P = 0⋅004; 95 % CI 2⋅1, 39⋅8), those who experienced illness , those who experienced hunger  and those with high LPI  presented increased odds of delivering preterm babies compared with those who have had secondary education, did not experience any illness, were not hungry or having low LPI, respectively. Pregnant adolescents who used insecticide-treated net (ITN)  presented reduced odds LBW children; while those who experienced illness , poorer pregnant adolescents  and those who experienced hunger  presented increased odds of LBW children compared with those who used ITN, were not ill, were not poor or did not experience hunger. Adverse birth outcomes were associated with ANC compliance and socioeconomic factors of the pregnant adolescents. Hence, strengthening antenatal uptake and compliance by pregnant adolescents, promoting their livelihood and socioeconomic status, and interventions to prevent teenage pregnancies are strongly recommended.Adolescent pregnancy is associated with adverse birth outcomes. However, the determinants of these outcomes are understudied. The present study sought to identify the predictors of adverse birth outcomes among pregnant adolescents in Ghana. In this prospective health centre-based study, 416 pregnant adolescents, aged 13–19 years old, were followed, and 270 birth outcomes were evaluated. We collected data on socio-demographic variables, eating behaviour, household hunger scale (HHS), lived poverty index (LPI) and compliance to antenatal interventions. The prevalence of low birth weight (LBW) and preterm births (PTB) were 15⋅2 and 12⋅5 %, respectively. Pregnant adolescents with no formal education (AOR 9⋅0;  Birth outcomes, including birth weight, gestational age, abortion, neonatal mortality and stillbirths, are a measure of babies’ health at birth. Of these, the two most studied indicators are birth weight and gestational age, yet their causes are not fully understood. Worldwide, low birth weight (LBW) is estimated at 15–20 % births, and 1⋅1 million babies die as a result of preterm birth complications annually. The WHO estimates that more than 9 million infants were dying within their first birthday or even before birth every year, especially in developing countries. The inequality in birth outcomes between low- and high-income countries is attributed to poor antenatal care (ANC) received by pregnant women in low-income countries. Birth outcomes are generally related to social, economic, biological and environmental factors–10.Events that occur during the first 1000 d (from conception through to 2 years) in a child's life, including birth outcomes, are significant. They contribute to the commencement of proper development and impact future health–14. A study conducted in Ghana on birth weight concluded that mothers with adequate dietary practices were less likely to have babies with LBW. Poor maternal dietary habits have been related to rural living, food insecurity and poverty. Moreover, unfavourable birth outcomes have been related to low socioeconomic status such as low education level, low income, poor access to health facilities and poor housing conditions,18. Adverse birth outcomes have also been related to maternal morbidity and insufficient maternal care–21, thus, early identification of complications of pregnancy during antenatal is vital.Maternal nutrition practices, child growth period and the intrauterine environment during pregnancy may also affect birth outcomes. According to the WHO, ANC is part of the three most important care given to pregnant women and a crucial indicator of reducing the global maternal mortality ratio as specified in target 3 of the Sustainable Development Goal (SDG). Accessing ANC services have been directly linked to better birth outcomes and a decrease in infant mortality and malnutrition among low-income and middle-income countries. ANC services are also related to socio-demographic or reproductive characteristics, and consequently birth outcomes–28. The Government of Ghana endorsed the Focused Antenatal Care (FANC) strategy of the World Health Organization (WHO) in 2002 to address the significantly higher maternal mortality rate and to increase access, quality and consistency of ANC for pregnant women. ANC is a focal point for pregnant women and their fetuses for receiving a wide variety of preventive and healthcare activities, treatment, monitoring during pregnancy up to delivery. There is late initiation of ANC attendance among pregnant adolescents as they are more likely to hide their pregnancy due to doubt and naivety, lack of finance and stigmatisation. Studies among pregnant adolescents have reported a high risk for adverse birth outcomes, such as preterm, fetal death or LBW–35. Furthermore, findings have reported an even higher risk for unfavourable birth outcomes in much younger adolescents,37. The WHO reported an estimation of 12⋅8 million births (44 births per 1000 adolescent girls) of teenage girls between 15 and 19 years in 2018, with the highest occurrence in low-income countries (8 times higher), compared with high-income countries.ANC is the basic component of maternal care on which the life of mothers and babies depend. Among these women of reproductive age, the prevalence of adolescent pregnancy was 14⋅2 %, with stillbirths, miscarriages and induced abortion recording 1⋅3, 6⋅8 and 18⋅8 %, respectively. Live births among this group were the least (73⋅1 %) as compared with the adult group (77⋅4 %), who were between 20 and 34 years. A study conducted in Kumasi, Ghana, recorded a prevalence of 19 % adverse birth outcomes while an earlier one reported a 44⋅6 % prevalence among pregnant women. Among adolescents in Kumasi, the second-largest city in Ghana, 23 % had LBW.A maternal health survey conducted in 2017 in Ghana identified 12 % miscarried pregnancies, 2 % stillbirths and 10 % induced abortions among women aged 15–49 years. Despite this, adolescent pregnancies seem to be on the rise. To prepare them for desirable birth outcomes, a better understanding of the determinants of birth outcomes in this group is required. WHO's global target for 2025 is to reduce LBW by 30 %, that is, a 3 % annually reduction. It is expedient that we identify the factors which lead to these adverse birth outcomes among this age bracket. The present study was, therefore, conducted to explore the predictors of adverse birth outcomes among pregnant adolescents in Ashanti Region, Ghana.The seventh target of the SDG 3 seeks to ensure universal access to sexual and reproductive healthcare services. To achieve this goal, the Ministry of Gender, Children and Social Protection in Ghana developed a five-year strategic plan (2018–22). The plan seeks to reach adolescents with the correct information and insight and to provide them with training and services to protect them from early and unintended pregnanciesIn this prospective health centre-based study, 416 pregnant adolescents (aged 13–19 years old) with a maximum of 32 gestational weeks were recruited from May to December 2018 and followed until they gave birth between January and July 2019.. The prevalence of adolescent pregnancy in the region is 12⋅2 %, according to a recent survey conducted in 2017. We recruited participants from health centres serving communities in three urban districts  and five rural districts  in Ashanti Region, Ghana. We recurited participants at selected Community-based Health Planning Services (CHPS) compounds, health centres and hospitals in the selected districts.Ashanti Region, the most populated region in Ghana, makes up 19 % of Ghana's total population, which is about 5 792 187 people: n =  2(Z α/2  +  Z β )2 p(1 − p)/(P1 − P2)2. Where n is the sample size, Z α/2 = 1⋅96 at type 1 error of 5 %, Z β = 0⋅84 at 80 % power, P1 is the LBW in pregnant adolescents with adequate nutritional status, P2 is the LBW in pregnant adolescents with poor nutritional status, P1 − P2 is the difference in the prevalence of LBW between pregnant adolescents with adequate nutritional status at birth and those with inadequate nutritional status, and P is pooled prevalence = (P1 + P2)/2. Based on a previous pilot study by Ayensu et al., which reported 23 % LBW prevalence, we proposed that LBW in pregnant adolescents with adequate nutritional status would be 11⋅4 %, while those with poor nutritional status would remain 23 %. Using the above descriptives, the sample size n = 2(1⋅96 + 0⋅84)2 × 0⋅1735(1–0⋅233)/(0⋅114–0⋅233)2, n = 2⋅09/0⋅01, n = 209 was calculated, which implied we needed to recruit 209 participants in each arm of the study  making 418 participants to show a significant association between poor nutrition and LBW. We added 10 % attrition to give 460 participants who were needed.The sample size was statistically calculated using the sample size-based proportion formula byHowever, 416 pregnant adolescents were recruited on a first-come, first-served basis for the baseline study. Trained enumerators visited hospitals/health centres selected for the study on antenatal clinic days for pregnant adolescents. All pregnant adolescents within the inclusion criteria who gave written consents were written. In the rural areas, announcements were made at the community information centres to invite participants to the health centres on specific days. These announcements were necessary as some pregnant adolescents refused to visit the health centres for ANC to fear being stigmatised. We trained enumerators in a two-day workshop on each data collection tool used. We obtained birth outcome data from 270 (birth weight) and 303  participants out of the 416 recruited during the baseline study as some participants were lost to follow-up.Ethical approval for the study was obtained from the Committee on Human Research Publication and Ethics (CHRPE) of the Kwame Nkrumah University of Science and Technology, KNUST,  (CHPRE/AP/236/18). Study protocols/aims were first explained to all participants in their local language. Written and signed informed consent was obtained from all participants by following CHRPE regulations before recruiting for the study.A structured questionnaire was used to collect data on the socio-demographic variables, dietary diversity, eating behaviours , food deprivation , availability of necessities (lived poverty index – LPI), antenatal interventions compliance , maternal factors  and birth outcomes  of the pregnant adolescents. Data on age and parity were verified from their National Health Insurance Identification cards and maternal health record book. The questionnaire was pretested at selected health centres and validated to ensure appropriate responses from participants. Birth weight and gestational age were the dependent variables.A previous day's 24-h dietary recall method was used to assess dietary diversity among the participants. The FAO's Minimum Dietary Diversity for Women (MDD-W), was used to determine maternal dietary diversity using ten food groups. The MDD-W score obtained was then used to identify whether maternal dietary diversity was adequate (5–10 food groups) or not (0–4 food groups).Questions on whether or not the participants were practising food cravings, pica and food aversions were asked. Each question had a yes/no optional response. to assess