Introduction: We undertook a literature review of the use of levonorgestrel-releasing intrauterine devices when utilized for heavy menstrual bleeding and/or dysmenorrhea. Methods: A narrative review of articles in the Scopus and Medline databases was conducted. Results: A number of options exist for the management of both abnormal uterine bleeding (AUB) and dysmenorrhea, and evidence is accumulating that the insertion of a levonorgestrel-releasing intrauterine system (LNG-IUS) represents a useful option for their long-term treatment. The idea of using a progestogen released in utero was initially conceived to achieve long-term contraception, but it was quickly found that these systems could be utilized for a number of therapeutic applications. The first device to be made commercially available, Progestasert, was withdrawn from the market because, in the event of contraceptive failure, it caused a disproportionate percentage of extrauterine pregnancies. On the other hand, the LNG-IUS continues to be successfully utilized in its various variants, releasing 20, 13, or 8 μg/day. These devices have a respective duration of action of 7 (possibly 8), 5, and 3 years, and there exist versions of frameless systems affixed to the myometrium of the uterine fundus. In the present review, following a brief description of the major causes of AUB and dysmenorrhea, the molecular bases for the use of the LNG-IUS are summarized. This is followed by a compendium of its use in AUB and dysmenorrhea, concluding that the insertion of the system improves the quality of life, reduces menstrual blood loss better than other medical therapies, and decreases the extent of dysmenorrhea and pelvic pain. In addition, there is no evidence of a significant difference in these outcomes when the use of the LNG-IUS was compared with improvements offered by endometrial ablation or hysterectomy. Possibly, the most important mechanism of action of the system consists of its ability to induce amenorrhea, which effectively eliminates heavy bleeding and dysmenorrhea. However, no method is ideal for every woman, and, in the case of the LNG-IUS, younger age and severe dysmenorrhea seem to be associated with a higher risk of discontinuation. Conclusion: The higher-dose LNG-IUS is a useful tool for HMB and dysmenorrhea in women of all ages. The low cost and ease of use make the LNG-IUS an attractive option, especially when contraception is also desired. In their recent comprehensive review of the regulation of menstruation, Critchley et al.  remindedIn addition, a comprehensive review of longitudinal, case–control, and cross-sectional studies found a wide difference of between 16% and 91% in the prevalence of dysmenorrhea in women of reproductive age and that 2–29% of them suffered severe pain. Factors linked to reduced risk are older age, higher parity, and the use of oral contraceptives. High stress and a family history increase the risk of dysmenorrhea. There is inconclusive evidence about the role of smoking, diet, obesity, depression, or abuse . DysmenoIn recognition of the magnitude of the problem, the plethora of possible and often coexisting causes and the inconsistency in the nomenclature used to describe AUB, the International Federation of Gynecologists and Obstetricians (FIGO)  proposedAn illustration of the PALM-COEIN system is provided in A number of options exist for the management of both AUB and dysmenorrhea. In 2016, Bradley and Gueye  summarizWith regard to dysmenorrhea, a recent review by McKenna and Fogleman  recommenHormonal contraception should be considered for women with menorrhagia who may desire future pregnancies… Data on the effects of the levonorgestrel intrauterine system on dysmenorrhea are limited, but because the device reduces or eliminates menstruation for many women, these benefits seem consistent with the mechanism of action… The levonorgestrel intrauterine system reduces blood loss by up to 86 percent after three months, and by up to 97 percent after 12 months”.In clinical practice, AUB and dysmenorrhea often coexist , and theIn the last few years, new drugs, such as dienogest, selective progesterone receptor modulators (SPRMs), and GnRH antagonists, have become available for the management of HMB and dysmenorrhea due to uterine fibroids and adenomyosis. However, the use of SPRMs is restricted by European Medicine Agency (EMA) warnings, and GnRH antagonists are still very pricy. Given the importance of the benefits of the LNG-IUS for these two indications and its low cost and excellent safety profile, we decided to critically review the molecular, biological, and clinical information on the use of the LNG-IUS to treat AUB and dysmenorrhea.This narrative review is based on articles identified through a search of Scopus and Medline databases until March 2022 using the headings HMB, menorrhagia, dysmenorrhea, and AUB, together with levonorgestrel (or norgestrel) intrauterine device or system and progestogen intrauterine device or system. We searched for major publications, including systematic reviews, meta-analyses, randomized controlled trials (RCTs), and consensus concerning the utility of the LNG-IUS in the treatment of abnormal uterine bleeding and dysmenorrhea. The reference lists of identified articles were used to search for any additional relevant references. Articles published in languages other than English were excluded. This article consists of a narrative review to synthesize the findings in the literature, which was conducted following the Scale for Assessment of Narrative Review Articles (SANRA).As mentioned, there is a comprehensive definition and classification system for all types of AUB, “PALM-COEIN” . More spIn routine clinical practice, measurements are seldom carried out. Warner et al.  found thIn contemporary times, HMB has been defined as excessive menstrual blood loss (MBL) that disrupts the physical, social, emotional, and/or material quality of life . Over thOf particular relevance here is the Cochrane review of the use of progestogen-releasing intrauterine systems by Bofill Rodriguez et al.  that incThe definition of heavy menstrual bleeding has evolved over time. The current interpretation places it within the broad classification of abnormal uterine bleeding or AUB.Dysmenorrhea is defined by the presence of pain during menstruation. Pain can start before the onset of bleeding. It represents the most common menstrual symptom among adolescent girls and young women. If painful menstruation occurs in the absence of pelvic pathology, this is referred to as primary dysmenorrhea ,25. DysmFollowing a critical review of published information, Iacovides et al.  concludeGuidelines for the management of dysmenorrhea have been produced by the UK National Institute for Health and Care Excellence (NICE) ; in addip < 0.001); interestingly, CA-125 was significantly reduced only among users of the ENG implant (p < 0.05). Unfortunately, no correlation was observed between the reduction in biomarkers and improvements in visual analog scale (VAS) pain and dysmenorrhea scores. They then carried out a randomized comparative clinical trial of the ENG implant and the LNG-IUS and found that both systems significantly improved the mean VAS score. In addition, health-related quality of life improved significantly, with the most common bleeding pattern for the LNG-IUS at 180 days of follow-up being infrequent bleeding and spotting, as shown in The management of endometriosis-associated pelvic pain and dysmenorrhea has been specifically investigated by Bahamondes and his group ,28,29. FDysmenorrhea is a very common presentation and is linked to a reduced quality of life. The use of the LNG-IUS improves the quality of life and pain scores, but there is no correlation with pain biomarkers.Contrary to a commonly held view, the concept of using a progestogen released in utero for contraception dates back more than fifty years: the first experimental device, reported in 1968, utilized medroxyprogesterone acetate (MPA) , but thep = 0.01) [p = 0.001).In spite of its short commercial life, a number of interesting observations of the biological effects of Progestasert were published. In particular, the mechanism of action was evaluated in the 1970s and 1980s, showing that, with time, the intrauterine administration of progesterone causes the increasing suppression of the proliferative activity of the endometrium, a clear pre-decidual stromal reaction, poorly developed glands, and a decrease in vascularity, accompanied by an increase in the proportion of small vessels with defects ,38,39,40In conclusion, the early stages of development of progestogen-releasing devices utilized MPA; this was followed by the use of progesterone microcrystals. The development of both types of devices was discontinued because of high expulsion rates in the case of the MPA device and because of the increased risk of ectopic pregnancy with the progesterone device.In 1975, an international group under the auspices of the Population Council  began teIn the following year, the same group  carried Since the early experience, it has become clear that the system has a positive effect on the amount of blood loss, as documented by Nilsson  See Fig.Endometrial changes were also evaluated with devices releasing either 20 or 40 μg/day, observing a uniform suppression of the endometrium with glandular atrophy and the decidualization of the stroma .By 1986, information had become available proving that the device’s effectiveness as a contraceptive lasted 5 years , and in p < 0.001) in serum ferritin [p < 0.001) and tranexamic acid (p < 0.01) [As mentioned, a reduction in MBL has been observed since the very early clinical experience, and this led to the utilization of the device in subjects with HMB. The first application dealt with the prevention and treatment of iron-deficiency anemia , followeferritin . Soon af < 0.01) .By the turn of the millennium, besides menorrhagia and iron-deficiency anemia, several additional therapeutic indications were identified; these included: protection of the endometrium in estrogen replacement therapy; dysmenorrhea; endometrial hyperplasia; ovarian endometrioma; adenomyosis; and endometrial protection in women treated with tamoxifen during breast cancer treatment ,53. In ap < 0.001). Overall, 94.6% of the participating women claimed to have received additional benefits besides contraception.An interesting point was raised by Cristobal et al. , who proIn conclusion, as stressed by Gemzell-Danielsson et al. , the avaThe successful development of the LNG-IUS has had a considerable impact beyond its use as an effective contraceptive. The LNG-IUS has proven to be an effective alternative to hysterectomy for HMB.The characteristics of levonorgestrel-releasing intrauterine systems (LNG-IUSs) available at present are summarized in (1)LNG-IUS-20: Total content of 52.5 mg; LNG is initially released at a rate of 20 μg/day, and—as already mentioned—in 2021, the US FDA approved its use for contraception for up to 8 years [ 8 years . It is l(2)LNG-IUS 12: Total content of 19.5 mg; LNG is initially released at a rate of 13 μg/day and has a duration of action of 5 years [ 5 years . The dev(3)LNG-IUS 8: Total content of 13.5 mg; LNG is initially released at a rate of 8 μg/day and has a duration of action of 3 years [ 3 years . The devBasically, four types of systems have been marketed: the first three utilize a T-shaped IUD, the vertical arm of which contains different quantities of LNG:The fourth system consists of a 3.5 cm-long