While several studies have shown that milk formula feeding is associated with faster infant weight gain compared with exclusively breast feeding (EBF), we explored the possible reverse association that infant weight gain influences the duration of EBF.Prospective birth cohort study (Cambridge Baby Growth Breastfeeding Study) born 2015–2018.Cambridge, UK.Full-term, singleton, normal birthweight infants who received EBF for 2–5 completed weeks (n=54), 6–11 weeks (n=14) or 12 or more weeks (n=80).Weight gain from birth to 2 and 6 weeks.Duration of EBF.Faster infant weight gain during EBF predicted longer duration of EBF. Among all 148 infants, each +1 unit gain in weight SD score (SDS) between birth and 2 weeks  reduced the likelihood of stopping EBF between 2 and 5 weeks by ~70% . Similarly, among infants EBF for 6 or more weeks (n=94), each +1 unit gain in weight SDS between birth and 6 weeks reduced the likelihood of stopping EBF between 6 and 11 weeks by ~80% .Slower early infant weight gain was consistently associated with subsequent earlier discontinuation of EBF. We conjecture that broader recognition of the wide range of normal infant growth might encourage parents to not stop EBF earlier than they intended. In this longitudinal cohort study of term, singleton, normal birthweight, initially exclusively breastfed infants, slower weight gain while exclusively breast feeding was associated with higher likelihood of introduction of infant milk formula in subsequent follow-up periods, between 2 and 11 weeks. Several studies show that formula feeding is associated with faster infant weight gain compared with exclusively breast feeding (EBF).Conversely, growth charts based on breastfed infants describe heavier infant weights in the first 2–3 months compared with charts based on mostly formula-fed infants.In this cohort of initially EBF infants, slower weight gain while EBF was consistently associated with higher likelihood of introduction of infant milk formula during the subsequent follow-up periods, between ages 2 and 11 weeks.We conjecture that broader recognition of the wide range of normal infant growth might encourage parents to not stop EBF earlier than they intended.Current growth references, based on infants who were exclusively or predominantly breast fed for at least 4 months, may overestimate early weight gain in the wider population of infants who start EBF.Several studies have reported that formula-fed (FF) infants grow faster than those who are exclusively breast fed (EBF).However, not all data are consistent with this notion. First, in some resource-poor settings, FF infants show slower weight gain than EBF infants, plausibly due to the relatively high cost of infant formula and the high absolute risks of gastrointestinal and respiratory infections associated with FF in those settings.10.1136/archdischild-2022-323999.supp1Supplementary dataSuch age-graded differences in growth between FF and breastfed infants are at odds with the possible mechanisms. Consistently, FF infants have higher energy and protein intakes than breastfed infants.2), any significant maternal illness or pregnancy comorbidity, use of antibiotics or steroids in 30 days before delivery and regular consumption of probiotics. In total, 150 mother-infant pairs were recruited of whom 148 infants received EBF for at least 2 weeks and 94 were EBF for at least 6 weeks and were therefore eligible for further follow-up. Study size was determined by feasibility to assess breastmilk intake volumes using a deuterium-labelled water technique, which were used to inform other study aims.The Cambridge Baby Growth Breastfeeding Study (CBGS-BF) is an observational cohort study that recruited mother-infant pairs at birth from a single centre, the Rosie Maternity Hospital, Cambridge, UK.Birth weight at delivery was taken from routine medical records. Other birth measurements  were conAge-adjusted and sex-adjusted SDS for weight were calculated according to the current UK guideline .Of the 148 infants who received EBF for at least 2 weeks, n=54 stopped EBF between 2 and 5 completed weeks, n=14 stopped EBF between 6 and 11 weeks and the remaining n=80 continued EBF for 12 or more weeks. All infants who stopped EBF at 2–5 or 6–11 weeks started on infant formula . These groups did not differ in any maternal or birth characteristic .Prior to 2 weeks, while all infants were EBF (n=148), weight gain was fastest in infants who received EBF for 12 or more weeks (n=80) compared with infants who stopped EBF between 2 and 5 weeks  reduced the likelihood of stopping EBF between 2 and 5 weeks by ~70% . Similarly, among infants EBF for 6 or more weeks (n=94), each +1 unit gain in weight SDS between birth and 6 weeks reduced the likelihood of stopping EBF between 6 and 11 weeks by ~80% . Infants who continued on EBF for 12–25 weeks (n=52) or 26 or more weeks (n=28) showed similar growth patterns from birth to age 52 weeks .10.1136/archdischild-2022-323999.supp2Supplementary dataIn this observational study, slower weight gain while infants were receiving EBF was associated with subsequent earlier discontinuation of EBF. Similar ORs were seen for weight gain from birth to 2 weeks and birth to 6 weeks on the likelihood of subsequently stopping EBF at 2–5 weeks and 6–11 weeks, respectively. While most other studies aim to understand the question ‘how does infant feeding influence growth?’, these findings indicate ‘reverse causality’; that is, early infant growth rate influences feeding choice. Thereafter, beyond age 12 weeks, infants who changed from EBF to infant formula or mixed feeding gained weight more rapidly than infants who continued EBF.Reverse causality has been identified to affect other infant feeding and growth relationships. For example, earlier age at introduction of solid foods has been widely associated with larger infant body size and higher obesity risk, and therefore has been proposed as an early life intervention target for obesity prevention. However, we recently reported that, in most studies that collected data on infant growth before the age window for solid food introduction, rapid weight gain preceded the earlier introduction of solids, rather than vice versa.We acknowledge that our study has a number of limitations. The sample size was small compared with other birth cohorts, which reflects a trade-off between study numbers and frequency and nature of assessments. Stringent inclusion and exclusion criteria were applied, in particular the exclusion of small babies and mothers with obesity, and the reliance of a single site with predominant white Caucasian population might limit the applicability of the results to more diverse populations. The exclusion of infant-mother pairs who did not receive EBF for at least 2 weeks has advantages and disadvantages. While this focused study sample minimised the confounding effects of many environmental factors, it limited the number of subjects eligible for inclusion.These findings have a number of potential implications. Even among this highly educated study population who intended to EBF, only a minority 28/150; 18%) met the WHO and UNICEF recommendation to EBF for the first 6 months of life (26 or more weeks). We speculate that slower infant weight gains might have influenced some parents’ decisions to stop EBF before age 6 or 12 weeks. In the UK Infant Feeding Survey, ‘worry over not having enough milk’ was a major reason for stopping breast feeding and the majority of mothers who stopped would have liked to breast feed for longer.0; 18% meIn conclusion, in this cohort of initially EBF infants with frequent assessments of feeding and growth, we identified a ‘reverse’ relationship between slower initial weight gain and subsequent early introduction of FF. While we recognise there may be many reasons why infants stop EBF, we conjecture that broader recognition of the wide range of normal infant growth might encourage some parents to not stop EBF earlier than they intended.


Previous studies that used traditional multivariable and sibling matched analyses to investigate interpregnancy interval (IPI) and birth outcomes have reached mixed conclusions about a minimum recommended IPI, raising concerns about confounding. Our objective was to isolate the contribution of interpregnancy interval to the risk for adverse birth outcomes using propensity score matching.For this retrospective cohort study, data were drawn from a California Department of Health Care Access and Information database with linked vital records and hospital discharge records (2007–2012). We compared short IPIs of < 6, 6–11, and 12–17 months to a referent IPI of 18–23 months using 1:1 exact propensity score matching on 13 maternal sociodemographic and clinical factors. We used logistic regression to calculate the odds of preterm birth, early-term birth, and small for gestational age (SGA).p < .05).Of 144,733 women, 73.6% had IPIs < 18 months, 5.5% delivered preterm, 27.0% delivered early-term, and 6.0% had SGA infants. In the propensity matched sample , odds of preterm birth were increased among women with IPI < 6 and 6–11 months  and not with IPI 12–17 months ; a similar pattern emerged for early-term birth. The odds of SGA were slightly elevated only for intervals < 6 months (OR 1.10, 95% CI 1.00–1.20, This study demonstrates a dose response association between short IPI and adverse birth outcomes, with no increased risk beyond 12 months. Findings suggest that longer IPI recommendations may be overly proscriptive.The online version contains supplementary material available at 10.1007/s10995-022-03388-4. Most clinical and public health recommendations define a short interpregnancy interval as < 18 months, though the evidence supporting this target has been called into question, citing concerns about confounding.Using propensity score matching to address confounding, we found a dose response association between interpregnancy interval and preterm birth. This study bolsters the evidence for a connection between interpregnancy intervals < 6 months and adverse birth outcomes and reveals a modest or null association for IPI durations beyond 6 months. These findings suggest that reconsideration of clinical and public health birth spacing targets may be warranted.Short interpregnancy interval (IPI), commonly defined as < 18 months between a livebirth and subsequent conception , and smoking during pregnancy. Previous preterm birth was determined by gestational age at birth of the first delivery, according to vital records. Characteristics obtained from hospital discharge records were: gestational diabetes, gestational hypertension, preeclampsia, drug or alcohol use during pregnancy, and mental health diagnosis (Online Resource 1).IPI was measured as the time between the delivery of the first pregnancy to the expected last menstrual period of the second pregnancy. Expected last menstrual period was calculated by subtracting gestational age at birth of the second delivery from the birth date of the second infant. To facilitate comparison to most prior studies of short IPI and birth outcomes , early-term birth (37–38 weeks of gestation), and small for gestational age (SGA). We obtained gestational age at birth (best obstetric estimate) and birthweight from vital records. Preterm birth was subgrouped into preterm prelabor rupture of membranes (PPROM), spontaneous labor with intact membranes, or provider-initiated preterm birth. As previously described  and 95% confidence intervals (CIs) for preterm birth, early-term birth, SGA, PPROM, spontaneous preterm labor, and provider-initiated preterm birth for IPI < 6 months, 6–11 months, or 12–17 months, with a referent IPI of 18–23 months. We then calculated adjusted RRs for all maternal characteristics considered . Women with an IPI between 6 and 11 months or 12–17 months did not have a significantly increased risk of having an SGA infant for compared to women with an IPI of 18–23 months  Table , Fig. 3.p < 0.05). Women with an IPI between 6 and 11 or 12–17 months were not at increased odds of an SGA infant  to between-women  analyses; after adjusting for eight covariates, Shachar et al. found a dose response pattern of increased risk for preterm birth after short IPIs of up to 18 months . In the Providing additional useful context, Howard et al. similarly compared the results from conventional multivariable regression to a propensity matched model. The models produced parallel findings, which was also true of the present study. The study by Howard et al. used different IPI categories (< 9 months versus 9–24 months), which limits comparison to the present study in further detail.Taken together with other studies in high resource settings, our findings suggest that, for the purpose of optimizing birth outcomes, U.S. clinical guidelines and public health objectives may be overly conservative in recommending an IPI of > 18 months. The most recent clinical guidelines published in 2019 by the American College of Obstetricians and Gynecologists and Society for Maternal–Fetal Medicine offer a more nuanced take on birth spacing, specifying a strong (grade 1B) recommendation to prolong the IPI to > 6 months, alongside a weak (grade 2B) recommendation for an IPI of > 18 months  a clear dose response association between IPI and preterm birth and (2) the similar findings from conventional multivariable versus propensity score-matched regression models. To address the limited availability of social covariates in birth and hospital records, richer databases comprised of survey data for representative samples may be useful in unpacking associations among detailed social and structural factors, pregnancy intention and acceptability, IPI, and birth outcomes. Future research should additionally assess the impact of changes in clinical guidelines or public health initiatives aimed at reducing short IPI to evaluate their impact on pregnancy spacing and birth outcomes. Research investigating methods for incorporating IPI evidence into patient-centered approaches to family planning discussions with women Below is the link to the electronic supplementary material.