hunger (HHS) among participants. The responses to these questions were then coded and scored. Scores between <2 meant little or no hunger, 2–3 meant moderate hunger and 4–6 meant severe hunger. LPI was assessed by asking questions on the availability of food, water, cash income, medical care and cooking fuel over the past year. The responses were coded and scored. A score of 0 meant no lived poverty, while the scores of 1–4 meant the absence of one or more necessities. The averages of the scores were then categorised into low (0–1⋅0), moderate (1⋅01–1⋅5) and high (>1⋅5) LPI.We collected data on food availability and deprivation over the past month using standardised close-ended questionnairesA structured questionnaire was administered to participants to identify their compliance with the antenatal interventions given at their various health facilities. Participants were asked if they received nutrition education, tetanus injection, micronutrient supplements, malaria tablet, ITN, consumed daily micronutrient supplement, and whether they used the ITN given.. Preterm birth was defined as delivery less than 37 completed weeks of gestation. Questions on mode of delivery  and morbidity during pregnancy were asked.Follow-up data on several birth outcomes, including birth weight and gestational age at birth were obtained from their maternal health record books and were categorised as normal or adverse. LBW was defined as a birth weight of less than 2⋅5 kgχ2 (Fischer's exact test) and cross-tabulation to compare frequencies of all variables used  among community types. Frequencies of birth weight and gestational age were compared among socio-demographic variables, dietary diversity, eating behaviours, LPI, HHS, antenatal interventions compliance and maternal factors using Fischer's exact test. We used logistic regression to identify predictors of birth outcomes. We presented the data as frequency (%) and P values < 0⋅05 were considered significant.Microsoft Excel was used to clean the entered data, and Statistical Package for Social Sciences version 25  was used to analyse them. We performed . Effects of socio-demographic status on birth outcomes are presented in P = 0⋅006). Generally, preterm births (PTBs) decreased with increasing education level . PTBs showed slightly different trends by socio-demographic status. Older adolescents (16–19 years) recorded more PTBs (13⋅1 %) than adolescents in the younger bracket (5 %). Similarly, more PTB's were recorded among adolescents who were married (19⋅4 %) and employed (16⋅9 %) than among those who were single (13⋅8 %) and unemployed (10⋅9 %). LBWs were proportionally higher among adolescents who were younger than their older counterparts (22⋅2 % v. 14⋅8 %), married than single (19⋅4 % v. 13⋅8 %), employed than unemployed (16⋅9 % v. 15⋅6 %) and among those with high-income range than those without income (33⋅3 % v. 13⋅6 %).The distribution of socio-demographic characteristics of pregnant adolescents and among community types used for the present study has been presented in another studyP = 0⋅022), tetanus injection (P = 0⋅021), used insecticide-treated nets (P = 0⋅026) and mode of delivery (P = 0⋅009) varied significantly between rural and urban study participants. Generally, about half of pregnant adolescents (49⋅5 %) received nutrition education during antenatal services. Nearly 12 % more of pregnant adolescents from urban areas received nutrition education than their rural counterparts (P = 0⋅022). About 60⋅6 % received micronutrient supplements while only 46 % were taking their supplements daily. Four out of ten pregnant girls had not received tetanus injection. However, a more significant proportion of urban girls (P = 0⋅021) had received tetanus injection. About four to five out of ten had not received malaria tablets or insecticide-treated net (ITN). About 17 % of pregnant girls who had received the ITN were not using them. The use of ITN among rural girls was significantly higher (P = 0⋅026) than those in urban areas. Though not significant, LBW was higher among deliveries by rural girls (18⋅8 %) than girls (13⋅4 %). Also, preterm births proportion was higher among urban girls (13⋅1 %) than rural (11⋅9 %). About eight in ten pregnant girls delivered their babies using the vaginal method. Significantly, more rural girls (P = 0⋅009) than urban girls delivered through the vaginal method.P = 0⋅024). Also, PTBs were over twice more among those reporting ill (24⋅1 %) than those who reported no illness . LBW was significantly lower among participants who used ITNs  as compared with those who did not (19 %). Also, LBW was slightly lower among adolescents who received nutrition education but higher among those who took micronutrient supplements, and malaria tablets, tetanus injection, than their counterparts who did not though these did not reach a statistical significance. Though not significant, participants who delivered through caesarean section (20⋅7 %) gave birth to a greater proportion of babies with LBW as compared with those who gave birth through the vaginal delivery method (15⋅8 %).P = 0⋅006) and PTB (P = 0⋅028), whereby adolescent girls who suffered hunger had a larger proportion of LBW  and PTB . Likewise, poorer pregnant adolescent had significantly more LBW (P = 0⋅029) and PTB (P = 0⋅006). Although not statistically significant, LBW was lower among those with adequate MDD (11⋅4 %) as compared with those with inadequate MDD (17⋅9 %), while PTB was rather lower among those with inadequate MDD (11⋅6 %) than those whose MDD were adequate (13⋅7 %). Similarly, those who practiced PICA had more LBWs (16⋅2 %) and less PTBs (10⋅7 %) than those who did not .P = 0⋅013; 95 % CI 0⋅2, 0⋅9) of giving birth to babies with LBW compared with those who did not use them. Those who were poorer, using LPI presented increased odds  of delivering LBW babies than those with low LPI. Also, pregnant adolescents who were moderately hungry had a higher risk of delivering LBW babies  compared with those who were not hungry. Maternal morbidity increased odds  of babies with LBW as compared with those who did not experience any sickness.P = 0⋅004; 95 % CI 2⋅1, 39⋅8) of having PTB compared with those with formal education. Adolescents who suffered hunger had increased odds  for PTB, compared with those who were not hungry. Poorer pregnant adolescents presented increased odds  of delivering preterm babies than those who were not poor. Experiencing maternal morbidity increased the odds  of having PTB as compared with those who did not experience any form of morbidity.. Our population of adolescents is, therefore, similar to the national average with regards to LBW and lower for PTB. Compared with other studies around the world, our findings regarding LBW and PTB were higher,50 but lower from other results,52. Within Ghana, a study in Cape Coast reported a similar LBW prevalence of 14⋅3 % among pregnant adolescents.The present study identified predictors of adverse birth outcomes among pregnant adolescents in Ghana. The findings indicated that the use of ITN, maternal education status, hunger (HHS), poverty (LPI) and maternal morbidity were the main determinants of adverse birth outcomes (LBW and PTB) among pregnant adolescents in Ghana. The prevalence of LBW and PTB reported in the present study was 15⋅2 and 12⋅5 %, respectively. Similarly, the LBW prevalence for Western Africa and Ghana reported in 2019 were 15⋅2 and 14⋅2 %, respectively. Compared with their adult counterparts, pregnant adolescents are likely to access ANC services later during pregnancy,54. Among all the ANC interventions and compliance assessed, adolescent girls from the urban areas were better off than their rural counterparts. More urban pregnant adolescents received nutrition education (0⋅022), tetanus injection (0⋅021) and had access to ITNs  compared with their rural folks. Tanya and Goldenberg identified the inability to pay for services, lack of transport and prior negative experiences as barriers to healthcare services among rural women. For the present study, we think low socioeconomic status and less access to health care in rural areas are possible reasons for the lower uptake of interventions by rural girls.Generally, access to ANC interventions among pregnant adolescents used in the study was relatively low. For example, less than half (49⋅5 %) of the participants reported having received nutrition education at ANC. The uptake of the interventions by adolescents was also low. Four in ten participants did not take their micronutrient supplements, nor used the ITNs, and a few took their malaria tablets (40⋅4 %). The low compliance may negate the benefits of attending ANC, as the mere attendance to ANC sessions is not the fundamental objective. This calls for programmes, including pregnant women's education in general, on the benefits of complying with these interventions. The low compliance may also be due to the fewer number of ANC sessions attended. Pregnant adolescents are likely to delay pregnancy disclosure due to uncertainty and vulnerability, especially during the first trimester, lack of funds and stigmatisation. Since 2000, mass and continuous distribution networks have substantially increased access to ITNs in Ghana. Notwithstanding these achievements, a significant gap exists between ITN access and usage. In our study, 58 % of the pregnant adolescents reported having received ITN, while 41 % were using them. Low use of ITN has been reported and associated with discomfort from the smell of chemical used, heat and difficulty installing the net. Younger women (under 19 years of age) and women with less education or less hurdles to ITN usage include low awareness of ITNs by women, household or cultural constraints such as low social status or economic dependence, age, marital status, education, employment status, knowledge of malaria/ITN and IPTp reception. However, our study reported a 10 % less LBW deliveries in ITN non-users than among ITN users . This disparity may be related to the possibility that despite these adolescents receiving antenatal interventions, they were at a higher risk of other relating factors such as maternal underweight, hunger, poverty directly associated with LBW compared with those who did not receive antenatal interventions, and these factors may have confounding effects on their birth outcomes rather than the antenatal interventions.The consistent and appropriate use of ITN has been one of the efficient means in preventing malaria infection by limiting the contact and bite of mosquitoesPlasmodium falciparum infection during pregnancy is a prominent cause of LBW. In our findings, the use of ITN was significantly associated with LBW; those who used the ITN presented reduced odds of delivering babies with LBW. Similar to this result, other studies–61 have reported the association of ITN use with birth outcomes. For instance, a significant reduction in the risk of LBW in healthy malaria transmission regions has been associated with the use of antimalarial intermittent pregnancy prevention (IPTp) and ITN during pregnancy. A higher reduction rate of LBW (23 %) and fetal loss (33 %) with the use of ITN has also been reported among women of low gravidity in Africa. Kubi Appiah