coaxial fibrous LNG delivery system with an approximate release of 14 μg/day. The calculated duration of release from the device is at least 3 years .p < 0.01 in all groups).In China, a similar frameless LNG-IUS affixed to the myometrium has been tested in patients with adenomyosis and HMB  in a comThe introduction of frameless devices is claimed to overcome cramps as a symptom in some users of framed devices. It may also be suitable in the presence of fibroids that distort the uterine cavity .p-value < 0.0001).As shown in Recently, the WHO recommended that the classification system used for intrauterine contraception be made clearer. For instance, the WHO recommended that the type of hormone be specified  . The recAs seen from the FIGO classification, the causes of AUB can be attributable to PALM-COEIN . HMB is HMB has been linked to systemic causes, including hematological or thyroid disorders, as well as local uterine causes, such as fibroids or adenomyosis. However, a large proportion of women with HMB have no systemic or structural abnormalities, and the underlying mechanisms reside in the endometrium.COX-2), a gene coding for the rate-limiting prostanoid-synthesizing enzyme, is elevated, resulting in subsequent increased levels of prostaglandins (PGs), particularly PGE2 and PGF2α [2 signaling, along with the endometrial generation of the vasoconstrictor PGF2α, leads to local hypoxia in the upper functional layer of the endometrium. This is marked by the activation of hypoxia-inducible factor 1α (HIF-1α), the master regulator of cellular hypoxia, which, as such, establishes an endometrial microenvironment that is conducive to tissue repair and angiogenesis [2 signaling in the endometrium will impair endometrial repair, causing HMB [Following progesterone withdrawal in the late secretory phase in the absence of pregnancy, the endometrial expression of cyclooxygenase-2  that specifically convert the precursor PGH2 to PGE2 [2 production and signaling subside [2 degradation, as seen in the increased expression of the PGE2-degrading enzyme 15-hydroxy-prostaglandin dehydrogenase (PGDH) in the fibrotic lung [2,s as well as HIF-1α signaling in adenomyotic lesions and their EMI and endometrium, with ensuing impaired endometrial repair and, ultimately, HMB. Indeed, endometriotic stromal cells cultured on a stiff matrix display reduced expression of COX-2, prostaglandin E2 receptor 2 (EP2), and EP4 [However, despite this knowledge, the more detailed mechanisms underlying adenomyosis-, endometrial-polyp-, and uterine-fibroid-induced HMB are largely unknown. For example, submucosal fibroids are more likely to be associated with HMB , but whysing HMB . This issing HMB ,79,80. A to PGE2 , PGE2 pr subside ,83,84,85 and EP4 .The molecular mechanisms underlying dysmenorrhea are thought to be more complex. Conceivably, however, uterine hyperactivity, hyperinnervation within the uterus, the release of inflammatory cytokines and pain mediators by fibroids or adenomyotic lesions, and central sensitization may collectively contribute to dysmenorrhea.The high local concentration of the progestin steadily released by the LNG-IUS suppresses the cellular proliferation of endometrial cells , thus inThe progestins contained in the LNG-IUS can also suppress uterine contractility ,89,90, rProgesterone is central in endometrial remodeling and acts on both the epithelial and stromal compartments. Since a progestin is the major active agent within LNG-IUS, and since the action of progesterone/progestins is mediated through progesterone receptors (PRs), the ultimate efficacy of the LNG-IUS hinges critically on the expression levels of PRs, particularly PR isoform B (PR-B) in the endometrium and myometrium. In both adenomyotic and endometriotic lesions ,95 and iHowever, in many cases, the induction of PR expression can be difficult, if not impossible. For example, PR-B has been reported to be hypermethylated ,101 and In addition, for uterine leiomyoma, progesterone/progestins may actually stimulate cellular proliferation and fibrogenesis, effectively accelerating the disease progression ,104,105,Then, why is the LNG-IUS still useful in treating HMB and dysmenorrhea caused by endometriosis, adenomyosis, or leiomyoma? The LNG-IUS is effective in reducing menstrual blood loss. Among women using the LNG-IUS for contraception, amenorrhea or spotting was reported in approximately 50% of users during the last 90 days of the first year after insertion; with time, 80% experienced amenorrhea, spotting, or light bleeding only . After 6In conclusion, although the molecular mechanisms are incompletely understood, the LNG-IUS proved effective in primary and some cases of secondary dysmenorrhea and in reducing HMB, including in women with fibroids.By the end of the previous millennium, several investigators had tested the use of the LNG-IUS in the treatment of AUB. In 1997, two reports provided evidence of a positive effect in subjects with heavy bleeding: Fedele et al.  insertedp < 0.001), with a good satisfaction rate in 89% of all cases. It can be concluded that the LNG-IUS is effective in controlling both menorrhagia and/or frequent irregular uterine bleeding related to the presence of myomas, though with no significant effect on the myoma size.A series of investigations tested the efficacy of the LNG-IUS in women harboring leiomyomas, with interesting results ,123,124.In an RCT that included women with idiopathic HMB, the LNG-IUS was more effective than cyclical MPA given for 10 days starting from day 16 of the cycle. The LNG-IUS was linked to a greater absolute and percentage reduction in menstrual blood loss and a higher likelihood of success .Using the “frameless” LNG-IUS, Wildemeersch and Schacht  evaluatep = 0.012) and severe dysmenorrhea  being associated with a higher risk of discontinuation. Anticipatory counseling can reduce premature removal of the device.An interesting investigation aimed at determining whether the size of the uterine cavity is a determining factor in causing bleeding and pain in nulligravid women using the LNG-IUS , and theA recent investigation enrolled a cohort of 1714 subjects and followed them for 5 years, with 495 participants finishing the entire period. As shown in It is important to mention that Cho et al. , on the This may be due to a reduction over time in the amount of LNG released by the system. According to the FDA, the initial release of the steroid is 20 μg/day, but this is reduced to around 10 ug/day over time. In terms of plasma levels, from the initial 150–200 pg/mL during the first weeks, there is a reduction to 180 ± 66 pg/mL, 192 ± 140 pg/mL, and 159 ± 59 pg/mL at 12, 24, and 60 months, respectively .To conclude, a 2015 systematic review  found thIn conclusion, the effectiveness of the LNG-IUS in women with HMB is well documented, but anticipatory counseling is important for avoiding premature removal. The LNG-IUS that releases 20 ug/day is required to control HMB. Its use is associated with endometrial pseudo-decidualization.The link between abnormal bleeding and hematological disorders has been recognized for some time . AttentiAt that time, tranexamic acid (TxA) and desmopressin acetate were utilized to control menorrhagia in these women; then, in 2004, the London Group, for the first time, proposed using the LNG-IUS . They caSoon after, another investigation explored the use of the LNG-IUS during anticoagulant therapy through the distribution of a questionnaire, with 17 responders . The stup < 0.01).The results of the long-term follow-up  of 26 subjects with IBDs were presented by Chi et al. : they foTwo important complications of the LNG-IUS in these subjects, malposition and expulsion, were evaluated by Rimmer et al. , startinA small study from China reported on the successful use of the LNG-IUS in two adolescents with Glanzmann’s Thrombasthenia, an IBD caused by defects in the platelet membrane glycoproteins IIb/IIIA. Insertion of the system produced a significant reduction in menstrual blood loss . Anotherp < 0.001). At that time, 70% of the subjects were amenorrheic. Finally, there was a substantial (p < 0.001) improvement in eight parameters of quality of life (QoL), as well as in the levels of hemoglobin, ferritin, and serum iron.With time, more substantial cohorts became available: Brull et al.  reviewedAt present, guidelines are available for the gynecologic and obstetric management of women with vWD derived from three systematic reviews of the literature comparing the effects of desmopressin, hormonal therapy, and TxA on HMB . When coLocally released LNG has a profound effect on the endometrium: as already mentioned, back in 1978, changes in the endometrium were evaluated with devices releasing either 20 or 40 μg/day, observing a uniform suppression of the endometrium . Under tIn an early investigation, Nilsson  quantifiSome 35 years later, Lowe and Prata  carried An investigation in India  comparedThe early investigation by Barrington and Bowen-Simpkins  observedOver the years, additional information has become available: Yucel et al. , in subjIn a longitudinal population study, Lindh and Milsom  addressep < 0.001). This drop was accompanied by a significant decrease in the uterine volume, and the overall satisfaction rate for the treatment was 72.5%.Kelekci et al.  comparedInformation is also available on the “frameless” LNG-IUS (FibroPlant) developed by a Belgian Group. In a preliminary trial, Wildemeersch et al.  tested tIn conclusion, LNG-IUS and frameless devices have been linked to an improvement in dysmenorrhea.For decades, it has been maintained that intrauterine contraception is contraindicated in adolescents and young and nulliparous women, in spite of evidence to the contrary ,157.Buhling et al. , in eighBack in 2010, a short-term comparative trial  showed tClear advantages exist in treatment with the LNG-IUS in adolescents with HMB, dysmenorrhea, and pelvic pain/endometriosis, and, indeed, good results have been reported in young women with AUB, dysmenorrhea, and pelvic pain related to endometriosis .A description of the adverse effects of the LNG-IUS is beyond the scope of this review; the reader may refer to review articles on the subject e.g., ,165,166),166165,1On the other hand, it is perfectly relevant to briefly summarize existing views on the pathophysiological mechanism through which side effects manifest themselves.Jimenez et al.  tried top = 0.012) and severe dysmenorrhea  to be associated with a higher risk of discontinuation.An attempt to identify factors associated with the failure of the LNG-IUS in controlling HMB was made by Beelen et al. , who useOver the last quarter of a century, evidence has been accumulating showing that the LNG-IUS, in all of its variants, represents a useful tool to combat both AUB and dysmenorrhea in women of all ages. Almost all published trials have reported improvements for both conditions. Perhaps the most important mechanism of action of the LNG-IUS is attributable to its ability to induce amenorrhea, which effectively eliminates HMB and dysmenorrhea. While new generations of therapeutics are now becoming available, the low cost and ease of use make the LNG-IUS very attractive, especially when contraception is also desired. Still, for large uteri, the LNG-IUS may be less effective, and there has been limited level I data on its efficacy in treating endometrial-polyp-induced HMB. Regardless, the LNG-IUS is and is expected to remain, in the foreseeable future, a viable option for treating AUB and dysmenorrhea.


