Background: ExtraUterine Growth Restriction (EUGR) is a common definition for in-hospital growth failure of very preterm infants. Wide heterogeneity is found in definitions and anthropometric charts used to describe EUGR.Aim: We aim to compare two traditional definitions of EUGR with a newly proposed one, based on a longitudinal evaluation, that takes into account the physiological period of fluid loss after birth. We also wish to detect which definition could better predict neurodevelopmental impairment at 24 months of corrected age (CA).Methods: A total of 195 infants with GA < 30 were included. EUGR was calculated both for weight and head circumference (HC). Cross-sectional EUGR was defined as measurements < 10th percentile at discharge; longitudinal EUGR was defined as Δz-score < −1 between birth and discharge measurements. The new longitudinal “post-loss” EUGR definition was proposed as Δz-score < −1 between measurements taken at 14–21 days of life and at discharge. Longitudinal postnatal Intergrowth-21st charts specifically built on preterm infants were used. Association with major and minor neurodevelopmental impairment at 24-month CA was assessed for each definition. K coefficient and ROC curve were evaluated.Results: Longitudinal “post-loss” definition of EUGR for HC is the one predicting minor neurodevelopmental impairment at the multivariate analysis (OR = 3.94), and it is also associated with a worse General Quotient. The chosen cut-off (Δz-score < −1) is the proper one.Conclusion: HC in-hospital growth could be a more accurate tool than weight to predict neurodevelopmental outcomes and especially minor neurological impairment. Longitudinal “post-loss” definition of EUGR assessed on longitudinal charts for preterm infants could be the most appropriate definition from the methodological, clinical, and prognostic point of view. In recent literature, the term ExtraUterine Growth Restriction (EUGR) is found as a common definition for growth failure that may occur early in postnatal life of very preterm infants , due to in utero have been questioned by many authors, and Villar et al. , head circumference, or length using specific anthropometric charts. There is increasing evidence to suggest that early postnatal weight and head circumference growth is related to long-term outcomes in preterm infants, especially with reference to neurodevelopment . Accordir et al.  have reccross-sectional definitions of EUGR, defined as a measurement lower than a previously set percentile or z-score, generally at 36 or 40 weeks of postmenstrual age (PMA) or at discharge; and (II) longitudinal definitions of EUGR, defined as a Δz-score lower than −1 (or −2), generally between measurements at birth and at 36 or 40 weeks of PMA or at discharge. It is evident that the two types of definitions just refer to two different and not interchangeable conditions: while longitudinal EUGR is the expression of a dynamic process, cross-sectional EUGR is statically defined and could depend more upon birth status than upon actual growth process   process , 8.longitudinal EUGR, but many authors  EUGR was compared to the two “traditional” cross-sectional and longitudinal ones, using the new Intergrowth-21st longitudinal Charts specifically constructed to monitor preterm infants.The aim of this present study is to compare three different definitions of EUGR to detect the most useful one as a possible predictor of neurodevelopmental impairment at 24 months of corrected age. In doing so, the new definition of Infants born before 30 weeks of gestational age (GA) and assisted at the Neonatal Intensive Care Unit of University of Turin between January 1, 2006, and December 31, 2016, were retrospectively enrolled. By predefined criteria, infants were excluded if they died or were transferred to another NICU before discharge, had a diagnosis of major congenital malformation or major cerebral lesion , did not have any anthropometric measurement recorded between 14 (−3) and 21 (+3) days of life, or did not complete 24 months of corrected age follow-up. Neonatal clinical data were collected according to the Manual of Operations edited by Vermont Oxford Network  and extrBirth weight was measured within 1 h of delivery, and infant weight was then measured daily until discharge with an electronic weighting scale and recorded to the nearest 1 g. Birth crown–heel length (BL) and head circumference (HC) were measured within 1 day of delivery and then weekly and at discharge with the Harpenden neonatometer and an non-extendable measuring tape, respectively, recorded to the nearest millimeter. Measurements were taken by trained personnel according to the techniques described by Cameron .cross-sectional EUGR was defined as a measurement < 10th percentile at discharge (occurred between 36 and 40 weeks of PMA); (II) longitudinal EUGR was defined as Δz-score < −1 between birth and discharge measurements; and (III) longitudinal post-loss EUGR was defined as Δz-score < −1 between measurements taken in the time interval between 14 (−3) and 21 (+3) days of life and measurements at discharge. The chosen cross-sectional definition (definition I) is definitely the most common definition found in Literature to describe postnatal growth restriction , the authors generally use a Δz-score cut-off of −2 to define severe EUGR and a Δz-score cut-off of −1 (as in this present study) for mild to moderate EUGR  is now proposed according to the suggestions by Fenton et al.  triction . Regardiate EUGR . In addin et al.  and ColeAll the 195 infants have been classified using EUGR definitions for weight; 134 infants had complete data for HC measurements and could be classified also on the basis of HC.Z-scores values were assessed at birth according to the Intergrowth-21st Newborn Size for Very Preterm Infants  months of corrected age were analyzed considering the neurological, ophthalmologic, and audiologic diagnoses performed by a multidisciplinary team with standardized protocols and recorded during the follow-up visits at the Neonatology Unit of the University of Turin. Minor neurodevelopmental impairment, major neurodevelopmental impairment, and General Quotient (GQ) at the t Scales , 20 wereThe Griffiths Mental Development Scales Revised (Griffiths) assess the neurodevelopment from birth to 24 months, scoring performances in five domains . Standardized scores for each subscale and a composite General Quotient are given. Minor neurodevelopmental impairment is a condition that limits the child in learning and adaptation. The presence of minor impairment was evaluated by a trained developing age specialist and was intended as the presence of at least one of the following: mild motor impairment, gross or fine motor coordination difficulties, muscle tone imbalance, but without definite signs of cerebral palsy , lower vK coefficient  was evaluated by estimating crude Odd Ratio and relative 95% confident interval.The association between weight or HC z-scores , sex, and weeks of GA were also considered as adjustment factors.The association between the three EUGR definitions and neurodevelopmental outcomes (major and minor impairment) was assessed using Logistic regression models. Models were performed separately for EUGR for weight and for HC. Morbidities that occur during hospital stay and are unequivocally associated both to early postnatal growth and to neurodevelopmental outcomes were considered as confounding factors. They are the following: bronchopulmonary dysplasia (BPD), i.e., request for oxygen support at 36 weeks of PMA, necrotising enterocolitis (NEC) requiring surgery, and retinopathy of the premature (ROP) requiring surgery , 26. Thez-scores) on the neurodevelopmental impairment. Results are shown by estimating the area under the curve (AUC) and the relative 95% confidence interval. Youden's index was used to define the best cut-off .longitudinal post-loss definition, than the cross-sectional or longitudinal ones. Indeed, a significant loss in z-scores (p < 0.001) is evident for both weight and HC measurements taken between birth and 14–21 days of life, which is as expected  between the cross-sectional and the longitudinal definition; K = 0.30 (95% C.I. from 0.17 to 0.42) between the cross-sectional and the longitudinal post-loss definition; and K = 0.41 (95% C.I. from 0.29 to 0.53) between the longitudinal and the longitudinal post-loss definition. Regarding the EUGR definitions for HC, a discreet concordance is found only between the traditional cross-sectional and longitudinal definitions , whereas longitudinal post-loss definition is discordant with both the cross-sectional and the longitudinal definition . For this reason, the association between EUGR and neurological outcomes was assessed separately for each of the proposed definitions. Prevalence of major and minor neurodevelopmental impairment at 24 months of corrected age in the study population is shown in Concordance among subjects defined as EUGR for weight using the three different definitions is low: z-scores at birth and minor developmental impairment is statistically significant, as shown in z-scores as confounding variables for the evaluation of minor impairment in our study population. Results of the analysis performed to assess the possible association between different EUGR definitions and neurological outcomes are presented in cross-sectional EUGR for weight and longitudinal post-loss EUGR for HC definitions are both associated with minor impairment. After adjustment for the confounding variables, only the longitudinal post-loss definition maintains a statistically significant predictive value. Difference in GQ between the two populations (EUGR infants vs. not-EUGR) was thus assessed only for the longitudinal post-loss definition regarding HC: EUGR infants have a statistically significant worse GQ, as shown in longitudinal post-loss definition of EUGR for HC as a discriminating measure . This means that subjects defined as longitudinal post-loss EUGR are almost three times more likely to develop minor impairment than not to develop it.The association between weight and HC  measure . A deepecross-sectional and longitudinal category (cf. methods). Moreover, to our knowledge, this is the first time the longitudinal post-loss definition of EUGR is applied despite it having been proposed since 2014 by the group led by Cole , whereas the longitudinal post-loss EUGR is calculated on a single, postnatal longitudinal chart.In this regard, a main difference between the traditional cross-sectional definition of EUGR only require one-time measurement assessments, but this is not the best way to define postnatal growth restriction since it does not reflect the dynamic process of growth. In our population, this is demonstrated by the fact that 100% of SGA newborns (having weight measurement under the 10th percentile at birth) are EUGR, according to the cross-sectional definition, even if they have not experienced a z-scores fall; for HC, the results are similar.In contrast, It is well-known that very preterm infants are at risk of neurological impairment during childhood , 32, andcross-sectional definition of EUGR seems not to be associated to adverse neurodevelopment on the whole  is itself the resulting effect of many perinatal variables and conditions, but it is not directly associated with neurodevelopmental impairment: weight is a rough indicator of growth.Considering weight growth in our study population, univariate analysis shows a statistically significant association between longitudinal way, and they observe an association with non-optimal neurodevelopmental outcome at 24 months of corrected age. Furthermore, small HC z-score at birth (lower than −2) and suboptimal head growth have a synergic effect in increasing the