and others also reported increased odds of normal birth weight deliveries  to be associated with women who received a long-lasting ITN from ANC clinics., and in two meta-analysis,64. We understand the correlation between maternal education and maternofetal outcomes by the more likely disposition of women of higher education having a greater understanding of prenatal care, early initiation of prenatal care, more ANC consultations as prescribed and higher socioeconomic status,65. Contrary to our findings, maternal education among Mexican American had little effect on birth outcomes. They observed that the Mexican American presented the least infant mortality rate as compared with the other populations used.The study predicted that among all socio-demographic factors used, the education status of the mother was significantly associated with PTB. Among pregnant adolescents who had no formal education, 40 % delivered PTB babies. This suggests that maternal education level affects birth outcomes. Access to education can expose an individual to information healthier lifestyles during pregnancy, preventing adverse effects. Similar results of low maternal education level associated with adverse birth outcomes were reported in Quebec, Canada. During pregnancy, the intake of adequate dietary diversity diet offers the required micronutrients that are important for the growth and development of the fetus. However, our findings did not present a significant relationship between dietary diversity and adverse birth outcomes though a greater proportion of LBW babies were found among adolescents with inadequate dietary diversity as compared with those with adequate dietary diversity. Contrary to our findings, Quansah and Boateng found inadequate dietary diversity to be associated with higher odds of LBW babies. Maternal nutritional status can have an impact on fetal development. The proper growth and development of the fetus requires the consumption of food items from the various food groups in order to prevent deficiencies of essential micronutrients. Thus, adequate dietary intake is critical in preventing adverse birth outcomes. In developing countries, poor nutritional status is a determining factor of LBW due to low nutrient flow to the developing fetus. Experiencing hunger during pregnancy can be devastating and can be subsequently linked to poor nutritional status as the pregnancy period requires a significant increase in macronutrients and adequate micronutrients. According to a study on fetal response to satiation and hunger, 74 % of pregnant women experienced an increase in fetal activity when they were hungry. The paper further stated that women with increased fetal activity gave birth to smaller babies. Studies have related poverty to adverse birth outcomes such as LBW, PTB and fetal loss,70. Tanya further asserted that the poor might have less access to healthcare systems and maternal care during emergencies. A high risk of malnutrition and subsequent adverse effect on babies leading to nutritional and developmental deficiencies have also been related to poverty.Hunger and poverty presented significant associations with adverse birth outcomes. Hunger led to an increased likelihood of having adverse birth outcomes in the present study. Pregnant adolescents who experienced hunger and were poorer using HHS and LPI, respectively, presented significantly higher odds of giving birth to LBW and preterm babies than those who did not experience any hunger or deprivation. The possible reason for more adverse birth outcomes among pregnant adolescents who experienced poverty and hunger is inadequate maternal dietary intake and low nutritional quality diet, as these have been related to adverse birth outcomes, maternal malnourishment and insufficient maternal care are high risks for the development of diseases and death during delivery. This is expected since maternal illness can affect fetal growth and development. Some of the conditions that these pregnant adolescents went through during pregnancy were pregnancy induced hypertension, antepartum haemorrhage and prolonged labour. These findings seem to be consistent with earlier research which reported that participants who experienced morbidity had about five to seven times increased risk of adverse birth outcomes,72,73.Maternal morbidity was significantly associated with birth outcomes in the present study. The odds of having LBW and PTB among those who got ill during pregnancy were thrice more than those who did not experience any illness. This implies that the health of the mother can be a contributory factor to birth outcomes. According to Tinker, but contrary to other studies in Ghana,75,76, which reported a higher prevalence of LBW among urban than rural participants. A higher prevalence of LBW is expected in rural areas due to poorer socioeconomic conditions, food insecurity, low nutrition knowledge and limited access to health care–79. In the present study, the prevalence of caesarean delivery, 11⋅8 %, was similar to studies conducted in Ghana but lower than two studies conducted in Bangladesh and Pakistan, which recorded 23⋅9 and 26⋅4 %, respectively. A greater proportion of caesarean deliveries in this study (16⋅4 %) were from the urban centres. This may seem to be due to urbanisation and access to qualified personnel to carry out the section. Hasan also presented similar findings where the rate of caesarean deliveries was relatively high in urban women than in rural women. Caesarean sections are less accessible among poor or low-income countries. Generally, about 21 % of those who delivered through caesarean section gave birth to LBW babies. Literature suggests that caesarean sections are usually performed as emergencies without adequate preparations and can lead to a challenge in the newborn's proper initial development.Generally, the effect of geographical location, environmental conditions, socio-cultural practices, eating behaviour and maternal factors on birth outcomes have been mixed. For instance, in the present study, LBW was more prevalent among rural girls (17 %) than the urban participants (13⋅7 %), similar to a study conducted in Malaysia–86. Furthermore, poor socioeconomic status and its consequences, such as less access to health facilities and low levels of education have been associated with adverse birth outcomes,88. Moreover low birth weight have been associated with pregnant women with chronic anaemia, diabetes and hypertension,89.The overall nutritional status such as weight gain, health, parity, previous birth outcomes and biochemical status of the mother during pregnancy may affect birth outcomes. Some studies have presented an increased odds of obstetric, placental and medical complications with increasing parityIn summary, this study explored the predictors of adverse birth outcomes among pregnant adolescents, and among many factors found that hunger, poverty and lack of formal education predicted preterm births. Pregnant girls with no formal education had nine times increased odds for PTB compared with those with at least secondary education. Girls with high LPI had two and a half increased odds for PTB compared with those with no poverty, and those who experienced moderate hunger were about two and a half times increased odds for PTB compared with those with no hunger. Finally, those who were ill during pregnancy were thrice increased odds for PTB compared those who were not ill. For LBW, the significant predictors were similarly hunger, poverty and maternal morbity. The levels of the odds recorded for the predictors of LBW were simlar to that of the PTB. On the other hand, the use of ITN reduced the odds for LBW deliveries by about 60%.The study had a significant dropout as less than 75 % of baseline participants were followed up for the birth outcomes study. Future studies should be designed to reduce this, either by increasing the sample size or improve measures for tracking participants.The risk of adverse birth outcomes observed among the pregnant adolescents were associated with ANC compliance and maternal socioeconomic factors. Strengthening antenatal services, promoting girl education, livelihood support for pregnant girls, and interventions to improve socio-economic status and to address hunger and poverty are broad and targeted interventions to both reduce the incidence of adolescent pregnancies, and reduce the risk for adverse birth outcomes among those who still become pregnant. Focused care to encourage attendance to ANC and improve compliance to ANC interventions by pregnant adolescents is strongly recommended. Food security and hunger should be evaluated during antenatal services to identify and address the vulnerable.


Symptomatic congenital biliary dilatation (CBD) during early infancy is always characterized by cystic dilation of the common bile duct with a narrow segment connecting the pancreatic duct.In two consecutive infants with a prenatal diagnosis of CBD, we found that biliary sludge had formed in the cyst upon the appearance of symptoms including acholic stool and hypertransaminasemia. Infrared absorption spectrometry revealed that the sludge consisted of calcium bilirubinate.We suggest that overproduction of bilirubin by neonatal hemolysis causes sedimentation of bilirubin calcium, resulting in obstruction of the narrow segment and development of symptoms. Congenital biliary dilatation (CBD), also known as a choledochal cyst, is a malformation characterized by a dilated common bile duct and pancreaticobiliary maljunction . ChildreAt 27 weeks’ gestation, ultrasonography revealed a cyst in the abdomen. A female neonate was born at 40 weeks’ gestation. A huge choledochal cyst was confirmed by ultrasound and magnetic resonance cholangiopancreatography. The neonate was asymptomatic until she developed acholic stool at 37 days of age. At 45 days, ultrasonography revealed debris in the cyst Fig. b, and laAt 29 weeks’ gestation, ultrasonography revealed a cyst in the abdomen. A female neonate was born at 40 weeks’ gestation. A 3-cm-diameter choledochal cyst was confirmed by ultrasound. The neonate was asymptomatic, and her serum transaminase levels were not elevated . The total bilirubin and direct bilirubin levels in the bile were respectively 14.50 mg/dl and 12.27 mg/dl.Symptomatic CBD during early infancy is inevitably of the cystic-dilated type and is accompanied by a narrow segment distal to the cyst , 6. The The occurrence of obstruction depends on the amount of debris and caliber of the narrow segment. Our first patient had a relatively large caliber of the narrow segment but had a large amount of bile sludge, resulting in obstructive symptoms including elevated transaminase levels. However, incomplete obstruction did not cause complete obstructive jaundice Fig. . The secWe perform operation for prenatally diagnosed CBD soon after the symptoms and signs of the biliary obstruction occur, which were the elevated levels of transaminase and gamma-glutamyl transpeptidase in Case 1 and acholic stool in Case 2. We wait operation unless obstructive symptoms, because congenital biliary stenoses around the hepatic hilum are more easily treated in older infants. Leaving the stenoses causes later hepatolithiasis .