The aim was to compare the diffusion tensor imaging (DTI) indices derived from human hearts between 1.5 T and 3.0 T scanners. Additionally, the reproducibility of DTI indices was assessed between 1.5 T and 3.0 T scanners.A total of 18 ex-vivo hearts were derived from patients who underwent heart transplantation. The DTI schemes were performed at 1.5 T and 3.0 T, respectively. Then, the same slices from each ex-vivo heart were selected for image analysis. The student’s t-test or Wilcoxon-rank test was used to compare the statistical differences. The agreement of DTI indices was mainly reported as the interclass correlation coefficient (ICC).P > 0.05) were found in the DTI indices between 1.5 T and 3.0 T scanners. Interestingly, the ICC of all DTI indices was relatively lower with a low b-value. The reproducibility of the helix angle (HA) was relatively lower when compared to the other DTI indices.No significant differences (all The DTI indices of ex-vivo human hearts between 1.5 T and 3.0 T scanners had no significant differences. The consistency of DTI indices needed caution using a low b-value with different field strengths, and the relatively low reproducibility of HA should be considered.The online version contains supplementary material available at 10.1186/s12880-023-00969-9. Recently, cardiovascular magnetic resonance (CMR) diffusion tensor imaging (DTI) has emerged as a promising technique for the determination of myocardial fiber orientation , 2 and tTheoretically, the DTI indices should remain constant at different field strengths . Since DWith the growing interests of CMR DTI, it has been performed in human hearts with various MRI systems at different field strengths, mainly at 1.5 T , 11, 12 A total of 18 ex-vivo hearts were derived from patients who had undergone heart transplantation due to various cardiovascular causes in Guangdong Provincial People's Hospital from April 2020 to January 2021. This study was approved by the Institutional Review Board of Guangdong Provincial People's Hospital (reference number: KY2020-039–01-01).The ex-vivo hearts from patients were collected and fixed in 10% buffered formalin within 1 h of excision from the recipients at the time of heart transplantation. All ex-vivo hearts were fixed in 10% buffered formalin for at least 24 h before the CMR examination, and the average time between fixation and CMR examination was three days. It has been reported that CMR DTI indices remained constant 24 h after the initial cross-linking by formalin fixation for several weeks .2, 400 s/mm2, 600 s/mm2, 800 s/mm2 and 1000 s/mm2, respectively. The detailed imaging parameters are shown in Table The DTI sequence was scanned at a 3.0 T scanner  and a 1.5 T scanner , respectively. A sixteen-channel receiving array coil was used for the 3.0 T MRI scanner and an eight-channel receive array coil was used for the 1.5 T MRI scanner. The DTI was performed with a multi-shot spin-echo sequence with an EPI readout. Multi-slice short axis views of the heart were acquired covering the entire left ventricular. And a 4-chamber 3D T1WI scan was performed to localize the ex-vivo hearts, and ensured that imaging planes were placed in short-axis view orientation at apical, mid-ventricular and basal. Five diffusion series with 5 different b-values were performed separately on ex-vivo hearts, including b-values of 200 s/mmDiffusion tensors were calculated on a pixel-by-pixel basis from the CMR diffusion images and diagonalized to yield three eigenvalues  and eigenvectors . The mean diffusivity (MD), fractional anisotropy (FA), helix angle (HA), E2 angle (E2A), HA transmural gradient and transverse angle (TA) were obtained by the diffusion tensor eigensystem, and E2A values were stated as absolute from 0 to 90 degrees –19. The In the present study, we selected only one slice without any myocardium excision for the image analysis of each ex-vivo heart. All the DTI indices were reported as the average values over the entire left ventricular myocardial area on the selected slice for each ex-vivo heart. All the post-processing computation was performed as Fig. Continuous variables were described as mean ± standard deviation. The normal distribution of variables was tested using the Shapiro–Wilk test. The Student’s t-test was used to compare the means of normally distributed variables, while the Wilcoxon-rank test was used to compare the median of skewed variables. The agreement of DTI indices between 1.5 T and 3.0 T scanners was tested by calculating mean bias and 95% limits of agreement on a Bland–Altman test, and interclass correlation coefficient (ICC).P values < 0.05 were considered statistically significant.For the reproducibility analysis, we randomly selected one slice from each ex-vivo heart and sketched the region of interest (ROI) on the left ventricular myocardium. To assess intra-observer reproducibility, the first experienced observer was blinded to the clinical information, and then sketched ROIs twice at 2-week intervals. For inter-observer reproducibility, another experienced observer did the same thing in the selected images. The agreement of reproducibility was also tested by calculating mean bias and 95% limits of agreement on a Bland–Altman test, and ICC. All tests were two-sided, and All statistical analyses were performed with the statistical software GraphPad Prism  and in R version 3.4.1 .A total of 18 patients  were included in the analysis who had undergone heart transplantation. In detail, nine patients had dilated cardiomyopathy, five had coronary heart disease, one had rheumatic heart disease, one had Arrhythmia right ventricular cardiomyopathy, one had cardiac malignancy, and one had myocarditis proven by pathology.P > 0.05) were found between 1.5 T and 3 T scanners , 0.937 , 0.957 , 0.835 , 0.400 , and 0.306 , respectively, when the b-value equaled 1000 s/mm2  at 3.0 T. In addition, HA, E2A, HA transmural gradient and TA at both 1.5 T and 3.0 T did not show any statistical difference with different b-values.As the b-value increased, MD decreased at both 1.5 T and 3.0 T scanners, while FA, HA, E2A, HA transmural gradient, and TA did not show significant trend varied with b-values, which were shown in Fig. The intra- and inter-observer reproducibility of DTI indices were shown in Table The DTI has emerged as a promising technique in CMR, which was mainly performed with human hearts at 1.5 T or 3.0 T scanners. Given present trends, the DTI scanning in ex-vivo human hearts was performed, and the DTI indices and reproducibility were compared between 1.5 T and 3.0 T scanners. The main findings of our study were included as follows: (1) There were no significant differences in DTI indices between 1.5 T and 3.0 T; (2) the ICC of all DTI indices between 1.5 T and 3.0 T was relatively low with a low b-value; (3) the reproducibility of HA was relatively lower compared with the other DTI indices.Theoretically, DTI indices should not be influenced by the external magnetic field. However, the comparison of DTI indices at 1.5 T and 3.0 T scanners seemed to reveal contradicting findings in clinical practice. In the evaluation of the brain, Hunsche et al. concluded that MD and FA did not differ significantly comparing 1.5 T and 3.0 T , while G2 to 1000 s/mm2 in recent research [2. In the present study, the ICC of FA and MD was the highest when the b-value equaled 1000 s/mm2, which was similar to the results of Chou et al.The difference of DTI indices varied with b-value in CMR DTI has not been reported yet, and the b-value mostly ranged from 200 s/mmresearch , 22, 23.research . The repThe reproducibility of the DTI indices was also essential, in line with other similar studies in different organs , 24. In There were several limitations in the present study when interpreting the results. First, the sample sizes of the study need to be improved, and the results should be also proved using the MRI systems from other manufacturers as well in the future. Second, the excision of the ex-vivo hearts could be found in some of the slices, but we only analyzed the slices without myocardium excision to address this problem. Third, the ex-vivo hearts were fixed by formalin, and the DTI indices could be different from the ones from in-vivo hearts. However, the present study focused on comparing the DTI indices between 1.5 T and 3.0 T scanners, given the same ex-vivo hearts. At last, the inconsistent echo time and large slice thickness might be the potential limitations in the present study.In conclusion, the magnetic resonance DTI indices of ex-vivo human hearts between 1.5 T and 3.0 T showed no significant difference in the present study. However, the consistency of DTI indices needed caution using a low b-value with different field strengths, and the relatively low reproducibility of HA should be considered in clinical research or clinical practice in the future using the CMR DTI technique.Additional file 1. Supplementary figures.


