a giant left temporal glioma surrounded by bunches of fiber tracts. Multiple iUS scans were utilized to assess the resection process serially and helped the surgeon find the residual tumor. Case three was a low-grade glioma growing along the cingulate gyrus. 3D iUS helped the surgeon choose a safe corridor between functional areas and delineate the anatomical structures surrounding the tumor. The small residual tumor was found by iUS and confirmed by iMRI. The authors concluded that using 3D iUS in relation to iMRI had practical benefits for glioma surgeries and challenges.We agree with the authors’ opinion regarding the advantages and limitations of the iUS and iMRI. Combining these two techniques in glioma surgery seems reasonable and promising. Their conclusions are well supported by the data and illustrated cases. In addition to congratulating the authors, we would like to point out a few issues.The initial surgical treatment of glioma aims to obtain the maximal extent of resection (EOR) while preserving neurological function , 3. HoweiUS has been used in neurosurgery since the 1980s and is significantly correlated with preoperative MRI assessment of tumor volume –7. MountiMRI system was introduced into neurosurgery in the 1990s. Modern iMRI generates excellent images with few artifacts . AccumulThe complementary characteristics of iMRI and iUS raise the possibility of integrating them into glioma surgery. Firstly, iUS can generate nearly real-time intraoperative images . With iUBastos’s study supported the feasibility of integrating these two intraoperative imaging techniques. iUS provided much complementary intraoperative information to help the surgeon identify brain shift (case one), perform resection control serially (case two), and choose a safe surgical corridor (case three). On the other hand, iMRI approved residual tumors that were not detected by iUS in 8.7% of patients. In the end, they achieved good surgical results by combine using these two techniques.We commend the authors for their interesting study elucidating the utility of 3D iUS together with iMRI. This is a valuable exploration of the surgical strategy of glioma. However, it would be more helpful if the following questions could be addressed in their future studies.The training level of the team members in the iUS and iMRI was not mentioned in the paper. The learning curve of understanding the ultrasound image was steep, especially in the intraoperative circumstance . The 3D A 100% concordance rate between 3D iUS and iMRI was reported in the study, which is different from those reported in the literature . ConsideThe complexity of introducing iUS into iMRI-assisted surgery was not mentioned and assessed in the study. To our opinion, this is a question that should be considered before using this technique. Using the modern high field iMRI system has inevitably increased the system complexity and the surgical time and cost . ExtensiThe study enrolled patients with a higher risk of postoperative neurological complications. In 65% of selected patients, the tumors were located near the eloquent areas. The functional result after surgery was also excellent compared with the literature data , 24. PreThe study did not explicitly discuss the advantages of combining iUS with iMRI for intraoperative decision-making. A significant benefit of intraoperative imaging is that it aids in intraoperative decision-making . With iMAll authors have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Mothers with chronic diseases are associated with BDs. It is very important to set up a policy to decrease the prevalence of these maternal chronic diseases; then, we can reduce the incidence of BDs.Birth defects (BDs) are an important cause of abortion, stillbirth, and infant mortality that may cause lifelong disability. The defects can be caused by genetics, environmental exposure, or maternal chronic diseases. We conducted a study to analyze the association between maternal chronic diseases and BDs and to evaluate the effect of decreasing the prevalence of maternal chronic diseases on reducing BDs. The data of newborns and their mothers were concatenated and analyzed from three national population databases: the National Health Insurance Research Database, the Birth Certificate Application, and the Birth Registration Database in Taiwan during the period of 2005 to 2014. Codes 740-759 of the International Classification of Diseases 9th Revision—Clinical Modification (ICD-9-CM) were used as the diagnosis of BDs. The prevalence of BDs was 2.72%. Mothers with cardiovascular diseases, hypertension, anemia, genitourinary tract infections, renal diseases, neurotic or psychotic disorders, gestational diabetes mellitus (DM), and pregestational type 1 or type 2 DM had a significantly higher prevalence of BDs. The population attributable risk percent (PAR%) of BDs was 1.63%, 0.55%, 0.18%, 1.06%, 0.45%, 0.22%, 0.48%, and 0.24% for maternal hypertension, cardiovascular disease, renal disease, genitourinary infection, anemia, neurotic and psychotic disorders, gestational DM, and pregestational type 1 or type 2 DM, respectively. The percentage change  of maternal disease and the predicted number of live births was used to estimate the decrease in the number of newly diagnosed BDs in 2034. By using the middle-estimated number of live births in 2034, we predicted that the number of BDs would decrease by 302, 102, 33, 196, 83, 41, 89, and 44 with a −5% prevalence of maternal hypertension, cardiovascular disease, renal disease, genitourinary infection, anemia, neurotic and psychotic disorders, gestational DM, and pregestational type 1 or type 2 DM, respectively. We conclude that mothers with chronic diseases, including cardiovascular diseases, hypertension, anemia, genitourinary tract infections, renal diseases, neurotic or psychotic disorders, gestational DM, and pregestational type 1 or type 2 DM, have a significantly higher ( Birth defects (BDs) are structural or functional anomalies that occur during intrauterine life and can be identified prenatally, at birth, or later in infancy . Causes Many previous studies have reported the epidemiology and prevalence of BDs ,7,8,9,10We conducted