Supratentorial arachnoid cysts are usually asymptomatic and may be discovered by chance at autopsy; however, infratentorial arachnoid cysts, which correspond to liquid forms enclosed by an arachnoid sheet but whose pathogenesis is unknown, might cause symptoms. They don't need to be treated if they're asymptomatic and were discovered by chance. A variety of neurological symptoms can be present depending on their localization. Intracranial dermoid cysts are uncommon tumours that develop from ectopic epithelial cells in the brain. They are benign, slow-growing, and rarely rupture. The association between the two diseases is extremely rare and when it is present may suggest the existence of a common factor. We present a unique case of a young girl who developed headache and ataxia as a result of an intracranial infratentorial dermoid cyst and an arachnoid cyst of the cerebellopontine angle. Complete removal of the dermoid cyst and drainage of the cyst leads to a full recovery. Dermoid and arachnoid cyst are two pathologies with a possible common embryogenic factor, early surgery can give a better outcome in the long term. In 1855, Quain presented the first description of a supratentorial cerebral arachnoid cyst. Arachnoid cysts in the posterior fossa were first reported by Maunsell in 1889. Under the term “chronic cystic arachnoiditis”. Craig attributed the clinical picture to an inflammatory reaction of the leptomeninges. Many hypotheses offered to explain the development of these cysts have included congenital malformation, infection and trauma. Arachnoid cysts have been reported in connection with tumours in the posterior fossa, and are thought to be caused by a transudate .Dermoid cysts are a rare benign tumour of the central nervous system and accounts for 0.1 to 0.7% of all intracranial processes. It is formed by a thick wall, lined by a keratinizing squamous epithelium and its content is composed of dermal elements, hair, teeth and sebaceous glands. It is a congenital tumour due to a developmental abnormality between the third and fifth week of embryonic life, its clinical manifestation is mainly in young adolescents . The assPatient information: we report a case of a 3-year-old child, born of a completed pregnancy, fourth of four children, she has been suffering from mild intensity headache for the past 6 months treated by simple analgesics.Clinical and radiological findings: our patient has been admitted to A&E for headache, nausea, vomiting and loss of consciousness. On examination, she had a GCS 12, slight macrocrania, static cerebellar syndrome makes of an eccentric gait. Computed tomography (CT) scan visualized two cystic formations of the posterior cerebral fossa with active tri-ventricular hydrocephalus  was performed later on and has confirmed the arachnoid cyst of the cerebellopontine angle (CPA) and vermian dermoid cyst which compress the brainstem anteriorly , fenestration of the wall (endoscopy and microscopy), and cysto-peritoneal and cysto-subdural shunts . The preThe therapeutic strategy used in this patient included ventriculoperitoneal bypass as the first step, dermal cyst surgery as the second, and arachnoid cyst surgery as the third step. The unconscious state due to active hydrocephalus justified the emergency ventriculoperitoneal bypass, the static cerebellar syndrome due to the dermoid cyst justified the scheduling of a cyst surgery in the second place, and the second appearance of a lateral deviation of the eyes, after the two previous surgeries, due to arachnoid cyst compression of the brainstem, justified the scheduling of a cyst surgery in the third place. This therapeutic timeline was based on clinical manifestations when the arachnoid cyst was bigger and compressing the brainstem radiographically. Wasn't it more prudent to begin with the treatment of the arachnoid cyst, which, due to its size and compression of the brainstem, posed a serious risk, notwithstanding the dermoid cyst's clinical manifestation of a simple eccentric gait?The arachnidian cyst, like the dermoid cyst, is a rare pathology, and the relationship between these two cystic structures at the level of the posterior cerebral fossa is particularly exceptional. The proximity of these two lesions raises the idea of a similar factor causing embryonic development issues, both at the level of the neural tube, where the dermoid cyst forms, and at the level of the sub-arachnidian region, where the arachnoidian cyst forms.


Details of the farrowing process were recorded, and umbilical cord blood was collected from piglets at birth and evaluated on an iSTAT machine using an Abbott EC8+ test cartridge. There were no differences in total born, number born alive, stillborns, mummies, or assistance needed during farrowing. Induced sows were more likely to farrow by day 115 compared to naturally farrowing sows (P = 0.02). Sows in the OXY24 treatment tended to have longer farrowings when compared to both NO and OXY6 . Colostrum from OXY6 sows tended to have a greater amount of lactose present than NO and OXY24 (P = 0.05). Colostrum from sows with longer gestation lengths had a higher percentage of fat (P = 0.03). Piglets born from NO sows had higher base excess, total carbon dioxide, and glucose, which suggests that these piglets had prolonged moments of asphyxiation (P < 0.01). OXY24 piglets had the lowest blood pH which is indicative of hypoxic birthing conditions (P < 0.01). Preweaning mortality was driven largely by a low birth weight coupled with low colostrum intake (P = 0.03). All piglets, regardless of treatment, displayed signs of stress during farrowing. Induction did not influence preweaning mortality but has the potential to decrease the incidence by increasing attended farrowings.Historically, sows have been induced to farrow using prostaglandin followed by an injection of oxytocin 24 h later. Benefits of induction can include decreased rate of stillbirths, dystocia, and postnatal mortality along with increasing the likelihood of farrowings being attended. Several studies have indicated that oxytocin administration may negatively impact fetal oxygen supply during parturition, potentially from umbilical cords breaking prior to birth, resulting in increased preweaning mortality. Therefore, the objective of this study was to determine if various induction protocols impact umbilical cord breakage and fetal blood parameters at birth. Fifty-eight primiparous and multiparous sows were assigned to one of three treatments: no induction (NO;  Genetic selection for highly prolific sows and increased total born has consequently resulted in longer farrowing duration and higher occurrences of low birth weight piglets, which negatively impacts preweaning survival through decreased colostrum intake . Longer One common farrowing induction method is to administer prostaglandin followed by an injection of oxytocin 24 h later. Benefits of induction with prostaglandin and oxytocin include decreased rate of stillbirths, dystocia, decreased farrowing duration, and postnatal mortality along with the possibility of increasing the chance of farrowings being attended . A greatn = 24), 2 cc prostaglandin  administered on day 114 of gestation followed by 1 cc of oxytocin 24 h later , or 2 cc prostaglandin administered on day 114 of gestation followed by 0.5 cc of oxytocin at 6 and 12 h after prostaglandin . Administration of prostaglandin was performed at 1000 h intramuscularly in the neck of each sow using an 18-gauge, 40-mm needle. Oxytocin was administered subcutaneously in the crease between the vulva and ham using a 20-gauge, 12-mm needle. Data collected included induction-to-farrowing interval, farrowing duration, farrowing assistance, time of birth for each piglet, umbilical cord breakage, number of piglets born alive, stillborns, mummies, and whether feed was present in the feeder at farrowing. Umbilical cords were classified as broken if the piglet’s cord was no longer attached to the mother at birth.All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee (PACUC #1902001856). Confirmed pregnant sows were moved into farrowing crates on day 112 of gestation at the Animal Sciences Research and Education swine facility at Purdue University. On day 114 of gestation, 58 sows were blocked by parity  and assigned one of three treatments: no induction . Fat percentage was calculated as the ratio between fat length and total sample length, multiplied by 100. Protein concentration was determined by diluting homogenized colostrum with phosphate buffered saline (1:100). Ten microliters of colostrum were mixed with 250 uL of Bradford reagent . Color development in samples and standard curve  was measured with a spectrophotometer . Lactose was extracted from 200 µL of skimmed colostrum by adding 800 µL acetonitrile. Extracts were centrifuged at 3,220 × g at room temperature for 10 min to remove precipitated proteins. Before injecting samples, they were diluted 1:5 with acetonitrile and spiked with 1,000 ng of D-lactose-13C . Liquid chromatography was performed using Intrada Amino Acid 3 μm, 2 × 150 mm column  connected to an Agilent 6470 QQQ LC-MS/MS system . Acetonitrile with 0.3% of formic acid and acetonitrile with 100 mM ammonium formate solution (20:80 v/v) were used as mobile phases.Within 12 h of the birth of the first piglet, a 50-mL colostrum sample was collected by milking the front, middle, and back teats and stored in −80 ºC until further analysis for total fat, protein, and lactose. Prior to analysis, all samples were thawed at 4 °C overnight in a continuous rotator in order to homogenize samples. Fat percentage was measured in triplicate by loading samples in a nonheparinized capillary tube, which were centrifuged at 12,000 × Plus blood glucose monitor  and the HemoCue Hb 201+ Hemoglobin Analyzer . The end of farrowing was characterized by placental membranes expelled from the sow. Sows were provided manual assistance if the birthing interval between piglets exceeded 30 min. All farrowings were attended 24 h a day until all sows farrowed.Blood samples were collected from the ear veins of sows at the time of the birth of the first and sixth piglets and the end of farrowing and evaluated for glucose (Glu) and hemoglobin (Hgb) levels using an AimStrip n = 118; OXY, n = 105; OXY6, n = 79), the umbilical cord blood was collected and immediately placed in a Microtainer Lithium Heparin/PST Gel 600-uL tube  and inverted to prevent clotting. Blood samples were analyzed with the iSTAT portable clinical analyzer using the EC8+ cartridge  for sodium (Na), potassium (K), ionized calcium (iCa), Glu, Hematocrit (Hct), Hgb, pH, partial pressure of carbon dioxide (pCO2), partial pressure of oxygen (pO2), base excess (BE), bicarbonate (HCO3), total carbon dioxide (tCO2), and oxygen saturation (sO2). Piglets were dried using bath towels and allowed to nurse normally. Piglets were weighed at birth and 24 h after to calculate colostrum intake using the equation previously described  with treatment and parity