Normal birth has significant benefits for mothers and infants. However, the advancement of technology has led to increased medicalization of childbirth. Midwives play a pivotal role in promoting normal birth, and positive outcomes are seen in births led by a midwife. The purpose of the study is to gain a deeper understanding of midwives’ experiences of facilitating normal birth in midwifery-led units.The study has a qualitative design. It was conducted in 2022 and included semi- structured interviews with seven midwives throughout Norway. They were all currently working, or had previously worked, in a midwifery-led unit. The data material was analyzed using systematic text condensation.The data analysis resulted in three result categories. The first category concerned the importance of relationships, continuity and a safe atmosphere. The second concerned being a midwife in the hand, in the heart, and in the mind. The third related to having confidence in the physiological process of childbirth, midwifery autonomy, and a common ideology.The study highlights several elements that may help to promote normal birth in midwifery units. Relationships, midwifery skills, confidence in normal birth and a supportive collegial environment that fosters midwife autonomy, are prominent factors. These elements were viewed by the midwives as key to their ability to promote normal birth in a midwifery-led unit. The World Health Organization (WHO) defines normal birth as: ‘... spontaneous in onset, low risk at the start of labor and remaining so throughout labor and delivery. The infant is born spontaneously in the vertex position between 37 and 42 completed weeks of pregnancy. After birth mother and baby are in good condition’4. However, the use of medical technology in obstetrics has led to over-medicalization and interventions in many healthy women who expect a normal birth7. Interventions that are performed inappropriately or routinely can, in the worst cases, lead to harm and adverse outcomes for mother and child8.A normal birth has several positive consequences, both for the mother and the child, such as an improved birth experience for the mother, more rapid initiation of breastfeeding and the forming of a close bond between mother and child9. The differentiation is to ensure that women’s needs for a varied provision of prenatal and obstetric care are met, and that this is based on a risk assessment according to stipulated criteria and the woman’s wishes10. Obstetric care is differentiated into three levels according to the risk of the expectant mother. University hospitals and central hospitals (level 1) provide advanced obstetric, pediatric and anesthetic services, including intensive care for the newborn. Small and medium sized hospitals (level 2) offer obstetric and anesthetic services, and level 3 units comprise free-standing and in-hospital  midwifery-led units. Level 3 units provide care for low-risk women, levels 1 and 2 provide care for all women, regardless of risk11. For the last decades, maternity care in Norway has been characterized by a process of centralization. In 1967, Norwegian women could choose to give birth in 182 different institutions12. Today, less than 50 institutions are left. Midwifery-led units have suffered a similar fate. Today, six free-standing units are located within an area of 90–190 km from a hospital and three midwifery-led units are located within hospitals13. Obstetric care in Norway is of a high standard in an international context, but improvements are still needed10. Preliminary statistics from 2022 show that 30% of births in Norway were induced. Synthetic oxytocin was used to stimulate contractions in 46% of primigravida women and 9% of multigravida women, while 44% of women in labor received an epidural anaesthesia14.According to Norwegian recommendations, prenatal and obstetric care should be continuous and differentiated15. Midwives are able to facilitate the physiological process of childbirth and limit unnecessary interventions, whilst also providing comprehensive care for the woman in labour18. A review comparing midwife-led continuity models of care with other care models found that women who received midwife-led models of care were less likely to experience interventions, such as regional analgesia and instrumental vaginal birth, and episiotomy. They were also more likely to experience spontaneous vaginal birth19. A study exploring women’s experiences with the promotion of normal birth in a combined low- and high-risk hospital unit described how a positive and supporting approach from the midwife helped them manage labor without pain relief18. Thus, midwives play a crucial role in promoting normal birth in all settings.Comprehensive antenatal, perinatal, and postpartum care must be in accordance with the WHO’s principles for obstetric care. Normal birth care should be demedicalized and based on appropriate and necessary technology20. This is partly explained by the lack of evidence-based practice, an overriding focus on procedures, and selection criteria and technology that replace the use of traditional midwifery skills. A systematic review from 2021 shows that a risk-based approach informs practices in obstetric units, and that the loss of midwifery knowledge and skills is one of the barriers to implementing a physiological approach to childbirth21.Nevertheless, midwives sometimes find it challenging to promote normal birth in a high-tech hospital unitPrevious research has explored midwives experiences with promoting normal birth in a medicalized context. In this study, we explore midwives’ experiences of facilitating normal birth at midwifery-led units in hospitals and free-standing midwifery-led units. None of the units offered caseload midwifery, but some offered continuity-of-care models where women received care from a team of midwives.22.The study has a qualitative design, as the purpose is to gain an understanding of the characteristic features and qualities of midwives’ experiences of facilitating normal birth23 by posting information about the study in the Facebook groups Jordmødre i Norge (midwives in Norway) and Hjemmefødsel i Norge (home birth in Norway). We also had telephone contact with several free-standing midwifery-led units, and after verbally informing them about the study, we emailed information to the contact person in these units.We recruited a purposive sampleThe inclusion criteria were that the midwives were working or had previously worked in a free-standing midwifery-led unit or a midwifery-led unit in a hospital. Eight midwives expressed their interest in participating, but one subsequently withdrew. Three of the midwives worked in a midwifery-led unit in a hospital, and three worked at free-standing midwifery-led units. One of the midwives worked in a hospital maternity unit, but was included because of her 33 years of experience in a free-standing midwifery-led unit. Six midwives had previous experience from a hospital maternity unit. All the midwives were aged >45 years, and all were currently employed and had 20–40 years’ experience as a midwife. The geographical spread was from Northern Norway to Eastern Norway. In the results section, the midwives are anonymized through the use of fictitious names.23, consisting of four open-ended questions related to the purpose of the study. The participants spoke freely about the main topics, and follow-up questions were asked where necessary.Semi-structured individual interviews were conducted from January to February 2022, and lasted 40–75 minutes. Two authors conducted six interviews, while the last interview was carried out by one of the authors. Five interviews took place remotely, via Zoom, and two were held in person in a public library and at the informant’s home, respectively. An interview guide  with a p22. An example of the analysis process is given in The interviews were recorded using the Diktafon app (an app used to make secure recording on a mobile device) and transcribed verbatim. The transcribed text was analyzed using systematic text condensation (STC), a method for thematic cross-case analysis inspired by Giorgi’s phenomenological analysis method22. The analysis led to three result categories. Relevant quotes are included to illustrate the categories. STC consists of four steps. In the first step, we read through the transcribed text several times to get an overall impression of preliminary themes, such as preparing for childbirth, time, and hormones. The second step consisted of a systematic review of the text, where we identified meaning units, line-by-line, that helped to elucidate the research aim. These meaning units were sorted into code groups. In the next step, we went through one code group at a time and organized the content of each individual group into different subgroups, all of which highlighted different aspects within the group. The content of each subgroup was rewritten as condensates , with the intention of summarizing and reproducing the content of the relevant subgroups. In the fourth step of the analysis, the material was reformulated into analytical text and the headings were refined24, and was approved by the Norwegian Centre for Research Data . Prior to the interviews, the participants were sent an information letter. Before the interview, they were informed that participation was voluntary and that they could withdraw from the project at any time without any repercussions. Consent to participate was given in writing or by approving participation in a Zoom meeting by clicking on a link.The project was carried out in accordance with the ethical principles of the Declaration of HelsinkiThe first category concerned the importance of relationships, continuity and a safe atmosphere. The second concerned being a midwife in the hand, in the heart, and in the mind. The third related to having confidence in the physiological process of childbirth, midwifery autonomy, and a common ideology.The midwives emphasized the importance of forming a good relationship with the women. They argued that if the women felt safe during labor and a closeness was established between the woman and the midwife, this facilitated a positive birth experience. Many emphasized the importance of being present without being a disruptive force, allowing the woman to go into her ‘birthing bubble’. One midwife described how they almost imperceptibly overlapped each other at the change of a shift, without noisy knocking on doors or other disruptive elements. Several midwives spoke of the advantages of the women writing a note or birth plan about what they felt was important during labor, and what they needed to feel safe and well cared for. For the midwife, this could be a shortcut into the relationship:‘The first thing I think, which I always have in the back of my mind, is what can I as a midwife do to make this woman feel safe and well cared for? How can I ensure that she can be herself when she is giving birth to her child, and that I can give her, to the greatest extent possible, what she needs and wants? I have to “tune in” to this woman, to the woman in labor.’ (Hilde)A common feature of the midwives was that they emphasized facilitating continuity. They believed that being familiar with the midwife and with the ward helped to give the women a sense of security, and could increase motivation before and during labor. According to the midwives, this was an important factor in being able to facilitate normal birth. The established relationship also included the knowledge about the individual woman: what she is all about, what resources she has, and where her personal boundaries lie:‘If we are lucky, many of the women have had prenatal check-ups with me. We've therefore ensured continuity. So that sense of security and confidence are kind of in the box from the start.’ (Anne)The environment was highlighted as an important part of the effort to facilitate normal birth. Several participants enthusiastically described in detail the surroundings into which they invite the expectant mothers. Inviting the women into a room where they feel comfortable, with nice colors, subdued lighting, a calm and safe atmosphere, helps to promote normal birth. The midwives also talked about the importance of having enough space to move around and the option to use a bathtub, birthing ball, mats, and a double bed. One midwife had experienced that women who had previously given birth in a traditional hospital maternity ward were more relaxed and more confident in the free-standing midwifery-led unit. Wires and medical equipment were absent, and the midwife had time for the woman and was present:‘So just being able to provide a free-standing midwifery-led unit that I can vouch for as being nice and cozy makes me feel that I have done a lot to promote normal birth.’ (Anne)The midwives described their profession and practical skills with passion. Several referred to being a midwife as an art form, a craft, or a talent. They believed that anyone could learn technical skills and procedures, but that alone is not what makes a good midwife. Some told of an almost intuitive skill that was difficult to put into words, but which was about ‘using oneself’ to read the woman, her partner and the atmosphere in the free-standing midwifery-led unit:‘I hear how people breathe, and I hear when their contractions start and stop, and I see how the women move, so that's my most important instrument. I don't have to listen so much to fetal sounds when I know she has good breaks between contractions. Because that tells me that the baby is getting oxygen in between times.’ (Grethe)All the midwives described a calmness and presence that was in stark contrast to the fast pace of a high-tech hospital maternity ward. Several highlighted the balance between an almost imperceptible presence and jumping into action when required. Experience with normal births in clinical practice over many years had given them confidence to detect any deviations from the normal. Several explained that along with their independent work, there was also a constant awareness of the risk of adverse events. They believed that the ability to think ahead was a prerequisite for providing a high standard of care. The women were transferred to a hospital maternity ward if they expressed a desire for this, or if medical interventions were required:‘We always take action if the situation becomes uncertain. If the midwife's gut is telling her that this is not good, then we transfer the woman. But, no, we don't keep them here any longer in the hope of tormenting them into giving birth. And if she loses her courage, and the midwife starts to lose her courage, then it's a vicious circle.’ (Ingrid)The midwives described how they tuned into the women’s body’s inherent resources and natural hormone production. It is important that the woman is given enough time, that she feels safe and that the body’s reserves can be replenished with fluid and nutrition. Which interventions are initiated and when depends on the stage of the labor. Several midwives compared childbirth to extreme sport, where their basic needs must be met for a good outcome. Everyone highlighted the importance of balancing rest and sleep, activity and changing position. They also highlighted natural pain relief methods, such as acupuncture, massage, warm compresses, running water and baths. All of the midwives emphasized that they take a hands-off approach. No interventions, such as catheterization, vaginal examinations or amniotomy, were initiated without a clear indication:‘But the changing of position, especially at the dilation stage, trying different positions, standing, kneeling, some want to rest, on a bean bag, lying on your side, all of that ... well, birth is movement. And it's important, and it’s important to move.’ (Marit)All the midwives had a strong belief in the physiological process of childbirth. Some emphasized that if the midwife does not have this belief, this is transferred to the woman. Preparing the women well for childbirth was emphasized by several midwives. This entailed allaying any fears about the birth process, and reassuring the women and their partners that giving birth is a natural process that the female body can handle. One of the midwives referred to the ability to make women understand and believe that they can do it themselves as an art. Some described the efforts they made to maintain the women’s belief in their own bodies and to listen to their instincts. They knew when to praise and encourage the women:‘It’s an art, I think, to help the woman see that she can do it herself, and to believe in it. ... “When you think you're exhausted, you're halfway there. Then your body can at least do twice as much. And you don't believe it, but I do.” Then you see that they get on board in a way.’ (Bente)The midwives said that they feel that their profession and their identity as a midwife are to some extent threatened by invasive procedures and the introduction of technology to the free-standing midwifery-led unit. They described feeling reassured by the knowledge that their colleagues share a common ideology, and they discuss midwifery, research and philosophy. One of the midwives emphasized the importance of knowing that at shift change, the next midwife takes over responsibility for the woman in labor in the same spirit and in the belief they can facilitate normal birth. The midwives were very aware of the conditions for using a partograph, for example not starting it too early. They said that this is one of several factors that help to optimize the potential for the woman giving birth with as few disruptions as possible:‘You tend to cheat a bit on the partograph, yeah. And you have to do that because otherwise hardly anyone would be able to give birth in peace. And don't open the partograph too early. You can of course be lucky if you do that, but it's a bit sad that it has to be like that.’ (Nina)The midwives emphasized the importance of maintaining a high standard of care. They considered themselves a vulnerable group, and it was important to them that they could not be accused of anything. This also applied to protecting the women’s right to co-determination. The women were encouraged to take their share of the responsibility for their own birth process, but it is the midwife’s job to reassure her that her body can give birth to a child. If the decision is made that a woman will give birth in a free-standing midwifery-led unit, a normal labor is expected. Most of the midwives had experienced challenges in facilitating normal birth when they were previously employed in a hospital maternity ward. Several midwives mentioned an overriding risk surveillance approach and fear that the unborn child is in danger, and that this insecurity transfers to the women. Some said they did not speak the same language as the midwives in the hospital maternity wards, or that they felt misunderstood by them. At worst, they felt that they were polar opposites. Reassurance is important for maintaining progress in childbirth, but the views on the place of technology in this process varied. One of the midwives had recently conducted her annual practice at a hospital maternity ward and shared the following reflection:‘We practice in the maternity ward once a year, you know, it's in our criteria. And [during the hospital stay] I always think that it will be good to come home to reassurance. … We're not there to manage a woman's labor, we have time, not least, time is extremely important. Give the women time and reassurance. It's incredibly important.’ (Marit)25 point out that in addition to other conditions that contribute to promoting normal birth, the importance of the caring relationship in particular must be recognized and considered. In order to form a reassuring relationship, the midwives placed an emphasis on providing continuous antenatal, perinatal, and postnatal care. Continuous care can increase the likelihood of a spontaneous vaginal delivery and reduce the number of women receiving epidurals, episiotomies, and instrumental deliveries26.A reassuring relationship was a key element of the midwives’ efforts to facilitate normal birth. The importance of good relationships in obstetric care has previously been highlighted. Hunter et al.9, but this is sometimes difficult to achieve as the responsibility for this care is divided between the primary health service and regional health authorities10. However, many pregnant women are followed up by one midwife, or just a few, during pregnancy, which provides a continuity. Through prenatal care, the midwives we interviewed gained knowledge about the individual woman and her resources, in parallel with childbirth preparation work and motivation. Thus, the relationship was already established when labor started, which can make it easier for the woman to enter her ‘birthing bubble’. Vedeler et al.27 indicate that women want to feel a sense of security during labor, without unnecessary stress and interventions. The midwives in the free-standing midwifery-led units had time to be present during the women’s birth. Their continuous presence during the birth gave them more opportunity to support the woman and her partner, and to make observations. This presence can help to facilitate normal birth and shorten labor. It can also reduce the number of cesarean sections, instrumental deliveries and the use of epidurals, giving a better birth experience for the mother29.Comprehensive obstetric care is one of the goals of Norwegian health policy31. The midwives talked about how women who had previously given birth in a hospital maternity ward were more relaxed when they arrived at the free-standing midwifery-led unit because the absence of medical equipment gave them a greater sense of calm. However, experiencing a ‘sense of security’ involves more than ‘being safe’. For some, the sense of security entails having technology close-by, while for others it is the absence of technology27.The environment was highlighted as playing an important role in the reassuring relationship. The importance of the environment is also examined in previous studies32. The absence of medical technology challenges the midwives to use their own senses as tools, and their continuous presence gives them a sense of security, where time is an important resource. This does not entail excluding technology, but recognizing when it needs to be used. This is in line with the WHO’s evidence-based recommendations for intrapartum care6.The midwives enthusiastically described how being a midwife is about more than handling practical skills. It was difficult to put into words how they work, and terms such as ‘the art of midwifery’, ‘using one’s whole self’, ‘tune in’ and ‘midwifery talent’, were used. The midwifery profession represents an old craft and traditions, which are sometimes felt to be under threat from the gradual introduction of technology, including in low-risk units. Physical proximity to this equipment can influence the threshold for putting it into use. Advanced medical equipment is vital for some, but it can also lead to unnecessary interventions or continuous monitoring, which in turn can lead to adverse outcomes in healthy pregnant women33. One such example is conscious use of the partograph. It is not necessarily expected that labor will take place within a linear timeframe as suggested by this graphical record of key data. A normal birth often takes time. If mother and child are doing well, calmness and patience are a resource. If the partograph is started too early, it can limit the potential for giving birth without disruptions. There is little evidence of the independent significance of the partograph for the outcome of a birth34. Several studies confirm that midwives who take a physiological approach in a risk-managed ward tailor their choice of action in a similar way21. Allowing laboring women enough time and calm to give birth with as few disruptions as possible, was highlighted. Here, a dilemma arises between being preemptive, identifying acute situations and acting accordingly, whilst also holding back. Some highlight the desire to ‘be a midwife’. This implies