Vaccine-derived poliovirus (VDPV) is a potential threat to polio eradication because they can reintroduce into the general population and cause paralytic polio outbreaks, a phenomenon that has recently emerged as a prominent public health concern at the end of global polio eradication. This study aimed to describe the epidemiology and genetic characteristics of the first VDPV identified from a patient with acute flaccid paralysis (AFP), with four doses of inactivated polio vaccine immunization in Henan Province, China in 2017.The patient was diagnosed with type 3 VDPV. Subsequently, a series of epidemiological approaches was implemented, including a retrospective search of AFP cases, rate of vaccination assessment, study of contacts, and supplementary immunization activities. Fecal samples were collected, viral isolation was performed, and the viral isolates were characterized using full-length genomic sequencing and bioinformatic analysis.P2 region. Nucleotide substitutions, including U → C (472) and C → U (2493), have been identified, both of which are frequently observed as reversion mutations in neurovirulent type 3 poliovirus. A unique aspect of this case is that the patient had been vaccinated with four doses of inactive polio vaccine, and the serum neutralizing antibody for Sabin types 1 and 3 were 1∶16 and 1∶512, respectively. Thus, the patient was speculated to have been infected with type 3 VDPV, and the virus continued to replicate and be excreted for at least 41 d.Phylogenetic analysis showed that the viral isolates from the patient were different from other reported genetic clusters of type 3 VDPV worldwide. They were identified as a Sabin 3/Sabin 1 recombinant VDPV with a crossover site in the The existence of this kind of virus in human population is a serious risk and poses a severe challenge in maintaining a polio-free status in China. To the best of our knowledge, this is the first report of VDPV identified in the Henan province of China. Our results highlight the importance of maintaining a high-level vaccination rate and highly sensitive AFP case surveillance system in intercepting VDPV transmission.The online version contains supplementary material available at 10.1186/s40249-022-01028-1. Owing to the success of worldwide vaccination campaigns, the burden of poliomyelitis has radically decreased . In OctoVP1) coding region. VDPVs have the potential for sustained circulation in areas with low OPV immunization, and many outbreaks of circulating VDPVs (cVDPVs) have been reported worldwide in recent years  were constructed based on regions before and after crossover site of Henan type 3 VDPV  coding region, which caused an amino acid substitution in VP3–91: Phe to Ser) did not revert  did not revert –164: Asn to Asp, and], and the other is in NAg3b (VP3–77: Asp to Asn). Strain CHN21006-3 also had another amino acid replacement in NAg3b (VP2–172: Glu to Lys)  was used in SIAs, instead of the trivalent OPV (tOPV).The full-length genome sequences of Henan type 3 VDPV strains CHN21006-1, CHN21006-2, and CHN21006-3 described in this study were deposited in the GenBank database under the accession numbers ON221307- ON221309.This study reported a VDPV case detected by AFP case surveillance in Henan Province in 2017. After the case was identified as type 3 VDPV by the National Polio Laboratory, the emergency response of grade IV was immediately launched in Henan province. A timely emergency response was conducted, including an epidemiological investigation, and SIAs were performed in time to prevent the possible circulation of VDPV in the population and outside environment. Based on active searches of AFP cases, these preventive approaches proved to be effective and successful, and no poliovirus was detected in the close contacts and surrounding environment of the patient. In addition, through a comprehensive risk assessment, the risk of VDPV transmission was small, and cVDPV did not occur during the epidemic events.In 2000, the WHO Western Pacific region, which includes China, declared that China had entered the stage of maintaining the polio-free status. In the process of eradicating polio and maintaining polio-free status, the occurrence of VDPV cases in some countries and regions in recent years is a newly emerging problem. For many years, massive OPV immunization campaigns worldwide have substantially reduced the number of cases of poliomyelitis caused by WPV. Nevertheless, challenges originating from low polio vaccine coverage could lead to the emergence of VDPVs or the reintroduction of WPV from disease-endemic countries, which might threaten the success of poliomyelitis eradication programs . Based oReports of type 3 VDPV are relatively rare compared to those of types 1 and 2 VDPVs. In addition, only 11 records of type 3 VDPV sequences are available in GenBank as of April 2022. Both Chinese and global data show that type 2 VDPV account for the vast majority of all VDPVs. However, since the global switch from tOPV to bOPV in April 2016, the prevalence of types 1 and 3 VDPV may have changed .A unique aspect of this case is that the patient had been vaccinated with four doses of IPV, and the serum neutralizing antibody in the serum for Sabin types 1 and 3 were 1:16 and 1:512, respectively. Since the titer of anti-type 3 poliovirus antibody was significantly higher than that of anti-type 1 poliovirus antibody, it is speculated that the patient was infected with type 3 VDPV from other asymptomatic infected individuals or from the environment, and the virus continued to replicate and be excreted for at least 41 days (from the date of the first stool sample collection to the date of the third stool sample collection). The presence of this kind of virus in the human population is a serious risk and undoubtedly poses a severe challenge in maintaining a polio-free status in China. At the same time, we reviewed the follow-up records of children who received the same batch of IPV as this child, and there were no records of adverse events following immunization with same batch the vaccine, indicating that this batch IPV itself was qualified.How the virus infected this patient remains unclear. All stool samples collected from patients with AFP, meningitis, or hand, foot, and mouth disease in 2016–2017 were tested for virus isolation; however, no signs of poliovirus circulation were found before or after the isolation of CHN21006. Environmental surveillance was strengthened by collecting more wastewater samples from different areas of Zhumadian City; however, this did not lead to the isolation of similar viruses for the second time.The emergence of the Henan VDPV has important implications for present and future polio immunization policies. This case report clearly showed that Henan type 3 VDPVs were aVDPVs, and the epidemiological data reported that they did not belong to cVDPVs or iVDPVs, that is, no other patients were found to have AFP associated with these VDPVs. Furthermore, no similar VDPVs could be isolated from their contacts. In addition, no signs of immunodeficiency, such as abnormal immunoglobulin levels or signs of abnormal T cell and B cell function, appeared in patients from whom VDPVs were isolated at the time of AFP presentation. Fortunately, no evidence of transmission of this VDPV among the general population was observed. Nevertheless, finding the source of the virus is difficult and remains unclear.As the world approaches the goal of polio eradication, the WHO is developing corresponding strategies to minimize the risk of paralysis caused by poliovirus, including WPV and VDPVs. Stopping the use of type II OPV is an important part of the strategies in the later stages of polio eradication, thereby switching from tOPV to bOPV. Since May 1, 2016, China has begun to implement the sequential immunization program of one dose of IPV plus three doses of bivalent OPV (containing type 1 and 3 OPV). Since January 1, 2020, China changed its immunization strategy again and began the sequential immunization procedure of two doses of IPV plus two doses of bivalent OPV (containing type I and type III OPV). This program has a good protective effect, prevents the transmission of imported poliovirus, and reduces the incidence of VAPP and VDPV cases. As the last case of WPV 3 was observed in 2012, the WHO declares type 3 poliovirus eradicated after a 31-year campaign . Under tOur study described the genetic characteristics of Sabin 3/Sabin 1 recombinant VDPV, which seems to have the characteristics of an iVDPV. Although the observed antigenic changes will help the virus escape vaccine-induced immunity in human populations, evidence of virus transmission was not observed. To the best of our knowledge, this is the first report of VDPV identified in the Henan province of China. The existence of this kind of virus in human population is a serious risk and poses a severe challenge in maintaining a polio-free status in China. Our results highlight the importance of maintaining a high-level vaccination rate and highly sensitive AFP case surveillance system in intercepting VDPV transmission.Additional file 1: Table S1. Nucleotide and amino acid substitutions in the Henan type 3 VDPVs compared to Sabin strains. UTR untranslated region, VP1 viral protein 1, VP3 viral protein 3.