as main effects. Binomial variables were analyzed using the GLIMMIX procedure. Sow blood Glu and Hgb were evaluated using the MIXED procedure for repeated measures with treatment and parity as fixed effects and whether the sow ate prior to farrowing as a covariate in the model. The MIXED procedure of SAS 9.4 was also used to evaluate piglet blood parameters using treatment, parity, and birth order as main effects and sow as a random effect. Birth order classes were created to evaluate birth order as a main effect: birth order class 1 (piglets 1–5); birth order class 2 (piglets 6–10); birth order class 3 (piglets born after the 10th piglet). Parity classes were also created as follows: parity class 1 (gilts and parity 1) and parity class 2 (parity 2+). For colostrum quality analysis, the MIXED procedure of SAS was used with treatment as a fixed effect and gestation length as a covariate. A Tukey’s means comparison was used to determine differences among means for piglet data and colostrum quality. Significance was defined as P = 0.096). Interestingly, sows that were parity 2+ required more assistance than parities 0–1 . Although treatment did not have an effect on the percentage of sows who farrowed during the work day or within 36 h of induction, sows were more likely to farrow by day 115 who were induced compared to naturally farrowing sows .Sow blood Hgb remained constant throughout farrowing regardless of treatment . YoungerP < 0.001) with survivability increasing with higher birth weights and colostrum intake (P = 0.363) and consumed about 15 g less of colostrum on average (P = 0.208). Average daily gain from birth to weaning was influenced by colostrum intake and birth weight where lighter pigs consumed less colostrum and, therefore, gained less (P < 0.001). It was also observed that animals who died prior to weaning lost weight on average compared to piglets that survived . Induction did not influence fat or protein content in colostrum, but OXY6 tended to have a greater amount of lactose present when compared to NO and OXY24 . Piglets born from greater parity sows who farrowed naturally had higher BE, tCO2, pCO2, and Glu  and Hgb are correlated  and posiSodium, potassium, and calcium are all integral in the pathway associated with hypoxic events . In ordeDespite these few alterations in piglet blood indicators of hypoxic events, piglet ADG and survivability to weaning was not affected by farrowing induction. Similar to many other research trials, preweaning survival was driven by birth weight and colostrum intake .Although treatment did not influence preweaning mortality or colostrum intake, it is interesting to note that the percentage of lactose was higher in colostrum from OXY6 sows, which indicates that the secretory activation in the mammary gland was happening sooner than the other treatments. Similar increase of lactose in colostrum was found in sows induced with alphaprostol . In thatIn conclusion, induction does not negatively impact the farrowing process or fetal blood oxygen at birth. Birth weight and colostrum intake were the main drivers of preweaning mortality in this study with ADG from birth to weaning being higher in animals who survived. Although birth order did not impact preweaning mortality or colostrum intake, piglets born later in the litter did show signs of asphyxia, which may impact overall lifetime growth and development of the animal. Both induction protocols and natural farrowings showed at least some signs of asphyxia, but it did not increase preweaning mortality or ADG after birth. Therefore, induction can be used to encourage sows to farrow by day 115 of gestation without negatively impacting piglets.


Low birth weight (LBW) and fetal growth restriction are associated with the development of cardio-metabolic diseases later in life. A recent Mendelian randomization study concluded that the susceptibility of LBW infants to develop hypertension during adulthood is due to the inheritance of hypertension genes from the mother and not to an unfavorable intrauterine environment. Therein, a negative linear association has been assumed between genetically estimated maternal blood pressure (BP) and birth weight, while the observed relationship between maternal BP and birth weight is substantially different from that assumption. As many hypertension genes are likely involved in vasculature development and function, we hypothesized that BP-increasing genetic variants could affect birth weight by reducing the growth of the placenta, a highly vascular organ, without overtly elevating the maternal BP.Using a birth cohort in the Japanese population possessing time-series fetal growth velocity data as a target and a GWAS summary statistics of BioBank Japan as a base data, we performed polygenic score (PGS) analyses for systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure. A causal mediation analysis was performed to assess the meditation effect of placental weight on birth weight reduced by maternal BP-increasing PGS. Maternal genetic risk score constituted of only “vasculature-related” BP single nucleotide polymorphisms (SNPs) was constructed to examine the involvement of vascular genes in the mediation effect of placental weight. We identified gestational week in which maternal SBP-increasing PGS significantly decreased fetal growth velocity.We observed that maternal SBP-increasing PGS was negatively associated with offspring birth weight. A causal mediation analysis revealed that a large proportion of the total maternal PGS effect on birth weight was mediated by placental weight. The placental mediation effect was remarkable when genetic risk score was constituted of “vasculature-related” BP SNPs. The inverse association between maternal SBP PGS and fetal growth velocity only became apparent in late gestation.Our study suggests that maternal hypertension genes are strongly associated with placental growth and that fetal growth inhibition is induced through the intrauterine environment established by the placenta.The online version contains supplementary material available at 10.1186/s12916-021-02131-0. The increasing prevalence of cardio-metabolic diseases leading to premature death is a raising concern . AlthougRecent MR studies have reported that maternal systolic blood pressure (SBP)-increasing polygenic score (PGS) causes lower birth weight through elevated maternal SBP, independently of direct fetal genetic effects , 10. HowFGR pathophysiology and etiology are complex, but most cases are thought to arise from placental dysfunction , 11. GenSince the mediating role of the placenta was never been examined, we investigated whether maternal SBP-increasing PGS is inversely associated with placental weight and whether the placental weight mediates the effect of maternal SBP PGS on birth weight. Furthermore, by constructing a genetic BP-increasing risk score composed exclusively of vasculature-related SNPs, we aimed to clarify that the role of placental weight in the effects of vasculature-related BP SNPs on birth weight. We also aimed to confirm by haplotype analysis that maternal transmitted and non-transmitted BP-increasing alleles, but not paternal transmitted alleles, are inversely associated with birth and placental weight. Lowering of birth weight can be caused by deceleration of fetal growth velocity during pregnancy. Motivated to understand the indirect effect of maternal SBP PGS on fetal growth velocity, reflecting the fact that placental growth precedes fetal growth, we aimed to determine that maternal SBP PGS significantly decreases fetal growth velocity at the very end of pregnancy. Thus, our study uncovered that maternal genetic risk of hypertension inhibits fetal growth through the intrauterine environment established by the placenta.The characteristics of the two cohorts analyzed in this study are presented in Additional file n = 126). All the participants provided written informed consent. Parents/guardians provided consent for their children to participate. Ninety-three mother-child pairs of Japanese ancestry, whose genotype information were available, were included in this study. There was neither HDP nor chronic hypertension.Clinical information and genotype data were obtained from the Birth Cohort Gene and ENvironment Interaction Study of Tokyo Medical and Dental University (TMDU) (BC-GENIST) project, which is a prospective mother-offspring cohort designed to evaluate the effects of prenatal environment and genotype on the epigenetic state of mothers and their offspring . During Clinical information including maternal BP and birth outcome were obtained from the retrospective cohort of women who gave birth at TMDU Hospital from 2013 to 2017 . The eliThis study was approved by the Institutional Review Board of TMDU and was conducted according to the Declaration of Helsinki.The relationship between observational BP and birth weight was analyzed using the TMDU pregnant women cohort. BP was measured at prenatal check-ups scheduled every 4 weeks until 24 weeks, every 2 weeks between 24 and 36 weeks, and weekly beyond 36 weeks of gestation. Pulse pressure (PP) was calculated by subtracting the diastolic blood pressure (DBP) from the systolic blood pressure (SBP). The PP was divided by three and added to the DBP to calculate the mean arterial pressure (MAP)   whereas the average direct effects (ADE) was − 0.049  , and PP-PGS  estimated that 70% and 72%, respectively, of the effect of maternal BP-increasing PGS on birth weight was mediated by placental weight  = − 0.06 ; p = 2.5 × 10−2) and placental weight , “unlikely-related” genetic risk score was associated neither with birth weight (p = 0.087), nor with placental weight (p = 0.083). Causal mediation analysis estimated nearly 100% of the effect of “vasculature-related” genetic score on birth weight was mediated by placental weight  = − 0.26 ; p = 3.6 × 10−3) and placental weight . Causal mediation analysis estimated 96% of the “vasculature-related” PGS effect was mediated by the placental weight . On the contrary, we did not observe any correlation between paternally inherited haplotype genetic score and birth weight , whereas there was no association with paternally inherited haplotype genetic score  and estimated the weekly values of EFW by smoothing splines interpolation Fig. a. We theThis is the first study to show that placental weight mediates the effect of maternal SBP-increasing PGS on lowering birth weight. While we found a notable inverse association between maternal genetic score and placental weight, observational BP traits were not associated with BP genetic score. In addition, placental weight well correlated with birth weight, whereas no correlation was observed between observational BP and birth weight. PGS constituted of BP SNPs only related to the vascular system also had a reducing effect on birth weight, and this effect was mediated by the placental weight. Additionally, we put in evidence that both maternal transmitted and non-transmitted alleles