risk for neurocognitive impairment.By contrast, HC is more related to brain growth , thus itlongitudinal post-loss EUGR for HC is significantly associated with minor neurodevelopmental impairment at 24 months of CA after the correction for the confounding variables.In this context, our findings underline the predictive value of HC, and show that Consistently with the results shown above, these infants also have a lower GQ. Normally, GQ is impaired by major motor deficit, often associated with serious brain injury. However, in our study population there is only a limited number of infants presenting major neurodevelopmental impairment; in this case, therefore, a lower GQ mainly reflects a minor developmental impairment and is probably related to worse cognitive abilities.cross-sectional nor the traditional longitudinal definition of EUGR for HC are associated with outcomes in our study population: this observation supports the fact that the longitudinal post-loss way to describe EUGR may be the most suitable in predicting neurodevelopmental prognosis.Neither the Our study has some limitations: it has been conducted on a relatively small number of patients with single-center design, and retrospective enrollment of patients led to the exclusion of 159 subjects. HC postnatal missing data caused a further reduction of the population considered to calculate EUGR for HC (from 195 to 134 infants).However, the analysis performed to compare the fortuitously excluded, and the included population has shown no significant differences. Follow-up drop out was <15%, which is an indicator of validity of long-term outcomes assessment. The included population is restricted to a narrow range of GA, and all the subjects received uniform feeding and care practices; moreover, anthropometric data, and neurological assessment have been computed by the same trained operators.longitudinal post-loss EUGR definition in clinical practice. Further research could apply our proposed definition to a greater number of multicentric populations, performing prospective enrollment of patients with ad hoc data collection.Our study could be considered as a preliminary study to assess the value of longitudinal post-loss definition of EUGR could be appropriate from a methodological and clinical point of view to describe in-hospital postnatal growth failure in very preterm infants, and it has been demonstrated to be associated with minor neurodevelopmental impairment and worse GQ at 24 months of corrected age.HC growth during hospital stay could be a more accurate indicator to predict neurodevelopment than weight growth and should be carefully monitored by Neonatologists. Postnatal measurements of preterm infants should not be plotted on neonatal or fetal–infant charts but on longitudinal charts specifically built for preterm infants, such as the Intergrowth-21st longitudinal Charts for Postnatal Growth of Preterm Infants. EUGR for HC could be a useful tool to identify infants with a higher risk of long-term adverse outcomes, but a consensus regarding its definition is needed. Our proposed The data analyzed in this study is subject to the following licenses/restrictions: to protect proprietary information, dataset access is restricted to operators of the Neonatal Care Unit of the University of Turin. Anyway, anonymous data could be available upon request. Request to access these datasets should be directed to the corresponding author.The studies involving human participants were reviewed and approved by Comitato Etico Interaziendale—AOU Città della Salute e della Scienza di Torino, Turin, Italy. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.GMa and GMi equally contributed to the work. GMa, FC, and AC conceptualized and designed the study. GMa, CP, and BT collected the data. GMi conceptualized and conducted the statistical analysis. GMa, EB, and SD drafted the initial manuscript. FC, CP, BT, FG, and AC reviewed and revised the manuscript. EB and AC supervised the work. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Non-epithelial ovarian cancers are divided into sex cord-stromal tumours (SCSTs) and germ cell tumours (GCTs). Whereas parity and other pregnancy-related factors are protective for epithelial ovarian cancer, their associations with SCSTs and GCTs remains unclear.n = 420) or GCTs (n = 345) 1970–2013 with up to 10 parous controls  matched on the cases’ birth year and country. We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) of associations between pregnancy-related factors and SCSTs and GCTs.Using data from the medical birth registries from Denmark, Finland, Norway and Sweden, we compared all parous women with a diagnosis of SCSTs ]. The risk of SCSTs (but not GCTs) also decreased with shorter time since last birth. Number of births, preterm birth, preeclampsia, and offspring size were not associated with risk of SCSTs or GCTs.We found a decreased risk of SCSTs with higher age at last birth and shorter time since last birth. The risk of SCSTs (but not GCTs) may be influenced by the woman’s reproductive history. The biology and tumour development are poorly understood and rarely studied in SCSTs and GCTs. Both are located in the interior of the ovaries, and many of the subtypes produce hormones. SCSTs develop in women of all ages, with a peak incidence between 50 and 55 years.5 prior studies evaluating SCSTs or GCTs have been largely inconsistent with respect to the role of number of births and age at births on risk. These inconsistencies could be due to the small number of cases studied .9 In the largest study published to date, including 330 SCSTs and 149 GCTs, Adami et al. reported an association between increasing number of births and decreased risk of SCSTs and a borderline association with decreased risk of GCTs.10 Intrauterine factors have been suggested to have an impact on risk of both SCSTs and GCTs in the mother11 as well as in the offspring.13 Hence, there is reason to further investigate the influence of other pregnancy-related factors that might reflect hormonal exposure during pregnancy and a women’s life, such as pregnancy length, age at births and offspring size.Whereas increasing number of births and higher age at birth are protective for epithelial ovarian cancer,We have performed a population-based case-control study with pooled data from four Nordic countries to allow an investigation of a large number of non-epithelial ovarian cancer cases. Our aim was to evaluate the risk of SCSTs and GCTs (in the mothers) in relation to pregnancy and birth characteristics. To have a homogenous study group with data on the factors of interest for this study, only parous women were included. By analysing the patterns of possible associations, we hope to increase our insight in the development of these rare tumours.5 The MBRs contain information from antenatal, obstetric, and neonatal medical records and are based on mandatory reporting of all births since 1973 (Denmark), 1987 (Finland), 1967 (Norway), and 1973 (Sweden).18 The cancer registries are based on compulsory reporting of all incident tumours and cover the entire population since 1943 (Denmark), 1953 (Finland and Norway), and 1958 (Sweden). Case reporting is essentially complete and data validity high.22 The unique identifier assigned to each citizen in the Nordic countries at birth or upon immigration made accurate record linkages across the registries possible.This case-control study was based on linked data from the nationwide and population-based medical birth registries (MBRs) and cancer registries in a Nordic collaboration, and the methods used have been described recently.23 were used to identify SCSTs and GCTs . Information on pregnancy length (in completed weeks) and offspring’s birth length and weight were recorded based on the most recent pregnancy before the case’s diagnosis to evaluate the most complete data.p-het) of associations between countries in stratified analyses, using a likelihood ratio test. R version 3.3.2 was used for all analyses.24We estimated odds ratios (ORs) with 95% confidence intervals (CIs) for the association between number of births and risks of subsequent SCSTs and GCTs using conditional logistic regression models (conditioned on birth year of the case and country). Analyses of other pregnancy and neonatal characteristics were analysed in models conditioned on matching factors and additionally adjusted for number of births. Birth length/weight, adjusted for pregnancy length (as a continuous variable), were assessed as a measure of foetal growth. All factors were examined as categorical variables, and as ordinal variables to test for trend . In analyses of pregnancy length, and birth length/weight of offspring, women who were diagnosed with non-epithelial ovarian cancer within six months after giving birth were excluded , to minimise the possibility that associations were influenced by preterm delivery due to cancer. We performed a sensitivity analysis in which we excluded women who had only given birth once, since their age at first and last birth is the same. We also evaluated continuous time since last birth in categories of age at last birth to better clarify the relationship between these factors. All results were tested for heterogeneity  at diagnosis and 345 cases of GCTs in parous women, with a median age of 37 years (range 18–79). Maternal characteristics and data on the offspring from the most recent pregnancy, stratified by case/control status, are presented in Table –71 at diHigher age at last birth was associated with decreased risk of SCSTs . A similar trend was seen with higher age at first birth . SCST risk decreased gradually with higher age at first or last birth (Table Age at birth was not associated with GCTs [i.e. last birth at age 30–39 versus before 25 years: OR 1.01 (95% CI 0.68–1.49)], nor were time since birth, number of births [per birth: OR 0.99 (95% CI 0.90–1.10)], or any of the other investigated factors.We performed a sensitivity analysis for SCSTs in which we excluded women who had only given birth once, but the results were not altered . The proportion SCSTs and GCTs differed between the Nordic countries, with a higher percentage of SCSTs in Norway and Sweden and a higher percentage of GCTs in Denmark and Finland , and a study of Swedish women born 1925–1960 who were diagnosed with ovarian cancer during 1958–1984 (hence partly overlapping with this study), showed higher age at first birth tended to be associated with a decreased risk of SCSTs.10 In contrast, an older American study6 published in 1992 with 45 SCSTs found an increased risk with higher age at first birth and SCSTs. In this study, nulliparous women were included, and the results were based on only seven SCST cases that were over 29 years of age at their first birth, and the effect of age at last birth was not evaluated, restricting the generalisability of the findings.The evidence of a relation between age at birth and risk of SCSTs have so far been limited by few, and often small studies  on risk of non-epithelial ovarian cancer have not been performed. Our study does not, however, support associations between these characteristics and subsequent risk of SCSTs in the mother.11 However; effects of 17-OH-progesterone might differ from those of progesterone, and timing of hormonal exposure in pregnancy may be important. Another Finnish study25 measured hormone levels during the first trimester in women with singleton pregnancies, and found that maternal age was associated with sex steroids concentrations, with higher progesterone concentrations and lower androgen and oestradiol in women >30 years of age. An American study from 2008,26 found similar results with a positive association between higher maternal age and levels of progesterone, and inverse