a study to analyze the association between maternal chronic diseases and BDs and to determine the effect of decreasing maternal chronic diseases on reducing the prevalence of BDs.We linked three databases, including the National Health Insurance Research Database (NHIRD), the Birth Certificate Application (BCA), and the Birth Registration Database (BRD) between 2005 and 2014 in Taiwan. The National Health Insurance program was implemented in 1995; it covers more than 99% of the residents in Taiwan and contracts more than 97% of medical providers. The National Health Insurance Research Database (NHIRD), which contains registration files and reimbursement data, was created for research purposes. The deidentified NHIRD has become one of the best databases in the world for population-based studies, as it includes more than 99% of the population. . These dn = 2,498,573) between 2005 and 2014 were identified. The children  for whom we were unable to identify the ID number of the mothers from the BCA or BRD were excluded. A total of 2,033,004 newborn infants with complete health insurance, birth, and mothers’ data between 1 January 2005 and 31 December 2014 were included in this study. Codes 740-759 of the International Classification of Diseases 9th Revision-Clinical Modification (ICD-9-CM) were used as the diagnosis of BDs. We followed up every infant for one year. A diagnosis of BDs was made when an infant had a diagnosis with the code 740-759 and at least 2 outpatient visits or 1 admission record.The birth records , atrial septal defect (ASD), patent ductus arteriosus (PDA), congenital laryngomalacia, and undescended testis were diagnosed when the infants were more than 6 months old. Preterm infants with PDA were excluded from this study because most preterm infants with PDA might close spontaneously later; however, infants more than 6 months old with PDA were included in this study. A total of 55,229 infants were diagnosed with BDs during the study period. Associated maternal diseases were also recorded. We used the report of the National Development Council Population Projections in Taiwan to calculate the high, middle, and low estimates for the population of infants between 2016 and 2034 in Taiwan . Figure p-value < 0.05 was considered to be statistically significant. Population attributable risk percent (PAR%) = (proportion of diseases in population x relative risk (RR) − 1)/(1 + proportion of diseases in population × (RR − 1)). The percentage change in the prevalence of maternal disease in 2034 was compared with the prevalence of maternal disease in 2005–2014. The prevalence of maternal disease was defined as y, and 3 parameters  of percentage change in maternal disease ((y in 2034 − y in 2005–2014)/y in 2005–2014) was used to estimate the decreased number of newly diagnosed BDs in 2034. The decreased number of newly diagnosed BDs in 2034 by reducing the maternal disease prevalence can be defined as (predicting rate of BDs in 2034) × ) × . Institutional review board (IRB) approval was obtained from the ethical committee at Chung Shan Medical University Hospital (CSMUH No: CS17044).The prevalence of defects was calculated using the method recommended by EUROCAT as follows. The prevalence = the total number of cases divided by the total number of births (live births and stillbirths). The categorical data of the groups were analyzed by a Chi-square test. The crude relative risk (RR) of BDs was defined as the crude prevalence rate in children with maternal disease exposure/crude prevalence rate in children without maternal disease exposure. We used SAS 9.4 software to perform the analysis in this study. A p = 0.2819). The prevalence rate of BDs was 86.1 for the cardiovascular system, 57.6 for the genitourinary system, 48.7 for the musculoskeletal system, 25.7 for the digestive system, 21.5 for the respiratory system, 17.8 for cleft palate with or without cleft lip, 14.8 for chromosomal abnormalities, 13.9 for the nervous system, and 6.7 for eye, ear, face, and neck defects per 10,000 births in 2014. VSD and ASD were the most common BDs.p < 0.01).The relative risk, maternal chronic diseases, and population attributable risk percent (PAR%) of BDs are summarized in An estimated 295,000 newborns die within 28 days of birth every year worldwide due to BDs . BDs canOur previous study showed that BDs most commonly involved the cardiovascular system, followed by the genitourinary system, musculoskeletal and skin system, digestive system, respiratory system, cleft palate with or without cleft lip, chromosomal abnormalities, the nervous system, and the eyes, ears, face, and neck. It was reported by Boyd et al. that the most frequently reported BDs were serious cardiac diseases . There wp < 0.01) prevalence of BDs. The same findings have been reported previously [2 [Our data showed that mothers with chronic diseases, including cardiovascular diseases, hypertension, anemia, genitourinary infections, renal diseases, neurotic or psychotic disorders, gestational DM, and pregestational type 1 or type 2 DM, had a significantly higher , and this is more efficient for estimating the decrease in the number of BDs by the prevention of maternal disease than the adjusted RR. However, the adjusted relative risk can provide a more accurate estimation of BD prevention, but information on important covariates is not always available in health monitoring systems, especially in developing countries.p < 0.001) prevalence of BDs. Although BDs can be caused by genetic and/or environmental factors, maternal chronic diseases have an association with BDs. Care before, during, and after pregnancy, including healthy nutrition, proper exercise, and avoiding stress and anxiety, can play a useful role in decreasing maternal chronic diseases. The early identification of high-risk pregnant women with such chronic diseases is important. Mothers with such chronic diseases should control their diseases to minimize the risk of BDs.Mothers with chronic diseases, including cardiovascular diseases, hypertension, anemia, renal diseases, genitourinary infections, neurotic or psychotic disorders, gestational DM, and pregestational type 1 or type 2 DM have a higher (