Sex and fetal genome influence gene expression in pig endometrium at the end of gestation.

BACKGROUND: A fine balance of feto-maternal resource allocation is required to support pregnancy, which depends on interactions between maternal and fetal genetic potential, maternal nutrition and environment, endometrial and placental functions. In particular, some imprinted genes have a role in regulating maternal-fetal nutrient exchange, but few have been documented in the endometrium. The aim of this study is to describe the expression of 42 genes, with parental expression, in the endometrium comparing two extreme breeds: Large White (LW); Meishan (MS) with contrasting neonatal mortality and maturity at two days of gestation (D90-D110). We investigated their potential contribution to fetal maturation exploring genes-fetal phenotypes relationships. Last, we hypothesized that the fetal genome and sex influence their endometrial expression. For this purpose, pure and reciprocally crossbred fetuses were produced using LW and MS breeds. Thus, in the same uterus, endometrial samples were associated with its purebred or crossbred fetuses. RESULTS: Among the 22 differentially expressed genes (DEGs), 14 DEGs were differentially regulated between the two days of gestation. More gestational changes were described in LW (11 DEGs) than in MS (2 DEGs). Nine DEGs were differentially regulated between the two extreme breeds, highlighting differences in the regulation of endometrial angiogenesis, nutrient transport and energy metabolism. We identified DEGs that showed high correlations with indicators of fetal maturation, such as ponderal index at D90 and fetal blood fructose level and placental weight at D110. We pointed out for the first time the influence of fetal sex and genome on endometrial expression at D90, highlighting AMPD3, CITED1 and H19 genes. We demonstrated that fetal sex affects the expression of five imprinted genes in LW endometrium. Fetal genome influenced the expression of four genes in LW endometrium but not in MS endometrium. Interestingly, both fetal sex and fetal genome interact to influence endometrial gene expression. CONCLUSIONS: These data provide evidence for some sexual dimorphism in the pregnant endometrium and for the contribution of the fetal genome to feto-maternal interactions at the end of gestation. They suggest that the paternal genome may contribute significantly to piglet survival, especially in crossbreeding production systems.

Expectant management of preeclampsia with severe features diagnosed at less than 24 weeks.

BACKGROUND: The recent American College of Obstetricians and Gynecologists Practice Bulletin offers no guidance on the management of preeclampsia with severe features at <24 weeks of gestation. Historically, immediate delivery was recommended because of poor perinatal outcomes and high maternal morbidity. Recently, advances in neonatal resuscitation have led to increased survival at periviable gestational ages. OBJECTIVE: This study aimed to report perinatal and maternal outcomes after expectant management of preeclampsia with severe features at <24 weeks of gestation. STUDY DESIGN: This was a retrospective case series of preeclampsia with severe features at <24 weeks of gestation at a level 4 center between 2017 and 2023. Individuals requiring delivery within 24 hours of diagnosis were excluded. Perinatal and maternal outcomes were analyzed. Categorical variables from our database were compared with previously published data using chi-square tests. RESULTS: A total of 41 individuals were diagnosed with preeclampsia with severe features at <24 weeks of gestation. After the exclusion of delivery within 24 hours, 30 individuals (73%) were evaluated. The median gestational age at diagnosis was 22 weeks (interquartile range, 22-23). Moreover, 16% of individuals had assisted reproductive technology, 27% of individuals had chronic hypertension, 13% of individuals had pregestational diabetes mellitus, 30% of individuals had previous preeclampsia, and 73% of individuals had a body mass index of >30 kg/m2. The median latency periods at 22 and 23 weeks of gestation were 7 days (interquartile range, 4-23) and 8 days (interquartile range, 4-13). In preeclampsia with severe features, neonatal survival rates were 44% (95% confidence interval, 3%-85%) at 22 weeks of gestation and 29% (95% confidence interval, 1%-56%) at 23 weeks of gestation. There were 2 cases of acute kidney injury (7%) and 2 cases of pericardial or pleural effusions (7%). Overall perinatal survival at <24 weeks of gestation was 30% in our current study vs 7% in previous reports (P=.02). CONCLUSION: For cases of expectant management of preeclampsia with severe features at <24 weeks of gestation, our findings showed an increased perinatal survival rate with decreased maternal morbidity compared with previously published data. This information may be used when counseling on expectant management of preeclampsia with severe features at <24 weeks of gestation.

Prediction of perinatal survival in early-onset fetal growth restriction: role of placental growth factor.

OBJECTIVE: To analyze the ability to predict perinatal survival and severe neonatal morbidity of cases with early-onset fetal growth restriction (eoFGR) using maternal variables, ultrasound parameters and angiogenic markers at the time of diagnosis. METHODS: This was a prospective observational study in a cohort of singleton pregnancies with a diagnosis of eoFGR (< 32 weeks of gestation). At diagnosis of eoFGR, complete assessment was performed, including ultrasound examination (anatomy, biometry and Doppler assessment) and maternal serum measurement of the angiogenic biomarkers, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF). Logistic regression models for the prediction of perinatal survival (in cases diagnosed at < 28 weeks) and severe neonatal morbidity (in all liveborn cases) were calculated. RESULTS: In total, 210 eoFGR cases were included, of which 185 (88.1%) survived perinatally. The median gestational age at diagnosis was 27 + 0 weeks. All cases diagnosed at ≥ 28 weeks survived. In cases diagnosed < 28 weeks, survivors (vs non-survivors) had a higher gestational age (26.1 vs 24.4 weeks), estimated fetal weight (EFW; 626 vs 384 g), cerebroplacental ratio (1.1 vs 0.9), PlGF (41 vs 18 pg/mL) and PlGF multiples of the median (MoM; 0.10 vs 0.06) and lower sFlt-1/PlGF ratio (129 vs 479) at the time of diagnosis (all P < 0.001). The best combination of two variables for predicting perinatal survival was provided by EFW and PlGF MoM (area under the receiver-operating-characteristics curve (AUC), 0.84 (95% CI, 0.75-0.92)). These were also the best variables for predicting severe neonatal morbidity (AUC, 0.73 (95% CI, 0.66-0.80)). CONCLUSIONS: A model combining EFW and maternal serum PlGF predicts accurately perinatal survival in eoFGR cases diagnosed before 28 weeks of gestation. Prenatal prediction of severe neonatal morbidity in eoFGR cases is modest regardless of the model used. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Perinatal outcome in monoamniotic twin pregnancies during a 10-year period: a single center, descriptive study.