associations with androgen and oestrogen. This could be a possible explanation for the decrease in risk of SCSTs with higher age at last birth, with progesterone levels associated with a decrease in risk and androgens with an increase in risk. A risk decrease with increasing progesterone levels has been raised as a potential protective factor for epithelial ovarian cancer through cell clearance of pre-malignant cells (reviewed in ref. 27) and indicates similar mechanisms for SCSTs and epithelial ovarian cancer. The increased risk with increasing androgen and oestradiol concentrations is generally consistent with SCSTs being rare before puberty, when hormone levels are low. These hormones are likely needed for tumour development or progression.In summary, data from our large study suggest that older age at last birth, and shorter time since last birth affect risk of SCSTs. Results from previous studies are somewhat conflicting ,8 found an increased risk of GCTs with high-aged childbirths. This result was, however, based on only 40 parous women. As in previous studies,10 we saw no association between number of births and GCTs. Neither did we see any associations between the analysed pregnancy and birth characteristics and subsequent risk of GCTs in the mother.Our finding of a lack of association between age at birth and GCTs is consistent with two previous studies.29 but not SCSTs. This suggests that development of GCTs is more genetically controlled, given that gonadal dysgenesis is secondary to chromosomal anomalies or mutations in genes related to the urogenital ridge or sex differentiation.28 This genetic component may also explain why there are no specific reproductive risk factors for GCTs, as opposed to SCSTs. Changes in hormone levels during puberty might play a role, while the greater alterations during pregnancy have a more limited ability to affect risk because affected individuals would need to be very young at childbirth.To summarise, a woman’s reproductive history does not seem to influence her risk of GCTs. Gonadal dysgenesis is associated with risk of GCTs,This population-based study is based on the largest number of SCSTs and GCTs reported to date. Despite the comparably larger sample size, statistical power was still limited, and confidence intervals were often wide suggesting that even larger studies are needed to reach firmer conclusions about associations that are likely modest. The cases numbers also limited our ability to separate the effect of the correlated factors of higher age at last birth and shorter time since last birth.22 enabled identification of cancer cases in a similar and standardised manner. However, the proportions SCSTs and GCTs differed between the Nordic countries, which could imply differences in coding, genetics, or other risk factors, although there was no evidence of heterogeneity in the ORs by country.Among the strengths of this study is the almost complete information on the studied perinatal factors, based on mandatory reporting to birth registries which avoids recall bias. The nationwide cancer registries in the four Nordic countries31 but since data are scarce, their impact on SCSTs and GCTs remains uncertain. We also lacked information on oophorectomy/salpingectomy or hysterectomy, and thus could not exclude controls that had undergone gynaecological surgery. However, since the prevalence of women having gone through a oophorectomy/hysterectomy in the Nordic countries is low , and probably even lower in this young cohort, it is unlikely to have had a major effect on our risk estimates.32 Because our aim was to study the impact of pregnancy-related factors on risk of SCSTs and GCTs, we only included parous women in our study and results are thus generalisable to parous women only. This resulted in a higher mean age of GCT cases than in the general population and our inability to investigate the influence of early pregnancy loss (prior to week 22).While there are few, if any, established risk factors for non-epithelial ovarian cancer, it is unclear if the current study was missing information on important confounding factors, such as obesity, breast-feeding and oral contraceptive use. Oral contraceptives are associated with decreased risk of epithelial, and possible non-epithelial, ovarian cancer,In this population-based case-control study, including 420 cases of SCSTs and 345 cases of GCTs among parous women, higher age at last birth, and shorter time since last birth, were both associated with a decreased risk of SCSTs, similar to results for epithelial ovarian cancer. Thus, it is possible that hormonal mechanisms or other mechanisms related to this aspect of reproductive history influence the development of both SCSTs (but not GCTs) and epithelial ovarian cancer. Number of births was not associated with the risk of SCSTs or GCTs. We found no associations with any of the investigated pregnancy-related factors and GCTs, suggesting that reproductive factors may have limited impact on risk of these uncommon tumours.Supplementary files


Ziziphi Spinosae Semen  Hu ex H. F. Chou) is used as a traditional Chinese medicine referred to as Suan zao ren (酸枣仁). This paper aims to provide a systematic review of its traditional uses and its botanical, phytochemical, pharmacological, pharmacokinetic, and toxicological characteristics. The future development and research prospects for ZS have also been discussed in detail. To date, over 150 compounds have been identified in this plant, including terpenoids, alkaloids, flavonoids, fatty acids, volatile oils, polysaccharides, and others. Both extracts and purified compounds have excellent biological activities, especially sedative and hypnotic effects. Other effects include ameliorating effect of learning and memory, anti-inflammation, antioxidation, blood pressure and lipid lowering, antiaging, and antitumor effects. Thus, this traditional Chinese medicine can be used to treat many diseases such as insomnia, forgetfulness, headaches, and dizziness. Although many of the traditional uses of ZS are well established, the relationship between structure and function still needs to be further studied. In order to better pave the way for research and the establishment of quality control standards for ZS, it will be very important to elucidate its pharmacological mechanisms of action and explore new clinical effects. Ziziphi Spinosae Semen (ZS) has a long history as an effective traditional Chinese medicine [medicine . ZS mainmedicine .Presently, more than 30 prescriptions for ZS are listed in the Pharmacopoeia of the People's Republic of China (ChP). These prescriptions have been used to treat palpitations, insomnia, dizziness, headache, nausea and vomiting, coughs, depression, anxiety, and other diseases. More than 150 compounds have been isolated from ZS, including terpenoids, alkaloids, flavonoids, fatty acids, volatile oils, polysaccharides, and some inorganic compounds . ZS is mIn this review, we collected the relevant literature, ancient books, and Ph.D. and MSc dissertations related to ZS from a range of scientific databases including PubMed, Baidu Scholar, Vepsa, Wanfang Med Online, CNKI, and others and have summarized the various aspects of ZS, such as its traditional uses and its botanical, phytochemical, pharmacological, pharmacokinetic, and toxicological characteristics. Finally, current problems and research directions for ZS have also been discussed in this paper.Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chou (Rhamnaceae) is a deciduous shrub or small arbor approximately 1–3 m in height  monograph during the Eastern Han Dynasty) under the name “Suanzao.” Medical books about ZS first appeared in “ShanghanZabingLun” (Eastern Han Dynasty) which was famous for the decoction of spine date seeds, and “Suanzaoren” was first listed in “Materia Medica ChengyaBanju.” Therefore, ZS has more than 1700 years of medicinal history. In “Chinese Materia Medica,” ZS trees were referred to as “Qi,” “Jing,” “Shanzao,” and “Yezao” [Ben Cao Shu Gou Yuan” stated that ZS trees were used as medicines in“Shen Nong's herbal classic” (Qing Dynasty), but, currently, the seeds (ZS) are used as a traditional Chinese medicine [Shen Nong's herbal classic” gave ZS a top grade and noted that it is an effective medicine for regulating the five Zang organs  and longevity [Ben Cao Bian Du” noted that fried ZS can cure insomnia of colic asthenia and raw ZS can cure sleepiness caused by colic heat. In addition, according to “Bie Lu” (Western Han Dynasty), ZS could treat cold sweat and polydipsia. “Ben Cao Zai Xin” described the qi and hidroschesisas tringing function of ZS, in addition to benefiting ambition and nourishing the ear and eye [Shen Nong's herbal classic.”The cultivation of ZS tree has a history of nearly 2000 years. Particularly in the Loess Plateau of China, clusters of ZS tree have been growing since ancient times, and there is one of the oldest ZS trees which has been growing for more than 2000 years in Shanxi Province of China. ZS can be used as effective medicine to nourish the brain and promote hemogenesis, and it is the first type of fruits that can be used for medicinal purposes and as a food that has been promulgated by the Ministry of Health . ZS was  “Yezao” . In anciongevity . It is uongevity . “Ben Ca and eye . It alsoCurrently, ZS is an important Chinese medicine for the treatment of insomnia clinically. It can also be used to treat palpitations, dizziness, dietary intolerance, nausea and vomiting, coughs, and other diseases. Spine date seed decoction, a classical clinical prescription, can be used to treat many diseases, including psychiatric disorders such as depression and anxiety, neurological disorders such as headache and vertigo, and circulatory diseases . There aThe chemical composition of ZS is extremely complex. It has been studied for more than 30 years. Over 150 different chemical components, including terpenoids, alkaloids, flavonoids, fatty acids, volatile oils, and polysaccharides, have been isolated and identified . The spe3pseudo-ginseng and ginseng. It is generally believed that it is an effective sedative component of ZS and has a strong central inhibitory effect. Jujubosides have been extensively studied. Otsuka et al. first obtained jujuboside A and jujuboside B from a methanol extract of ZS in 1978 [The main chemical compositions in ZS are saponins such as jujuboside A (No. 12), jujuboside B No. 13), and jujuboside C (No. 16), a triterpenoid, which are closely related to the active ingredient saponin in  in 1978 . Followi in 1978 . Lupinan, and juj1 (No. 53) and G2 (No. 54), and aporphinoid alkaloids such as sanjoinine E (No. 50), K (No. 45), la (No. 46), and lb (No. 47), were discovered [The research level of alkaloids in ZS is far less than that of terpenoids. Two alkaloids, lysicamine and juzirine, were first isolated from ZS by Yin et al. in 1997 . Followi G2 No. 5, and apoFlavonoids are one of the main active constituents in ZS and all of them are flavone-C-glycosides. Won et al. first isolated spinosin (No. 66) from methanol extract of ZS in the late 1970s . Followi2 extraction [ZS oil is stable on oxidation and has oil content as high as 31.8% and total vitamin E content of 0.1867 mg/g . In 2006traction . In 2001traction . A summaZS polysaccharide is a kind of polysaccharide extracted from ZS. Previous studies have shown that ZS polysaccharide had obvious anti-inflammatory and immune-regulating biological activities , 25. In ZS also has various trace elements and eight amino acids that are essential to humans , 28. NonZS-derived extracts are pharmacologically active and exert many effects, including that on the central nervous system and the cardiovascular system. The main pharmacological effects of ZS