The incidence of birth defects is 2-3% in the genera! population but it is increasing. An estimated 303,000 newborns die within 4 weeks of birth every year, worldwide, due to congenital anomalies. The objective of this study was to find out the prevalence of birth defects among newborns in a tertiary care centre.A descriptive cross-sectional study was done in the Department of Obstetrics and the Gynaecology and Department of Paediatrics from 15 June 2016 and 14 June 2019. Ethical approval was obtained from the Institutional Review Committee (Reference number: 142/077/078-IRC). Data of newborns were collected from the hospital records. Convenience sampling method was used. Point estimate and 99% Confidence Interval were calculated.Among 32,695 newborns, birth defects were seen in 169 (0.51%) . The most common birth defect was musculoskeletal defects seen in 60 (35.50%) newborns followed by central nervous system defect seen in 30 (17.75%) newborns.The prevalence of birth defects among newborns was lower than in other studies done in a similar setting. The prevalence of congenital anomalies requires adequate reporting to identify the burden of disease. Adequate data on prevalence and pattern are required to establish baseline rates, provide ideas on the aetiology and help prevention of preventable birth defects and timely intervention for the termination in the poor foetal outcomes.The aim of this study was to find out the prevalence of birth defects among newborns in a tertiary care centre.A descriptive cross-sectional study was conducted among newborns delivered at the Department of Obstetrics and Gynaecology and Department of Paediatrics at B.P. Koirala Institute of Health Sciences. Ethical approval was obtained from the Institutional Review Committee of the same institution (Reference number: 142/077/078-IRC). Data from 15 June 2016 to 14 June 2019 was collected from hospital-based records. Cases were taken from labour room records and case records from the nursery or neonatal intensive care units (NICU) of the paediatric ward in which birth defects were detected after admission or later. All the delivery within the institute during the study period were included in the study. All the defects were detected, either antenatally while doing an anomaly scan after 20 weeks of gestation, immediately after delivery of the baby, or during the postnatal period after evaluation by the paediatrician. The pregnancy with antenatal diagnosis of malformation was admitted and delivered subsequently. Thus, all cases who were detected as malformed during the antenatal, intranatal or postnatal period were enrolled. Children with birth defects who were referred from other hospitals were excluded. Convenience sampling method was used.The sample size was calculated using the following formula:Where,n = minimum required sample sizeZ = 2.576 at 99% Confidence Interval (CI)4p = prevalence of birth defect, 2.39%q = 1-pe = margin of error, 1%After doubling the calculated sample size we have included 32,695 newborns for the study.4Birth defects were classified according to the International Classification of Diseases (ICD) classification of birth defects.Data were entered and analysed using Microsoft Excel 2013 and IBM SPSS Statistics 16.0. Point estimate and 99% CI were calculated.Among 32,695 newborns, birth defects were seen in 169 (0.51%) . Birth defects were found in 116 (68.54%) newborns born to mothers aged 16 to 25 years .The most common birth defect was musculoskeletal defect seen in 60 (35.50%) newborns followed by central nervous system defect in 30 (17.75%) .Out of the 169 newborns with birth defects, 106 (62.72%) were males and 2 (1.18%) were ambiguous newborns .A total of 133 (78.69%) birth defects were detected only after delivery of the newborn. A history of parental consanguinity was present in 3 (1.77%) newborns .Foetal alcohol syndrome was found in 3 (1.77%) newborns .5 Congenital heart disease was one of the common birth defects in their study. In a study done in a maternity hospital in Rio de Janeiro, Brazil, the prevalence was 1.7% which was similar to our study. Neural tube defects were the most frequent malformation in their study.6 The most frequent birth defect in our study was a musculoskeletal deformity, and club foot/congenital talipes equinovarus (CTEV) were the most common.The prevalence of birth defects in our centre was around 50 per 10,000 which was lower than the prevalence in the general population which is 2-3%. A study was done on the prevalence of birth defects in Glasgow, the United Kingdom the Glasgow Register of Congenital anomalies for the period of 1980-1997 found a prevalence of 382 per 10,000.7 Another reason could be the poor detection rate of birth defects during antenatal, intranatal and postnatal periods. Only obvious gross malformation of the newborn were detected while malformations that were not obvious might go unnoticed owing to poor diagnostics tools. None of the stillbirth newborns was autopsied for the cause of the death which could largely miss the malformation in the newborn.The low prevalence of birth defects in our study could be due to parental age where most pregnancies occur between 20-30 years of age. Younger parents (<25 years) are less likely to have a malformed fetus.8 This could be probably due to a lack of folic acid intake and for causal relation, we need further study. Our study showed birth defects predominantly among the male newborns (62.70%) which was in contrast to the study in Kathmandu where the prevalence was 34.60% among males.9 However, a study done in the UK on sex prevalence of major congenital anomalies showed a male:female ratio of 1.26,10 which was slightly lesser than our study.Neural tube defect was the second most common birth defect in our study which is similar to the study done in the United States.In our study, the majority of diagnoses, i.e, 133 (78%) birth defects were detected postpartum thereby emphasising the need for proper diagnostic tools like anomaly scan/targeted sonography in the second trimester, serum analytes like a triple or quadruple marker, amniocentesis need for regular antenatal care (ANC) visits.11In our study, 139 (80%) of all birth defects were live birth while 17.80% were stillbirths with birth defects. Those birth defects that were alive but had poor neonatal outcomes were mostly left neglected by the parents denying further treatment in Nursery and NICU highlighting the poor socioeconomic background. We were unable to follow the outcome of those neonates as those neonates were taken home without further treatment with leave against medical advice. According to European Surveillance of Congenital Anomalies (EUROCAT), 80% of birth defects were live birth similar to our study.Prevalence of chromosomal anomalies was poorly detected in this study. We recommend future studies with chromosomal study amongst the newborn with suspected chromosomal disorders.The prevalence of birth defects was lower than in the other studies done in a similar setting. Early detection and intervention could have an impact on the prevalence of this condition. This might guide the policymakers to increase the surveillance and raise awareness regarding the impact of the birth defect.


Both environmental and social factors have been linked to birth weight and adiposity at birth, but few studies consider the effects of exposure mixtures. Our objective was to identify which components of a mixture of neighborhood-level environmental and social exposures were driving associations with birth weight and adiposity at birth in the Healthy Start cohort.Exposures were assessed at the census tract level and included air pollution, built environment characteristics, and socioeconomic status. Prenatal exposures were assigned based on address at enrollment. Birth weight was measured at delivery and adiposity was measured using air displacement plethysmography within three days. We used non-parametric Bayes shrinkage (NPB) to identify exposures that were associated with our outcomes of interest. NPB models were compared to single-predictor linear regression. We also included generalized additive models (GAM) to assess nonlinear relationships. All regression models were adjusted for individual-level covariates, including maternal age, pre-pregnancy BMI, and smoking.Results from NPB models showed most exposures were negatively associated with birth weight, though credible intervals were wide and generally contained zero. However, the NPB model identified an interaction between ozone and temperature on birth weight, and the GAM suggested potential non-linear relationships. For associations between ozone or temperature with birth weight, we observed effect modification by maternal race/ethnicity, where effects were stronger for mothers who identified as a race or ethnicity other than non-Hispanic White. No associations with adiposity at birth were observed.NPB identified prenatal exposures to ozone and temperature as predictors of birth weight, and mothers who identify as a race or ethnicity other than non-Hispanic White might be disproportionately impacted. However, NPB models may have limited applicability when non-linear effects are present. Future work should consider a two-stage approach where NPB is used to reduce dimensionality and alternative approaches examine non-linear effects.The online version contains supplementary material available at 10.1186/s12940-022-00934-z. At the population level, seemingly small shifts in mean birth weight over the past few decades have been associated with population-level increases in the proportion of neonates born low birth weight  or small for gestational age  . SGA andstation) –10. Simistation) , 12.The existing literature demonstrates the ability of both individual-level and neighborhood-level exposures to influence birth weight and adiposity in the neonatal period. Individual-level factors include maternal characteristics such as age and race/ethnicity, maternal behaviors such as active smoking and physical activity, and metabolic factors such as obesity or gestational diabetes –15. At ti.e., physical, social, and chemical exposures). There is growing interest in understanding the joint effects of both environmental hazards and social stressors to understanding how total neighborhood contexts can impact early life outcomes [Although there is evidence to suggest that both social and environmental factors are associated with birth weight and adiposity, few studies have examined the combined effects of exposures to hazards in multiple domains  within the prenatal exposure mixture measured were driving associations with lower birth weight and adiposity.Using data from the Healthy Start cohort, we expanded upon our previous study by employing a non-parametric Bayes shrinkage (NPB) approach to examine linear associations between our neighborhood-level determinants and neonatal outcomes. For this data set, we needed to identify a statistical method that would be capable of handling variable selection among potentially highly correlated exposures within the context of interactions between exposures and between exposures and covariates. NPB is designed to facilitate selection among a large number of correlated predictors in a single model, thus having an advantage over traditional multipollutant models , 43. We i.e., we included pre-, full- and post-term births). All mother–child dyads who had an address at enrollment within the study area were eligible for this analysis. The Healthy Start study protocol was approved by the Colorado Multiple Institutional Review Board.We used data from the ongoing Healthy Start pre-birth cohort study for this analysis. Details on the Healthy Start cohort are available elsewhere . BrieflyAlthough the Healthy Start study originally recruited participants from the nine county Denver metropolitan area, the study area for this analysis consisted of most census tracts within a smaller three county area . These counties were included due to the availability of exposure data (described next). We excluded the two eastern most census tracts within these counties because they were rural and not considered part of the metropolitan area. Census tracts were chosen to represent neighborhoods as they were the smallest spatial unit for which reliable exposure data were available.We selected our environmental and social exposures based on the indicators used by the CalEnviroScreen tool , 46 with2.5) and ozone (O3) and a variable for temperature. Monitoring data collected between 2009 and 2014 were obtained from the US Environmental Protection Agency [2.5 and temperature we used the mean of all 24-h measurements and for O3 we used the mean of all daily 8-h maximum concentrations recorded during the two-week period. We used ordinary kriging to estimate biweekly measurements at each census tract centroid. Biweekly air pollutant and temperature exposures were then assigned to each participant based on the address at enrollment and the timing of conception and delivery and averaged over the duration of the pregnancy.We included two measures of ambient air pollution, fine particulate matter  These included: the mean percent tree cover and mean percent impervious surface within the