Alphapapillomavirus species 9  together with other carcinogenic types , but is the only alpha-9 type defined as possibly carcinogenic. This study aimed to determine whole-genome sequences of HPV67 isolated from Japanese women with cervical cancer or cervical intraepithelial neoplasia (CIN) to better understand the genetic basis of the oncogenic potential of HPV67.Human papillomavirus (HPV) type 67 is phylogenetically classified into Total cellular DNA isolated from cervical exfoliated cells that were single positive for HPV67  was subjected to PCR to amplify HPV67 DNA, followed by next generation sequencing to determine the complete viral genome sequences. Variant lineages/sublineages were assigned through viral whole-genome phylogenetic analysis. The transcriptional activity of the virus early promoter was assessed by luciferase reporter assays in cervical cancer cell lines.E2 gene. The long control region of the HPV67 genome did not induce transcription from the virus early promoter in HeLa cells, but showed weak transcriptional activity in CaSki cells.Phylogenetic analyses of HPV67 genomes from Japan (n = 12) revealed that 11 belonged to lineage A  and one belonged to lineage B. All cancer cases contained sublineage A1 variants, and one of these contained an in-frame deletion in the The single detection of HPV67 in cervical cancer and precancer specimens strongly suggests the carcinogenic potential of this rare genotype. The phylogenetic analysis indicates a predominance of lineage A variants among HPV67 infections in Japan. Since only 23 complete genome sequences of HPV67 had been obtained until now, the newly determined genome sequences in this study are expected to contribute to further functional and evolutionary studies on the genetic diversity of HPV67.The online version contains supplementary material available at 10.1186/s12985-022-01894-z. Approximately 13 genotypes of human papillomavirus (HPV) are responsible for the development of cervical cancer . The degHPV67 was originally isolated from a Japanese woman with vaginal intraepithelial neoplasia , but it Alphapapillomavirus species 9  together with other highly carcinogenic types, HPV16, 31, 33, 35, 52 and 58 [Based on the viral whole-genome sequence, HPV67 is phylogenetically classified into In the present study, we sought to determine whole-genome sequences of HPV67 isolated from Japanese women with cervical lesions, and analyzed viral variant lineages/sublineages and genetic variations. Moreover, the transcriptional activity of the virus long control region (LCR) was compared between HPV67 and other carcinogenic types using cervical cancer cell lines.Cervical exfoliated cells were collected using a cytobrush from Japanese women who visited the Department of Gynecology at Keio University Hospital, NTT Medical Center Tokyo, and Showa University Hospital, as outpatients having some sort of symptoms or referred by primary care physicians for further examination, from 2009 to 2018. Total cellular DNA was extracted from the collected cells using the MagNA Pure LC Total Nucleic Acid Isolation kit  on a MagNA Pure LC 2.0 (Roche), and subjected to HPV genotyping by PGMY PCR followed by reverse line blot hybridization as described previously .Two overlapping PCRs that cover the whole-genome sequence of HPV67 were performed with HPV67-positive DNA samples using PrimeSTAR® GXL DNA polymerase  or KOD One® PCR Master Mix  with the following primers: HPV67-631F (5′-CTG CTA TGA GCA ATT GCA TGA CAG CTC-3′) and HPV67-4627R (5′-CCA GAT GCT GTT GGA ATA GAT GGT GCA-3′); HPV67-4261F (5′-CTA CAA GGC GCA AAC GTG CCT CTG CAA CAC-3′) and HPV67-1100R (5′-CAC TAC CAG TGT CAG ATG CAT CCT CAT CCT-3′). The PCR protocol included 38 cycles of 98 °C for 15 s, 55 °C for 30 s, and 68 °C for 2 min. The amplified DNA, separated on an agarose gel and purified with the Wizard gel purification kit , was converted to a short-fragmented DNA library using the Nextera XT DNA sample prep kit , followed by size selection with SPRIselect . The multiplexed libraries were then sequenced on a MiSeq (Illumina) or an iSeq100 (Illmina). The VirusTAP pipeline [The HPV67 genome sequences newly determined in this study and those from GenBank  were aligned with each other using MAFFT v7.309. A maximum likelihood tree was constructed using RAxML HPC v8.2.9 under the general time-reversible nucleotide model with gamma-distributed rate heterogeneity and invariant sites (GTRGAMMAI) employing 1000 bootstrap replicates. The constructed phylogenetic tree was visualized in FigTree v1.4.3.AAG CTT TTG TAT GAC TGT TGT GTG TTT GTA-3′) and HPV67A1-R (5′-CAT GCC ATG GAT TTC TTG CAC TGT AGG TGG ACA C-3′); HPV67B-F (5′-CCC AAG CTT TTG TAT GAC TGT TTT GTG TTT GTA-3′) and HPV67B-R (5′-CAT GCC ATG GAT TTC TTG CAC TGT AGG TGG ACA C-3′); HPV31-F (5′-CCC AAG CTT TGG ATG TGT ATG TAA TAC ATG TGT-3′) and HPV31-R (5′-CAT GCC ATG GCG TCT GTA GGT TTG CAC AAA AT-3′); HPV52-F (5′-CCC AAG CTT CCA TTG TCT GTT GGG TAA TTG-3′) and HPV52-R (5′-CAT GCC ATG GCC GTG CGT TAG CTA CAC TGT G-3′); HPV58-F (5′-CCC AAG CTT TTG TTG TGG TAC TTA CAC TAT TT-3′) and HPV58-R (5′-CAT GCC ATG GTC CTG CAG TAG CCT ACC AAA A-3′) (HindIII and NcoI sites are underlined). The PCR products were digested with HindIII and NcoI, and inserted between the HindIII/NcoI sites in pGL3-Basic (Promega), a promoter-less reporter plasmid. The reporter plasmids containing the LCR of HPV16 [The LCR sequences of HPV67, 31, 52 and 58, were amplified from corresponding clinical samples by PCR with KODplus DNA polymerase (Toyobo) and the following primers: HPV67A1-F  on an ARVO MX luminescence counter , and the level of transcription was quantified as the ratio of the two luciferase activities.HeLa cells were seeded in 24-well plates at a density of 16,000 cells/well and grown for 24 h, followed by transfection of 200 ng of the LCR reporter plasmids or pGL3-Basic together with 5 ng of pGL4.75 using the FuGENE6 reagent (Promega). CaSki cells were seeded in 24-well plates at a density of 50,000 cells/well and grown for 6 h, followed by transfection of 500 ng of the LCR reporter plasmids or pGL3-Basic together with 5 ng of pGL4.75 using the X-tremeGENE HP reagent (Roche). At 48 h after transfection, E6, E7, E1, E2, E4, E5, L2 and L1 genes, the LCR and a non-coding region between E5 and L2. Accession numbers for these HPV67 genomes are shown in Table Of 7169 genotyped samples, 12 (0.2%) were found to be single positive for HPV67 by sequencing analysis of hybridization-negative PCR products. The histological diagnoses of these samples were as follows: negative for intraepithelial lesion or malignancy (NILM), n = 1; CIN1, n = 2; CIN2/3, n = 7; SCC, n = 2. The mean and standard deviation of the patients’ age was 43 ± 12 years. These HPV67-positive DNA samples were subjected to overlapping PCR covering the entire HPV67 genome, followed by next generation sequencing (NGS). Viral whole-genome sequences were then de novo reconstructed from short read sequences, resulting in determination of 12 complete genome sequences of HPV67. The lengths of the reconstructed genomes ranged from 7729 to 7819 bp  predicted potential binding motifs for cellular transcription factors, NFI, FOXA1 and GATA3, in the duplicated sequence.As shown in Fig. Luciferase reporter assays were used to investigate the transcriptional activity of the LCR of the HPV67 genome. HPV67 LCR from sublineage A1, with or without the 16-bp duplication (#12 and #11), and that from lineage B #04) were cloned into a luciferase reporter plasmid, and examined for their transcriptional activity in HeLa and CaSki cells, in comparison with LCR from other carcinogenic types. Although LCR of HPV16, 18, 31, 52 and 58 demonstrated considerable promoter activity, none of the HPV67 LCRs induced detectable luciferase activity in HeLa cells , suggesting a high prevalence of HPV67 lineage A variants in Japan. The reference genome of sublineage A1 (D21208)  was also. reported that out of 16 cervical cancer cases that were initially HPV-negative in liquid-based cytology samples, eight became HPV-positive by E6/E7-based PCR typing of microdissected archival tissue samples, among which two were HPV67 single-positive [The presence of HPV67 single-positive ICC cases in the current study strongly supports the pathogenic role of HPV67 in generating cervical cancer. Indeed, eight probably/possibly carcinogenic types  were previously shown to be biologically active in cervical cancer tissues, expressing both viral mRNA and cellular marker proteins indicative of HPV infection . Furtherpositive . In thatComparison of amino-acid sequences in the E6 protein between HPV67 and the other alpha-9 types revealed that HPV67 E6 has tyrosine-to-phenylalanine and glycine-to-asparagine substitutions at amino-acid positions 79 and 130 (Y79F and G130N), respectively . InteresE2 gene in the HPV genome is frequently disrupted by integration into the host genome in cervical cancer [E6/E7 oncogene expression, inactivation or dysfunction of E2 can lead to up-regulation of E6/E7, thereby contributing to the development of cervical cancer. In this study, one HPV67-positive ICC case (stage IIIB) had an in-frame 90-bp deletion in the E2 gene, which results in a 30 amino-acid deletion from position 252 to 281 of the E2 protein. Since this region corresponds to the hinge region that connects the N-terminal transactivation domain and the C-terminal DNA-binding domain [The l cancer . Since tg domain , the delE6/E7 PCR [Although epidemiological and clinical evidence is accumulating on a causal role of HPV67 in generating a minor fraction of cervical cancers, it is difficult to determine the exact prevalence of HPV67 infections in healthy women and compare that to the prevalence in women with cervical lesions. The reason for this difficulty is an inability of most HPV genotyping assays to conclusively detect HPV67. A recent systematic review that evaluated HPV genotyping assays suitable for cervical screening reported that out of 24 commercial HPV typing assays examined, only three  covered detection of HPV67, and only one of these (HPV-Risk Assay) fulfilled the validation criteria for use in cervical screening using clinician-collected specimens . Other H6/E7 PCR , both of6/E7 PCR , 20. In 6/E7 PCR , 27. Bec. reported that the frequency of HPV67 infection was about 3.6% in a general population [. demonstrated that 5 out of 93 cases (5.4%) diagnosed as atypical squamous cells of undetermined significance were positive for HPV67 in cervical-vaginal self-collected samples [Recently, NGS technology has been applied to detect multiple HPV types in cervical cell samples in an unbiased manner. By performing high-throughput sequencing coupled with rolling circle amplification of HPV genomes, Latsuzbaia et alpulation . That st samples . These eFinally, whether rarely detected but potentially carcinogenic HPVs, such as HPV67, should be targeted in cervical screening tests remains a matter of debate because inclusion of these types in screening tests would decrease specificity and positive predictive value with little or no increase in sensitivity or negative predictive value for detection of ICC or precancer , 6. It sThe current study reported that lineage A variants are dominant among HPV67 infections in Japan and for the first time assessed the transcriptional activity of HPV67 LCR in cervical cancer cells. Given the scarcity of HPV67 complete genome sequences so far, the HPV67 genome sequences that were newly determined in this study will contribute to further functional and evolutionary studies on HPV67 genetic variability.Additional file 1. Multiple sequence alignment of available HPV67 whole genomes.