include sedation and hypnosis, ameliorating effect of learning and memory, anti-inflammation, antioxidation, anticonvulsion, blood pressure lowering, lipid lowering, antiplatelet aggregation, enhancement of immune function, antihypoxia, antimyocardial ischemia, antiarrhythmia, and antiaging. In this section, the different pharmacological activities of ZS have been introduced and analyzed. A summary of pharmacological effects of ZS is shown in Wang et al. studied the effects of ZS flavonoids (0.1 g/kg) on improving the learning and memory ability in memory-impaired mice by using dark-avoidance test and maze test. The data showed that flavonoids could prolong the latent period of mice, reduce the erroneous times, and shorten the time of electric shock . In the Os Draconis and ZS decoction (6.25 g/kg), they concluded that ZS could inhibit the spontaneous activity, enhance the rate of falling asleep induced by sodium pentobarbital (in subthreshold dose), prolong the sleep time induced by sodium pentobarbital (in suprathreshold dose), and resist convulsion of mice [2+. These results show that jujuboside A can inhibit glutamate-mediated signaling pathways in the hippocampus [When You et al. compared the sedative and hypnotic effects of  of mice . Later,  of mice . Zhao et of mice . It was  of mice . In 2003pocampus .Zhang et al. first treated spontaneously hypertensive rats by gavage with ZS total saponins (5 mg/kg) and showed that they had a clear effect on reducing blood pressure . Followi2 (TXB2) [Experiments in other studies have also shown that ZS has an antiarrhythmic effect. In one experiment, rats were given a sublingual intravenous injection of an ethanol extract of ZS solution (2 g/kg), which was shown to inhibit the arrhythmia induced by aconitine and barium chloride . Followi2 (TXB2) .The sedative and hypnotic effects are the main pharmacological effects of ZS . Wu et a2 extraction, in mice. The results showed that both methods could reduce the spontaneous activity of mice, shorten the sleep latency of mice induced by a suprathreshold dose of sodium pentobarbital, and increase the sleep rate in mice induced with a subthreshold dose of sodium pentobarbital [Drosophila during both the day and night. The dosage of 1 mg/mL was the best concentration and 3 days was the best time for administration [in vitro and in vivo with a methanol extract of ZS showed that the inhibition of neuronal excitation was related to the activation of the γ-aminobutyric acid (GABA) system [In 2008, Li et al. studies the sedative and hypnotic effects of ZS oil (1.8 g/kg), obtained by a pressing method and supercritical CObarbital . It has stration . In addi) system . It was ) system .1 expression levels, a decrease in Glu content, and a decrease in NMDAR1 expression levels [In 2018, Hua gavaged ZS decoction (17.5 g/kg) to rats with anxiety and found that the expression of the c-Fos protein in the basolateral amygdale (BLA) neurons and the discharge frequency of the action potential in neurons were decreased . In 2014n levels . In addin levels .The antidepressant effects of ZS have also been studied. Zhang et al. compared the effects of a water decoction and ZS polysaccharides and alkaloids (2.0 g/kg) on depression in mice. The data showed that the water decoction had the best effect followed by that of the alkaloids and polysaccharides . In 2011Bao et al. studied the effects of ZS water extract (1 g/100 g) on capillary permeability  by intragastric administration in mice and on egg-white-induced foot swelling and granulation tissue proliferation in rats. The results showed that the ZS water extract could inhibit capillary permeability in the abdominal cavity, the back skin, and the auricle of mice. The anti-inflammatory effects of the extract on egg-white albumin-induced swelling in the hind feet and granuloma induction caused by implantation of paper under the axilla of rats were similar to those of prednisone .in vitro total antioxidant (TA) capacity, superoxide radical scavenging capacity (O2 • −), hydroxyl radical scavenging capacity (• OH), DDPH radical scavenging capacity, and antilipid peroxidation of ZS oil. The results showed that the scavenging ability of ZS oil toward hydroxyl radicals was lower than that of vitamin E (VE), whereas the total antioxidant capacity was equal to that of VE. In contrast, the DPPH radical scavenging ability, superoxide anion radical scavenging ability, and the antilipid peroxidation (ALP) effect were all better than those of VE. Experiments in vivo also showed that ZS oil could significantly reduce the malondialdehyde (MDA) content in the blood and liver of a D-galactose oxidation model in mice and significantly increase glutathione peroxidase (GSH-Px) activity [μg/mL) could significantly promote the proliferation of RAW264.7 cells. Western blot test showed that ZS polysaccharides could significantly promote the release of NO and the expression of stress response protein (COX-2 and iNOS) in RAW264.7 cells. In addition, ZS polysaccharides could significantly promote the phosphorylation of IκB-α and ERK protein, which also indicated that the polysaccharide has a certain immunomodulatory effect [Zhang et al. assessed the activity . Zhao etactivity . Howevery effect .In vivo). The study proved that ZS oil (0.35 mL/kg) could significantly prolong the survival in mice with cancer and inhibit body weight increases in mice with cancer in later life; it indicated that ZS had obvious antitumor effect on Ehrlich's ascites carcinoma [μg/mL) has neuroprotective effects. It could reduce beta-amyloid-induced cytotoxicity, lead to increasing a lifespan, and alleviate the oxidative stress. Furthermore, the functions are closely related to the promotion of autophagic activity [In addition to the pharmacological effects described above, ZS has other pharmacological effects. A study showed that oral ZS alcohol extract (5 g/kg) increased the appetite and weight of mice, enhanced the cellular and humoral immune functions (IF), and antagonized the inhibition of delayed hypersensitivity (DH) induced by cyclophosphamide in mice. All these indicate that ZS alcohol extract had an immunopotentiating effect . In 2010arcinoma . A separarcinoma . In addiarcinoma , 81. In activity .In summary, ZS has a wide range of pharmacological activities, which include effects on the central nervous and cardiovascular systems. The main pharmacological effects of ZS are sedation and hypnosis, anti-inflammation, antioxidation, anticonvulsion, blood pressure and lipid lowering, antiplatelet aggregation, enhancing immune function, antihypoxia, antimyocardial ischemia, antiarrhythmia, and antiaging. These findings show that this plant can be used to treat many diseases. Although there are many pharmacological studies using ZS extracts and some of the main components of ZS have been identified, many of their mechanisms are unclear. Therefore, the pharmacological mechanism of action should be further studied.−1, tβ) and area under curve (AUCt0-) of spinosin and ferulic acid in ZS-Fructus Schisandrae Chinensis and ZS-Salviae miltiorrhizae Radix groups were decreased, and the clearance rate (CL/F) was increased compared with the ZS group. However, the Zaoren Anshen prescription group showed higher Cmax and AUCt0- for spinosin and ferulic acid, but lower CL/F. Therefore, compared with ZS group, the prescription groups showed slower metabolism of spinosin and ferulic acid and higher bioavailability [T1/2), among other parameters, were different. The two compounds followed a first-order kinetics elimination process in vivo [Currently, little research has been performed to assess the pharmacokinetics of extracts and compounds derived from ZS. Liu et al. used LC–MS/MS method to study the pharmacokinetics of jujuboside A  in rats and successfully obtained the main pharmacokinetics: Kel = 0.1022 ± 0.023 h7 μg·L−1 . Zhang estration . Wang anstration , 87. Guontestine . In 2015lability . Qiao stIn summary, the bioavailability of jujuboside A after intragastric administration was very low compared with intravenous administration; preliminary speculation may be that the numerous drugs are in the form of prototype or present in the gastrointestinal tract after some transformation. In addition, different combinations of drugs have different effects on the pharmacokinetics of ZS and its main components in rats; this may be due to the fact that certain components of different drugs affect the rate of absorption and elimination in the process of drug combination. These speculations require further research to support.Chinese Materia Medica, ZS is toxic only at high doses. The dose of 150 g/kg was given to mice by intragastric administration without toxic symptoms. Chronic toxicity test in rats showed that its toxicity was extremely low too. The lethal dose of intraperitoneal injection in mice was 14.33 ± 2 g/kg [To date, ZS has been regarded as a traditional Chinese medicine with a high level of safety, and very few toxic reactions have been found in either dietary or clinical applications. According to the ± 2 g/kg . Sameena± 2 g/kg .Gastrodiae Rhizoma and ZS found no toxic effects or animal deaths at the maximum dosage (30000 mg) of the sample after gavage. Genetic toxicity tests including the Ames test, the mouse bone marrow cell micronucleus test, and the mouse sperm malformation test all showed negative results. Therefore, the capsule has no genetic toxicity as per the scope of the above tests and thus should be further researched and developed [A study exploring the toxicological characteristics of a compound capsule of eveloped . Acute aeveloped .50 was 27.5 g/kg with 95% confidence limits of 25.1–30.1 g/kg. An autopsy of the d animals showed no pathological changes in their main organs. However, no mice died in 14 consecutive days of observation after gavage administration of 340 g/kg of the same alcohol extract of ZS [Wang et al. injected different doses of an alcohol extract of ZS into the caudal vein of mice and found that some mice had a toxic reaction and died. The LDct of ZS . TherefoIn summary, ZS is a traditional Chinese medicine especially used in Asian countries. Presently, numerous chemical constituents have been isolated and identified from this plant. Several experts have studied the plant and made significant contributions in several areas. However, new problems and challenges remain in the research of it. In particular, we need further research and exploration to meet clinical requirements.in vivo to improve drug safety, to allow for further drug development that should lay the foundation for future clinical drug use. In China, there is a shortage of supply in the market as the wild ZS sources are decreasing each day, and thus, some fake plants, such as Lizaoren, ZhiqiZi, Dianzaoren, and Bingdou, have appeared in the pharmaceutical market [First, as a traditional Chinese medicine, although ZS has been studied extensively in recent years, the research has mainly concentrated on saponins, flavonoids, alkaloids, and so on; the actions of fatty oils and other chemical components are rarely reported. However, some fatty oils also have good pharmacological activity. For example, ZS oil has good antioxidant properties, and it is one of the important material bases to reflect the efficacy of ZS . Therefol market . In addil market . Fourth,This paper has systematically and comprehensively introduced the research status of ZS in recent years, including its botanical, and its traditional uses, phytochemical, pharmacological, pharmacokinetic, and toxicological characteristics. Although great progress has been made, several aspects are yet to be known.We hope that this paper can provide some suggestions for future research directions of traditional Chinese medicine.