a need to practice one’s profession, without the level of tension and tight time frames found in emergency nursing or obstetrics.The midwives in this study are aware that they occasionally use strategies that stretch the limits for certain procedures, without this increasing the risk for the women. Making conscious choices during childbirth can reduce unnecessary interventions, thereby helping to optimize the potential for a normal birth25, and it also plays a role in their choice of workplace. Working in a free-standing midwifery-led unit required not only a belief in the women being able to give birth, but also in themselves and their own knowledge. According to Hunter25, confidence in birth as a physiological process requires a safe and reliable relationship between the members of the midwifery team. The midwives we interviewed highlighted a common ideology as an important reason for facilitating normal birth. The security of knowing that colleagues shared the same approach to birth and the opportunity for professional discussion was highly valued, and a strong emphasis was placed on the art of transferring this to the women. Both WHO4 and the International Confederation of Midwives (ICM)35 emphasize that midwives must work to promote normal birth, which the midwives do by providing continuous antenatal care for the women. This gave the midwives the opportunity to provide information and to prepare and motivate the women for a normal birth, and they thoroughly enjoyed watching the women’s progress throughout their pregnancy.Midwives’ confidence in birth as a physiological process is crucial for promoting normal birth20. Several had experienced contradictions between midwifery theory and practice in previous jobs at a hospital maternity ward. They talked about the experience of being caught between technological procedures and professional autonomy. They perceive it as frightening when confidence in technology comes at the expense of clinical insight and knowledge acquired through many years of practice. The ward’s framework can govern how the midwives can facilitate normal birth. The reasons for the midwives’ previous experiences of resistance to a physiological approach to childbirth are complex, but include rigid timeframes and lack of continuity36. Centralization at organizational level also plays a role, as does the focus on risk surveillance behavior within wards at a professional level21. An overriding risk surveillance approach in hospital maternity wards is a factor that is known to inhibit facilitating normal birth in hospitals20. At the individual level, lack of knowledge, lack of autonomy and the feeling of ownership of one’s own birth process are barriers to the physiological birth process21. Conversely, women who give birth in a midwifery-led unit have made a conscious choice about their own childbirth experience.Shared collegial beliefs and positive cooperation can be at odds with previous research where midwives working in maternity wards find that impatient colleagues ruin the elements of time and patience, which are needed in a normal birth22. All of the midwives had positive experiences in promoting normal birth. They had extensive experience from a midwifery-led unit and were enthusiastic about their profession. This allowed for a rich dataset to be produced despite the small purposive sample. Nevertheless, a broader sample including midwives from non-Western cultures as well as less experienced midwives probably would have strengthened the study. Further, we used Zoom to conduct several interviews. This probably made it challenging to interpret non-verbal language, but on the other side, it enabled us to include midwives from a wide geographical spread. One of the study’s strengths is the close collaboration between the authors throughout the process. This helped prevent the authors’ own opinions and preconceptions becoming prominent.The use of a qualitative method with thematic analysis was a suitable approach for this study as we aimed to gain knowledge on the experiences of a small group of midwives in NorwayThis study sheds light on several aspects that help to facilitate normal birth in midwifery-led units in hospitals and free-standing midwifery-led units. Reassuring relationships, midwifery skills and the importance of believing in the birth process in a supportive working environment that facilitates the midwife’s autonomy, are prominent factors. The midwives had positive experiences in promoting normal birth. However, they also highlighted the challenges of working in a similar way in medicalized contexts.


This article examines pregnancy results in a changed metabolism, with more frequent glucose intolerance and subsequent gestational diabetes. Metabolic disturbances may significantly influence foetal development and neonatal health; therefore, a routine checkup of glucose tolerance is performed. Several factors may influence the prevalence of gestational diabetes, including ambient temperature, light exposure, and vitamin D levels. The published data related to seasonal impact are contradictory. We have retrospectively analysed a large cohort of newborns and their mothers. In total, 30,205 newborns and their epidemiological and clinical characteristics were evaluated. We documented that the prevalence of gestational diabetes in Central Europe varied depending on the season; that is, it appears more frequently during the summer, while its prevalence was lowest during the winter (seasons with higher vs. lower insolation). The seasonal variation in the prevalence of gestational diabetes affects both mothers of babies born at term and prematurely.p < 0.0001) lower in spring (14.71%) than in the other seasons (16.78%). A higher incidence of GDM was observed for mothers who underwent an oral glucose tolerance test from June to August compared to those who were tested from December to February . Similarly, there were significant differences between seasons with higher and lower insolation. The regression analysis revealed that seasonal patterns were significantly associated with the prevalence of GDM. In conclusion, this large retrospective cohort study demonstrated seasonal changes in GDM risk. The observed seasonal patterns may equally refer to mothers of babies born at term and prematurely. Further research concerning GDM risk and other seasonal and gender associations is warranted.The existing literature does not address the question of the seasonal impact on pregnancy in Central-Eastern Europe; therefore, this study was designed to investigate the seasonal variation in gestational diabetes mellitus (GDM) based on a recent Polish sample. The data of 30,205 newborns from singleton pregnancies and their mothers, including the date and gestational age of birth, neonatal sex and weight, maternal age and parity, mode of delivery, ethnicity, and a detailed list of comorbidities (including GDM), were retrospectively analysed. The prevalence of GDM was significantly ( Birth weight is one of the most critical neonatal health indicators, with low and high birth weights associated with subsequent health issues and measurable life outcomes . The sugThe relationship between vitamin D and GDM is relatively well established. This association is partly explained by higher body mass index (BMI) . Indeed,The existing literature does not address the question of the seasonal impact on pregnancy in Central-Eastern Europe. This region has a humid continental climate ,10 with 2/day according to www.gaisma.com (months >3.0 kWh/m2/day: April–August).This retrospective cohort study analysed data that were collected from the electronic database of gestations from February 2017 to February 2022 at Poznan University Hospital . All neonates were born from singleton pregnancies, and their mothers were included in the analysis. The analysed data included the date and gestational age of birth, neonatal sex and weight, maternal age, BMI and parity, mode of delivery, ethnicity, and a detailed list of comorbidities. Most of the study cohort were Caucasians. Gestational age was verified and confirmed by ultrasound in the first trimester. GDM was diagnosed according to the International Association of Diabetes and Pregnancy Study Groups (IDASPG) criteria  and Polip < 0.05, and a confidence interval of 95% was applied. The normality of the data distribution was assessed by the Shapiro–Wilk test, with Levene’s test used to assess the equality of variances. Numerical data were presented as mean and standard deviation (SD) and Boolean as number (percentage (%)). For continuous variables, unpaired t-tests were used to compare two groups, with an analysis of variance for months and seasons. Post hoc comparisons were performed with Tukey’s significantly different test. A Chi2 test was used for the analysis of categorical variables. Univariate (unadjusted) logistic regression analysis was subsequently performed to assess the relationship between season of birth, sex of infants, gestational age at birth, age of mother, BMI of mother, birth weight of infants, mode of delivery, gestational hypertension, and preeclampsia with the prevalence of GDM. To confirm the relationship between the season of birth and gestational diabetes, parameters that were used in the univariate analysis and those that were related to the season were entered into a multivariate logistic regression analysis and adjusted for birth weight ≥ 90 percentile, caesarean birth, age of mother ≥ 35 years, BMI of mother, gestational hypertension, and preeclampsia. Ethical approval was not required due to the retrospective character of the analysis [Statistical analysis was performed using the Statistica 13.0 software . The level of significance was set at analysis . HoweverIn total, 30,205 newborns were included in the final analysis, and their epidemiological and clinical characteristics are presented in Male infants were younger and had a higher birth weight compared to females. Furthermore, a higher proportion of boys were born prematurely .p < 0.0001). The season of conception was also associated with the prevalence of GDM (p < 0.0001). A higher incidence of GDM was also observed for mothers who underwent an OGTT between June and August compared to those who underwent the test between December and February . The prevalence of GDM in mothers who gave birth in spring (14.71%) was significantly lower (p < 0.0001) than in women who gave birth during other seasons of the year (16.78%).No differences in the sex, gestational age, prevalence of preterm birth, or birth weight of infants born in different seasons were documented . Table 2e of GDM . ConceptThe prevalence of GDM depended on the season that OGTT was performed for mothers of children born at term. This association was not statistically significant in mothers of preterm infants ; howeverThis retrospective study showed that the prevalence of GDM varies depending on the season, with GDM more frequently diagnosed during the summer while its prevalence was lowest during the winter. Similarly, there were significant differences in GDM prevalence between seasons with higher and lower insolation. The seasonal pattern remained significant, even after adjusting for covariates. Additionally, our analysis uncovered other noteworthy findings. For example, we found that caesarean sections were more common in pregnant women who delivered boys in December.It has been suggested that ambient temperature may influence glucose tolerance ,16,17. AThe results may have been influenced by the GDM screening and diagnostic criteria that were used in studies included in both systematic reviews ,29,30,31The present study demonstrated the noticeable impact of summer on the prevalence of GDM diagnoses according to international standards used in Poland , a countIn conclusion, we demonstrated a seasonal pattern of GDM risk in this large retrospective cohort study. The seasonal variation in GDM prevalence may equally refer to mothers of babies born in term and born prematurely. Further research concerning GDM risk and other seasonal and gender associations is warranted.