All participants are followed-up through an in-person interview at 20–23+6 weeks and again at 28–33+6 weeks of gestation, and at delivery, respectively. CBCS has been divided into three phases from 20th November 2017 to 31st December 2021, and the first two phases have now been completed on 29th February 2020, enrolling 120 377 eligible pregnant women during this period. During the same period a total of 40 837 participants had been followed up to the end of pregnancy. Study recruitment will continue until December 2021 to achieve the target of 500 000 participants. Meanwhile, biological samples including peripheral blood, amniocytes, cord blood, placenta, or umbilical cord tissue have been collected from participants according to various conditions. The incidence of birth defects in this group is 2.5% and congenital heart disease is the most common type of birth defect seen so far. A website is in the advanced stages of planning, to allow seamless data transfer and facilitate collaboration with groups around the world.The China birth cohort study (CBCS) is a prospective longitudinal, mega-cohort study and the first national-based birth cohort study, aiming to establish a birth cohort covering representative geographical areas of the whole of China to investigate risk factors for birth defects and develop strategies for their reduction. Pregnant women who are of Chinese nationality, are 6–13The online version contains supplementary material available at 10.1007/s10654-021-00831-8. Birth defects are an important cause of infant mortality and lifelong disability, which result in tremendous burden to families and the society. According to the 2010 Global Burden of Disease (GBD) study, 6.4% of neonatal infant deaths are attributed to birth defects, which ranked 5th among all causes of death . At the The China birth cohort study (CBCS) is a prospective, longitudinal, mega-cohort study ultimately aiming at prevention of birth defects in China. The CBCS aims to establish a birth cohort of 500 000 pregnant women covering all regions of China from 20th November 2017 to 31st December 2021. Compared with other Chinese cohorts mentioned above, CBCS is the both the most recent and the first nation-wide birth cohort study in China and on completion will be one of the world’s largest birth cohort studies.The main hypothesis of our research is that birth defects depend on many risk factors and exposures suffered even before pregnancy. Therefore, the objective is to establish and estimate the relationship between demographic, genetic, behavioural and environmental maternal exposures before and during pregnancy with birth defects. There are three major research interests: (1) Describing epidemiological characteristics of birth defects and other adverse outcomes; (2) Investigating the impacts of maternal exposure, including environmental determinants, on birth defects and other adverse outcomes (the exposotype); (3) Identifying risk factors specifically for congenital heart diseases, which constitute the most commonly diagnosed birth defect.The design phase of the CBCS started in 2015 at the Beijing Obstetrics and Gynecology Hospital, Capital Medical University. A multidisciplinary scientific panel, including public health experts, obstetricians, ultrasound specialists, prenatal screening specialists, geneticists, environmentalists, and microbiologists, were invited over a number of cycles to design the study, including the research protocol, standard operating procedures, questionnaire design, data collection forms and methodology for follow-up, as well as to assess overall feasibility. In addition, the Chinese Ministry of Science and Technology has prioritised the establishment of the CBCS to further investigate these issues, and has provided non-financial as well as financial support (¥60 million / USD 8.3 million).+6 weeks of gestation at the time of recruitment, including both natural pregnancy and conception using assisted reproductive technologies; (3) they plan to attend routine antenatal examination and deliver in the study site, and plan to continue to live locally for more than one year; (4) they have no notifiable infectious diseases such as hepatitis B, syphilis and HIV; (5) they are able to understand the study and willing to give informed, written consent. It is possible for included women to withdraw from the study at any stage.Pregnant women are eligible to participate in the study if (1) they are of Chinese nationality; (2) they are 6–13The first phase was a 5-month pilot study used to evaluate all elements, including data collection systems and implementation processes of the study, and assess variables collected in six research sites from 20th November 2017 to 31st March 2018.The second phase aims to evaluate the effectiveness of recruitment and follow-up procedures and the standardization of quality control procedures from 1st April 2018 to 29th February 2020.After the operationalization of these first two phases, and prior to the third phase, which aims to invite more research sites to enrol participants, we undertook this pre-planned interim assessment of all processes for the study. This is the subject of this report, and we were particularly interested to examine follow-up rates, and establish whether recruitment of more sites during the final phase (from 1st March 2020 to 31st December 2021) is required, thus ensuring that the study can be completed on time.The large sample size of CBCS will provide adequate power to investigate not just associations but also potential causal effects of different exposures on birth defects. The sheer size of the study means that detailed planning is necessary to ensure feasibility, effectiveness of recruitment and follow-up, and standardization of data collection as well as biological sampling / processing; for this reason, CBCS has been divided into three phases.The first two phases have now been completed, with phase 2 finishing, as planned, on 29th February 2020. On that date we had enrolled 120 377 eligible women in early pregnancy (less than 14 weeks of gestation at enrolment), accounting for just over 24.1% of the total target. This recruitment was completed at 38 research sites in 17 provinces, cities, autonomous regions and municipalities covering most areas of China . The first and second follow-up visits are undertaken mid-pregnancy at 20–23+6 and late pregnancy at 28–33+6 weeks of gestation, respectively. For all participants, questionnaires are completed at these two follow-up visits by in-person interviews at their routine prenatal examination. Corresponding clinical laboratory measures are collected at both of these follow-up visits (Supplementary table 1). The third follow-up visit is undertaken after delivery. The clinical information is recorded for all the participants by trained researchers, doctors or nurses.In CBCS, women are enrolled in early pregnancy, at 6–13If the participant has a miscarriage in early pregnancy, or a pregnancy loss during mid- or late pregnancy, all clinical information will be recorded by trained researchers, doctors or nurses. If a birth defect is found at any of these stages, clinical information, including ultrasound scan information on fetal defects, is documented, and biological samples collected by specially trained researchers, doctors or nurses according to standard operation procedures and protocols. For each case of a birth defect, two controls are identified with maternal age ± 2 years and gestational age ± 2 weeks. Figure The CBCS covers a wide range of areas, including demographic characteristics, health status, reproductive status, prenatal screening, genetic factors, medication exposure and medication, pre-existing chronic disease, nutrition, lifestyle, environment factors and clinical laboratory measurements. All the data collected via the questionnaires, clinical laboratory measurements, standardised ultrasound scans at the enrolment and at follow-up are shown in Table All clinical laboratory measures include routine blood tests, as well as blood biochemistry, thyroid function, coagulation function, vitamin level tests, screening for Toxoplasma, Rubella virus, Cytomegalovirus and Herpes virus, maternal serum alpha fetoprotein, oral glucose tolerance test (OGTT) and HbA1c (Supplementary Table 1). Biological samples collected at different periods during pregnancy include peripheral blood samples donated by all participants, and may include amniocytes for those women opting to have amniocentesis, tissue, placenta, cord blood or umbilical cord tissue donated by participants with pregnancy loss or birth defects, and, where appropriate, controls.All baseline, follow-up and outcome data, as well as clinical laboratory measurements and bio-banked samples, are managed through a secure cloud-based platform, including an electronic data capturing (EDC) and a bio-bank system. This platform can combine the information from the two systems automatically and is used to establish, manage and maintain the database. Data can be collected in different ways including on mobile phone, PC or data import. Logic check functions are programmed during data input or capturing in order to avoid data entry errors and missing items, and to ensure integrity and accuracy of the data. The logic validation is not only in each questionnaire, but also operates across different questionnaires for the same woman. Accounts have different levels of permissions for research staff, database administrators and investigators. The platform issues follow-up reminders to both administrators and participants at each follow-up stage. Overall, this cloud-based platform has been designed based on the main principles of data security; ongoing quality control; the ability to share data among different research sites; ease of usability; and extensibility.The data, including all the measurements in the questionnaire and biological information from each participating centre, are transferred into the central CBCS Database in real time when the information is submitted. Additionally, all collected data is backed up and sent to the central server once a week. The data is managed by professional data administrators and will not be exported until the CBCS steering committee agrees.Currently, as our study is still in progress, our data cannot be shared externally. However, the data is shared within the team and among participating centres. We will consider the time of data sharing externally when recruitment and follow-up is completed. There will be an application process for use of the data through the completion of a request form which will include the proposed analysis strategy. Applications will be evaluated and once approved by the CBCS committee, data will be shared; results from such analysis must be returned to the database, to allow further sub-analysis.2. However, more men (41.32%) had a BMI above 25 kg/m2. The vast majority of participants and fathers were of Han ethnicity (> 93%), which is slightly higher than reported in the China Statistical Yearbook 2019 (91.5%) [The current data are from the pre-planned interim analysis, prior to the third phase of the study, undertaken to ensure proper functioning of all processes, examine follow-up rates, establish whether recruitment of more sites is needed and highlight any problems. As the study is still ongoing, early findings are described below. Table  (91.5%) . RoughlyThe CBCS has a number of strengths. Most important is the very large sample size, the detailed, comprehensive information, and multiple biological samples collected. To our knowledge, this will be the largest birth cohort in the world and will provide adequate power to investigate the causal effects of different exposures on birth defects . The datOne weakness of this cohort is the selection bias which had been recognized. However, the main aim of this study is to explore the associations between maternal exposure and birth defects and other adverse outcomes, and the selection is balanced for maternal exposure and the outcomes since the pregnancy outcome is not known at recruitment. Another weakness of this cohort is the self-administered questionnaire at recruitment, with some data based on participant self-evaluation, including health-related variables. However, the questions are presented in simple language and have been piloted; comparison undertaken with forms completed by healthcare staff have demonstrated high concordance. Furthermore, we have collected many different types of biological samples, but we have not started to analyse these. However, genomic sequencing is planned, and we are keen to incorporate emerging new technologies.In our study, the neonatal outcome at delivery is the final end-point, and no further follow-up of participating mothers and their children is being carried out; this is a weakness when compared to other long-standing birth cohort studies, such as the Danish National Birth Cohort (DNBC) and the Norwegian Mother and Child Cohort Study (MoBa) –16. ThisThe increasing number of birth cohort studies over recent decades has given opportunities for projects to integrate multiple cohorts, such as the Environmental influences on Child Health Outcomes (ECHO) program which contains 84 observational cohorts and the EU Child Cohort Network which contains 19 pregnancy and childhood cohorts , 18. ComSupplementary file1 (DOCX 16 KB)Below is the link to the electronic supplementary material.