Migrant women may have an increased risk of adverse birth outcomes. This study analyses the occurrence of low birth weight, preterm birth and intrauterine growth restriction / fetal growth restriction (IUGR/FGR) in pregnant migrants.Cross-sectional study of 82 mother-child pairs of pregnant migrants attending medical care in Germany.The Median age was 27 years, 49% of patients were of oriental-asian ethnicity and median year of migration was 2015. At least one previous pregnancy was reported in 76% of patients, in 40% the delivery mode was caesarian section. Median gestational age was 39.7 weeks. Preterm birth occurred in 6.1% of pregnancies. Median gestational age for preterm birth was 32.3 weeks. Low birth weight (< 2500 g) occurred in 6.1%. Birth weights below the 10th percentile of birth weight for gestational age were observed in 8.5% of the total cohort.Compared to German data no increased occurrence of low birth weight, preterm birth or IUGR/FGR was found. We note that the rate of caesarian section births was higher than in the general population for reasons yet to be identified. The authors propose stratification according to migration status for the national documentation of birth outcomes in Germany.The online version contains supplementary material available at 10.1186/s12884-021-03620-z. The idea of intrauterine growth restriction (IUGR) was introduced in 1961 by Warkany et al. to describe the relationship between gestational age and birth weight . It is dMigration to Europe is a topical issue and the European Community (EU) is facing the greatest influx of refugees and migrants since the Second World War . A recenOlder international studies on birth outcomes in migrant populations show heterogeneous results. A systemic review from 2010 describes that south-central Asians were more likely to have low birth weight deliveries after migration to the US and Europe, while women from Sub-Saharan Africa, Latin-America and the Caribbean were more likely to have low birth weight deliveries in Europe only . The birTo the best of our knowledge, this is the first publication from Germany investigating the frequency of adverse birth outcomes in a migrant cohort from African and Oriental Asian countries adressing FGR, defined as birth weight below the 10th percentile of the reference curves, as primary endpoint.We conducted a prospectively ascertained cross-sectional study using mother-child data pairs in pregnant women with a migration history from Schistosomiasis endemic countries as defined by WHO  attendinClinicalTrials.gov Identifier: NCT03158298).The Recruitment phase spanned 18 month (March 2017 to September 2018). The study was registered with the US national library of medicine (Inclusion criteria: 1.) Pregnant women > 18 years, 2.) Written informed consent, 3.) Originally from endemic countries and areas for Schistosomiasis. Annotation: The corresponding countries of origin were in Africa and the Middle East.Exclusion criteria: 1.) Fetal structural malformations, 2.) Fetal chromosomal aberrations, 3.) Multiple pregnancy. Annotation: Patients with placental pathology due to any known cause and any other medical condition affecting fetal growth were excluded.A questionnaire was completed by each subject adressing demographics, age, medical history. Data concerning the primary (birth weight percentiles) and secondary pregnancy outcomes  were collected. The necessary values consisted of gestational age, weight and sex of the new born. Gestational age was determined by either ultrasound or by calculation of the last menstrual period. Blood was drawn from each woman to conduct Schistosomiasis Serology. No follow ups of newborns or mothers were performed.Data were collected with a standardized case report form (eCRF) and pseudonymised at source. Categorical variables were: smoking, alcohol, diabetes, baby gender, ethnic origin and parity. Continuous variables were birth weight, gestational age, maternal height and weight . The couClinicalTrials.gov Identifier: NCT03158298).The study was reviewed and approved by the Ethical Committee of the University Hospital Jena, Germany . Follow votes were obtained for study sites in Berlin, Munich, Halle and Walsrode. All women signed an informed consent form in their native language permitting the use of their data and serum sample for scientific purposes. The study was registered with the US national library of medicine  were considered to be significant. Birth percentiles for height, weight and head circumference were calculated according to Voigt et al. [. In the univariate regression model, known and unknown factors that could influence the birth weight percentile were evaluated. Individual confounders with a potential influence, which had a p-value < 0.05 in the univariate linear regression model, were checked for multicollinearity using Kendall-Tau-B correlation analysis and included in the multiple linear regression analysis if no correlation (r < 0.5) was present. The results of the multiple linear regression analysis were considered valid if the Durbin-Watson value was between 1 and 3, Variance Inflation Factor (VIF) was < 5, the largest condition index was < 30 and p < 0.05.The statistical evaluation of the data was carried out with using SPSS Statistics Version 25. The data were first assessed for normal distribution applying a Kolmogorov-Smirnov test. For normally distributed metric data a t-test was used for independent variables and a Mann-Whitney-U-test for non-normally distributed metric data. The χ2 test was used for the analysis of nominal or ordinary data. t et al. . In the Originally, our data collection aimed at examining the association between schistosomiasis seropositivity and adverse pregnancy outcomes. Schistosomiasis serology was negative for the whole study population. Hence, the original scientific question could not be addressed.n = 35) 42.7%, Walsrode (n = 21) 25.6%, Halle (n = 13) 15.9%, Munich (n = 8) 9.8% and Berlin (n = 5) 6.1%).82 mother-child data pairs were included. Patients were recruited at multiple sites in Germany . HIV status was unknown/not analyzed in 53.7%, negative in 45.1% and one woman reported to be HIV positive. Hepatitis B was negative for 91.5% and unknown/not analyzed in 8.5%. Hepatitis C was negative for 17.1% and unknown/not analyzed in 82.9%.75.6% of investigated women reported at least one previous pregnancy. 82% of previous pregnancies resulted in live births, 16% in abortions and 2% in stillbirthsGestational diabetes was reported in 8.5% and pregnancy-induced hypertension in 2.4% of patients. Pre-eclampsia occurred in 1.2%. Median weight of the mother at delivery was 78 kg (IQR 18.5). Concomitant medications during pregnancy were magnesium and methyldopa in 9.8 and 4.9%. Acetylsalicylic acid and metoprolol were not observed. Other medication was reported in 26.8%.Median percentile for weight was 35.0 (IQR 37.25). Median percentile for height was 38 (IQR 40.00) and median percentile for head circumference was 42.5 (IQR 41.25).52% of newborns were male. The delivery mode was spontaneous in 57.3% and assisted vaginal delivery in 2.4%. Primary caesarean section and secondary caesarean section were performed in 18.3 and 22%, respectively. Median gestational age was 39.71 weeks (IQR 2.43). Median length of newborns was 51 cm (IQR 3.0). Median birth weight and head circumference were 3318 g (IQR 623) and 35 cm (IQR 2.0), respectively. Median placental weight was 500 g (IQR 105.0). Median Apgar after five and ten minutes was 10 (IQR 1 and 0). Admission to NICU was reported in 21%. No newborns died. Median umbilical cord pH was 7.29 (IQR 0.14). Preterm birth (< 37 week) occurred in 5 cases (6.1%). Median gestational age for preterm birth was 32.3 weeks (IQR 6.5). Low birth weight (< 2500 g) occurred in 5 cases (6.1%), 4 of these were preterm. Median weight for low birth weight was 1700 g (IQR 1265). n = 7) of the cohort. There was no preterm birth (< 37 week) below 10th percentile of birth weight for gestational age. Gender-specific analysis showed a difference between female (4.7%) and male (12.8%) newborns (5 vs. 2). However, the gender difference was not significant (p = 0.25). Thus, we observed a fetal growth restriction (> 10% below the 10th birth weight percentile) for newborn boys in our migrant population.Birth weights below the 10th percentile of birth weight for gestational age were observed in 8.5% . Univariate regression models for birth weight revealed significant influence of: pregnancy induced hypertension, preeclampsia, previous diabetes, previous hypertension, transport to Europe by foot and number of previous birth .Univariate regression models for the birth weight percentile outcome revealed significant influence of: mother’s height, mother’s weight at delivery, transport to Europe by foot, transport to Europe by boat, number of previous pregnancies and number of previous birth (p < .01). Transport to Europe by foot and number of previous births turned out to be equally strong (both standardized regression coefficients are 0.28 and 0.27) whereby weight at delivery with beta = 0.33 shows a comparatively higher value. The non-standardized regression coefficients B show the change in the dependent variable in one step change in the factor. If the weight of the mother at delivery increases by one unit (kilograms), the birth weight percentile increases by 0.56 units (percentiles). I.e. if the weight increases by 2 kg on delivery, the birth weight is one percentile higher. The same applies vice versa: if the weight of the mother on delivery drops by 2 kg, the birth weight is one percentile lower. If the number of previous births increases by one unit, the birth weight is 5.8 percentiles higher. The opposite applies again when the number of previous births is one unit lower. If the transport to Europe was by foot , the birth weight was 16.1 percentiles higher than for migrants who used another means of transport.In the multiple linear regression models on birth weight percentiles with the factors transport to Europe by foot, number of previous births and mother’s weight at delivery, a quality of 0.30 (adjusted R-square) was achieved. The results of the analysis are shown in Table n = 4, Somalia, Nigeria and other countries respectively n = 1) is statistically insignificant (p = 0.277). Furthermore, there is no difference in occurrence after stratification by ethnicity , African-American: n = 3 (13%); p = 0.705).There were seven cases of FGR (birth weight < 10th percentile) in the cohort. The numerically higher number of mothers immigrated from Syria (Syria: p = 0.393) and only a very weak correlation between birth weight and country of origin , which, however, is no longer evident when stratified by the respective country of origin . Regression analyses showed that the different ethnicities do not differ in the degree of influence on the birth weight percentiles. Furthermore, it can be shown that none of the countries of origin has an influence on the birth weight percentiles .Correlation analyses according to Kendall-Tau-B showed no correlation between birth weight and ethnicity  and preterm birth (6.1%). Overall, preterm births in Germany occur in 6.6 and 10% of newborns are small for gestational age, i.e. below the 10th percentile of birth weight. Surprisingly, FGR is even somewhat rarer in our cohort than in a national comparison. The low rate of pregnancy-induced hypertension (2.4%) and preeclampsia (1.2%) in our cohort are in agreement with these findings. Overall, very few placental-associated pregnancy complications have been observed. However, the caesarean section rate in our cohort (40%), is remarkably higher than in the overall German data (30%). Whereas the combined endpoint of FGR and premature birth in Germany occurs in 10% but does not occur in our migrant cohort . SurprisThe quality of our data is emphasized by our regression analysis, where known positive factors influencing the birth weight were confirmed (previous births and mothers weight at delivery). So far, we have no explanation for the significantly positive influence of transport to Europe by foot on birth weight percentiles observed in this study. We actually expected a reversely