There is limited and inconsistent evidence, primarily from cross-sectional studies, linking mycotoxins to adverse birth outcomes. This study investigates the potential role of maternal dietary exposure to multiple mycotoxins in the development of several adverse pregnancy and birth outcomes. We analyzed data from 436 singleton pregnancies enrolled in a prospective cohort study in the rural Habiganj district, Bangladesh, between July 2018 and November 2019. Thirty-five urinary mycotoxin biomarkers were quantified using liquid chromatography coupled with tandem mass spectrometry and used to estimate dietary mycotoxin exposure. Multivariable regression models, adjusted for potential confounding and clustering, were fitted to assess the associations between maternal exposure to frequently occurring mycotoxins  and pregnancy loss, preterm birth (PTB), low birth weight (LBW), born small-for-gestational-age (SGA) and small-vulnerable newborn. The results indicate that only in 16 of 436 pregnancies (4%) were urine samples free from all investigated mycotoxins. Biomarkers for six major mycotoxins were detected in the urine samples. OTA (95%), CIT (61%), and DON (6%) were most frequently detected, with at least two mycotoxins co-occurring in the majority of women (63%). There was evidence that maternal dietary intake of OTA was associated with higher odds of having an LBW baby, with the odds increasing in a dose-dependent manner. We found no evidence of associations between pregnancy loss, PTB, SGA, small-vulnerable newborns, and maternal dietary exposure to OTA, CIT, and DON, albeit with large confidence intervals, so findings are consistent with protective as well as large harmful effects. Exposure to multiple mycotoxins during pregnancy is widespread in this rural community and represents a health risk for mothers and babies. Tailored public health policies and interventions must be implemented to reduce mycotoxin exposure to the lowest possible level.The online version contains supplementary material available at 10.1007/s00204-023-03491-7. In most developing countries, a substantial proportion of pregnancies end in miscarriage, stillbirth, or live birth with adverse pregnancy outcomes, such as low birth weight (LBW), small for gestational age (SGA), and preterm birth (PTB) , ochratoxin A (OTA), citrinin (CIT), zearalenone (ZEN), and deoxynivalenol (DON) in pregnant women  report high occurrences and concentrations of major mycotoxins such as aflatoxins (AFs), fumonisin B1) and higher occurrence of adverse birth outcomes in LMICs  checklist  study, a cluster-randomized controlled trial conducted in two sub-districts of Habiganj district under Sylhet division in Bangladesh . FAARM included 2705 young married women in 96 settlements (geographic clusters) who reported an age below 30 years, an interest in gardening, and had access to at least 40 m2 of land. Settlements were randomized into 48 intervention and 48 control clusters. The FAARM trial evaluates the impact of a homestead food production program implemented by the international non-governmental organization Helen Keller International on undernutrition in young children. Further information on the FAARM trial design is available in the study protocol . MEMAPO enrolled a subsample of FAARM women during early pregnancy. FAARM women were given calendars to record the first day of each menstrual period. Those with a known last menstrual period (LMP) that suggested a gestational age of < 20 weeks were considered eligible for MEMAPO. A total of 443 pregnancy events were identified through FAARM’s active house-to-house bi-monthly surveillance between July 2018 and November 2019. Pregnant women were consented to by field workers in the local language, and those consenting gave a urine sample for mycotoxin analysis. The MEMAPO open cohort followed up with pregnant women until the end of pregnancy to investigate the role of maternal exposure to mycotoxins for the development of specific adverse pregnancy outcomes . Trained field data collectors attempted to visit all newborn babies within 72 h of delivery for anthropometric measurements  using standardized equipment . For the current study, we analyzed data from 436 non-terminated singleton pregnancy events and 317 babies measured within 72 h of delivery  national wealth quintiles was calculated using the Equity Tool , rainy monsoon (June–October), and cool, dry winter (November–February) according to the sampling date. Women’s average dietary diversity scores were calculated using data from all surveillance rounds. Dietary diversity is the variety of foods pregnant women consume from ten food groups. These food groups include starchy staples, vitamin A-rich vegetables and fruits; dark green leafy vegetables; other vegetables; other fruits; meat, poultry, and fish; eggs and pulses/legumes; nuts and seeds; and dairy products , E is the excretion rate (%) of the mycotoxin, and V is the daily urine excretion volume (ml) for OTA and estimated maternal PDI of OTA. The scientific committee of EFSA and the WHO consider a MOE of 10,000 or more to be of low concern for public health  et al. Details of health risk characterization of the estimated maternal daily intake of individual mycotoxins based on their toxicity profiles are presented elsewhere  at delivery was calculated based on self-reported last menstrual period (LMP) and the child's date of birth. Furthermore, GA estimates based on head circumference measurements within 72 h of delivery were calculated using an excel-based gestational age calculator IG21  developeOur primary dependent variables included pregnancy loss and three established indicators of newborn vulnerability—preterm birth (PTB), low birth weight (LBW), and birth small-for-gestational-age (SGA). These three indicators  were assessed individually and combined to describe five identified vulnerable newborn phenotypes , history of pregnancy loss , antenatal attendance , iron supplementation , infant sex , household wealth index , average dietary diversity score , and food security status . For LBW and SGA, the following binarized variables: low maternal weight  and short maternal stature  were used as predictors, respectively, based on literature  (Stata Corporation Descriptive statistics are presented as mean ± SD or median [interquartile range (IQR)] for quantitative variables and as frequencies and percentages for categorical variables. Mixed-effect linear regression models were used to determine if maternal mycotoxin exposure was associated with GA at delivery, birth weight, birth length, and head circumference while accounting for other factors. Mixed effect binary logistic regression models were used to identify if maternal mycotoxin concentrations were associated with pregnancy loss, PTB, SGA, and small-vulnerable newborn status while accounting for other factors. Models were fit using mycotoxin exposure as a continuous variable after a zero-skewness logarithmic transformation (Stata command 10) for OTA / estimated PDI of OTA < 10,000). Thus, to define relatively high exposure of OTA, we explored the best functional form that described the relationship between PDI of OTA and LBW. A 1000 ng/kg bw/day cut-off was determined as the exponential curve’s turning point that best fit the data.In addition, the PDI of OTA, CIT, and DON were categorized into dichotomous variables to depict high exposure compared with established health-based guidance values by scientific committees, such as the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the EFSA EFSA . EstimatTo avoid over-adjustment and multi-collinearity across the covariates, different measures of collinearity were assessed using Stata’s collin command. Variance inflation factor < 6, tolerance < 0.01, and condition number > 10 were considered acceptable. Data management and statistical analysis were performed using Stata version 17.0 .A study flow chart is presented in Fig. The baseline characteristics of the 436 pregnant women with unterminated singleton pregnancies are shown in Table The characteristics of the 317 children measured within 72 h of delivery are shown in Table 1, OTA, and ZEN. Only 4% of the pregnant women included in this study had no detectable levels of the investigated mycotoxin biomarkers. About a third of each were exposed to one, two, and three detectable mycotoxin biomarkers  reduction of birth weight compared to newborns whose mothers consumed lower levels of OTA. We did not find evidence for the effect of increasing maternal OTA intake on the duration of pregnancy, birth length, and head circumference. Likewise, using the continuous (log-PDI), categorical (tertiles), and binarized (high vs. low) exposure variables, we found no evidence for an association between higher maternal daily intakes of CIT and DON, and duration of pregnancy, birth weight, birth length, and head circumference at birth.Regression coefficients (β) along with a 95% confidence interval (95% CI) for the associations between anthropometric birth outcomes  and higher maternal dietary intake of OTA, CIT, and DON are presented in Table P = 0.026). Using the binary variable, a high maternal dietary intake of OTA (> 1000 ng/kg/day) was associated with a fourfold increase in the odds of having an LBW baby, with an OR between 1.25 and 12.5 reasonably likely (P = 0.019). For each tertile increase in maternal OTA intake from lowest to highest, the odds of having an LBW baby increase 1.7-fold . Breaking down the highest tertile into finer categories, the dose-dependent increase in the odds of having an LBW baby becomes much clearer (Supplementary Table S3), increasing from 2.03 (OTA intake: 401–1000 ng/kg/day) to 4.05 (OTA intake: 1001–1500 ng/kg/day) to 6.59 (OTA intake > 1500 ng/kg/day) (P for trend = 0.009). We found no evidence of an association between higher maternal dietary intake of OTA and other adverse birth outcomes, albeit with large uncertainties. For instance, among women with a high intake of OTA, the odds of SGA were more than double, with a halving of the odds and a nine-fold increase also reasonably likely. Similarly, our results provide no evidence of an increasing dose effect of maternal dietary