Mangifera indica), apple , and vegetable, i.e., bottle gourd (Lagenaria siceraria), and ridge gourd (Luffa acutangula) peels. The antioxidant activity and total phenolic content (TPC) were evaluated by using methanol extracts along with 2, 2-diphenyl-1-picrylhydrazyl (DPPH), Folin–Ciocalteu (FC) assay, respectively having Butylated hydroxytoluene (BHT) and Gallic acid (GA) as standard. The TPC and antioxidant activity in the peels ranged from 20 mg GAE/g to 525 mg GAE/g and 15.02% to 75.95%, respectively, which revealed that investigated fruit and vegetable peels are rich source of phytochemical constituents. Bottle gourd peels exhibited the highest value of DPPH compared to the rest of the peels included in the study. Likewise, mango peels had the highest TPC as compared to the rest of the fruit peels. This research showed that the utilization of agricultural wastes should be promoted at commercial level to achieve the nutritional benefit at zero cost and minimize the generation of biological waste.The present study assessed nutritional status, antioxidant activity, and total phenolic content in fruits, i.e., mango ( High-valued commercial crops such as fruits and vegetables are a vital subsector within agriculture. The development of fruits initiates from ovaries-specific tissues of the flower, or some additional tissues . The preKalpna and Mital  reportedMalus domestica commonly known as apple, member of the Rosaceae family, is widely consumed by human. It is beneficial to human health due to the presence of numerous biologically active compounds like monosaccharides, minerals, dietary fiber, and phenolic contents. These compounds play a crucial role in antioxidant functioning and are present in significant concentrations in apple peels as compared to flesh [Mangifera indica), belonging to the flowering plant family Anacardiaceae and Mangifera genus, is among the world’s highly attractive and well-consumed tropical fruits [Pakistan has significant production of fruits and vegetables; however, a large portion of the fruits and vegetables is dumped as waste . Malus dto flesh , 18. Theto flesh . Mango (l fruits . It is rl fruits .Lagenaria siceraria (Molina) Standley. The plants in this family are of medium size, including 118 genera and 825 species, all of which are widespread in the hot climatic regions of the world. These species are among the earliest cultivated plants used for medicinal and nutritional purposes. Bottle gourd (Lagenaria siceraria) is one of the most commendable vegetables because of high vitamin B content, fair vitamin C and phenolic content, and choline. It is considered an imperative source of beta-carotene, ascorbic acid, vitamin B complex, carbohydrates, pectin and dietary soluble fibers, minerals, amino acids, and other vitamins. It also contains phenolic acids, phenolic acid glycosides, terpenoids, flavonoids, and other vital oils [Luffa acutangula is known as ridge gourd, has great importance for its ethnomedicinal properties and widely used in most of the Asian countries. Like apple and mango peels, bottle and ridge gourd peels are also highly nutritious and contain many beneficial bioactive compounds.Agrawal et al.  demonstrtal oils . Luffa aBaiano et al.  revealedThe substitution of synthetic food antioxidants by natural ones has emerging trend in research on fruit and vegetables nutrition. Therefore, studies have been focused on plant-derived natural antioxidants in the recent decades . The preApple, mango, bottle gourd and ridge gourd samples were collected from the local market of Lahore, province of Punjab, Pakistan  as described by Nithya et al. . A totalThe antioxidant activity in terms of percent inhibition for peel extracts was determined using DPPH stable free radical assay easy. The 100 μl of the test sample was initially mixed with 2.7 ml of 0.1% methanol and then with 200 μl solution of 0.1% DPPH in methanol solution. Samples were then incubated for 30 minutes in the dark. Control samples containing the same amount of methanol and DPPH solution were also prepared. Subsequently, the absorption maxima of the solutions were measured using UV double beam spectra scan at 517 nm at 5-minute intervals. The percentage inhibition was then calculated using the following formula:The maximum antioxidant potential was found in bottle gourd and mango peels compared with the synthetic antioxidant butylated hydroxytoluene (BHT). The BHT is a chemical derivative of phenol  and acts as an antioxidant for the preservation of food as well as in pharmaceuticals, cosmetics, petroleum products.2CO3 followed by thorough mixing. The resulting solutions could then stand for 2 hours at room temperature. After incubation, the absorbance was measured at 765 nm by using UV/Vis Shimadzu–Japan spectrophotometer. The calibration curve was obtained using gallic acid as standard with concentrations ranging from 100 to 1000 mg/ml. The results of TPC were expressed as gallic acid equivalent (GAE) per gram of dry sample concerning the gallic acid standard curve (R2 = 0.900). All samples were analyzed in triplicate and averaged.Total phenolic content (TPC) was measured for the determination of antioxidant ability of fruit and vegetable peels by following the Folin-Ciocalteu (FC) method with slight modifications as described by Srinivas et al. . BrieflyThe descriptive statistics was determined using Statistica software. Correlations of the antioxidant activity and total phenolic content between fruits and vegetables extract samples were determined using Minitab version 17. One way ANOVA  and t-teThe nutritional composition of fruits and vegetables are presented in The ash content in fruit and vegetable peels ranged from 2.56 ± 0.52 to 8.52 ± 0.27% of dry matter. The lowest ash contents were noted in apple and mango peels and the highest in bottle and ridge gourd peels. Ash contents in the vegetables were significantly higher than fruits (p<0.050). The observed ash contents for the vegetable peels are significantly lower as compared to earlier reported studies, i.e., Saeed et al. . While tThe lipid (fat) content ranged from 0.15 ± 0.025 to 0.34 ± 0.046% of dry matter. Bottle gourd peels had the lowest lipid content and mango peel had the highest lipid content. Aziz et al.  and HungThe crude fiber content and protein content ranged from 4.5 ± 0.22 to 17.6 ± 0.24% and 1.24 ± 0.045 to 16.52± 0.18% of dry matter, respectively. The vegetables had significantly higher contents of fiber (p = 0.050) and protein (p = 0.050) than fruits. The results indicated fruits and vegetables with higher protein content are more vulnerable to fungal degradation. Therefore, the overall results are consistent with those reported in Arumugam and Manikandan , who repThe carbohydrate content in the fruit and vegetable peels varied from 47.3± 0.76 to 78.5 ± 0.24% of dry matter. Fruit peels had significantly higher values of carbohydrate content as compared to vegetable peels (p = 0.050). This indicates that the fruit peels are potentially more useful for producing animal feed.The energy contents ranged from 256 ± 2.08 to 335 ± 1.15 kcal/100g. The fruit peels had significantly higher values than vegetable peels (p = 0.050), possibly due to their different carbohydrate contents and minimum in ridge gourd peels. The results are slightly higher than Mukhtar et al. . Energy Percentage inhibition of fruit and vegetable samples with BHT standard is shown in The percentage inhibition shown in fruits (apple and mango) was 67.27% and 73.16%, respectively, whereas for vegetables (bottle gourd and ridge gourd) it was 54.23% and 75.95%, respectively. The percentage inhibition in fruits and vegetables was compared with BHT, which was 77.12%. Comparison of percentage inhibition of fruits and vegetable peels with BHT indicated that minimum inhibition capacity was found in apple 29.11%, mango 34.28%, bottle gourd 34.12%, and ridge gourd 15.02%.Phenolic contents have gained considerable interest because of their potential beneficial effects on human health. Phenolic contents have been reported to show antiviral, anti-allergic, antiplatelet, anti-inflammatory, anticancer, and antioxidant activities . QuantifThe total phenolic content ranged from 228 to 503 mg gallic acid equivalents (GAE)/g of fruit peel samples and 23 to 91 mg GAE/g of vegetable peel samples. On average, the two fruits had significantly higher phenolic content than vegetables (p = 0.05). This indicates that peels of the two fruits considered here may be used to produce natural antioxidant supplements in food and pharmaceutical industry.Food waste mostly fruits, and vegetable peel contains essential nutrients required for better human health. The present investigation showed that fruit peels are more nutritious for carbohydrates and contain significant amount of total phenolic content. This study focused on improving the extraction proficiency of polyphenols and antioxidants from fruits and development of strategies to utilize them in food and pharmaceutical manufacturing. This research showed that utilization of agricultural wastes such as fruit and vegetable peel waste should be promoted at commercial level. They are cost-efficient and organic-rich compounds having safe health benefits. Commercial preparations of natural fruits and vegetable peels to extract valuable bioactive components and to utilize them as a source of natural antioxidants support the basis of the present study as they are very high-value products, and their recovery can be economically attractive.