significant result and debated better physical training condition of the mothers due to the positive physical strain of long walking distances in the past. There is no data on this specific finding in the literature and we suggest further detailed investigation in other migrant populations.Data on birth outcomes of the migrant population currently entering Europe are scarce; so far, no data were available for Germany. Only three European publications reflect the relationship between gestational age and birth weight to measure the frequency of adverse birth outcomes in migrant populations. Li et al. investigated more than 1 million births in Sweden from 1982 to 2006. The authors found that 4.1% of newborns born to non-Swedish mothers met the criteria for SGA, compared to 3.3% in the Swedish population . In DenmOur study was conducted in a cross sectional setting without a comparison group. We found fetal growth restriction in 8.5% of the investigated population. Compared to the results of Li et al. with data from 1982 to 2006, FGR was twice as common in our cohort (8.5% vs. 4.1%) and newborn boys were more likely to be small for gestational age (boys 12.8% vs. 4.7%). Previous studies did not differentiate by gender .Taking into account that one third of our study population migrated from Syria in 2015, it can be suspected that the sequelae of war and the circumstances of forced migration entails consequences in the most vulnerable population group. This offers an explanation for our finding of a prevalence of FGR twice as high as reported by Li et al. in 2012. However, due to the small number of patients in the study subgroups, we could not confirm this assumption. On the other hand, our data are surprising compared to the German population, because they correspond to the national average both in terms of FGR and in terms of prematurity. However, the comparison of the Swedish data from 2012 with German data from 2016/2017 suggests that FGR is less common in the naïve-Swedish population than in Germany. However, the data from Germany do not include a delimitation of births of women with a migration background compared to births of naïve mothers, but are a mixture of all births in 2016/2017.While comparing the migrant specific data from Scandinavia with our cohort the assumed increase in negative birth outcomes in migrant populations should prompt us to reconsider medical strategies for refugees in Germany, and pregnant refugees should receive particular medical attention to protect the most vulnerable group from further health damage. Especially in view of the high rate of caesarean sections in the Scandinavian study of women from Somalia (OR up to 5fold) and our secondary section rate of 22%, we should consider that we might not guide migrant women sufficiently through birth possibly due to a lack of communication which could eventually support spontaneous vaginal delivery . The reaCompared to German data no increased occurrence of low birth weight, preterm birth or IUGR was found. Of note, rate of caesarian section was higher than in the general population for reasons yet to be identified. We propose stratification according to migration status for the national documentation of birth outcomes in Germany.Additional file 1.


Choledochal cyst originating from the cystic duct is a very rare case and difficult to diagnose preoperatively, it is classified as Todani type VI choledochal cyst. Only three cases of type VI choledochal cyst have been reported in the literature.A 35-year-old woman came with an enlarged and palpable mass in the right upper abdomen. The initial abdominal contrast CT scan and MRCP supported the presentation of Todani type 1 choledochal cyst. Intraoperatively, we found a different diagnosis, it was not type 1 but Todani type VI choledochal cyst. We found a large cyst originating from the cystic duct, attached to the gallbladder, without any connection to the intra or extrahepatic bile duct. The patient underwent simple cholecystectomy as well as excision of the cyst. After the follow-up for 3 months, the patient was uneventfully cured.Preoperative diagnosis of type VI choledochal cyst seems to be difficult because it is a rare entity and it exhibits an ambiguous anatomic feature. Most cases may be misidentified as type I or II choledochal cyst before surgery. The diagnosis was made intraoperatively. Preoperatively the definitive anatomy may be delineated by ERCP if there is any high suspicion.Preoperative diagnosis of type VI choledochal cyst may be challenging and requires detailed radiological evaluation and multidisciplinary discussion. The cystic duct orifice and the diameter of the common bile duct are important to determine adequate management during the operation. The cla2A 35-year-old woman came to the hospital with chief complaint about the enlarged mass in the right upper abdomen accompanied by a history of pain for the last 2 years and was getting worse for the last 1 month. She also complained about feeling nauseous and vomiting. Other symptoms including fever and jaundice did not occur. From the physical examination of the abdomen, we found a palpable mass in the right upper abdomen, sized 20 cm in diameter, fixed to the surrounding structure and no sign of tenderness. There were no abnormal findings on the laboratory test. The abdominal ultrasonography showed a pancreatic head separated with liver cyst . AbdominDuring the operation, we found different choledochal cyst from those described by Todani classification. We found a large cystic fusiform sized 14 × 14 × 1 cm attached to the gallbladder, the edge of the cyst attached to segment 3, 4, and 5 of the liver . The galth day.After we performed simple cholecystectomy and excision of the cyst, we continued with intraoperative cholangiography and there was no dilatation of intrahepatic bile duct and extrahepatic bile duct . The sperd month, the patient had completely recovered but future annual follow-up will be necessary.Pathology reports revealed that the cyst duct was dilated with thickened fibrous wall infiltrated by polymorphonuclear and mononuclear leukocytes . The edg3Cystic malformation of the cystic duct was first suggested as another type of biliary cyst by Serena Serradel et al. It has been reported as isolated cystic duct dilation or cystic duct dilation associated with other findings, including fusiform dilation of CBD . The cliMultiple theories have been proposed to explain the origin of bile duct cyst. The most widely accepted hypothesis is Babbitt's theory which stated that cystic dilation of the bile ducts is related to an anomalous arrangement of the pancreaticobiliary ductal junction. The pancreaticobiliary junction is proximal to the sphincter of Oddi. An anomalous pancreaticobiliary junction is often associated with long common channel that predisposes to reflux of pancreatic juice into the biliary tree; leading to inflammation, ectasia, and finally dilation ,6,7. MosThe appropriate management of type VI choledochal cyst is guided by the morphology, based on the cystic duct opening to CBD. The surgery recommended for the type VI choledochal cyst with narrow-based cystic duct or normal cystic duct between the cyst and CBD is simple cholecystectomy with cyst excision neither open nor laparoscopic ,4,6,9. C4It is difficult to identify type VI choledochal cyst preoperatively. Preoperative diagnosis may be challenging and requires a detailed radiological evaluation and multidisciplinary discussion between the surgeon and radiologist. Knowledge of this anatomical variant is important to every hepatobiliary surgeon. The cystic duct orifice and the diameter of the CBD are important for determining adequate management during the operation. The surgical management of such cases ranges from simple cholecystectomy to biliary resection procedures.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Our case is exempt from ethical approval in our institute.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.Vicky S. Budipramana: study concept and design, paper writing and editing.Putu Ayu Saraswati: data collection.This manuscript is a case report, not a research study.The guarantor of this study is Vicky S. Budipramana.Not commissioned, externally peer-reviewed.We don’t have any conflicts of interest with any person or organization.


A parameatal urethral cyst is a rare finding in an otherwise well child. They can present as either congenital malformations or as a finding later in life, and may occur either unilaterally or bilaterally on the glans penis. Though they are benign, possible complications include impaired urinary stream flow, dysuria, or hindered cosmesis.We report a spontaneous resolution of large congenital parameatal cyst in an otherwise healthy neonate whose mother had a recent history of urinary tract infection. A spontaneous resolution of the cyst was reported at the age of one month.A small parameatal cysts have shown spontaneous resolution approximately 25% of the time. Treatment options should not include aspiration or marsupialization as many cases have shown recurrence. The role of antenatal infection in development of parameatal cyst not yet been determined.A large parameatal cyst could resolve spontaneously, routine observation recommended for majority of cases. They present more commonly in males than females, and usually before the onset of puberty . The eti2The NICU team was called to assist in the delivery of a 35-year-old G3P2 woman, pregnant at 38 + 6 weeks in for repeat caesarean. Labour had started 5 h prior with rupture of membrane at delivery. There was no maternal fever and the amniotic fluid was not malodorous. Delivery was unremarkable, with stimulation being required for resuscitation and Apgar scores of 5, 9, and 9 . During the physical exam, a large 5 mm cyst was found on the left lateral side of urethral meatus with no associated hypospadias or other abnormalities. The sac was large enough to completely obstruct the view of the urethra even after gentle pressure was applied. Inspection of the sac showed a fluid-filled cavity containing an off-white thickened liquid. The sac itself was not easily separated from the tissue with light pressure, and was non-mobile and non-tender (Figs. On review of the obstetrical history, the mother had a urinary tract infection positive for E. faecalis and E. coli during week 34 of pregnancy which was treated with Cephalexin. This may contribute to view of a concomitant infection or inflammation affecting the development of a cyst.3In the majority of cases, a small parameatal cyst is asymptomatic and does not require urgent interventions . There aTreatment options should not include aspiration or marsupialization as the described cases have shown recurrence or continuous drainage . SurgicaIt has not yet been determined if infection can contribute to a parameatal sac development, but interestingly the appearance of a large congenital cyst appeared in the context of a previous maternal UTI. Our patient was otherwise well and able to pass urine without difficulty, despite the size of the cyst. His urinalysis results were normal, with no signs of infection or inflammation. Renal ultrasound did not reveal any anomalies, and patient was discharged home. Follow-up with the family doctor was recommended to monitor for cyst evolution. No complications or associated symptoms were noted, patient was doing and growing well. A spontaneous resolution of the cyst was reported at the age of one month. As possible re-occurrence of parameatal cysts was reported in several cases , family None declared.Not funded.As per University of Saskatchewan REB publication of case report doesn’t require ethical approval if researchers protect the right to anonymity and confidentiality of the patient.As our patient is neonate parental consent to share history and photographs was obtained for this publication.Written informed consent obtained from the parents of the patient.Dr. Christiansen – patient care, data collection, literature review, manuscript preparation.Dr. Veronica Mugarab-Samedi – manuscript edition, literature review, patient follow up.Not required.Dr. Veronica Mugarab-Samedi.Editorially reviewed, not externally peer-reviewed.