intake of CIT and DON on adverse birth outcomes.The odds ratios (ORs) and 95% CIs for the associations between higher maternal dietary intake of OTA, CIT, or DON and adverse birth outcomes, –including pregnancy loss, babies born too soon (PTB), and those born too small – are presented in Table In multivariable logistic regression models investigating fixed-dose effects (i.e. detection above LOD), we found no evidence that maternal exposure to OTA alone versus in combination with other mycotoxins differed in their impact on adverse birth outcomes Table . HoweverLike in other resource-poor settings, exposure to multiple mycotoxins during pregnancy is common in Bangladesh  ended in a spontaneous miscarriage. This finding is similar to incidence estimates of miscarriage among pregnant women in two prospective Chinese studies   was much higher than the current national estimate of LBW, which is 16%  were free from all investigated mycotoxin biomarkers indicates that pregnant women have widespread exposure to mycotoxins in this rural community in Bangladesh. Considering that different mold species may contaminate a given food sample and that molds often require similar conditions for toxin production , and pregnancy loss, PTB, SGA, and small-vulnerable newborns. However, exposure was generally high. Under a moderate exposure scenario, the mean maternal PDI of OTA was up to 24 times higher than the previous health-based guidance value of 17.1 ng/kg bw EFSA . Using tAnimal studies have established that dietary exposure to OTA and CIT causes reduced maternal weight gain, impaired reproduction, reduced fetal weights and crown-to-rump lengths, and teratogenic effects , an odds ratio between 0.9 and 21 was also reasonably likely. As few women were exposed to DON in our cohort, the power to detect any true effects of DON exposure on adverse pregnancy outcomes was low. Nonetheless, experimental animal studies have shown that chronic low-dose exposure to DON may cause adverse effects such as anorexia, poor maternal weight gain, immunotoxicity, impaired reproduction, and decreased offspring weight Pestka .As intestinal epithelial cells are the first targets of ingested mycotoxins such as OTA, CIT, and DON, the mechanism of growth faltering is likely from mycotoxin-induced damage and inflammation of the intestinal mucosa resulting in poor maternal uptake and retention of nutrients leading to poor maternal weight gain and, consequently, growth faltering in the fetus , along with paired birth surveillance data (n = 317 within 72 h of delivery), and the estimation of maternal dietary intake of mycotoxins based on multiple urinary mycotoxin biomarker analyses. The longitudinal design ensures the temporality of exposure is established and thus allows for a causal investigation of the effect of prenatal exposure to multiple mycotoxins  on birth outcomes. We also investigated different mycotoxin exposure effects, including fixed-dose effects, and increasing-dose effects, controlling for the presence of other mycotoxins. Furthermore, our adjustment for the design effect and many important potential confounders reduce the potential for bias. Nonetheless, as with all observational studies, residual confounding from unmeasured confounders  cannot be ruled out. The applied analytical method for detecting urinary mycotoxins covered a broad spectrum of compounds but focused on the previously detected highly relevant mycotoxins OTA and CIT/HO-CIT Below is the link to the electronic supplementary material.


A meta-analysis of preterm delivery  revealed seven associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles  shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal–fetal relationship between gestational duration and birth weight.The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration ( Maternal genome-wide analyses identify variants associated with gestational duration and preterm delivery. Maternal alleles positively associated with gestational duration exhibit negative fetal effects on birth weight, likely reflecting antagonistic pleiotropy. Although the rate of neonatal mortality has substantially decreased in recent years, the reduction attributable to preterm delivery is one of the lowest among the major causes of mortality2. This fact partly reflects the relatively poor knowledge of the processes governing the timing of delivery in humans. Parturition may be initiated by a diversity of biological and mechanical pathways. Some of these are part of the physiological timing process, whereas others may override pregnancy maintenance with fail-safe mechanisms 3. The diversity of the mechanisms has led to the conceptualization of preterm delivery as a syndrome4, with various pathophysiological processes contributing to its etiology. Both maternal and fetal genomes are involved in these mechanisms. Yet, genetic studies have identified only a handful of loci associated with the timing of parturition6.In humans, similar to mammals broadly, the timing of delivery is crucial for neonatal survival and health. Preterm delivery is the world-leading direct cause of death in neonates and children under five years of age7, evidenced by half of twin pregnancies delivering preterm8. Both the maternal and fetal genomes contribute to birth weight as well, as revealed in recent genome-wide association studies (GWAS)10, and over evolutionary time may have even conflicted on gestational duration and birth weight, as proposed in the hypothesis of the genetic conflicts of pregnancy11. This hypothesis suggests that the maternal genome favors slightly shorter gestations and lower birth weight, whereas the fetal genome favors the opposite. Coadaptation theory, instead, suggests that maternal and fetal genomes may invest resources to achieve an optimal gestational duration or birth weight that increases fitness12. These known contributions, potential conflicts and coadaptation of gestational duration and birth weight may ultimately create a complex relationship between the two.Gestational duration is the major determinant of birth weight . At the same time, uterine load is one of the known triggers of parturitionWhat and how distinct are the maternal genetic effects on gestational duration and preterm delivery? What is the relationship between fetal growth and gestational duration? Is there evidence suggesting maternal–fetal coadaptation on these traits? To address these questions, we conducted a GWAS meta-analysis of gestational duration and preterm and post-term delivery in >190,000 maternal samples with spontaneous onset of delivery. We further analyzed these results using the parental transmitted and nontransmitted alleles in >135,000 parent-offsprings.5. After quality control (QC), genetic variants at 22 loci were associated with gestational duration at genome-wide significance  to 27 (MRPS22) hours of gestation per allele . Heterogeneity in the effect estimates was limited to loci previously identified , likely due to winner’s curse13 (Supplementary Table n = 6) showed that all four that were available after QC replicate at nominal significance  in induced pluripotent stem cells15, endometrium16, uterus, vagina and ovary17  and four non-coding genes colocalized with gestational duration. Furthermore, colocalization analysis with blood protein QTLs18 showed several trans associations: ZBTB38 with three proteins, and TCEA2/OPRL1 and WNT4 with one each. Particularly interesting are the associations with OPRL1 and POMC, which play a role in modulating nociception and pain perception; in vitro studies in tissues from pregnant rats and humans suggest that the administration of nociceptin inhibits uterine contractions, mediated by the OPRL1 receptors20.To prioritize candidate genes, we performed colocalization analysis21. Using stratified LD-score regression, we show that the heritability of gestational duration is enriched in regions harboring genes differentially expressed during labor  and post-term delivery   that showed weak evidence of association with gestational duration (P = 3.9 × 10−3).We also performed a GWAS meta-analyses of preterm delivery  = −0.72, −0.51) between gestational duration and preterm delivery, suggesting similarities between the two phenotypes , suggesting no differences in the maternal genetic effects on such traits.We observed a modest genetic correlation , and two were grouped as having a fetal-only effect: the first, independent of the parent of origin , and the second limited to the maternal transmitted allele (EEFSEC). Caution should be taken when interpreting the latter considering the low probability (0.47).The genetic effects on pregnancy traits may be driven by two correlated genomes: the maternal and the fetal. To investigate whether the gestational duration signals originate in either or both genomes, we used phased genotype data to estimate the effects of the parental transmitted and nontransmitted alleles from 136,833 parent-offspring trios or mother-child duos  had both maternal and fetal effects on gestational duration with the same effect direction. Interestingly, a SNP also located in the first intron of ADCY5 harbors maternal and fetal effects on birth weight, but in opposite directions, attributed to the fetal insulin hypothesis10. The two index SNPs for gestational duration (rs28654158) and birth weight (rs11708067) are located 50 kb apart from each other and are in low LD (r2 < 0.2). The birth weight SNP, also implicated in diabetes, likely acts through ADCY5 (ref. 24), but it is unknown whether the gestational duration variant also acts through the same gene, although it colocalizes with ADCY5 gene expression in the uterus 6 clustered as having a fetal-only effect (Supplementary Table P = 2.7 × 10−6).The only fetal index SNP identified to date in a GWAS (25) and estimated their effect on both traits. The polygenic score for gestational duration explains 2.2% of its variance . The lowest decile had a mean gestational duration of 278 days , whereas the highest decile had a mean of 283 days   using LDpred2 , testosterone  and sex hormone binding globulin  in women were modestly genetically correlated with preterm delivery, whereas there was little