census tract from the 2011 National Land Cover Database ; the meaSocial stressor variables were intended to capture socioeconomic status (SES), demographic trends, and susceptibility at the neighborhood level. We included five variables from the 2010–2014 American Community Survey: the percentage of the population with less than a high school diploma, that was unemployed, and that identified as a race/ethnicity other than non-Hispanic white and the percentage of household speaking limited English or in poverty . Crime iOur two outcomes of interest were birth weight and adiposity at birth. Birth weight was measured at the time of delivery or was abstracted from medical records. Fat mass and fat-free (lean) body mass were measured within three days of birth using air displacement plethysmography . Additional details on the PEA POD measurements for the Healthy Start cohort are available elsewhere . We calcWe selected our model covariates a priori by considering those included in our previous study  and otheBecause individual-level race or ethnicity may modify the relationships between exposures and neonatal outcomes , we condAll analyses were performed in R version 4.0.3 . Prior tOur goal for this paper was to select from a complex mixture of neighborhood-level factors exposures that were associated with birth weight and adiposity. Therefore, our primary analysis used NPB, which is a Bayesian statistical method that fits a linear model with main effects of all exposures and all pairwise interactions while implementing both variable selection and regularization . SpecifiOur NPB model has the following form:where age in R , 71. AddBecause variable selection by the NPB model may depend on the specification of hyperparameters, we conducted a sensitivity analysis in which the α and β values of the Gamma distributions for hyperparameters mentclass2pt{minimTo serve as a comparison to the NPB method, we fit separate linear regression models for each exposure-outcome pair. These linear models were adjusted for all relevant covariates listed in In a supplemental analysis meant to assess potential non-linear effects of our NPB-selected exposures of interest on birth weight or adiposity, we fit separate generalized additive models (GAMs) for any variables selected with NPB based on a PIP > 0.5. We used a smoothed term with penalized splines for the continuous exposures identified in the NPB model. Models were adjusted for all covariates listed in n = 51 were excluded because they were missing data on birth weight, n = 259 were excluded because they lived outside the three-county study area, n = 172 were excluded because they were missing data on smoking exposures, and n = 37 were excluded because they were missing data on infant sex. There were few differences between included and excluded study participants  and mean temperature across pregnancy. Correlations between environmental exposures and between environmental and social exposures were generally moderate (Pearson’s coefficients ranged from -0.5 to 0.7). Correlations tended to be stronger between the social determinants of health  and a 4.8 °F increase in mean temperature across pregnancy was associated with a 13.1 g increase . For every 1 SD increase in temperature, the decrease in birth weight for a 1 SD increase in ozone was 162.0 g (95% CI: -242.3 g to -117.8 g) greater than expected if effects of the two exposures were additive. A plot showing the relationship between predicted and observed birth weight is included in the Supplemental Materials  were associated with lower birth weight, though most confidence intervals for the coefficients were wide and contained zero , the linear regression models showed similar lack of association with most of the exposures of interest Table S. The str3 and temperature observations. Plots showing the full range of data are available in the SDC , we identified the interaction between mean O2.5 and birth weight in our cohort, which contradicts several other studies  [2.5 exposures in the study area. Average and maximum PM2.5 exposures across pregnancy in our cohort  were below the National Ambient Air Quality Standard for PM2.5 . A similar Healthy Start study relying on trimester-specific averages derived from monitoring data also reported no association between PM2.5 and birth weight or adiposity [2.5 tend to be relatively flat and regulatory monitors poorly reflect variability from local sources [Our results differ in some ways from other studies reported in the literature. For example, we did not identify an association between PM et al.) . Our inadiposity . In gene sources . Other p sources .3 on birth weight are more consistent with previous studies [3 exposures have been associated with lower birth weight (measured continuously) or increased odds of low birth weight  [3 on birth weight may be due to maternal systemic inflammation, which is known to influence fetal growth [Our results indicating an interaction between temperature and O studies . Althoug2,500 g) , 79. Ass2,500 g) –83. Both2,500 g) –88. Thusl growth .Importantly, our study provides additional evidence of effect modification by maternal race and ethnicity on associations between environmental hazards and child health outcomes. Associations between our exposures of interest and birth weight were stronger for mothers from historically minoritized race or ethnicity groups compared to non-Hispanic White mothers. Several studies in the past two decades have reported racial disparities in low birth weight, which is more likely as population mean birthweights shift downward, over the last few decades –92. RelaThere were important differences between the results of the single-exposure linear regression analysis and the results from the NPB model. In the linear regression models, higher exposures to social stressors tended to be associated with lower birth weights and adiposity in the linear regression models, though the confidence intervals for the regression coefficients tended to be wide and contain zero. These results are consistent with our previous index-based analysis which found that associations between a combined exposure index and birth weight were likely driven by the social stressor component of the score . Howevere.g., CalEnviroScreen [Additionally, differences between our NPB model and our original index-based approach also suggest that our combined exposure index may have characterized factors in the neighborhood that are not fully explained by any one variable. Notably, temperature was not included in our original index. Our exposures were originally chosen to reflect the combination of factors often included in screening tools for environmental justice concerns, roScreen  or EJScrroScreen ; thus, wThere are some important limitations to our approach that should be considered when interpreting these results. First, the census tract estimates of exposure generally have limited temporal resolution. Due to the limitations of publicly available data at the spatial resolution used here, we relied on annual or five-year average estimates for most of our exposures. Second, there is no universal definition for neighborhood, and census tracts may not be the most meaningful unit of analysis; boundaries that reflect policy or other jurisdictional boundaries  may be more appropriate for some exposures .Third, aDespite these limitations, our approach demonstrated the strengths of using NPB in a mixtures context. Our use of NPB allowed us to include a large number of correlated exposures, which would otherwise be a challenge in a multipollutant model due to the potential for multicollinearity and variance inflation . In this3 and temperature as important predictor of birth weight, and the GAM indicated these association may be non-linear. Our results suggest there is a potential role for neighborhood-level environmental and social stressors in the prenatal period to influence fetal growth, but that additional studies are needed to identify important drivers in this exposure mixture. Future work may consider imputing missing values for key covariates to increase the sample size available for more complex statistical approaches such as BKMR. Further, it will be crucial to examine non-linear dose response relationships when assessing the effects of joint exposures assessed at the neighborhood level. When non-linear relationships are anticipated, additional variable selection approaches could be considered [Overall, our NPB model, which was designed to select among a large number of correlated exposures, identified a joint effect of Onsidered .Additional file 1. Supplemental Materials.


Sleep deprivation and social support were predictive indicators of perceived stress in mothers with preterm infants. Conclusions: We suggest that the differences in stress and needs of mothers with singleton and multiple births should be recognized and addressed in clinics. The findings of this study serve as a reference for promoting better preterm infant care.Objective: The aim of this study was to explore mothers’ perceived level of stress one month after hospital discharge following the birth of singleton and multiple preterm infants. Design: A cross-sectional design was used to compare mother’s perceived stress in two groups of postpartum mothers and the relationship of the theoretical antecedents and these variables. Setting: A neonatal intensive care unit in a medical center in Taiwan. Participants: Mothers of 52 singletons and 38 multiple premature infants were recruited. One month after the infant was discharged, the participants completed a self-reported questionnaire that included demographic data about the mother and infant, the 21-item Social Support Scale, and the 15-item Perceived Stress Scale. This was returned by email or completed at the outpatient unit. Analysis: Descriptive and inferential analysis. Results: The mean social support scores were 76.6 and 76.5 (out of 105) for mothers with singleton and multiple birth infants, respectively. The most important supporter was the husband. The mean perceived stress scores of 25.8 and 31.0 for mothers with singleton and multiple birth infants, respectively, were significantly different ( Pregnancy and giving birth result in significant psychological changes for women. The health of women and children has become a priority, as evidenced by the World Health Organization (WHO) declaration, “Make every mother and child count” . PretermStress is a crucial issue for mothers with preterm infants. Perceived stress is defined as the thoughts and feelings an individual has about how much pressure they are under at a given time . Stress In societies, mothers are regarded as the primary caregivers of infants, and preterm infants are also responsible for nurturing and caring after they are discharged from the hospital. Many mothers report that they suffer from severe sleep disturbances ,14. OhaySocial support includes the emotional, tangible, informational, and companionship support that an individual receives through interactions with family members, friends, and other support networks . Social The birth of multiple infants is exciting yet stressful. Twins require the primary caretakers to deal with twice the workload as for a singleton infant, which can result in increased anxiety while adapting to the new roles . This caMost studies have focused on how parents adjusted to the birth of singleton preterm infants and coped with stress after discharge . There hThis was a descriptive, cross-sectional study using questionnaire. Mothers of preterm infants were contacted via phone or clinical follow-up one month after their infants were discharged from the hospital.The participants were mothers who gave birth to singleton or multiple preterm infants at a medical center in central Taiwan. They were recruited by purposive sampling, with the following criteria: the infant was born with a gestational age of less than 37 weeks and the mother was the infant’s primary caregiver within one month of the infant’s discharged. Mothers who had a disability, cancer, or mental illnesses and whose preterm infants had a congenital disorder were excluded from study. G*Power 3.1. software was used to estimate the sample sizes based on a pilot study of 10 participants. The sample size for detecting differences in social support was 36 participants per group . The sample size for detecting differences in perceived stress was at least 17 participants per group . Thus, the optimal sample size was at least 36 mothers with singleton and multiple preterm infants each, for a total of 72 participants. The final total was 90 participants, 52 mothers with singleton preterm infants, and 38 with multiple preterm infants; the study had a power of 90% to yield a statistically significant result.The study used a self-reported questionnaire in three scales. The first scale consists of demographic data that included both mothers’ and infants’ information. Sleeping quantity and quality were measured by mothers’ perception of sleeping more/less than 6 h and good/poor quality. The second scale was Perceived Stress Scale (PSS), a 15-item questionnaire modified from Cohen’s study . QuestioThe third scale was the Social Support Scale (MOS), modified from