Preterm birth infants are at a greater risk of mortality and a variety of health and developmental problems; reliable data support that this rate is increasing in almost all countries. The purpose is to find the magnitude of preterm birth and its associated factors among newborns delivered at Butajira Hospital, Southern Nations, Nationalities, and People's Region, Ethiopia. _21 in 2019. The data collection was performed using a structured case record form. The data were entered into EpiData software (version 3.1) and analyzed using SPSS software (version 21). Binary and multivariable logistic regression analyses were computed to identify the associated factors at 95% CI.  This hospital-based cross-sectional study was carried out on 304 maternity cards using the systematic sampling method during May 1 Overall magnitude of preterm birth was observed to be 15.5%. The factors significantly associated with the preterm birth were preeclampsia , and premature rupture of fetal membranes .  Preterm birth is still public concern in the study area. The concerned administrative body should implement health education programs and improve the quality of health care delivered to pregnant mothers to control these associated factors and, consequently, promote public health in the study area. The World Health Organization (WHO) defines a preterm birth as birth that occurs before 37 completed weeks of gestation, or fewer than 259 days from the first date of a woman's last menstrual period . PretermPrematurity has become the leading cause of newborn mortality worldwide, resulting in more than one million deaths each year. Responsible for 35% of worldwide neonatal deaths, the condition is the second leading cause of death among children under five after pneumonia . AdditioA variety of factors can contribute to preterm birth, including history of previous preterm birth , 13, preAt present, local data is crucial to implement an intervention in order to reduce the risk of preterm birth. In Ethiopia, as observed in different studies from across the country, the prevalence of preterm birth is estimated to be between as low as 4.4%  and as hA hospital-based cross-sectional study was carried out in Butajira Hospital from May 1 to 21, 2019. The study populations for the study were randomly chosen maternity cards for mothers who had given birth at the Butajira Hospital in the previous year prior to the data collection period.The sample size of 304 was calculated using a single population proportion formula with the following assumptions; the proportion of preterm birth was taken from the study conducted in Jimma University Specialized Teaching and Referral Hospital of 25.9% , with a A pretested case record form was used to review data from maternal cards, which was adapted from other related researches –23. Midwp value ≤.25 during the bivariate logistic regression analyses to identify factors associated with the outcome variable and to control for potential confounders. Association between independent and dependent variables were assessed using odds ratio with 95% confidence interval. At the end, p < 0.05 was considered as statistically significant in the multivariable model. Hosmer-Lemeshow goodness-of-fit statistic was used to check the necessary assumptions for multivariable logistic regressions was fulfilled.The collected data were coded and entered using EpiData version 3.1 software to minimize errors and design skipping patterns. Then, the data were exported and analyzed using SPSS version 24.0. Descriptive statistics, frequency, and proportions were computed to summarise the data. Bivariate analysis between outcome and independent variables was performed separately using binary logistic regression. The strength and direction of the association between an outcome variable and independent variables were expressed in odds ratio through 95% CI. To identify independent factors, the first bivariate logistic regression analyses were carried out to select a candidate for multivariable logistic regression analyses. Multivariable logistic regression analyses were done for variables that have Gestational age was estimated based on her last normal menstrual period, using an ultrasound report from chart review.This study was approved by Wachemo University, research and community services directorate office. Additionally, permission was obtained from the hospital authority before commencing the data collection.A total of 304 maternity cards were reviewed in this study, wherein the response rate was 100%. Two hundred forty-two (79.6%) of mothers were aged between 20 and 34 years. The majority of them, 300 (98.7%) were married, while 208 (68.4%) were urban residents. Regarding parity, 193 (63.5%) mothers were multigravida, and the other 28.6% were primipara. Thirty (9.9%) mothers had ever experienced abortion. More than half of the mothers 161 (53%) had four or more antenatal care visits. During their last pregnancy, 28 (9.2%), 10 (3.3%), and 17 (5.6%) of mothers faced the preeclampsia, antepartum haemorrhage, and premature rupture of fetal membranes, respectively..The majority of the mothers delivered 293 (96.4%) alive neonates. Of these, 27 (9.2%) were low birth weight. According to reports in the mothers' cards, 7 (2.3%) mothers were HIV positive, and in 27 (8.6%) of the mothers, the hemoglobin level was less than 11gm/dl .In this study, the overall magnitude of preterm birth was observed to be 47 (15.5%) .The outcome of bivariate logistic regression analysis showed that mothers aged ≥35 years, being rural residents, with history of previous preterm birth, grand multiparty, and less than 4 antenatal care visits were associated factors for preterm birth. However, in multivariable logistic regression, preeclampsia and premature rupture of fetal membranes were found to be significantly associated with preterm birth. Preterm birth was four times more likely to occur in mothers with preeclampsia in comparison to their counterparts . Also, mothers with premature rupture of fetal membranes were four or more times more likely to have a preterm birth than their counterparts  .In this study, the prevalence of preterm birth was observed to be 15.5% and is higher than those of other studies conducted in Brazil, India, Gondar (Ethiopia), and Iran, which were 11.5%, 5.8%, 4.4%, and 5.1%, respectively , 21, 23.The observed association between preeclampsia during pregnancy with preterm birth is consistent with studies conducted in Iran , India , 17, EthThe finding of this study also revealed that mothers with the premature rupture of fetal membranes were associated with preterm birth. This is comparable with studies done in Iran , India , 21, andThis study understandably shares the limitations of cross-sectional studies. First, as a cross-sectional study, the associations observed between the independent variables and the dependent does not show causal-effect relationship. Secondly, this is a hospital-based cross-sectional study whose findings are not generalized to a general population. Finally, it is important to mention here that data was collected from each mother's card; due to this, some important variables were missing, such as previously highlighted factors with preterm birth in different studies.In conclusion, preterm birth is still a public concern in the study area. Preeclampsia and premature rupture of fetal membranes were significantly associated with preterm birth. Therefore, the concerned administrative body should implement health education programs and improve the quality of health care delivered to pregnant mothers to control these risk factors and, consequently, promote public health in the study area.