of BP-increasing SNPs, but not paternal transmitted alleles, affect birth weight. The association between maternal SBP PGS and deceleration of fetal growth velocity only appeared later in gestation, consistent with a placental mediation of the effect of maternal hypertension genetic risk on birth weight.Previous MR studies of the European ancestry population have consistently reported an inverse association between maternal SBP-increasing PGS and birth weight , 8, 10. Using MR analysis, Tyrrell et al. estimated that every 10 mmHg increase of the maternal SBP is genetically associated with a 208-g decrease in birth weight , 44 alsoGenes associated with hypertension have been identified by recent GWAS –18, and To analyze the maternal genetic score as a proxy for the intrauterine environment, Beaumont, Warrington, and their colleague developed a method of analysis that distinguishes it from the effects of genetic factors shared by the fetus , 10. TheFetal growth restriction (FGR) is characterized as a growth deceleration from a certain point in the gestation period, resulting in fetus pathologically small for the gestation period (SGA), which is different from constitutionally SGA , 46. As The NICHD Fetal Growth Study, which explored the association between maternal SBP (or DBP)-increasing PGS and EFW for each trimester, has been recently reported . A uniquUp to now, maternal genetic scores associated with SBP, DBP, BMI, and T2D or birth weight-associated SNPs were used as a proxy for the intrauterine environment to validate Developmental Origin of Health and Disease (DOHaD) hypothesis –10. ReceR2, exceeded 0.2; therefore, we were able to perform statistically reliable association analysis with this sample size. Nevertheless, the results of this study will need to be replicated in another cohort possessing complete data of fetal growth velocity and placental weight. Second, we classified PGSs based on literature and open-source data on gene activities and chromatin status in vascular tissues for the genes affected by SNPs. Although these methods were commonly used in previous studies [The main strength of our study was using the cohort of mother-offspring pair cohort that contains unique phenotype data for time-series fetal growth velocity and placental weight as well as genotype. In addition, birth weight and placental weight were ideally adjusted for gestational age, fetal sex, and maternal parity to eliminate well-known confounding factors. Pre-pregnancy BMI was also considered as a confounding factor. Using causal mediation analysis, we found for the first time that the effects of maternal SBP PGS on birth weight are mediated by placental weight. However, some limitations should be noted. First, the sample size of the cohort with available genotype was small, around 100, which is the minimum target sample size for PGS analysis . The ass studies –18, someIn the present study, we show that maternal hypertension genes are strongly associated with placental growth and that maternal genetic risk of hypertension inhibits fetal growth through the intrauterine environment established by the placenta. Our finding is highly important for the perinatal management of FGR. Given that many FGRs are late-onset and difficult to diagnose , 11, 13,Additional file 1: Table S1. Characteristics of participants included in this study. Table S2. Genome-wide significant loci for blood pressure phenotypes and classification based on vasculature relevance. Table S3. Variants constituting SBP-increasing PGS at p value threshold of 1 x 10−6 and classification based on vasculature relevance. Table S4. Linear regression analyses for maternal SBP-increasing PGS predicting various traits including birth weight. Table S5. Linear regression analyses for maternal DBP-increasing PGS predicting various traits including birth weight. Table S6. Linear regression analyses for maternal MAP-increasing PGS predicting various traits including birth weight. Table S7. Linear regression analyses for maternal PP-increasing PGS predicting various traits including birth weight. Table S8. Linear regression analyses for maternal BP traits predicting placental weight. Table S9. Sensitivity analysis for estimates of the causal mediation analyses by excluding pleotropic SNPs from exposure PGS.Table S10. Linear regression analyses for BP-increasing allele predicting birth weight or placental weight.Additional file 2: Figure S1. Relationship between maternal BP in early gestation and offspring birth weight. Figure S2. Relationship between maternal BP in mid gestation and offspring birth weight. Figure S3. Relationship between maternal BP in late gestation and offspring birth weight. Figure S4. Estimates of mediation analyses with different PGS (exposure variable).


Patients who met the inclusion and exclusion criteria were divided into four groups according to their serum E2 level percentages on the day of trigger: <25th, 25th–50th, 51st–75th, and >75th percentile groups.We recruited patients in fresh SBT cycles (P > 0.05). We used this information to predict the rate of severe ovarian hyperstimulation syndrome (OHSS) area under the curve (AUC) = 72.39%, P = 0.029, cut off value of E2 = 2,893 pg/ml with the 75% sensitivity and 70% specificity. The 51st–75th percentile group had the highest rates of low birth weight infants (11.73% (19/162), P = 0.0408), premature delivery (11.43% (20/175), P = 0.0269), admission to the neonatal intensive care unit (NICU) (10.49% (17/162), P = 0.0029), twin pregnancies (8.57% (15/175), P = 0.0047), and monochorionic diamniotic pregnancies (8.57% (15/175); P = 0.001). We did not observe statistical differences in obstetrics complications, including gestational diabetes mellitus (GDM), gestational hypertension, placenta previa, premature rupture of membranes (PROM), and preterm premature rupture of membranes (PPROM).Although the rates of clinical pregnancy (85.57% (166/194)), embryo implantation 86.60% (168/194), ongoing pregnancy (71.13% (138/194)), and live birth (71.13% (138/194)) were lowest in the >75th percentile group, we did not observe any significant differences (all 2 levels on the day of trigger were not good predictors of live birth rate or perinatal and obstetrical outcomes. However, we found that high E2 levels may not be conducive to persistent pregnancies. The E2 level on the day of trigger can still be used to predict the incidence of early onset severe OHSS in the fresh SBT cycle.We concluded that serum E Howeveral cycle . High E2ion rate . A previon cycle .Gonadotropin releasing hormone agonist (GnRH-a) remains the most commonly-used peptide hormone in COH during ART treatments because it can obtain the most oocytes, prevent early-onset LH peaks, reduce luteinization, and improve cycle completion rates . PatientThe ultimate goal of ART is to deliver a single, healthy, living baby as quickly and economically as possible. Single-blastocyst-transfer (SBT) can prevent high incidences of complications such as multiple pregnancies and ovarian hyperstimulation syndrome (OHSS) which results in the continuous emergence of maternal and fetal related complications such as gestational hypertension, premature delivery and low-weight newborns .in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles, cryopreserved SBT may not be the best choice when compared to fresh SBT  level did not exceed 1.98 ng/ml on the day of trigger; and (4) they had one or more D5 3BC blastocyst.The inclusion criteria were as follows: (1) all candidates were between the ages of 20 and 42 years old and had infertility due to tubal obstruction, endometriosis (EMs), polycystic ovary syndrome (PCOS), or ovarian polycystic changes confirmed by transvaginal ultrasound, male factors, or idiopathic reasons; (2) the endometrial double layer thickness on the day of trigger was greater than 6 mm; (3) the serum progesterone (PThe exclusion criteria were as follows: (1) patients required all blastocysts to be cryopreserved on the day of fresh SBT treatment; (2) endometrial adhesion, submucosal myoma, or uterine diameters longer than 65 mm; (3) obvious infection after oocyte retrieval; and (4) complications with malignant tumors or other systemic diseases, such as an active stage of systemic lupus erythematosus, that were not suitable for pregnancy.The research was approved by the Research Ethical Committee of the Second Hospital Affiliated to Wenzhou Medical University .2 concentration amounts. We then used the PERCENTILE function in Microsoft Excel to calculate the corresponding E2 value percentiles. The four groups were: the <25th percentile group , the 25th–50th percentile group , the 51st–75th percentile group , and the >75th percentile group .In order to determine the effect of peripheral blood estrogen levels on clinical, maternal, and fetal perinatal outcomes of fresh SBT cycles during an early follicular phase prolonged protocol on the day of trigger, we divided the patients who met the inclusion standards into four groups according to their serum E2 level did not exceed 50 pg/ml, and the LH level was less than 5 IU/L, we determined that the pituitary desensitization was successful. Additionally, we used 87.5-375 IU of recombinant human FSH  for COH according to the patient’s age, BMI, antral follicle count (AFC), and levels of LH, P4, and E2 on the starting day.We injected a single full dose of 3.75 mg GnRH-a  during the D1-D3 menstrual cycle. The ovarian inhibition situation was evaluated 32 and 38 days after pituitary down-regulation. If there were no follicles greater than 8 mm, the E2 levels, and LH and P4 values. If the LH level did not exceed 0.5 IU/L and the follicular growth speed was not ideal, we added 75 IU of recombinant LH . When the average diameter of the two follicles reached 18 mm, we administered a single dose of 4,000–10,000 IU of human chorionic gonadotropin . Egg harvesting was performed after 34–36 h.We used timely ultrasonic and blood examination to monitor the patients’ follicular growth, ovarian response, peripheral serum EThe embryo culture program has been previously described and the embryo scoring standard referred to the 2011 Istanbul Consensus . A blastth day of fresh SBT, and we reduced the dose of luteal phase support drugs accordingly. The second ultrasound was given on the 40th day after SBT and the dose was reduced according to the patient’s condition. We used a maintenance dose until 2 to 4 weeks had passed after the second ultrasound test  to be taken orally daily and 200 mg progesterone soft capsules  each day following egg collection. The first transvaginal ultrasound was given to evaluate embryo implantation after the 26und test . The varth day following SBT. A clinical pregnancy was determined by the detection of an intrauterine gestational sac via transvaginal ultrasound 26 days after transfer. We considered an ongoing pregnancy after 12 weeks of clinical pregnancy. Early miscarriage occurred before 12 gestational weeks. Moreover, ectopic pregnancy was indicated by