genetic correlation with levels of the same hormones in men  compared to cohorts based on a random pregnancy , indicating an increased probability of preterm delivery with an increasing number of live births. We also detected a negative genetic correlation with age at first birth and age at menopause.To examine the potential shared genetic basis between the timing of parturition and other traits, we estimated the genetic correlations between 14 female reproductive traits and the maternal effects on gestational duration and preterm delivery Fig. . These e27 model between sex hormones and preterm delivery and gestational duration n = 46,105 parent-offsprings; Supplementary Table Using the parental transmitted and nontransmitted alleles in individual-level parent-offspring data from Iceland and Norway  and fetal-only effect . These models were obtained using weighted linear modeling and provide unbiased estimates for the maternal and fetal effects, respectively. The fetal effects on gestational duration were obtained from a previously published GWAS6. The more recent GWAS meta-analysis of fetal growth10 had >40% of samples adjusted for gestational duration, which is the reason why we did not use it in this section.We sought to understand the genetic relationship between gestational duration and birth weight and how the interplay between the maternal and fetal genomes affect this relationship. We used published summary statistics of birth weight  derived from two different modelsrg = 0.65; 95% CI = 0.54, 0.75). Conversely, neither the maternal  nor the fetal  effects on gestational duration were genetically correlated with the fetal-only effects on birth weight. We suggest the maternal effects on birth weight are at least partially mediated by gestational duration, whereas the effects of the fetus on birth weight are not.The maternal effects on gestational duration are strongly correlated with those on birth weight . Applying the same method on genome-wide significant variants classified with a maternal-only effect on birth weight9 provided very similar results (Supplementary Table 9).We then tested the extent of this mediation. Using multitrait COJO analysisIn summary, although the maternal effects on birth weight are partially driven by gestational duration, we found no evidence for this for the fetal effects on birth weight.It is widely accepted that longer gestations lead to heavier newborns. Here, we sought to obtain causal estimates of the effect of gestational duration on birth weight.9). The maternal nontransmitted gestational duration-increasing alleles were associated with higher birth weight . The estimated effect (approximately 23 g per day) is concordant with the phenotypic association between gestational duration and birth weight . We observed no effect from the paternal transmitted gestational duration-increasing alleles on birth weight. The LCV model confirmed a full or nearly full causal  than ultrasound. This result supports previous evidence showing faster fetal growth is associated with shorter duration of gestation30. To investigate whether this was due to antagonistic pleiotropy between the fetal effects on birth weight and the maternal effects on gestational duration, we assessed the relation between birth weight-increasing alleles and maternal effects on gestational duration. The fetal birth weight-increasing alleles were not associated with maternal effects on gestational duration  but was also observed for the maternal nontransmitted gestational duration-increasing alleles . The paternal transmitted gestational duration-increasing alleles were not associated with fetal-only effects on birth weight , the effects are partly mediated by gestational duration. This has implications for the interpretation of GWAS of birth weight and downstream analyses, such as Mendelian randomization. In contrast, the fetal genetic effects on birth weight are not mediated by gestational duration, suggesting the fetal genome mainly acts on birth weight by modulating fetal growth. Interestingly, the maternal gestational duration-increasing alleles have negative fetal effects on birth weight, likely reflecting antagonistic pleiotropy. The opposite was not true; fetal birth weight-increasing alleles were not associated with maternal effects on gestational duration. We speculate that the fetal effects on birth weight have likely co-adapted to increase the fitness of the fetus in pregnancies genetically predisposed to a shorter duration. It has been suggested that both gestational duration and birth weight are under balancing selection, with intermediate values of these traits having highest fitness33. As exemplified here, this could lead to antagonistic pleiotropy favoring the coadaptation of maternal and fetal effects to attain optimal gestational duration and birth weight12.Gestational duration is the major determinant of birth weight. Although the maternal genome affects offspring birth weight through many different causal pathways  and excluded preterm deliveries, which is likely to affect our analyses by reducing their power. Third, we assumed a causal association between gestational duration and birth weight. Although this is known to be true to some extent , pleiotropy between gestational duration and birth weight could be very well at play. Fourth, phenotypic heterogeneity between cohorts  may have hindered the identification of additional signals.The presented results have several limitations. First, we analyzed data from participants of European ancestry. Over 70% of the samples were obtained from Nordic countries, with genotype data linked to the Medical Birth Registers; in these countries, the preterm delivery rate is one of the lowest in the worldIn conclusion, the present results provide evidence of large genetic similarities between gestational duration and preterm delivery and further our understanding of the complex relationship between gestational duration and birth weight. Particularly, we show that the maternal effects on birth weight are largely driven by gestational duration and that the maternal and fetal genomes have antagonistic pleiotropic effects on gestational duration and birth weight.In this study, we included pregnancies with a singleton live birth and a spontaneous onset of delivery: medically initiated deliveries (either by induction or planned cesarean section) were excluded or part of controls for preterm delivery. Gestational duration in days was estimated using either the last menstrual period date or ultrasound. We excluded pregnancies lasting <140 days (20 completed weeks) or >310 days (44 completed weeks), as well as women with health complications prior to or during pregnancy and congenital fetal malformations. Spontaneous preterm delivery was defined as a spontaneous delivery <259 days  or by using the ICD-10 O60 code, and controls as a delivery occurring between 273 and 294 days . Post-term delivery was defined as a delivery occurring >294 days (42 completed weeks) or ICD-10 O48 code, and controls as a spontaneous delivery between 273 and 294 days . Given the perfect genetic correlation between gestational duration and post-term delivery GWAS, and the small power of the latter, all downstream analyses are focused on gestational duration and preterm delivery.35, deCODE genetics10, Trøndelag Health Study (HUNT)36, Danish Blood Donor Study (DBDS)37, the Estonian Genome Center of the University of Tartu (EGCUT)38 and summary statistics from FinnGen39 and from a previous GWAS of gestational duration and preterm delivery performed using 23andMe data5. A total of 18 different cohorts  and 131,279 samples for post-term delivery  of recent European ancestries . For binary outcomes (preterm and post-term deliveries), only cohorts with an effective sample size >100 were included. Detailed description of the cohorts included can be found in the This study consists of cohorts participating in the Early Growth Genetics (EGG) Consortium and the Norwegian Mother, Father and Child Cohort study (MoBa)P value < 1 × 10−6 or minor allele frequency <1%. Reference panels for imputation were either 1000 Genomes Project40, Haplotype Reference Consortium41, 10KUK or a combination of one of the mentioned reference panels and own whole-genome sequencing data . Each individual cohort performed a GWAS using an additive linear regression model adjusted for, at least, genetic principal components or relationship matrix on autosomal chromosomes and chromosome X. Summary statistics for each individual cohort were stored centrally and underwent QC procedures before meta-analysis . Genetic variants were excluded if genotype call rate <98%, Hardy-Weinberg equilibrium analysis .42 without genomic control correction. We also performed an analysis of heterogeneity of effects (Supplementary Table I2 statistic). After meta-analysis, we removed genetic variants reported in less than half the number of available samples for each phenotype, resulting in 9-10 million genetic variants. For example, the variant observed in the largest number of samples for gestational duration was available in 195,555 individuals; only variants reported in at least 97,778 were kept. Genomic inflation factors were low for all three phenotypes .Initially, we naively defined independent loci based on physical distance, where SNPs within 250 kb from the index SNP were considered to be at the same locus. Novel loci were defined as loci not overlapping previously reported gestational duration loci in the largest GWAS performed to date43 implemented in Genome-wide Complex Trait Analysis (GCTA) software44. We ran a stepwise model selection (-cojo-slct) to identify conditionally independent genetic variants at P < 5 × 10−8 for each of the genome-wide significant loci (using a radius of 1.5 Mb from the index SNP). Overlapping loci were merged into a single locus . LD between genetic variants was estimated from 19,092 maternal samples from the Norwegian Mother, Father and Child Cohort, after excluding variants with imputation INFO score <0.4. We converted the reference panel from BGEN files to hard-called PLINK binary format (.bed). As per default in COJO, genetic variants >10 Mb apart were assumed to be in complete linkage equilibrium.We looked for conditionally independent associations within each locus using approximate conditional and joint (COJO) analysis46. Next, we performed colocalization analysis for cis-eQTLs in 1,367 human induced pluripotent stem cell lines from the i2QTL resource (±250 kb from gene start and stop position)15, endometrium (± 250 kb from gene start and stop position)16 and uterus, vagina and ovary from GTEx (±1 Mb around transcription start site)17. None of the variants we identified were in LD (r2 > 0.6) with missense variants. To complement the prioritization of genes, we queried each of the index SNPs for blood protein QTLs18 (both in cis and trans). For all index SNPs that were protein QTLs (P < 5 × 10−6), we performed colocalization analyses (±1.5 Mb around the index SNP). We excluded the HLA region due to its large pleiotropic effects.To prioritize genes at the gestational duration loci identified, we set the baseline as the nearest protein-coding gene to the index SNP at each independent locus. Although naive, this approach has been consistently shown to outperform other single metrics for locus-to-gene mapping14, which evaluates, in a Bayesian statistical framework, whether a single locus from two different phenotypes best fits a model where the associations are due to a single shared variant or distinct variants in close LD  and with other female and reproductive traits. To this end, we applied COLOCclose LD .