Along with the low birth rate in Korea, the aging of mothers is progressing very rapidly. Recent studies have reported that the obstetric infrastructure is crumbling due to the accelerating closures of obstetric medical institutions resulting from the low birth rate and low reimbursement rates for obstetric procedures. The number of birth centers has also decreased, but women’s interest in natural birth has actually increased, such that deliveries at birth centers now account for 11.8% of deliveries in obstetric clinics. In the Netherlands, Japan, and the United Kingdom, initiatives to promote natural birth through care provided by midwives increased the rate of natural births, decreased the number of cesarean sections, and lowered the rate of postpartum complications. In light of these examples, South Korea should also encourage natural delivery by midwives. A national support system for midwife applicants is necessary, and the requirements for institutions that train midwives should be revised. Independent birth centers should have emergency prescription privileges, and women should be given the choice to have a natural delivery by creating birth centers within hospitals.  According to the Presidential Committee on Ageing Society and Population Policy, the budget to address the low birth rate in South Korea has increased by 21.1% per year on average since 2011, reaching 209.5 trillion Korean won (approximately 190.1 billion US dollars) in total during the last 10 years, but the total fertility rate nonetheless decreased by 0.32, from 1.24 in 2011 to 0.92 in 2019. South Korea’s total fertility rate (0.92) was the lowest among 37 Organization for Economic Co-operation and Development (OECD) member countries [In South Korea, the total number of births in 2019 was 300,787, which is 9.2% lower than the corresponding number in 2018 . The number of obstetric medical institutions also decreased dramatically from 808 in 2010 to 541 in 2019 [Along with the low birth rate, advanced maternal age in South Korea has reached an alarming level, with more than one mothers in five being older than 35 years. The obstetric infrastructure in South Korea is crumbling due to the accelerating closures of obstetric hospitals resulting from the low birth rate and low reimbursement rates for obstetric procedures . HoweverIn addition to hospitals and obstetric clinics, the number of birth centers where deliveries occur has steadily dropped from 126 in 2000 to 34 in 2014, 18 in 2016, 16 in 2017 and 2018, and 15 in 2019. There were 652 births in birth centers in 2010; this number increased to 1,260 in 2012 and 1,226 in 2016, before plunging to 912 in 2017, 712 in 2018, and 683 in 2019 [In 2019, there were 683 deliveries in 15 birth centers, corresponding to an average of 45.5 deliveries per birth center. Although this value is much lower than the average of 385 deliveries per hospital , the focus should be on the fact that 11.8% of deliveries at obstetric clinics occurred in birth centers [According to previous analyses, important factors contributing to women’s interest in delivering in a birth center include the trend for more women to refuse over-treatment that commonly occurs in-hospital settings and desiring baby- and family-focused natural birth that they can be active partners in .This article first discusses natural birth led by midwives in Australia, the Netherlands, Japan, France, and the United Kingdom, with a focus on mothers’ satisfaction and incidence of postpartum complications. This is followed by the second topic, the urgent need to promote midwives in South Korea.In a literature review that compiled 23 quantitative studies and nine qualitative studies from around the world about birth outcomes in birth centers, mothers who experienced delivery in birth centers reported trust in the professionalism of midwives, a comfortable and natural birth experience, and satisfaction with personal nursing care from midwives .In Queensland, Australia, delivery by midwives was found to be cost-effective, as the establishment of trust between mothers and midwives reduced women’s fear of delivery, which led to an increased rate of natural delivery and a lower rate of cesarean sections . In the Houm Birthing center and Houm OB/GYN Clinic (http://houm.co.kr) exist as an example of a birth center and an obstetrician operating in close collaboration.Japan experienced a shortage of obstetricians earlier than South Korea, starting in the 1990s. As a result, Japan experienced the social phenomenon of “birth refugees,” or women who did not have anywhere to deliver due to closure of regional obstetric clinics. This phenomenon resulted in a deterioration of maternal and child health, including suicide among pregnant women, mental health disorders, postpartum depression, and an increased rate of child abuse, which led to the enactment of the Comprehensive Support System for Children and Childrearing based on the Act on Children and Childrearing Support in Japan . The JapFrance is well known for its efforts to overcome low birth rates through policy measures, which have been implemented in various forms for over 100 years. All medical, hospitalization, and treatment fees that occur after the sixth month of pregnancy are covered by public health insurance (pregnancy insurance) with no out-of-pocket cost. The first prenatal check-up and postpartum check-up have to be done by physicians, but other prenatal and postpartum check-ups can be done by either midwives or physicians . AnotherIn order for South Korea to reap the benefits of the midwifery systems that have been implemented internationally, it is vitally urgent to implement a sustainable system of training a sufficient number of capable midwives. However, the number of midwives in training is small and this is related in part, to limitations in designated training centers. According to the Korean Midwives Association (KMA), there were seven trainees in Busan Ilsin Hospital, two in Gyeongbuk Andong Sungso Hospital, and four in Seoul Gangbuk Samsung Hospital in 2019; these trainees received training for 1 year, and 12 passed the exam in 2020, excluding one who failed . Busan IThe need to evaluate the adequacy of medical care in Korea is another issue. Although Korea's Article 38, Clause 1, Attached Table 5 of the Medical Act Enforcement Regulations stipulates that more than one-third of nurses in obstetrics should be midwives, there are no enforcement or intervention measures to support this specification. In 2019, 87% of vaginal births in Korea occurred in OB/GYN specialized hospitals or clinics .Due to issues such as the reimbursement rates for obstetrics being lower than the costs , nursingGovernment support for the midwife training process, which costs approximately 24 million Korean won  per person per year as of mid-December 2020, can be an important strategy for responding proactively to Korea's low birth rate. Moreover, the requirements for midwife training institutions need to be changed. Current legal requirement that the institution needs to be a training hospital for OB/GYN and pediatrics should be removed, as the number of such training hospitals is rapidly decreasing. The stipulation that the institution must perform more than 100 deliveries per month should also be relaxed, as the number of deliveries is decreasing due to the very low birth rate. As such, the range of institutions should be expanded to hospitals that are certified as medical facilities and perform more than 50 deliveries per month. Another alternative model is possibly adapting the training model of resident physicians, who work and are duly paid for their on-site training (80 hours/week). In similar context, nurses, already a licensed professional, should also be able to work and receive nominal payment as a midwife-in-training. If it were to be possible to employ labor and delivery unit nurses and offer concurrent midwifery training, i.e., aligning the same model that exists for resident training, this would facilitate more midwife training programs to function. The KMA can implement midwife training programs with these hospitals by signing memoranda of understanding. The government should also regulate and financially support obstetric hospitals so that they can abide by the current regulation stipulating that more than one-third of the nursing staff should be midwives.In Korea, a recent study found that midwives who work in hospitals reported considerably lower professionalism and job satisfaction than those who work in birth centers . In ordeThe rapid crumbling of the obstetric infrastructure due to the ultra-low birth rate is a serious reality that South Korea faces. In order to overcome this situation, the Korean government should support the training of capable midwives and establish a system that gives independent birth centers emergency standard prescription privileges, as in other countries. Women should be given the choice to receive midwife-led care for normal pregnancies by establishing birth centers in hospitals. If a pregnancy becomes high-risk, establishing a system to quickly transfer the patient to a hospital is also needed. These strategic measures will allow midwives to play a pivotal role in counter-acting the ongoing crisis of low birth rate in South Korea.