Sherbourne and Stewart’s study . The queThe instruments were used with the permission of the copyright holders. The instrument’s readability, accuracy, and adaptability were verified by a panel of experts and a pilot study of 10 mothers. Face validity was determined by experts’ panel review, with a content validity index (CVI) value of 0.95. Reliability and internal consistency measured by Cronbach’s alpha was 0.95 in the pilot study and 0.93 in the final study for the Perceived Stress Scale; and 0.97 in the pilot study and 0.95 in the final study for the Social Support Scale. t-tests, one-way ANOVA, and chi-square were used to summarize the demographic information and difference in two groups. Pearson’s product-moment correlations were used to examine the relationships between MOS and PSS. General linear regression was used to predict PSS of mothers in the two groups. The variable of infant gestational age was controlled in regression models. An alpha level of 0.05 was designed for statistically significant.Data were collected from March 2016 to November 2016. Mothers who gave consent were given questionnaires for completion via email or at the hospital. Data were compiled using SPSS version 22.0 for statistical analysis. Frequency distributions, t-test were used to test the homogeneity of the mothers and preterm infants in two groups. Only gestational age was statistically different in the two groups (o groups . The three open-ended questions were responded to by 46 (88.5%) mothers with singleton preterm infants and 36 (94.7%) mothers with multiple preterm infants. The answers from #1: “Which family member provides the most positive support when you are taking care of infants?” The frequent answer was husband  in the mothers with singleton preterm infants, as well as in the mothers with multiple preterm infants . Question #2: “Which family member causes the most negative impact when you are taking care of infants?” The most frequent answer was none  and mother-in-law  in the mothers with singleton preterm infants. Correspondingly, none  and mother-in-law  were the responses in mothers of multiple preterm infants. Question #3: “What type of support would you most need to receive while caring for your infant?” Answers were tangible support  and informational support  in the mothers with singleton preterm infants, and tangible support  and informational support  in the mothers with multiple preterm infants. p = 0.02). The mean scores  of the Social Support Scale were revealed, where the social support was a little higher in mothers with singleton preterm infants compared to mother with multiple preterm infants with no statistical significance (p > 0.05). The level of social support had negative association with the level of perceived stress in both groups . Higher support leads to less stress. In The analysis showed the factors related to the perceived stress of the mothers with singleton preterm infants were mother’s sleep time and quality, educational level, the mother’s perceived health status, education, assistance care infant by mother-in-law, and social support. The factors related to the perceived stress of mothers with multiple preterm infants included the mother’s sleep time and quality, assistance with caring for the infants, and social support. The factors related to both groups were the mother’s sleep time and quality, mother’s perceived health status, educational level, number of births, and social support .The General Linear Regression analysis showed that sleep quantity and quality and someone in assisting were the indicators of perceived stress in mothers with multiple preterm infants. The GLM resulted that sleep quantity and quality, and social support were prognostic indicators of perceived stress for the mothers with preterm infants. The gestational age was controlled in the Models .To our knowledge, this is the first study to explore and compare perceived stress in mothers with singleton and multiple preterm infants discharged one month at home in Taiwan. The main results showed that mothers with multiple preterm infants had higher perceived stress than the mothers with singleton preterm infants. One of the interesting findings from the statistics is that mothers-in-law were mentioned as having a negative impact on caring for infants in the open questions and the related factor of perceived stress for mothers with singleton preterm infants, but not in the mother with multiple preterm infants. The sleep quantity and quality and social support were beneficial factors for perceived stress among the mothers with preterm infants.The study explores the perceived stress and social support received by mothers of singleton and multiple preterm infants at one month discharged at home. The mean age of the mothers with preterm infants in this study was 33.7 years, which is in line with the age range of 30–34 years at which, on average, Taiwanese women give birth to their first child . In thisOur study showed that both groups of mothers received social support in a moderate level (76 score out of 105). This might be a result of the postpartum confinement and one-month postpartum traditional care, whereby mothers would get more family support in Taiwan than in other countries . RelyingHusbands provided the greatest social support for mothers with preterm infants in this study. Studies have shown that mothers adapt to their new roles more quickly and experience less stress when their husbands and other family members share in taking care of the infant. Thus, fathers of preterm infants can be considered the most important support for positive impact; they should, therefore, be included in health education before the preterm infants go home so they can provide more comprehensive support for the mothers.Another important support, information support, was displayed in the outcomes. Many mothers of preterm infants lack the confidence and skillset for preterm infant care. Study reported that parenting support occurs by proving consistent advice, providing sufficient information about self-management for mothers, involving parents in discharge planning, and enabling clinical care consistency ,29. HealMothers of multiple preterm infants had statistically higher perceived stress scores than the mothers with singleton preterm infants. Previous studies have reported that mothers with twins often feel anxious when adapting to their new roles, resulting in higher stress than experienced by mothers of singleton infants ,30,31; mThe results of the open question revealed that mothers-in-law help had a negative impact on infant care. Generational gaps in childcare philosophy, parenting perspectives, and childcare skills all added to the tension between the new mothers and their mothers-in-law ,33. In cInsufficient and poor sleep was the item in the Perceived Stress Scale that was most often selected by both groups of mothers in this study. In the present study, 65% of the mothers with singleton preterm infants and 82% of those with multiple preterm infants slept less than 6 h per night. This finding was consistent with Leonard and Denton’ study . MothersAnother reason of mothers’ insufficient sleep might be infants’ sleeping schedule and feeding needs at midnight. Culture is important here, as co-sleeping (sleeping side-by-side or in the same room) is very common in Taiwan. The sleeping environment would also affect both mothers’ and infants’ sleep. Coping strategies in sleep issues were recognized and recommended . ParentaThis study had several limitations. First, it was based on self-reported questionnaires; this might lead to the possibility of reporting bias because of social desirability. Second, the participants were recruited from a single hospital in a central Taiwan; thus, the results may not be generalized to all mothers with preterm infants in Taiwan. Third, cultural difference could be a bias in this group of participants; Asian families might experience more support/interference than Western families. Fourth, the excluded criteria might be part of the reason of the observed issues. Fifth, the study did not measure the psychological maternal status, which might reduce the validity of the results. Finally, a more rigorous design and a larger regional or national survey would enable to further assess social support and perceived stress in mothers with singleton and multiple preterm infants.Social support was found to be a benefit indicator of perceived stress in both groups of mothers with singular and multiple preterm infants. Moreover, poor sleep problems were also displayed as important indicators of mothers’ perceived stress, especially among mothers with multiple preterm infants. There is no standard care plan for multiple preterm infants. Clinical teaching should aim to develop such a plan to support those mothers with multiple preterm infants. Fathers and other family members (such as mothers/mothers-in-law) provide important social support for mothers with preterm infants, so it is recommended that they are taught the necessary aspects of childcare to allow them to be more effective in reducing the stress of the mothers and increase the well-being of the infants. Finally, it is recommended that health professionals evaluate the mothers’ sleep quality as soon as possible after preterm infants are discharged from the hospital. Ensuring that the mothers of preterm infants have enough sleep allows for a more effective support system and improves the quality of life of their families.


Although marriage is associated with favourable reproductive outcomes among adult women, it is not known whether the marriage advantage applies to girls (< 18 years). The contribution of girl child marriage (< 18 years) to perinatal health is understudied in the Americas.N = 23,117,661), Ecuador , the USA  and Canada . The joint associations between marital status and maternal age groups  with preterm birth (< 37 weeks), small-for-gestational age (SGA < 10 percentile) and repeat birth were assessed with logistic regression.National singleton birth registrations were used to estimate the prevalence of girl child marriage among mothers in Brazil (2011–2018, The proportion of births to < 18-year-old mothers was 9.9% in Ecuador, 8.9% in Brazil, 1.5% in the United States and 0.9% in Canada, and marriage prevalence among < 18-year-old mothers was 3.0%, 4.8%, 3.7% and 1.7%, respectively. In fully-adjusted models, marriage was associated with lower odds of preterm birth and SGA among 20–24-year-old mothers in the four countries. Compared to unmarried 20–24-year-old women, married and unmarried < 18-year-old girls had higher odds of preterm birth in the four countries, and slightly higher odds of SGA in Brazil and Ecuador but not in the USA and Canada. In comparisons within age groups, the odds of repeat birth among < 18-year-old married mothers exceeded that of their unmarried counterparts in Ecuador , the USA , and Canada , although minimally in Brazil .The prevalence of births to < 18-year-old mothers varies considerably in the Americas. Girl child marriage was differentially associated with perinatal health indicators across countries, suggesting context-specific mechanisms. Marriage is a social relationship that is associated with beneficial maternal and child health outcomes in high income countries –3. The mChild marriage (CM), defined as a marriage or union of an individual below 18 years of age, is considered by various international agencies a violation of human rights that may negatively affect the lives, health, and future development of girls , 6. ConsThis agenda is supported by a substantial body of literature originating from low- and middle-income countries, mainly Asia and Africa, where most early pregnancies take place within arranged marriages , 7. StudBoth the concepts of “child” and “marriage” are socially constructed entities that in practice show variation across time and space . For thiThis is a population-based cross-sectional comparative multi-country study. We used nationwide anonymised birth registrations available for the four countries at the time of the data analysis.The study populations were composed of the most recent live births registrations in Brazil (2011–2018), Ecuador (2014–2018), United States (2014–2018) and Canada (2008–2018). The study periods are expressed in calendar years and were determined based on the availability of information on marital status, consistency in data collection over time, and subgroup size considerations. Brazilian data was obtained from the Brazilian Information System on Live Births (SINASC) through the Department of Informatics of the Unified Health System (DATASUS) . EcuadorFor our first objective of determining the distribution of births according to maternal age and marital status, we included births to mothers ≤ 49 years and excluded births with missing information on these two variables Fig. .Fig. 1SaFor our second objective of examining the associations between maternal age and marital status with reproductive outcomes, we restricted the analytic sample to births of adolescent mothers ≤ 24 years, which allows to contextualise births to < 18-year-old mothers within the full range of adolescence , 28. We In the four countries, information