−4, 1 × 10−4, and 5 × 10−6, respectively), which are considered more conservative than the ones set by default47. Strong evidence of colocalization was defined as a posterior probability of colocalization >0.9.Prior probabilities for each for the non-null hypotheses were set as suggested by Wallace  and all other genes. Significance for this test was set at Bonferroni correction for the number of tissues (P < 0.05/61), and suggestive evidence at P < 0.1/61. At the genome-wide level, we performed partitioned heritability using LD-score regression to test for enrichment in 97 different annotations50, tissue-specific RNA expression using 205 different tissues/cell types51, using precomputed partitioned LD-scores for subjects of recent European ancestry (baseline-LD model v2.2) and for enrichment in regions harboring genes differentially expressed during labor in single cells from myometrium22.We tested for enrichment based on top loci and genome-wide using partitioned LD-score regression. To test for overrepresentation in tissue-specific RNA expression 52 locally using precomputed LD-scores from 1000 Genomes Project samples of recent European ancestry. The MHC region (chr6:28477797-33448354) was removed prior to running LD-score regression.We estimated genetic correlations by performing LD-score regression30. Once the transmitted allele was identified, the nontransmitted maternal allele was extracted. Briefly, parental origin of each allele was inferred using genotypes of relatives, reference cohort data, or distributions of genotypes within the cohort and LD measurements. Different methods were used for phasing in each of the cohorts providing data for this analysis56  in parent-offsprings or mother-child duos to infer the parent-of-origin of the genotyped/imputed alleles as previously describedMnT and MT refer to the maternal nontransmitted and transmitted alleles respectively, and PT refers to the paternal transmitted alleles. The latter is interpreted as a fetal-only genetic effect, whereas the effect of the maternal nontransmitted allele is a maternal-only genetic effect. We first estimated the effects of the index SNPs in each birth cohort separately; effect sizes were then combined through fixed-effect meta-analysis, totaling a sample size of 136,833  and Pan UK Biobank data 6, age at first birth, age at menarche , age at menopause57, number of live births , testosterone58, CBAT58, SHBG58, estradiol , pelvic organ prolapse (FinnGen), polycystic ovary syndrome (59 and FinnGen), endometriosis , leiomyoma uterus (FinnGen) and pre-eclampsia60. For polycystic ovary syndrome, we meta-analyzed summary statistics from the largest published GWAS59 and FinnGen. We estimated genetic correlations between gestational duration and preterm delivery and these traits, and latent causal variable analysis between sex hormones  and gestational duration and preterm delivery. We further explored causality using two-sample Mendelian randomization and inspected whether the effects originated in the maternal or the fetal genome . Finally, when one trait is causally upstream of the other, it is expected that the two traits would share a causal variant at some of the trait-associated loci. To test for this at the genome-wide scale, we performed colocalization analysis between sex hormones and gestational duration and preterm delivery using approximately LD-independent regions61.We obtained summary statistics for several female reproductive traits from different sources . We included summary statistics from the following traits: miscarriagen = 15,768) as the training cohort and the remaining 20%  as the validation cohort. LDpred2 was used for the calculation of the polygenic scores25. A description of polygenic score training can be found in To obtain an independent sample for training and validation of a polygenic score, the meta-analyses for gestational duration were rerun, excluding the MoBa cohort. These new meta-analysis results were used as the base data sets to calculate the polygenic scores. After applying the same exclusion criteria as used for the study samples in the meta-analysis, and removing duplicated samples and those with a kinship of greater than 0.125, the MoBa cohort was randomly split, using 80%  or full term (≥39 weeks and <41 weeks). Two models were analyzed, one assessing just the polygenic score and a second adjusting for five principal components and genotype batch. Receiver operating characteristic, area under the curve were calculated for each model and used as assessment of diagnostic accuracy.We performed Mendelian randomization to study the effects of gestational duration  on birth weight  and the effects of fetal growth  and sex hormones on gestational duration.9.To study the effect of gestational duration on birth weight, we employed two-sample Mendelian randomization. The 24 index SNPs  from the present gestational duration meta-analysis and the effect sizes from the parental transmitted and nontransmitted alleles analysis were used to instrument gestational duration. Birth weight was instrumented using summary statistics from a previous GWAS of offspring’s birth weight with minimal adjustment by gestational duration (<15% of samples)r2 > 0.001) using the following PLINK command:We assessed the effect of sex hormones  on gestational duration using two-sample Mendelian randomization and instrumenting the hormones using a polygenic score for the parental transmitted and nontransmitted alleles. For each sex hormone, we obtained a list of independent SNPs genome-wide associated with these traits . We subsequently constructed the polygenic score for the maternal transmitted and nontransmitted alleles and the paternal transmitted alleles in 46,105 parent-offsprings from Iceland and Norway. We estimated the effects of the maternal nontransmitted (MnTPGS) and transmitted (MTPGS) and paternal transmitted (PTPGS) alleles polygenic score using the following linear model:We also used a set of SNPs associated with testosterone, but with no aggregated effects on SHBG, as clustered inAgain, effects from each of the three data sets  were combined using fixed-effect inverse-variance weighted meta-analysis.9. Based on these 68 SNPs, we constructed a fetal growth polygenic score for the parental transmitted and nontransmitted alleles and regressed these on gestational duration . We estimated the effects of the maternal nontransmitted (MnTPGS) and transmitted (MTPGS) and paternal transmitted (PTPGS) alleles polygenic scores as above.To understand the impact of fetal growth on gestational duration, we used individual genetic data from 35,280  and 48,741  parent-offsprings from Iceland, the MoBa cohort and HUNT. To instrument fetal growth, we used 68 SNPs with fetal-only effect on birth weight as classified in Warrington et al. using Structural Equation ModelingEffect estimates from each of the three data sets  were pooled using fixed-effects inverse-variance weighted meta-analysis.29 analysis using summary statistics. The gestational duration GWAS was conditioned on the birth weight GWAS and vice versa ce versa , using bWe further investigated what are the fetal effects on birth weight for the maternal gestational duration-increasing alleles, and the maternal effects on gestational duration for the fetal birth weight-increasing alleles. To study this, we borrowed the inverse-variance weighted analysis from Mendelian randomization, but using the effects of two distinct genomes, the maternal and fetal. We caution that this should not be interpreted under a causal framework.To understand what the maternal gestational duration-raising alleles do to birth weight when present in the fetus, we used the effect sizes and standard errors of the parental transmitted and nontransmitted alleles for the 22 autosomal index SNPs on gestational duration and assessed its effects on the same SNPs with a fetal-only effect on birth weight. To understand what the fetal birth weight-raising alleles do to gestational duration when present in the mother, we used the effect sizes and standard errors of 68 autosomal SNPs associated with fetal effects on birth weight and the effect sizes and standard errors from the current maternal GWAS of gestational duration.23. This pipeline is designed to detect enrichment in evolutionary signals using a variety of sequence-based metrics of selection .Variants were annotated using Ensembl’s Variant Effect Predictor (hg19) command line toolFurther information on research design is available in the Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41588-023-01343-9.Supplementary InformationSupplementary Note and Supplementary Figures 1–16.Reporting SummaryPeer Review FileSupplementary Table 1Supplementary Tables 1–17.