Results. In the second five-year period, a decrease in prevalence of PGF was observed , an increase in growth rate in the first 28 days (5.22 (4.35–6.09) g/kg/day vs. 11.38 (10.61–12.15) g/kg/day, p < 0.0001) and an increase in height standard deviation (SD) at 2 years (−1.12 (−1.35–−0.91) vs. −0.74 (−0.99–−0.49) p = 0.023). Probability of short stature at 2 years was directly related to daily weight gain in the first 28 days. Conclusions: when comparing two five-year periods in the last two decades, growth in VLBW preterm infants has improved, both during neonatal period and at two years of age.The prevalence of postnatal growth faltering (PGF) in preterm infants with very low birth weight (VLBW) (<1500 g) is a universal problem. Growth improvement is expected as neonatal care is optimized. Objectives: To determine if there has been a decrease in the prevalence of PGF and an improvement in height at 2 years in appropriate for gestational age VLBW children in the last two decades. Methods: Clinical descriptive retrospective analysis of neonatal somatometry at birth and at two-year corrected age in VLBW preterm infants. Small for gestational age were excluded. Two cohorts (2002–2006,  In recent decades, advances in neonatology and obstetrics have led to both increased survival and reduced morbidity in very low birth weight (VLBW) infants <1500 g) [500 g 1,,3,4,5. HPGF is defined as insufficient postnatal growth that occurs after preterm birth. There is no consensus in how to define PGF. It can be defined in two ways: transversal (static) or longitudinal (dynamic). Static PGF is usually defined at discharge or at 36/40 weeks postmenstrual age, including those patients weighing less than the 3rd or 10th percentile ,12,13,14Traditionally, intrauterine growth references have been used as a reference for the postnatal growth of the premature . HoweverThe objective of our study was to assess whether there has been an improvement in height at 2 years of age in VLBW children when comparing two periods of time in recent decades in a cohort of Spanish VLBW children, and whether there was a decrease in the prevalence of PGF. SGA infants present growth impairment that does not have a postnatal origin in its entirety, but rather is the continuity of a process that began during fetal life . For thiA clinical descriptive retrospective study was designed. Two cohorts of patients that included premature infants  with birth weight less than 1500 g were separated in time into two five-years periods: 2002–2006 (quinquennium 1) and 2013–2017 (quinquennium 2).They were all born in the Neonatology Unit of the Central University of Asturias  and they were all included in a perinatal morbidity and two-year follow-up database (SEN 1500) after informed consent was given by their parents or legal guardian . Our hosExclusion criteria were: birth weight below the 10th percentile (INTERGROWTH-21st references), gestational age < 24 weeks, death, major congenital malformations, chromosomal abnormalities, congenital embryopathies, or the lack of outpatient follow-up until 24 ± 6 months of corrected age . Static PGF was defined if the weight at discharge was less than the 10th percentile (INTERGROWTH-21st references) and dynamic PGF if there was a decrease of more than 1 SD in the weight (INTERGROWTH-21st references). The rate of weight gain in the first 28 days (g/kg/day) was calculated using the formula: (Weight (g) 28 days − Weight (g) birth) ÷ 28 ÷ Birth weight (kg).2). Short stature was defined if the height was less than –2 DS, malnutrition if the BMI was less than −2 SD and microcephaly if the head circumference was less than −2 SD.At 2 years of corrected age, SD for weight, height, head circumference and BMI were calculated using the WHO charts . BMI was®). Qualitative variables are shown as absolute number and percentage; the quantitative ones as mean and SD or as median and interquartile range. “Chi-square test” or “Fisher’s exact test” were used for the comparison of qualitative variables and the “Student’s t” test or the “Mann-Whitney U” test for quantitative variables. ROC curves were used to estimate the predictive power of short stature at 2 years based on the lowest daily weight gain in the first 28 days.Data were analyzed using the IBM SPSS statistical software, version V22.0 (IBMThe significance level adopted was 5%.www.boe.es/eli/es/l/2007/07/03/14 (accessed on 1 October 2022)). and the Law of Protection of Personal Data of 2018 (Law 3/2018) (www.boe.es/eli/es/lo/2018/12/05/3/con (accessed on 1 October 2022)). The study was approved by the Research Ethics Committee of the Principality of Asturias (No. 2020.314).The study was carried out in accordance with good clinical practice and current legal regulations. The parents or legal guardians signed the informed consent before their inclusion in perinatal morbidity and two-year follow-up database (SEN 1500). The procedures performed in this study are part of the routine care of VLBW children. The data was managed ensuring the confidentiality of the data as stated in the Biomedical Research Law of 2007 (Law 14/2007) (n = 39) in quinquennium 1 to 10% (n = 20) in quinquennium 2 (p = 0.037), thus increasing survival from 83% to 90%.A total of 237 VLBW children were enrolled in the first five-year period and 206 VLBW children in the second five-year period. In all, 112 and 92 appropriate for gestational age (AGA) VLBW children, respectively, met the inclusion criteria and completed the follow-up to 2 years. Mean weight at birth was 1181 ± 238 g in quinquenium 1 and 1205 ± 211 in quinquennium 2 (differences were not significant). The characteristics of the population studied, as well as neonatal morbidity, are described in p < 0.0001).A statistically significant decrease was observed in the prevalence of PGF (static and dynamic) for weight and length, without changes in head circumference see . Weight p = 0.32). Neither in the first nor in the second period studied were differences in the prevalence of height <−3 SD . Moreover, in quinquennium 2 there was both, a significant increase in the mean height expressed as SD (−1.12(−1.35–−0.91) vs. −0.74(−0.99–−0.49), p = 0.023). See At 2 years, it was observed that the prevalence of short stature (<−2 SD) decreased from 20.5% in quinquennium 1 to 15.2% in quinquennium 2 (p = 0.045). See The probability of short stature (−2 SD) at 2 years was directly related to the daily weight gain in the first 28 days, as observed in the ROC curve: AUC = 0.606 , nonetheless, there were differences in the second five-year period , girls presenting a height 0.61 SD higher.Analyzing weight, length and head circumference, SD between birth, discharge and 2 years, it is observed in both five-year periods that height is the most affected parameter at 2 years, and it is less likely to achieve an adequate catch up . Howeverp = 0.08). It is also observed that these patients have a higher probability of height <−2 SD, but these differences are not statistically significant. See In quinquennium 1, patients who experienced PGF were more likely to have malnutrition  or with very preterm infants, as reflected in the review by Hollanders et al. [We obtained a significant improvement in survival when comparing the 2002–2006 and 2013–2017 cohorts. These findings were similar to those observed in other studies ,5. SurviIn our series, girls experienced an improvement in height at 2 years, that was significantly higher than boys in the second quinquennium. Other authors have also described a higher risk of postnatal growth restriction in males , as wellWe also observed that patients who experienced PGF in the first quinquennium had a significantly higher risk of malnutrition at 2 years than those who experienced PGF in the second quinquennium, which could be explained by a greater severity of PGF in the first quinquennium. Other authors, such as Takayanagui et al., observed a relationship between PGF and short stature and malnutrition at 6 years of age in VLBW children .Among the strengths of our study, we analyzed changes in the postnatal growth restriction, that has entirely a postnatal origin. We also use the new INTERGROWTH-21st references, based on the real longitudinal growth of premature infants with minimal morbidity. Among the limitations of our study, we must mention that it deals with data collected from a single center and the relatively small sample we analyzed. Additionally, we did not consider the height of the parents, the caloric intake received during admission or the different protocols applied in the neonatal unit for the management of premature infants in such a long period of time. We also consider as a limitation that the differences in the mean gestational age at birth and in the birth weight SD score that are observed between both five-year periods could influence the results. On the other hand, other factors such as maternal socioeconomic status were not included in the study. In addition to having excluded the SGA children, our results cannot be extrapolated with other VLBW series.Based on these results, we can conclude that both growth in the neonatal period and growth at 2 years have improved, when comparing two five-year periods in different decades. The prognosis is better for girls compared to boys.