on marital status was self-reported by the mother and was categorised into legally married and unmarried. Divorced, widowed, and separated mothers were classified as unmarried. Common-law unions, only collected in Brazil and Ecuador, were reclassified as unmarried.Maternal age represents the age in complete years at the time of the birth, which may differ from that of conception, and was categorised into < 18, 18–19, and 20–24 years.Preterm birth was defined as a birth before 37 completed weeks of gestation.Small for gestational age (SGA) was defined as a birthweight < 10th percentile for gestational age using the sex-specific INTERGROWTH-21 birthweight charts for infants born between 24–42 completed weeks of gestation .Repeat birth denotes that the current birth was preceded by one or more pregnancies resulting in a live birth.The distribution of births according to maternal age and marital status within countries was determined by cross tabulations. Logistic regression was used to model the joint associations of maternal age groups and marital status with each of the reproductive outcomes by adding a multiplicative interaction term between maternal age and marital status (3 × 2 groups). Based on the interaction model, adjusted Odds Ratios with 95% confidence intervals were estimated for the joint associations where births to unmarried mothers aged 20–24 years were the reference group. In the models of repeat birth, married women were compared to unmarried women within age group strata, because of the strong collinearity between maternal age and previous births. For preterm birth and SGA, we also compared births of married versus unmarried women within age groups but only reported the p-values in the figures while the adjusted odds ratios are provided in the text of the results section.The main model including the interaction term was run with two sets of control variables. For comparability, minimally adjusted models (Model 1) included common variables available in the four countries, infant sex, previous birth, and year of birth, where applicable. In a second model, we further adjusted for all meaningful variables to each perinatal outcome available in each country (Model 2): paternal age, maternal race, prenatal care initiated in 1st trimester, state, and age-appropriate low education in Brazil; maternal ethnicity, foreign-born mother, adequacy of the number of prenatal care visit for gestational age , maternaBrazilian, Ecuadorian and United States datasets are publicly available and therefore their use does not require review by Research Ethics Boards in their respective countries. Use of Canadian data was approved by the Canadian Research Data Centre’s Network from the Social Sciences and Humanities Research Council and by the Health Research Ethics Board of the University of Manitoba (HS24149 (H2020:356)). All methods were carried out in accordance with Statistics Canada’s vetting rules and the Helsinki Declaration.Overall, the proportion of total births increased with increasing maternal age group but varied significantly between countries. The percentage of births to mothers aged < 18 years was 9.9% in Ecuador, 8.9% in Brazil, 1.5% in the United States and 0.9% in Canada Fig. , panel AWithin age groups, the proportion of married mothers also varied between countries. More than 70% of 20–24-year-old mothers were married in the USA and Canada whereas around 45% were married in Brazil and Ecuador. Among mothers aged < 18 years, the percentage of births to legally married mothers was 4.8% in Brazil, 3.0% in Ecuador, 3.7% in the USA and 1.7% in Canada , indicating that the interplay of these two variables unequivocally shapes perinatal outcomes among child and adolescent mothers.The interaction between marital status and maternal age groups was statistically significant for the three outcomes in the four countries in both models   and in Ecuador , but not in the USA or Canada.In comparisons within age groups, married women had consistently lower odds of preterm birth than unmarried women in the 20–24-year-old group in the four countries in the two models (01) Fig. . HoweverRegarding SGA, compared with unmarried 20–24-year-old women, married < 18-year-old women only had higher odds in Ecuador but not in the other countries  and the USA  in the fully adjusted model. Among < 18-year-old mothers, being married was only associated with lower odds of SGA in Brazil .Comparisons between married and unmarried women within age groups were only consistently observed in the 20–24-year-old group. In all countries, married mothers aged 20–24 years had consistently lower odds of SGA than their unmarried counterparts, with the only exception of Canada in the minimally adjusted model (Fig. Unlike preterm birth and SGA, comparisons of repeat birth by marriage status were restricted within age group strata Fig.  because This cross-country population-based study indicates that the frequency of child marriage varies substantially in the Americas, from 1.5 per 10,000 births in Canada to 42.7 per 10,000 births in Brazil. Our main finding is that among girl and adolescent mothers, age and marital status interact to shape reproductive outcomes. Furthermore, we found that the interplay between age and marital status is context-dependent, as evidenced by differential patterns between countries. The well-documented perinatal health advantage associated with adult marriage was confirmed among births to mothers aged 20–24 years but was not consistently observed among births to 18–19-year-old and < 18-year-old mothers. The protective association of marriage with preterm birth among < 18-year-old mothers in Brazil and Ecuador was offset by increased odds associated with decreasing maternal age. Child marriage was strongly associated with repeat birth in all countries, except in Brazil, where marriage was also associated with lower odds of repeat birth among 18–19- and 20–24- year-old mothers.Our study confirms the advantage of marriage among 20–24-year-old mothers, as documented for preterm birth, SGA and other perinatal outcomes , 3, 4. THigher odds of repeat birth among married women in all age groups in the USA and Canada may simply reflect intended pregnancies towards the goal of family formation. However, married < 18-year-old women may have limited ability to negotiate contraceptive use and sexual intercourse frequency resulting in unintended high early fertility . InteresThere are a number of limitations. First, self-reported marital status within pre-established categories  may haveDespite the abovementioned limitations, this study provides a comparative view of the differential reproductive outcomes of married and unmarried girls and adolescent women in four American countries with different socioeconomic contexts and rates of girl child marriage. Among adolescents aged < 25 years, an interplay between maternal age and marital status shaping reproductive outcomes was observed in all countries but the patterns were different. This observation stresses the context-dependent nature of the joint influence of maternal age and marital arrangements on reproductive outcomes.


Most follow-up studies have focused on the long-term consequences of asphyxia at birth on the brain. The aim of this study was to investigate associations between low Apgar score and asphyxia-related complications and subsequent risks of cardiovascular diseases (CVD) in childhood and early adulthood.This population-based cohort study included 2,826,424 non-malformed singleton births, born at term (≥37 weeks’ gestation) between 1988 and 2018 in Sweden. Primary exposure was a composite of asphyxia-related complications, defined as a) Apgar score 0–3 at 1-min; or b) Apgar score 0–3 at 5-min; or c) neonatal seizures . Using Cox regression, we estimated the risk of CVD after 1 year of age, defined as stroke, coronary heart disease, heart failure, and atrial fibrillation.Overall, there were 4165 cases with cardiovascular diseases. Individuals with asphyxia-related complications had adjusted hazard ratios  of 1.90 (1.54 to 2.34) for cardiovascular disease, 2.29 (1.74 to 3.03) for stroke, 2.17 (1.37 to 3.42) for heart failure, and 1.38 (0.87 to 2.17) for atrial fibrillation. Hazard ratios for CVD were elevated among individuals with Apgar score 0–3 at 1 and 5 min, and those with neonatal seizures. Compared with unexposed individuals, neonatal seizures were associated with 5 times higher rates of stroke and heart failure, respectively.Asphyxia-related complications and its neonatal complications, especially low Apgar score and neonatal seizures, are associated with increased risks of CVD in childhood and early adulthood, although the absolute risk of CVD is low in young age.10.13039/501100004359Swedish Research Council and the 10.13039/501100003793Swedish Heart-Lung Foundation We searched PubMed for articles assessing risk of cardiovascular diseases in relation to low Apgar score and asphyxia-related complications at birth up to March 1, 2022, using the search terms “asphyxia”, “birth asphyxia”, “Apgar score”, “cardiovascular disorders”, “childhood cardiovascular diseases” and “risk”. We found no observational study examining the relationship between asphyxia-related complications and risk of cardiovascular disorders. Previous follow-up studies have focused on the long-term neurodevelopmental consequences of asphyxia, but we found no observational study examining the relationship between asphyxia-related complications and risk of cardiovascular disorders.In this population-based study, non-malformed term (≥37 weeks) infants experiencing asphyxia-related complications, especially infants with low Apgar scores (0–3) at 5 min and those with neonatal seizures, have increased risks of cardiovascular diseases (CVD) in childhood and early adulthood. In particular, increased risks were observed for stroke and heart failure.Although the absolute risk of CVD is low in young age, the present findings provide support that asphyxia-related complications and its neonatal complications, especially low Apgar score and neonatal seizures, are associated with cardiovascular morbidity later in life. Our findings need to be replicated, and possible underlying mechanisms, linking asphyxia-related complications to CVD, need to be identified.,Cardiovascular diseases are the leading causes of disability and death in most countries.,Asphyxia is characterized by tissue hypoxia and energy-failure that arises due to ischemia, globally occurs in about 4 million babies every year, approximately 1 per 1000 live births.Much of the research has been concentrated on long-term neurodevelopmental impairments after asphyxia, such as cerebral palsy,,This population-based cohort study included all live singleton births, born at ≥37 completed gestational weeks, who were recorded in the Swedish Medical Birth Register from January 1, 1988 to December 31, 2018. Using the person-unique national registration numbers of mothers and children,From 1988 through 2018, the Medical Birth Register recorded information for 3,181,285 live singleton births. We excluded 4108 births where either the mothers or the children had invalid national registration numbers, 151,845 preterm born singletons, 9593 who died before their first birthday, 8745 children who emigrated before one year of age (start of follow-up), 125 with missing information on child's sex or maternal age, 2463 who had an ICD code for the outcome during the first year of life, and 180 445 infants with congenital malformation diagnoses during the study follow-up time (see Our primary exposure was a composite of asphyxia-related complications diagnosed in the first 27 completed days of life (0–27 days), captured from the Medical Birth Register and the National Patient Register. Asphyxia-related complications was defined as a) Apgar score 0–3 at 1 min or; b) Apgar score 0–3 at 5 min or; c) seizures The primary outcome was the first cardiovascular disease (CVD) event recorded after 1st year of life. Outcome information was obtained by using ICD codes in the National Patient Register or the Cause of Death Register from 1989 through 2020, including primary or secondary diagnoses. The primary outcome was cardiovascular disorders of any type , all individuals with recorded ICD codes for CVD before 1 year of age were excluded from the study. The outcomes were not mutually exclusive. In addition, associations between asphyxia-related complications and subgroups of cardiovascular diseases were considered.2), and smoking during pregnancy. Maternal BMI in early pregnancy was calculated from self-reported height and weight measured at the first antenatal visit, which occurs within the first 14 weeks of gestation . Mothers who reported daily smoking at the first prenatal visit and/or at 30–32 gestational weeks were classified as smokers. Birth weight-for-gestational age was estimated using the sex-specific Swedish reference curve for normal fetal growth.All women in Sweden are offered ultrasound dating of pregnancy no later than early in the second trimester, and 95% of the women accept this offer.Results were presented as incidence rates per 10,000 person years with 95% confidence intervals (CIs) for CVD according to asphyxia-related