As the survival rates of very low birth weight (VLBW) infants have increased, their neurodevelopmental outcomes are of concern. This study aims to determine the demographic and perinatal characteristics of premature infant according to head growth, identify clinical factors affecting growth catch-up, and explore differences in developmental outcomes according to catch-up states.th percentile and a no catch-up (NCU) group with a head circumference below the 10th percentile at 18–24 months of corrected age (CA).This nationwide prospective cohort study of Korean Neonatal Network data analyzed premature infants with very low birth weight  between 2014 and 2017. A total of 253 eligible infants who had completed the Bayley Scales of Infant and Toddler Development, Third Edition, were assigned into two groups: a catch-up (CU) group with a head circumference above the 10P < 0.05). On multiple linear regression analysis, BPD status was the most influential clinical factor affecting catch-up head growth after adjusting for gestational age, birth weight, and birth head circumference . At 18–24 months of CA, the NCU group exhibited lower developmental indices and a higher rate of developmental delay than the CU group. Motor developmental delay was the most significant factor relevant to catch-up head growth, and the motor development difference between the two groups was only statistically significant after adjusting for four major neonatal morbidities: IVH, BPD, sepsis, and NEC status .Most  premature infants exhibited catch-up growth at 18–24 months of CA. Rates of microcephaly, intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), sepsis, necrotizing enterocolitis (NEC), length of NICU stay, ventilation care, and parenteral nutrition were significantly greater in the NCU group (As association was observed between head growth catch-up status and developmental outcomes in VLBW infants at 18–24 months of CA. Key clinical factors associated with catch-up status included BPD and NEC status, length of parenteral nutrition, and ventilator care. Further study is needed to establish causality and explore additional factors that may influence developmental outcomes in this population. Recent advances in neonatal and neonatal intensive care have improved infant survival rates. In Korea, the survival rate of very low birth weight (VLBW) infants has also increased from 34% in the 1960s to 77.5% in the 2000s [Of 8,945 VLBW infants born between January 2014 and November 2017 and registered in the database registry of KNN, 318 with completed Bayley scales of infant and toddler development (BSID) III at 18–24 months of corrected age (CA) were selected for this study. The BSID test was revised and reconstructed into the third edition, which included a separation of the mental developmental index into language scale. A total 65 infants were excluded due to gestational age (GA) > 32 weeks (42 infants), the presence of major congenital anomalies (8 infants), non-Korean (3 infants) parents, and the presence of post intraventricular hemorrhage (IVH) hydrocephalus (12 infants)  group whose head circumference was below the 10thpercentile at 18–24 month of CA. A cutoff was used because previous researches showed the impact of head growth degree and velocity on neurodevelopmental outcomes [Three growth parameters  were analyzed for a specific period of time, including at birth, at discharge from the neonatal intensive care unit (NICU), and at 18–24 months of CA. Patients were divided into two groups according to their head circumferences. The first group was the catch-up (CU) group whose head circumference was above the 10outcomes –9.Four major factors were compared: 1) demographic factors ; 2) maternal factors ; 3) neonatal morbidity related factors ; and 4) environmental factors . Multiple linear regression was employed to determine factors affecting the status of catch-up in head growth. Factors showing statistically significant difference between the two groups were selected and entered into a logistic regression model. When a correlation between clinical factor and catch-up status was found, the adjusted odds ratio was used to offset the impact of extremely early preterm, SGA, and microcephaly instead of the crude odds ratio. These correlations are expressed as an odds ratio with a 95% confidence interval (CI), with a value greater than one indicating increased odds of not achieving catch-up after adjusting for GA, birth weight, and birth head circumference. When comparing developmental outcomes between the two groups, the adjusted odds ratio was used after adjusting for four major neonatal morbidities: IVH, BPD, sepsis, and NEC status. A P-value < 0.05 indicated statistical significance. All statistical analyses were performed using SPSS software ver. 26.0 .Demographic and perinatal characteristics, head circumferences, and language test results were subjected to frequency analysis. Data are described as median (maximum-minimum) for continuous variables and as numbers for binary and categorical variables. The independent t test and chi square test were used to compare demographic and perinatal characteristics, language developmental results, and clinical characteristics between the CU and NCU groups (P < 0.001). Among the three parameters, head circumference showed the biggest difference between the two groups, decreasing from birth to discharge. However, it increased from discharge to 18–24 months of CA   vs. 31.6% (65/206), P = 0.005; BPD: 68.1% (32/47) vs. 30.6% (63/206), P < 0.001; sepsis: 31.9% (15/47) vs. 17.0% (35/206), P = 0.021; NEC: 17.0% (8/47) vs. 3.9% (8/206), P < 0.001; NICU stay: 90.6 vs. 74.3, P = 0.002; ventilator care: 27.4 vs. 11.9, P < 0.001; parenteral nutrition: 40.6 vs. 25.6, P < 0.001). Birth weight (BW), rate of low maternal education, and rate of nursery use were significantly lower in the NCU group  vs. 19.4% (40/206), P = 0.032; nursery use: 21.3% (10/47) vs. 37.9% (78/206), P = 0.031).The demographic and perinatal characteristics of VLBW infants according to catch-up status are shown in Table ) , only IVH, BPD, sepsis, NEC status, length of ventilator care, and parenteral nutrition were significantly associated with catch-up status. BPD status was the most significant clinical factor affecting catch-up head growth  Table .Table 3C–24 months of CA, the NCU group exhibited lower developmental indices and higher rate of developmental delay than the CU group . Motor developmental delay was the most significantly relevant factor associated with catch-up head growth. The motor development index difference between the two groups was only statistically significant after adjusting for four major neonatal morbidities: IVH, BPD, sepsis and NEC status   of infants exhibited no catch-up head growth at 18–24 months of CA. The developmental outcome depended on the catch-up status at 18–24 months of CA.This study analyzed 253 VLBW infants with birth weight under 1,500 g at a gestation age of 23 weeks to 31 weeks. The results demonstrated that the degree of head circumference, especially that during 18Head circumference is a valid indicator of total brain volume and it can be used as a proxy for brain growth. Measurement of postnatal head growth as determined by the change in head circumference has been associated with total brain tissue volume and neurodevelopmental outcomes including cognition. It has been reported that severe postnatal growth failure among VLBW infants is markedly influenced by intra uterine growth and major morbidities –5.In this study, the key perinatal factor determining catch-up status was the BPD. The pathophysiology that leads to infants with BPD having greater developmental delay is probably multifactorial, including chronic intermittent hypoxia, growth deficiencies, and altered environmental stimulation. First, central nervous system pathology in infants with BPD shows brain atrophy and gliosis compatible with chronic hypoxia. Second, recurrent oxygen desaturations in infants with BPD have been associated with poor weight gain which may give credence to the possibility of poor central nervous system growth. Third, environmental factors such as those associated with rehospitalization during the first year of life and feeding problems might ultimately affect mental development –20.–24 month of CA, especially in the motor developmental index. Several studies have documented significant deleterious effects for VLBW infants with head growth failure on motor outcome, showing early impairments specifically involving eye-hand coordination and postural balance [In this study, the NCU group exhibited lower developmental indices and a higher rate of developmental delay than the CU group at 18 balance , 22. TheJeng et al. (2008) have reported that the severity of BPD has a significantly negative linear relationship with motor developmental outcome in infancy after controlling for other risk factors . Keunen –24 months of CA with developmental outcome using brain magnetic resonance imaging.VLBW infants might have less prominent, more diffuse cerebral white matter injuries that are undetectable by ultrasound but which can cause developmental disorders. The diffusion-weighted magnetic resonance imaging technique provides exquisite soft tissue differentiation. Therefore, a further study is needed to investigate the association of head circumference at 18The strength of this study was that it included a prospective nationwide population-based cohort of VLBWI infants and used a newly revised developmental scale, BSID-III. This is a valuable aspect for analyzing various factors sequentially, including perinatal and postnatal factors. The results showed that developmental outcomes were significantly different between the CU and NCU groups.This study has some limitations. Developmental outcomes result from various factors combined, making it difficult to affirm that catch-up head growth is the sole decisive cause of developmental delay. Additionally, although the standard guidelines for measuring head circumference were followed, and steps were taken to minimize intra-observer and inter-observer errors by having trained nurses perform repeated measurements, the potential for human error in the measurement process cannot be entirely ruled out, as head circumference measurements can be subjective and may vary if not consistently conducted by the same person.–24 months of CA depended on whether head growth was caught up. Key clinical factors affecting the catch-up head growth were BPD, NEC status, length of parenteral nutrition, and ventilator care. These results showed the importance of head circumference measurement at 18–24 months of CA. Since infant developmental outcomes can predict school-age academic functioning, our results suggest that close follow-up and early intensive interventions are needed for VLBW infants with catch-up growth failure. Further research is needed to establish causality and explore additional factors that may influence developmental outcomes in this population.In conclusion, the developmental level of a VLBW infant at 18