Transferring blastocysts frozen on day 6 (D6) may adversely affect the pregnancy rate compared with day 5 (D5). Moreover, it remains unclear whether delayed embryo transfer affects neonatal birth weight.A retrospective cohort study consisting of 17,127 singleton births from single frozen embryo transfer (FET) cycles, between January 2011 and January 2020, was performed including 14,166 blastocysts frozen on D5 and 2,961 on D6. The primary outcomes of this study were neonatal birth weight and incidence of small for gestational age (SGA), large for gestational age (LGA), low birth weight (LBW), and macrosomia.The mean neonatal birth weight in the D5 group (3.47 ± 0.49 kg) was significantly higher compared with the D6 group (3.45 ± 0.50 kg), although the discrepancy was only 0.02 kg. Multiple linear regression analysis for birth weight between the two groups showed no statistically significant difference . Logistic regression analysis revealed that the risks of SGA , LGA , LBW , and macrosomia  were similar in the two groups after adjusting for confounders.In the FET cycle, the neonatal birth weight and incidence of LGA, SGA, LBW, or macrosomia were similar between the D5 and D6 groups, suggesting that delayed blastocyst transfer would not affect the neonatal birth weight. Embryo transfer (ET) at the blastocyst stage has been widely recommended in assisted reproductive technology (ART), especially in the single ET program. Theoretically, prolonged in-vitro culture to blastocyst from the cleavage stage allows for better selection of the implantation potential of the embryo, thereby improving the pregnancy rate. Moreover, single ET reduces the incidence of multiple pregnancy rates, which is associated with a higher risk of maternal and neonatal complications . BlastocThe birth weight of neonates has long been regarded as an indicator of the offspring’s health. Chiavaroli et al. have reported that infants born with small-for-gestational-age (SGA) or large-for-gestational-age (LGA) show adverse cardio-metabolic profiles during childhood and adolescence, leading to an increased risk of cardiovascular diseases later in life . In addiWe performed a retrospective cohort study including 17,127 singleton live births after the transfer of frozen-thawed blastocysts from January 2011 to January 2020. Live birth was defined as a birth exhibiting life signs with ≥24 gestational weeks . This stIn vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) was performed after oocyte collection by the routine procedure. On D3 after insemination, embryos were observed and graded by morphological criteria based on the number and size of the blastomere.The extended culture of embryos was determined according to the quantity and quality of cleavage-stage embryos, in combination with the request of patients and the evaluation of clinicians. On D3, embryos were removed from the cleavage medium and placed in the blastocyst medium, followed by incubation to D5 or D6, and even D7 until the blastocyst formed. The blastocyst quality was assessed based on the Gardner score system , which wEndometrial preparation was carried out under natural cycles, stimulation cycles, and artificial cycles, depending on the clinician’s discretion. In a natural ovulation regimen, detection of spontaneous or triggered ovulation was the indication of timing for FET. Oral dydrogesterone was administered for luteal phase support after ovulation . The single frozen-thawed blastocyst was transferred on the 5th day after ovulation. If pregnancy was achieved, dydrogesterone was continued until the 10th week of gestation. In the artificial cycle, oral estradiol  was taken once a day from day 1-3 of the menstrual cycle. Oral  and transvaginal progesterone  or  and transvaginal progesterone  was added when the endometrium reached 7 mm or more. Single FET was performed on the sixth day of the progesterone exposure. If pregnancy occurred, estrogen supplement was stopped at the 8th week of gestation and progesterone support was continued until the 10th week of gestation. For stimulation cycles, letrozole or human menopausal gonadotropin (HMG), either alone or in combination, was given from day 3-5 of the menstrual cycle. Ultrasound monitoring was repeated every 1-3 days according to follicle growth until ovulation triggering. When the dominant follicle reached a diameter of 17–20 mm, human chorionic gonadotropin (hCG) at a dosage of 5,000-10,000 IU was administered to trigger ovulation. Other procedures were the same as the natural cycle.The primary outcomes included birth weight (including absolute birth weight), SGA [defined as weighing less than the 10th percentile of birth weight ], LGA d], and prBaseline characteristics and neonatal outcomes were compared between the study groups by t-test (for continuous variables) or chi-square test (for categoric variables). A multiple linear regression analysis was performed to assess the relationship between the blastocyst development rate and birth weight with adjustment for potential confounding factors, including maternal age (continuous variable), parity (binary variable), basal follicle-stimulating hormone , FET regimens for endometrial preparation (binary variable), fertilization method (binary variable), embryo quality (binary variable), and developmental stage (binary variable). Logistic regression analysis was performed to evaluate the effect on the incidence of LGA/SGA after adjustment for the potential confounding factors. Odds ratios (OR) and 95% confidence intervals (CI) were used. P<0.05 was considered statistically significant. All statistical analyses were performed in SPSS version 22 software.A total of 17,127 women who met the study inclusion criteria were enrolled, including 14,166 cases in the D5 group and 2,961 cases in the D6 group. To the best of our knowledge, our current study was, to date, the largest investigation on the effect of embryonic development duration before freezing at the blastocyst stage on neonatal birth weight after FET. The results of this retrospective cohort study indicate that embryonic development duration before freezing at the blastocyst stage did not affect neonatal birth weight, confirming the findings of previous small-scale retrospective studies , 17. MeaIt remains unclear whether the blastocyst development rate affects the perinatal outcomes. Several studies have found that slow-growing blastocysts with delayed expansion on D6 have no impact on clinical results after transferring good-quality embryos, suggesting that delayed blastulation is not related to viability , 19. In in vitro culture contributes to the heavier birth weight. Nevertheless, they have not reported the outcomes with adjustment for gestational age and gender , thyroid-stimulating hormone (TSH), and polycystic ovary syndrome (PCOS) might be related to neonatal birth and endometrial thickness of HCG day (the day of HCG administration day) these variables were not available or had extensive missing data (>50%), and could not be included in this study. Second, in some cycles, top-quality embryos on D3 were transferred as a priority, while the morphologically poorer embryos were placed in extended culture until the blastocyst stage. The blastocyst quality was graded before being frozen, which might bias the difference. Third, most of the neonatal outcomes were accessed by telephone interview, which might result in underestimated birth defect rates. Finally, we showed that the rate of cesarean section was higher in the D6 group compared with the D5 group, while no statistically significant differences were found in the analysis of gestational age between the two groups. Moreover, there might be other factors that were not included in this study since the database was not fully completed. Further studies should investigate the mechanisms underlying the effect of delayed blastulation on neonatal outcomes.In summary, neonatal birth weight and the proportion of LGA, SGA, macrosomia, or LBW were similar between the D5 and D6 groups. We concluded that frozen and delayed blastocysts would not affect neonatal birth weight. However, further large prospective studies should be carried out to confirm these results and the underlying mechanisms should also be investigated.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Hospital’s Ethics Committee for Reproductive Medicine. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.JY contributed significantly to analysis and wrote the manuscript. ZW performed the data analyses and manuscript preparation. HC, LL, QY and HX helped perform the analysis with constructive discussions. RT contributed to the conception of the study. All authors contributed to the article and approved the submitted version.This study was supported by the Shandong Province Medical and Health Technology Development Project (2016WS0442) and the National Key Research and Development Program of China (2017YFC10010004).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Birth asphyxia is the inability of a newborn to start and conserve breathing immediately after birth. Globally, 2.5 million infants die within their first month of life every year, contributing nearly 47% of all deaths of children. It is the third cause of neonatal deaths next to infections and preterm birth. Ethiopia is one of the countries with the highest neonatal mortality and high burden of birth asphyxia in the world. The state of birth asphyxia is about 22.52% in Ethiopia, with incidence of 18.0% in East Africa Neonatal mortality incidence ratio was 9.6 deaths per 1000 live births among which 13.5% of neonatal mortality cases were due to birth asphyxia in southern Ethiopia. The effect of birth asphyxia is not only limited to common clinical problems and death; it also has a socio-economic impact on the families. Therefore, this study is aimed to identify determinants of birth asphyxia among newborn live births in public hospitals Southern Ethiopia.p-value ≤ 0.05 along with corresponding 95% CI of AOR used to declare statistical significance. Results: Anemia during pregnancy , breech presentation , meconium stained amniotic fluid , cord prolapse , intrapartum fetal distress  and instrumental delivery  were significantly associated with birth asphyxia.An Institution based unmatched case–control study was conducted among newborn live births in public hospitals of Gamo & Gofa zones, with a total sample size of 356  from March 18 to June 18, 2021, after obtaining ethical clearance from Arba Minch University. Cases were selected consecutively and controls were selected by systematic random sampling method. Data were collected using an adapted pretested semi-structured questionnaire through face-to-face interviews and record reviews using an extraction checklist for intrapartum & neonatal-related information. The collected data were entered into Epi data version 4.4 and exported to STATA version 14 for analysis. Finally, bi-variable and multivariable logistic regression analyses were performed to identify determinants of birth asphyxia. Statistical significance was declared at The study revealed that anemia during pregnancy, breech presentation, meconium-stained amniotic fluid, cord prolapse, intrapartum fetal distress, and instrumental delivery were identified as determinants of birth asphyxia. Therefore, health professional and health institutions should give emphasis on care of mother and the newborn in actively detecting and managing asphyxia.The online version contains supplementary material available at 10.1186/s12887-022-03342-x. Birth asphyxia is the inability of a newborn to start and conserve breathing immediately after birth . It is tth minute is less than seven by the two levels, which is given a score of 0, 1, or 2 accordingly .Newborns with the breech presentations had nearly four times higher odds of birth asphyxia compared to neonates with vertex presentation .The odds of having meconium-stained amniotic fluid was about six times higher in asphyxiated neonates than non-asphyxiated neonates .Similarly, newborns with a history of cord prolapse had increased the risk of having birth asphyxia nearly five folds than those without a history of cord prolapse .Newborns delivered through instrumental delivery had six times higher odds of birth asphyxia than those delivered through spontaneous vaginal delivery .Neonates with intrapartum fetal distress had approximately ten times higher odds to have birth asphyxia when compared with neonates with normal fetal heart .The study aimed to identify determinants of birth asphyxia among newborn live births in public hospitals of the Gamo and Gofa zones. In this study maternal history of anemia, instrumental delivery, intrapartum fetal distress, meconium-stained aspiration fluid, and cord prolapse were identified as independent determinants of birth asphyxia.Neonates born from anemic mothers during the pregnancy period were nearly four times more likely to develop asphyxia compared with newborn neonates born from mothers who did not have anemia during pregnancy. This result is further confirmed by a study conducted in Dilla, Ethiopia , and JerNewborns with meconium-stained amniotic fluid were about six fold more likely to have birth asphyxia compared to those newborns with clear amniotic fluid. This finding is supported by studies obtained from Addis Ababa, Arsi, Amhara, Tigray regions of Ethiopia , 24–26, Newborns with the breech presentations had nearly four-fold higher odds of birth asphyxia compared to neonates with vertex presentation. This result is supported by other studies from different parts of Ethiopia , 30–32, Newborns delivered via instrumental vaginal delivery had six times higher odds of developing birth asphyxia than those delivered through spontaneous vaginal delivery. This finding is further confirmed by different studies , 31, 35.Neonates with history of intrapartum fetal distress had approximately ten times higher odds of birth asphyxia when compared with neonates with normal fetal heart-beat. A result is consistent with previous studies obtained from Gonder, Ethiopia , KarachiThis study also found that newborns with a history of cord prolapse had nearly five-fold higher odds of birth asphyxia compared to those without a history of cord prolapse. This finding is similar to previous study findings conducted in Wolaita Sodo . The posAPGAR score and physician confirmation were used to identify birth asphyxia.This study recognized the following limitations: Some variables were collected from records and were difficult to get a few of them, conducted at institution level only, was subjected to recalling bias, and selection biases might result because it is conducted by case–control study design.The study identified Anemia during pregnancy, instrumental delivery, intrapartum fetal distress, meconium-stained amniotic fluid, breech presentation, and cord prolapse as determinants of birth asphyxia. Thus, health professional and health institutions should give emphasis on care of mother and the newborn in actively detecting and managing birth asphyxia.Additional file 1.