complications. Cumulative hazard curves were used to compare rates of CVD over time according to asphyxia-related complications as a composite and each component separately. The primary and secondary outcomes of time to first CVD event were analyzed with Cox proportional hazard regression models with age as the time scale, and are presented as crude and adjusted hazard ratios (HR). The time to first CVD event was calculated from one year of age until first diagnoses of CVD, death, loss to follow-up (e.g. emigration), or end of study , whichever came first. All HRs are presented with 95% CI.First, rates of CVD were compared between categories of maternal and neonatal characteristics. Next, rates of CVD within each asphyxia-related complication were estimated. Adjusted HRs were obtained from multivariable Cox models with covariates, including maternal age, parity, mother's country of origin, education level, cohabitation with partner, height, smoking, child's sex, and year of delivery. In addition, associations of asphyxia-related complications with CVD subtypes were examined. As clustered robust standard errors (to account for clustering of siblings) only changed confidence intervals in the third decimals, confidence intervals are reported with normal standard errors without adjustment for clustering. In sensitivity analyses, additional adjustments were made for birth weight. As maternal BMI was missing in 542,408 (19.2%) women, adjustment for maternal BMI was only carried out in sensitivity analyses. We also tested the cross-product interaction terms between asphyxia-related complication and child's sex with the use of a Wald χ2 test. All analyses were carried out with the use of Statistical Analysis Software version 9.4 .The funders had no role in the study design, data collection, analysis, interpretation, writing the report, or the decision to submit the manuscript for publication. The corresponding author had full access to the data and had final responsibility for data integrity and data analysis, and the decision to submit for publication.With a total of 44,998,488 million accumulated person-years, the median follow-up time was 15.9  years for exposed and 15.4 (IQR 7–25) years for unexposed individuals. The median age at diagnoses of CVD was 20.3 years. During the follow-up time, we recorded 4165 CVD events; 471 (11.3%) were diagnosed with CVD between 1 and 4 years, 859 (20.7%) between 5 and 16 years, 888 (21.3%) between 17 and 20 and 1937 (46.5%) and between 21 and 32 years .2), maternal smoking, vaginal instrumental delivery, elective and emergency cesarean delivery, male sex, low birth weight for-gestational-age (<3rd percentile), or high birth weight for-gestational-age (97th percentile) were associated with increased rates of CVD , followed by atrial fibrillation . AsphyxiIn this nationwide cohort study of more than 2.8 million individuals, we found that non-malformed term infants experiencing asphyxia-related complications at birth had higher risks of cardiovascular diseases in childhood and early adulthood. In particular, risks of stroke, and heart failure were increased, although absolute risks were low. These associations remained strong even after adjustment for birth weight and potential confounders. Especially those with Apgar score 0–3 at 5 min and those with neonatal seizures – indicating moderate to severe hypoxic-ischemic injury – had substantially increased risks of cardiovascular diseases.,Our finding of an association between asphyxia-related complications and increased risk of cardiovascular diseases later in life has not been demonstrated before.Low birth weight has previously been associated with increased risks of ischemic heart disease and stroke in later life.,Asphyxia typically triggers events within the cardiovascular system, ranging from heart rate and systemic blood pressure variations to more profound changes, like myocardial dysfunction, myocardial ischemia, and pulmonary artery hypertension.Our data also provide some reassurance that the cardiovascular system may be more resilient to asphyxia insult at birth than the brain. For instance, among children born between 2015 and 2019 in Sweden, those who were treated with therapeutic hypothermia for asphyxia (242/401), after 2 years of follow-up, 16% needed habilitation services, 12% were diagnosed with cerebral palsy, and 7% suffered from developmental delay.The key strengths of our study are the long and virtually complete follow-up, outcome data were collected prospectively and independent of exposure data, and the use of multiple health and population-based data sources. Information on exposures and outcomes and other high-quality registry data minimize the possibility of selection and information bias. We also adjusted for a number of important parental confounders, including maternal body mass index, and smoking during pregnancy. In addition, to avoid measuring CVD as a neonatal or infancy complication, all individuals diagnosed with CVD before 1 year of age were excluded. Lastly, we excluded all individuals with congenital malformations during the study period.This study is also subject to some limitations. First, our cohort only allowed for a follow-up time reaching into young adulthood, and conclusions about possible associations between asphyxia complications and cardiovascular events should be restricted to this age period. Second, the validity of reported CVD diagnoses may be a concern. Nevertheless, the positive predictive values for stroke and acute myocardial infarction diagnoses are very high in the Swedish National Patient Register.Although the present findings provide support that asphyxia-related complications, especially low Apgar score and neonatal seizures, are associated with cardiovascular morbidity later in life, the absolute risk of CVD, at least in young age, is very low. Our findings need to be replicated, and possible underlying mechanisms, linking asphyxia-related complications to CVD, need to be identified.Drs Razaz had full access to all of the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analyses.Study concept and design: Razaz, Norman, Cnattingius.Acquisition of data: Razaz.Drafting of the manuscript: Razaz.Critical revision of the manuscript for important intellectual content: Razaz, Norman, Alfvén, Cnattingius.Statistical analysis: Razaz.Obtained funding: Razaz.The data sets generated and analyzed during the current study are not publicly available. The Swedish Secrecy Act does not permit data sharing of data sets based on individualized personal data.We declare no competing interests.


According to recent studies and observations in clinical practice, uterine fibroids increase the risk of preterm birth. There are several theories on the pathogenesis of preterm birth in the presence of fibroids. One theory proclaims that fibroid necrosis leads to preterm birth, though pathophysiological mechanisms have not been described. Necrotic tissue secretes specific cytokines and proteins and we suggest these to be comparable to the inflammatory response leading to spontaneous preterm birth. We hypothesize that fibroid necrosis could induce preterm parturition through a similar inflammatory response. This new hypothesis generates novel perspectives for future research and the development of preventative strategies for preterm birth. Moreover, we emphasize the importance of the recognition of fibroids and especially fibroid necrosis by clinicians during pregnancy. Uterine fibroids are the most common pelvic neoplasms in women of reproductive age, with a prevalence ranging between 5% and 69% . The mosWomen with fibroids more frequently experience reproductive related problems; the chances of natural conception are lower and the miscarriage rate is higher compared to women without fibroids. However, chances and incidence rates vary widely depending on fibroid characteristics, in particular their localization ,8,9. DurA leading cause of perinatal morbidity and mortality is preterm birth . GloballWe hypothesize that fibroid necrosis may trigger an inflammatory response leading to spontaneous preterm birth. This pathway could resemble the inflammatory response seen in spontaneous preterm birth. Understanding this necrosis-induced inflammatory pathway is a first and essential step to develop preventative strategies for spontaneous preterm birth in women with fibroid necrosis. First, we illustrate the pathophysiology of inflammation-induced spontaneous preterm birth, after which we demonstrate the similarities to the necrotic pathway. During labor, irrespective of gestational age, an inflammatory activation ensues which is self-propagating. A specific balance in pro- and anti-inflammatory factors induces adequate timing of cervical ripening, rupture of the membranes and uterine contractions, which are key events to achieve a normal term delivery . In pretThe oxytocin receptor plays a pivotal role in the initiation of normal parturition, as this receptor is increasingly present in the myometrium of the uterus around the onset of labor ,27,28. I2 and PG-F2α, also have a central role in initiating labor in all phases of parturition [Prostaglandins (PGs), specifically PG-Eturition . They inturition ,33,34. Pturition ,36. Duriturition . Additioturition ,29. To iturition ,39,40.The high mobility group 1 protein (HMGB1) seems to play a crucial role in inflammatory induced spontaneous preterm birth . EvaluatNext to HMGB1, NF-κB pathway activation is associated with the onset of labor in both term and preterm births . The oxyBalance in reactive oxygen species (ROS) and antioxidants is important for tissue homeostasis, and an imbalance can lead to oxidative stress. In the uterus, excessive production of ROS may result in pregnancy complications such as preeclampsia, fetal growth restriction and preterm birth. ROS are an inseparable component of inflammation, as they can regulate inflammatory cytokines ,53. The Recently, microRNAs (miRNAs) have been found to be involved in parturition by influencing hormone responsiveness, regulating key gene expression pathways, and increasing myometrial sensitivity to oxytocin ,54. For The process of inflammation-induced preterm birth is complex, and more pathways are involved which we have not all described in this narrative review. Nevertheless, we have attempted to describe the most important pathways which could possibly be comparable to the inflammatory response leading to spontaneous preterm birth after fibroid necrosis.The timing of the formation of the first fibroid is not known. However, clinical data indicate that fibroids are rare during the early reproductive years. Because the majority of women have asymptomatic fibroids, these can typically be diagnosed during the first routine ultrasound during pregnancy . During Immunoblotting and immunostaining demonstrated that HMGB1 is passively released during necrosis, promoting inflammation by stimulating the production of TNF-α. Conversely, apoptotic cells do not excrete HMGB1, even after secondary necrosis or partial autolysis, and therefore are unable to inducing inflammation via this pathway . FurtherParallel to the release of HMGB1, necrotic cells activate the NF-κB pathway by the secretion of heat shock proteins (HSPs) . HSPs arNecrosis can be the result of oxidative stress, and the source of this is not ROS per se but the imbalance of ROS production and detoxification . ROS canMiRNA-145 was found to be upregulated in steroid-induced necrosis of the femoral head . FurtherThese pathways, all activated during necrosis, could hypothetically also be activated during fibroid necrosis in pregnancy, where they can lead to the upregulation of oxytocin receptors and cause an increase in PG production in myometrial cells  fibroids are prospectively followed during pregnancy and compared to women without fibroids. Blood serum and plasma of the patient could be tested by multi-parameter techniques, like a Luminex or MesoScale, focusing on necrosis associated interleukins and TNF-α . SamplesInterventions to prevent preterm birth are widely studied . ProgestAnti-TNF-α does not seem to affect preterm birth risk, although this has only been studied in an observational setting in patients who used anti-TNF-α because of inflammatory bowel disease . It woulIdeally, we would be able to identify patients at risk for developing fibroid necrosis during early pregnancy or even antepartum. With the development of a prognostic model based on uterine fibroid characteristics, we might be able to predict which patient is at risk for fibroid necrosis during pregnancy and consider myomectomy before conception. However, no preventive therapy exists for fibroids. Nonetheless, research on dietary interventions such as prophylaxis, like vitamin D supplementation, seems promising but still needs to be tested in randomized controlled trials .In conclusion, we hypothesize that fibroid necrosis can lead to spontaneous preterm birth through a similar pathway as inflammation-induced spontaneous preterm birth. A better understanding of the pathophysiological mechanisms causing preterm birth in pregnancies complicated by fibroid necrosis is essential to develop strategies to prevent this unfavorable outcome in women with uterine fibroids.