ultrasonographic findings of the ectopic gestational sac and/or primitive cardiac tube pulsation. Additionally, we defined monozygotic twins as two fetuses sharing the same gestational sac.We confirmed biochemical pregnancy using the serum β-hCG levels, which needed to be at least 10 IU/L on the 12A preterm delivery was regarded as occurring between gestational weeks more than 28 and less than 37. A pregnancy with 42 gestational weeks or more was considered a post-term pregnancy. Structural or functional metabolism abnormalities of the embryo or fetus during intrauterine development were considered birth defects. Low birth weight infants were newborns with birth weights less than 2,500 g. Very low birth weight infants weighed less than 1,500 g at birth, and infants with birth weights of more than 4,000 g were considered macrosomia. The various rate calculation methods are shown in Pregnancy complications include gestational diabetes mellitus  11 code, JA63), placenta previa , premature rupture of membranes , gestational hypertension , hyperthyroidism , oligohydramnios , and prenatal hemorrhage , which has a standard diagnosis .P value less than 0.05 indicated that the difference was statistically significant.Continuous variables were delivered using mean values, standard deviation, and dichotomous variables stated by percentage (n). One way ANOVA or was used for the continuous variables in accordance with the homogeneity of normal distribution variance and Tukey’s multiple comparison correction was used for multiple comparisons among groups. When the data was not normally distributed or the variance was uneven, Kruskal Wallis H test of K-independent sample test in non-parametric test will be used and Mann–Whitney U test or Holm correction were then used for multiple comparisons. 2 levels on the day of trigger could be used to predict the rates of blastocyst implantation, clinical pregnancy, ongoing pregnancy, early abortion, live birth, and early-onset severe OHSS.Univariate logistic regression analysis was used to test the correlation of related variables including BMI, LH level, and the AFC on the commencing day, etc., and live birth rate. A forest map was drawn to see whether the above confounding factors affect the live birth rate. Receiver operating characteristic (ROC) curves were used to show whether serum EThe statistical analysis of all data was performed using GraphPad Prism Software  and SPSS Software .2 levels on the day of trigger, baseline information, COH, and laboratory parameters. Baseline information was similar across the four groups, except with regards to BMI; BMI decreased as E2 levels increased on the day of trigger . The 25th–50th percentile group had the highest E2 level on the commencing day and the days of stimulation were highest . The <25th percentile group had the highest P4 level on the commencing day (0.52 ± 0.32 ng/ml P < 0.001). LH levels on the day of trigger were highest in the 51st–75th percentile group . The >75th percentile group had the highest levels of total E2, E2 per follicle, P4 and endometrial thickness on the day of trigger . However, initial and total Gn doses were highest in the <25th percentile group   .th percentile group had the highest number of retrieved oocytes, double pronuclear (2PNs), cleavage embryos, D3 embryos, good quality D3 embryos, culture D3 embryos into blastocysts number, blastocysts, and good quality blastocysts per cycle  . Conversely, the rates of blastocyst formation and good quality blastocyst formation were highest in the 25th–50th percentile group   . The rat= 0.037) . Our come groups .th percentile group had the lowest rates of clinical gravidity, embryo transplantation, persistent pregnancy, and living birth, there were no significant differences (85.57% (166/194), 86.60% (168/194), 71.13% (138/194), and 71.13% (138/194), respectively; all P > 0.05). Additionally, rates of severe OHSS, early miscarriage, and ectopic pregnancy showed no significant differences  of 44.59%; the cut off value for E2 was 2,893 pg/ml with the 75% sensitivity and 70% specificity , twin pregnancies, and monochorionic diamniotic pregnancies (11.73% (19/162), P = 0.0408; 11.43% (20/175), P = 0.0269; 10.49% (17/162), P = 0.0029; 8.57% (15/175), P = 0.0047; and 8.57% (15/175); P = 0.001, respectively) ), but we did not find any significant differences when compared to the other three groups. The 51ctively) . Additioctively) .2 levels on clinical and maternal-fetal perinatal outcomes under a full long acting GnRH-a regimen on the day of trigger. Our results indicated that E2 levels on the day of trigger are not effective when used as a predictor for the clinical and perinatal outcomes of mothers and fetuses. However, we found that E2 levels could still be used to predict early-onset severe OHSS in IVF/ICSI patients with fresh SBT cycles.Few studies have examined the influence of fresh SBT EThere is growing interest in the safety of IVF/ICSI for mothers and newborns, and a great number of doctors and patients in reproductive centers around the world are using SBT because fresh blastocyst stage transfer is a better choice compared to fresh cleavage stage embryo transfer . No cons2 levels influence fresh SBT’s clinical and maternal-fetal perinatal outcomes under this protocol.Prolonged pituitary down-regulation before starting Gn resulted in higher live-birth rates during fresh embryo transfer due to the greater endometrial receptivity during embryo implantation . In our 2 elevated the P4 levels, which reduced endometrial receptivity  had the lowest average age, basal FSH level, and FSH/LH ratio, indicating that this group may have better ovarian reserve function  in regards to this prolonged regimen, clinicians should strictly measure Gn dosages during the final stage of COH for patients with good ovarian function, and should be cautious when increasing the Gn dosage in order to better control the risk of early-onset severe OHSS.In this study, we mapped the relationship between Ecificity . The meath, 25th–50th, and 51st–75th groups was between 11.04 and 15.44, and the clinical outcomes were encouraging. This result was in accordance with the previous studies, suggesting that a prolonged protocol combined with fresh SBT would be beneficial for most suitable patients.Previous studies have confirmed that retrieving 11–15 oocytes produces satisfactory live birth rates and cumulative live births with the lowest rate of OHSS, while retrieving more than 15 oocytes can critically increase the risk of OHSS without increasing the live birth rate . In thisst–75th percentile group (8.57% (15/175), P = 0.0047). The incidence of monozygotic twins is 0–13.2% during blastocyst transplantation . What is noteworthy is that ROC curve of E2 level and early set-on OHSS had moderate intensity correlation, of which AUC was 72.39%, P value was 0.0292, youden index (YI) was 44.59% and the cut off value of E2 was 2,893 pg/ml with the 75% sensitivity and 70% specificity (Shown in F).ROC was used to further analyze the correlation between EClick here for additional data file.10.7717/peerj.11785/supp-3Supplemental Information 3Click here for additional data file.


To determine how subcategorizing unexplained infertility based on female laparoscopy and total‐motile‐sperm‐count assessment would impact cumulative live‐births after one in‐vitro fertilization (IVF) cycle.Seven hundred twenty one IVF cycles from Jan 2014‐April 2019 performed at a single‐center were retrospectively analyzed. Couples with unexplained infertility having normal uterine and endometrial morphology were subcategorized into three cohorts, UI (1): those with no tuboperitoneal pathology on laparoscopy and total‐motile‐sperm‐count (TMSC) ≧20 million: n = 103; UI (2): tuboperitoneal pathology on laparoscopy or TMSC <20 million, n = 86; and UI(3): tuboperitoneal status not known: n = 114. Controls were severe male factor, bilateral tubal block, and grade 3/4 endometriosis: n = 418. Primary Outcome was cumulative‐live‐birth‐per‐initiated‐IVF cycle (CLBR). Odds ratio for live‐births were adjusted for confounding factors.P = .04); but similar in UI2 and UI3 vs. controls.  and . After adjusting for age, infertility duration, past live‐births, and AMH, the adjusted odds for CLBR in UI1 was 0.48 .The CLBR in UI1 cohort was significantly lower than controls (29.1% vs 39; OR = 0.62; 95%CI = 0.39‐0.98; Unexplained infertility when defined after a normal laparoscopy and TMSC significantly lowered cumulative‐live‐births‐per‐initiated‐IVF cycle when compared with traditional diagnosis of tubal, endometriosis, or male factor infertility. In UI subcategory with abnormal laparoscopy or TMSC, CLBR remained unaffected. This information could be useful for counseling couples prior to IVF. Large‐scale prospective studies are needed to confirm this observation. This retrospective analysis of 721 cycles segregates unexplained infertility into a subcategory with normal female laparoscopy and total motile sperm count and finds that adjusted odds for live‐births is significantly lowered in this sub‐category vis‐a‐vis a known cause infertility after IVF treatment. The analysis makes adjustments for female age, infertility duration, past live‐births, past treatments, and AMH. In a retrospective analysis of 121 744 women undergoing their first cycle of autologous IVF between 2000‐2007, the authors found that UI had a better prognosis for live births vis‐à‐vis tubal or male factor infertility.This ambiguity in live‐birth prognosis could be because UI cannot be considered a monolith etiologically. It is a heterogenous condition encompassing subtle abnormalities in one or more of the following units: the fallopian tube, oocyte, sperm, or the endometrium.Laparoscopy has been used to reasonably rule out tubal and peritoneal factors associated with unexplained infertility that cannot be diagnosed with tests such as HSG alone.2The study was approved by the institutional ethics committee vide registration number EC/01/19/1465. Data of all couples undergoing IVF cycles performed between Jan 2014‐April 2019 at a tertiary care‐multiple‐provider set up was collected. The diagnostic categories of male, tubal, endometriosis, and unexplained infertility were included in the study. Exclusions were donor‐recipient cycles, preimplantation genetic testing, presence of gross uterine factor  and incomplete cycles; defined when embryos from one oocyte aspiration cycle remained unutilized, in the absence of a live‐birth or ongoing pregnancy.The diagnostic categories of male, tubal, and endometriosis were regrouped into the control cohort. The diagnostic category of UI was subcategorized into three cohorts based on previous laparoscopy and TMSC findings as shown in Figure Semen reports of UI cycles were analyzed next. At least two semen reports (WHO 2010 standard) were available for all couples; one done prior to IVF initiation and one on IVF day. The poorer report was considered to calculate TMSC using the formula: total volume X