The aim of this review was to summarize the available evidence about the use of levonorgestrel-releasing intrauterine system (LNG-IUS) as a contraceptive method in nulliparous women. For this purpose, studies evaluating the efficacy, safety, bleeding pattern, satisfaction and discontinuation of the levonorgestrel-releasing intrauterine system in nulliparous women were analyzed. Only original research articles published in English between 1990–27th March 2020 were considered eligible. Reviews, book chapters, case studies, conference papers, opinions, editorials and letters were excluded. The systematic literature search of PubMed/MEDLINE, Scopus, Embase and Cochrane Library databases identified 816 articles, 23 of which were analyzed. The available evidence indicates that LNG-IUS is an effective and safe contraceptive method for nulliparous women that achieves high levels of satisfaction among patients. Moreover, nulliparous women seem to experience fewer expulsions than parous ones. Bleeding pattern is acceptable for the majority of patients, and bleeding disorders mainly occur in the first months after the insertion. More in-depth, long-term prospective studies are needed in this patient group to determine risk factors for the occurrence of side effects and associated discontinuations, which should not, however, delay the wider use of the method in this group, given the number of advantages. Contraception (or birth control) is a deliberate use of methods or devices to prevent pregnancy as a consequence of sexual intercourse. Birth control has been used since ancient times, but its efficacy and safety has always been a problematic matter. A great progress in contraception research was observed in the 20th century, when contraceptives improved women′s quality of life (QoL) and reduced various health conditions related to unplanned pregnancies ,2. Due tIntrauterine devices are a form of long-acting reversible contraception (LARC) methods. They are placed in a woman′s uterus. The new era of hormonal intrauterine devices (IUD) started when Luukkainen 1976) replaced the IUD copper filament with a small reservoir releasing constant daily doses of levonorgestrel . Most of replacedMost gynecological societies support the use of hormonal IUDs, e.g., the American College of Obstetricians and Gynecologists (ACOG) has stated in their guidelines that LARCs are a safe and acceptable means of LARC for both adults and adolescents, as well as parous and nulliparous women . In mostTo this day, several systematic reviews on the use of IUD in adolescents and nulliparous women have been conducted. Among those published in the recent years, the main topic became the IUD insertion procedure and pain management in this specific population ,23,24. TIn summary, as concerns about the use of LNG-IUS in nulliparous women may still limit the its availability in a large group of patients, an up-to-date overview on the available evidence is needed. Therefore, the objective of this systematic review was to summarize and critically appraise the available evidence about the use of LNG-IUS as a contraceptive method in nulliparous women.https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=139169.The protocol for this systematic review was registered at PROSPERO—an International Prospective Register of Systematic Reviews (CRD42019139169), and may be accessed at The inclusion and exclusion criteria are summarized in Papers regarding the insertion procedure itself or pain perception and management were not considered, since major systematic reviews on the topics have been published by other authors in recent years ,23,24.The following LNG-IUS outcomes were taken into account: efficacy (the rate of unintended pregnancies and Pearl Index (PI)), safety (the rate and kind of side effects), bleeding pattern, satisfaction (various satisfaction rates) and continuation (the rate of continuation and reasons for discontinuation). PI was defined as the number of pregnancies that occurred divided by the number of treatment cycles multiplied by 1300 times .Four electronic databases were searched: MEDLINE (through PubMed), Scopus, Embase and CENTRAL. The search strategy for each database are presented in A systematic literature search retrieved 816 studies. Duplicates were removed using the automatic EndNote X9  duplicate finder, followed by a manual search. Titles and abstracts of remaining articles were independently screened by three study authors. Full-text versions of studies potentially eligible were assessed by three other authors. Details regarding the selection process are summarized in a custom-built PRISMA flow chart in The risk of bias for the interpretation of the data on the use of LNG-IUS in nulliparous in the selected studies was analyzed with the use the Newcastle-Ottawa Quality Assessment Scale, modified by the authors for the needs of this review  Table S. A studyAs a result of the described search procedure, 23 articles that meet all the inclusion criteria were retrieved ,50,51,52In only one of the studies that met the previously assumed criteria, the study group consisted of patients using low-dose IUS . Both LNA total of 12 out of 23 articles reported data on the pregnancy rates in groups of nulliparous LNG-IUS users ,49,50,51A total of 14 out of 23 articles investigated the occurrence of expulsion in the analyzed population ,46,49,51A total of 15 out of 23 articles reported data on the continuation rates in the studied population ,49,51,52It is worth noting in this section that the number of patients continuing a contraceptive method to some extent reflects the degree of patient satisfaction and adjustment of the method to her needs. It may also provide information about her cooperation with the doctor . TherefoBleeding profile disturbances are a rare yet probable scenario during LNG-IUS use, including among nulliparous women. The unacceptable bleeding pattern was one of the most common reason for LNG-IUS discontinuation, but still, such a situation occurred within a very small percentage of nulliparous users—from 2% during the first year of use, up to 6% during the fifth year of usage ,32,49,51Among the retrieved articles, only one partial perforation, a case of myometrial embedment, was reported by the authors of the studies . MoreoveThere is still relatively little data in the available literature regarding the long-term safety of IUD use, especially regarding fertility. Nevertheless, those available do not indicate an increased risk of infertility ,60.Only five out of 23 studies reported on the satisfaction with contraception method in nulliparous LNG-IUS users, and the rates ranged from 76% to 96% ,42,45,52It is worth mentioning that Suhonen et al. reported that significantly more LNG-IUS users wanted to continue the method after the study than in case of OC group (88% vs. 68%) . MarionsN = 12, 52%). Nevertheless, the remaining 11 studies was characterized by moderate or high bias risk (N = 2 (9%) and N = 9 (39%) respectively). Most of them rated low in the Comparability section, mainly due to the fact that nulliparous population has not been minutely characterized, which may potentially be the source of some bias. For details of the assessment see The greatest advantage of this review is the fact that it contains the most up-to-date and extensive summary of the available data on the use of LNG-IUS in nulliparous women. Conversely, one of the biggest limitations is the paucity of quantitative analyses. This is due to the fact that the individual studies mostly used different methods to assess the various aspects of LNG-IUS use. Another noteworthy aspect is the problem with the nomenclature and different inclusion criteria of nulliparous or nulligravidas women in analyzed studies. Very few studies have defined this population in detail, e.g., by reporting the percentage of women who have undergone early pregnancy termination, which may be the source of some bias. Regrettably, not all reported basic outcomes, e.g., about the occurrence of unwanted pregnancies or perforations. In addition, the studies differed from basic characteristics of the population to the type of LNG-IUS applied. The vast majority of them investigated Mirena or other comparable in levonorgestrel dose and size IUS, which did not allow us to analyze the impact of these factors on outcomes of interest. What is more, in the generally available literature, there are still very few studies directly comparing different types of IUDs, which might be particularly important from a clinical point of view . NeverthThe review indicates that LNG-IUS is an effective and safe contraceptive method for nulliparous women, which also achieves high levels of satisfaction among patients. In addition, nulliparous women seem to experience fewer expulsions than parous ones. Bleeding pattern is acceptable for the majority of patients, and any bleeding profile disorders mainly occur in the first months after the insertion. Further in-depth, long-term prospective studies on different types of LNG-IUS in size and dosage are necessary in this patient group, to determine risk factors for the occurrence of side effects and associated discontinuations, which should not, however, delay the wider use of the method in this group, given the number of advantages and relatively few disadvantages.


Finally, clinical aspects of the timing and type of treatment is discussed, and future perspectives are addressed. Current evidence corroborates a risk of birth defects associated with MMI while more evidence is needed to determine the teratogenic potential of PTU. Detailed assessment of type and timing of exposure in large cohorts are needed. Moreover, studies investigating alternative or new treatments are warranted.Antithyroid drugs (ATDs) are preferred for the treatment of hyperthyroidism caused by Graves’ disease in pregnant women. The drugs have been a recognized treatment for decades, and a general risk of side effects is known. For the use of ATDs in pregnancy, a concern about teratogenic side effects has been brought forward since the 1970s. In more recent years, a number of large observational studies have added new evidence and quantified the risk of birth defects associated with different types of ATDs. The findings that both Methimazole (MMI) and Propylthiouracil (PTU) are associated with birth defects have challenged the clinical recommendations on the treatment of hyperthyroidism in pregnancy, and certain aspects remain unclarified. In this review, the current evidence on the risk of birth defects associated with the use of ATDs in early pregnancy is described, and determinants of causality are discussed. This includes the current evidence of a biological gradient and the role of maternal thyroid function per se Antithyroid drugs (ATDs) have been used in clinical practice for the treatment of hyperthyroidism for more than half a century and constitute a recognized treatment in non-pregnant and in pregnant individuals . In preg. Finally, perspectives on the timing of exposure and alternative or new treatments in pregnancy are introduced.In this review, the current state of the art on the risk of birth defects associated with maternal use of ATDs in pregnancy is described, and methodological aspects are discussed. Furthermore, the review specifically addresses the existing knowledge on determinants of causality including the impact of the dose of ATDs and maternal thyroid function per seATDs are thionamides that block the synthesis of thyroid hormones . The facA possible link between the use of ATDs and birth defects was first described 50 years ago. From the early report in 1972 . These fConsidering PTU, this drug had not been linked to birth defects by the turn of the century  and the When considering the findings and the disparity in results from different studies, details of outcome assessment may be of importance. Birth defects, also known as congenital malformations, are by definition present at birth . HoweverStrength, consistency and specificity are some of the key determinants of causality in observational studies . Anothern = 50) and controls (n = 1181), p = 0.13. Notably, it appeared from the description of individual cases that the mean daily dose of MMI was 9 mg in cases of aplasia cutis (n = 8), 17 mg in omphalocele (n = 8), and 13 mg in cases of omphalomesenteric duct anomalies (n = 8), but no measure of comparison to exposed non-cases was reported [n = 36 of 278; 13.0%) as compared to 1–126 mg ; adjusted odds ratio 1.87 : 1.06–3.30). This was not the case for PTU with a similar prevalence of birth defects among children exposed to a cumulative dose of > 8600 mg  as compared to 1–1850 mg ; adjusted odds ratio 0.90 (95% CI: 0.72–1.12) [Considering information on the dose of ATDs used for the treatment of hyperthyroidism in early pregnancy, this information was reported in a subset of observational studies Table . The tworeported  Table 1n = 50 an72–1.12) . No info72–1.12)  to suggeAnother key aspect to consider in terms of causality from observational findings is analogy . Namely,n = 5 of 167; 3.0%) than in euthyroid women , p < 0.01, however, the number of exposed cases was small, and the low prevalence of birth defects in non-exposed children is not in accordance with findings in later thorough studies. In the later and larger Japanese study by Yoshihara et al. [The study by Momotani et al.  Table 22 includea et al.   as compared to the group treated with MMI , p < 0.05, including a lower prevalence of the severe malformations previously described as part of the MMI embryopathy. There was no difference between the two groups in terms of gestational age at birth, birth weight or perinatal losses, but the frequency of early pregnancy loss was higher in the MMI group  as compared to the iodine groups , p < 0.05. The authors speculated whether this finding was related to maternal thyroid function in early pregnancy [Considering alternative treatments, a focus on the feasibility of using potassium iodide has emerged from studies in Japan , 37. In regnancy . A generAnother pertinent question is the possibility of other treatments or the development of new treatment. This perspective of alternative treatments on the one hand and the proposal of treatment withdrawal in early pregnancy on the other hand call for further research. Clinical studies are needed and basic scientific work is important to support the clinical data and to develop our understanding of the mechanisms by which ATDs cause teratogenic side effects. Furthermore, different types of research serve to determine the role of maternal thyroid function and the role of the autoimmune mechanisms associated with the hyperthyroidism of GD. MMI and PTU are considered to equally cross the placenta , to be eA link between the use of ATDs for the treatment of hyperthyroidism in early pregnancy and birth defects has been brought forward over the past 50 years, and large observational studies have quantified the risk of birth defects associated with different types of ATDs in more recent years. Current evidence substantiates a risk of birth defects associated with the use of MMI and these malformations may be severe. On the other hand, further studies are needed to settle the teratogenic role of PTU and the role of maternal thyroid function and thyroid autoimmunity. Detailed clinical data on the timing and type of exposure in early pregnancy are needed to inform clinical practice on the choice of treatment and the possibility of treatment withdrawal in selected patients. Furthermore, basic scientific work is important to address the mechanisms underlying the development of birth defects, and to precede the development of alternative or new treatments with less severe side effects.