sperm concentration X percentage of progressively motile sperm. TMSC of ≧20 million was deemed non‐sperm factor UI, and TMSC <20 million was labeled as mild‐sperm‐factor UI.Hamilton et al (2015) have argued and shown that TMSC is a better parameter than WHO 2010 criteria to assess discriminating potential of sperm for natural pregnancy as it takes the absolute value of three semen parameters into consideration simultaneously.Unexplained infertility cycles were finally subcategorized into three cohorts namely UI1: having non‐tuboperitoneal and non‐sperm factor unexplained infertility; UI2: having mild tuboperitoneal and/or mild‐sperm‐factor unexplained infertility; and UI3: having indeterminate factor, labeled so because in the absence of laparoscopy, a tuboperitoneal factor could not be ruled out. The distribution of different sub etiologies within the three cohorts of UI is shown in Table 2.1At the center of study, laparoscopy is not the first investigative modality to assess fallopian tubal patency. It is usually offered to women with at least three failed IUIs, UI with prior pelvic surgery, long‐duration UI usually exceeding two years, and positive pelvic findings on ultrasound or hysterosalpingography. Operative measures are undertaken during laparoscopy to address peri‐adnexal adhesions, cornual block, and endometriosis. Infertility state continuing after a period of one year with active attempts at pregnancy is considered failed laparoscopy, and IVF is offered subsequently.In women with advanced age, long infertility durations, or with low AMH, an early IVF is offered and sometimes as the first treatment modality.2.2The protocol for IVF and transfer has been defined previously.Demographic characteristics like age, infertility duration, past pregnancies, past infertility treatments, serum anti mullerian hormone(AMH) (ng/mL), and body mass index (BMI) were compared between the four cohorts. AMH was measured using Beckman Coulter Gen II assay till September 2016 and Access chemiluminescence assay subsequently. Values were reported in ng/ml. Where reported as pmol/L, (prior to September 2016) the values were converted into ng/mL using a divisor of 7.18.2.3Primary outcome variable was live‐birth resulting from the transfer of embryos generated per oocyte aspiration cycle. Live‐births were defined as all births at or beyond 26 weeks of gestation with survival for at least a day as per the hospital's neonatal intensive care guideline on the age of viability and active neonatal resuscitation policy. Crude and adjusted odds ratio for live‐births were calculated for all UI cohorts against controls.Other outcomes assessed were total retrieved oocytes, mean total utilizable embryos, total‐eggs‐to‐utilisable‐embryo‐ratio, total‐eggs‐to‐live‐birth‐ratio, and mean‐transfers‐to‐one‐live‐birth. Total utilizable embryos were a sum of embryos/blastocysts transferred and embryos/blastocysts frozen in one oocyte retrieval cycle.2.4P value of <.05 was considered significant. All analyses were made on SPSS version 25.Data were expressed as mean ± 2 SD for gaussian variables and as median, interquartile range (IQR) for non‐gaussian variables. Independent samples t test and one‐way ANOVA were used to compare means between two groups and more than two groups, respectively, when the studied variable had a Gaussian distribution. Independent samples Kruskal‐Wallis test was used to compare medians for variables with non‐gaussian distribution. (Skewness quotient outside −1 to +1). Fischer's test and Chi‐square test were used to compare qualitative data when there were 2 and more than 2 groups, respectively. Binary logistic regression analysis was performed to calculate adjusted Odds ratio for live‐births adjusting for all confounders. A 33.1Nine hundred forty seven oocyte retrieval cycles were undertaken in the period of study. Two hundred twenty six were excluded on account of being incomplete (21), employing donor eggs (150) or preimplantation genetic testing (16), oocyte freezing (6), or having a visible uterine factor (33). Finally, 721 IVF cycles were analyzed. The overall mean female age in the included cycles was 32.56 ± 4.3 years, (range: 21‐44); median infertility duration was 6 years, (IQR: 4‐9); and previous live birth rate was 14%. 7.6% (n = 55) of cycles had no embryos for transfer, 74.3% (n = 536) had embryos for a single transfer only and 18.1% (n = 130) had embryos for ≥two transfer cycles. In 63.7% (n = 459) of cycles, fresh embryos were transferred and in 28.7%, (n = 207 cycles) only frozen embryos were transferred. A total of 788 transfers yielded 273 live‐births in this study giving a live‐birth rate of 34.6% per embryo transfer cycle and 37.9% per started cycle.3.2The number of cycles with diagnoses of UI1, UI2, UI3, and controls were 103, 86, 114, and 418, respectively. A comparison of pretreatment variables between the four cohorts is given in Table 3.3P = .04) the median utilizable embryos remained at 2 for both these etiological categories. (P = .6). The live‐births per started cycle were significantly lower in UI1 compared with controls. . The eggs‐to‐utilizable‐embryo‐ratio,  eggs‐to‐live‐birth‐ratio, , and mean‐transfers‐to‐one‐livebirth  was poorer for UI1 compared with controls.Despite a significantly higher numbers of oocytes retrieved in UI1 vs controls,  as were the median oocytes recovered , the median utilizable embryos  the total‐eggs‐to‐live‐birth‐ratio , and mean‐transfers‐to‐one‐live‐birth  when compared with controls. . The adjusted odds ratio for live‐births adjusting for confounding variables age, infertility duration, past live‐births, past treatments, and AMH was 0.48 . The crude and adjusted odds ratio for live‐births in the UI2 and UI3 subcategory against controls were not significant  encompasses various conditions arising due to defects in one or the other unit of reproduction and is considered a diagnosis of exclusion incumbent upon normalcy of semen analysis, tubal patency, and ovulation tests. The greater the armamentarium of investigations employed, the narrower the prevalence of UI is likely to be.In a study that employed routine laparoscopy in women with UI, , 25% additional cases of pelvic pathology could be discovered, encompassing severe tubal disease (4%), peri‐adnexal adhesions (8%), and Grade 1/2 endometriosis (13%).On the question of whether uncovering these subtle pelvic pathologies made a difference in terms of IUI results, the same authors, . The difference in live‐births remained significant, infact even more enhanced after adjusting for cofounding factors. , suggesting that if age, infertility duration, past live‐births, and AMH were equal in the two groups, the odds for a live‐birth after one cycle of IVF in couples with UI1 would be reduced to half when compared with couples with a known factor infertility.This study showed that couples with UI defined after normal laparoscopy and TMSC of ≧20 million  had fewer live‐births per started cycle compared with couples undergoing IVF for a severe tuboperitoneal or severe sperm factor.  versus controls. The higher age at IVF in UI could be a result of longer time spent in other infertility treatments like expectant management or IUI as can be seen from Table It is imperative to note that the median infertility duration of couples in all cohorts in this study was 6 years. . This is higher than the median infertility durations of 4 years (IQR 3‐6) stated in other studies that employed the HFEA databaseIt is also essential to note that median AMH is higher in UI1 cohort compared with controls despite median age being contrarily higher. The higher AMH in UI1 cohort could reflect a selection bias probably suggesting either an elimination of women with very low AMH or an inadvertent inclusion of more women with PCOS. Could a higher prevalence of PCOS in UI1 have negatively influenced outcomes?P = .001). However, the low, average, and high AMH categories represented by 18.5%, 28.1%, and 52.4% of the UI1 cohort, accounted for 0%, 16.66%, and 83.33% of the total live‐births in that cohort. This suggested that a higher prevalence of AMH >3.5 in UI1, probably representing PCOS, did not negatively affect live‐births in this cohort. If at all, the results suggest, that if the UI1 cohort was matched with controls by AMH, the live‐birth rates in UI1 would have been even lower than that obtained in this study.To answer this question, an analysis of AMH distribution among the four cohorts was done Table . A signiThe findings that a rigorous categorization of UI might have implications for prognosis in IVF are novel. It attempts to glean information from already available data like previous laparoscopy and total motile sperm count to identify couples with poorer prognosis in IVF without additional cost to couples. This information when coupled with known predictors like age, infertility duration, past live‐births, and ovarian reserve parameters might add to the predictive value of existing models of live‐birth prediction in IVF.This is a retrospective analysis and although attempts have been made to address biases, the study needs external validation through prospectively done studies within more strictly selected populations.In conclusion, unexplained infertility, when defined after a normal laparoscopy and a normal total motile sperm count significantly lowers cumulative live‐births‐per‐started‐IVF cycle when compared with traditional diagnosis of tubal factor, endometriosis‐associated, or male factor infertility. The difference persists despite adjustments for age, previous live births, AMH, and infertility duration. In unexplained infertility subcategory with abnormal laparoscopy or TMSC, the live‐birth rates in IVF remain unaffected when compared with couples with traditional diagnosis of tubal factor, endometriosis‐associated, or male factor infertility. This information could be useful for counseling couples prior to IVF. Also, based on the mean embryo to live‐birth ratio and the mean transfer to live‐birth ratio, the couple with true unexplained infertility, especially those with long‐duration infertility, could be counseled that, they may need more total cycles to achieve a live‐birth than their other counterparts.Conflict of interest statement: The authors declare that they have no conflict of interest.Human rights statements and informed consent: This was a retrospective observational study. All data were anonymized and consent waiver sought from the ethics committee of the institution for this retrospective observational study. Approval was granted by the institutional ethics committee via registration number EC/01/19/1465.Animal studies: This article does not contain any studies/intervention with human/animal subjects performed by any of the authors.Approval by ethics committee: The study was conducted after the due formal approval of institutional ethics committee vide registration number EC/01/19/1465.Clinical trial Registry: Not applicable. This was a retrospective observational study.