PURPOSE: To retrospectively investigate perinatal outcome of monoamniotic twin pregnancies in a tertiary center during a 10 year period. METHODS: A retrospective analysis of all monoamniotic pregnancies managed at Karolinska University Hospital, Stockholm, Sweden 2010-2019 was performed. The primary outcomes were live birth rate, neonatal death and perinatal survival. The secondary outcomes were late miscarriage, gestational age at delivery and frequency of fetal complications. RESULTS: Twenty-two monoamniotic pregnancies, with 44 fetuses, were identified. Thirty-five of 44 fetuses (80%) were liveborn. Of 36 fetuses reaching 24 weeks gestation, 35 (97%) were liveborn. There were no neonatal deaths, thus the perinatal survival was 97%. The mean gestational age at birth was 32.5 weeks (SD ± 1.5). CONCLUSIONS: The live birth rate and perinatal survival of monoamniotic pregnancies managed at Karolinska University Hospital was high and comparable to previously published data.

Perinatal outcome of pregnancies with prenatal diagnosis of vasa previa: systematic review and meta-analysis.

OBJECTIVES: To derive accurate estimates of perinatal survival in pregnancies with and without a prenatal diagnosis of vasa previa based on a systematic review of the literature and meta-analysis. METHODS: A search of MEDLINE, EMBASE and The Cochrane Library was performed to review relevant citations reporting on the perinatal outcomes of pregnancies with vasa previa. We included prospective and retrospective cohort and population studies that provided data on pregnancies with a prenatal diagnosis of vasa previa or cases diagnosed at birth or following postnatal placental examination. Meta-analysis using a random-effects model was performed to derive weighted pooled estimates of perinatal survival (excluding stillbirths and neonatal deaths) and intact perinatal survival (additionally excluding hypoxic morbidity). Incidence rate difference (IRD) meta-analysis was used to estimate the significance of differences in pooled proportions between cases of vasa previa with and those without a prenatal diagnosis. Heterogeneity between studies was estimated using Cochran's Q and the I2 statistic. RESULTS: We included 21 studies reporting on the perinatal outcomes of 683 pregnancies with a prenatal diagnosis of vasa previa. There were three stillbirths (1.01% (95% CI, 0.40-1.87%)), five neonatal deaths (1.19% (95% CI, 0.52-2.12%)) and 675 surviving neonates, resulting in a pooled estimate for perinatal survival of 98.6% (95% CI, 97.6-99.3%). Based on seven studies that included cases of vasa previa with and without a prenatal diagnosis, the pooled perinatal survival in pregnancies without a prenatal diagnosis (61/118) was 72.1% (95% CI, 50.6-89.4%) vs 98.6% (95% CI, 96.7-99.7%) in cases with a prenatal diagnosis (224/226). Therefore, the risk of perinatal death was 25-fold higher when a diagnosis of vasa previa was not made antenatally, compared with when it was (odds ratio (OR), 25.39 (95% CI, 7.93-81.31); P < 0.0001). Similarly, the risk of hypoxic morbidity was increased 50-fold in cases with vasa previa without a prenatal diagnosis compared with those with a prenatal diagnosis (36/61 vs 5/224; OR, 50.09 (95% CI, 17.33-144.79)). The intact perinatal survival rate in cases of vasa previa without a prenatal diagnosis was significantly lower than in those with a prenatal diagnosis (28.1% (95% CI, 14.1-44.7%) vs 96.7% (95% CI, 93.6-98.8%)) (IRD, 73.4% (95% CI, 53.9-92.7%); Z = -7.4066, P < 0.001). CONCLUSIONS: Prenatal diagnosis of vasa previa is associated with a high rate of perinatal survival, whereas lack of an antenatal diagnosis significantly increases the risk of perinatal death and hypoxic morbidity. Further research should be undertaken to investigate strategies for incorporating prenatal screening for vasa previa into routine clinical practice. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

The impact of introducing ambulance and delivery fees in a rural hospital in Tanzania.

BACKGROUND: Access to health care facilities is a key requirement to enhance safety for mothers and newborns during labour and delivery. Haydom Lutheran Hospital (HLH) is a regional hospital in rural Tanzania with a catchment area of about two million inhabitants. Up to June 2013 ambulance transport and delivery at HLH were free of charge, while a user fee for both services was introduced from January 2014. We aimed to explore the impact of introducing user fees on the population of women giving birth at HLH in order to document potentially unwanted consequences in the period after introduction of fees. METHODS: Retrospective analysis of data from a prospective observational study. Data was compared between the period before introduction of fees from February 2010 through June 2013 and the period after from January 2014 through January 2017. Logistic regression modelling was used to construct risk-adjusted variable-life adjusted display (VLAD) and cumulative sum (CUSUM) plots to monitor changes. RESULTS: A total of 28,601 births were observed. The monthly number of births was reduced by 17.3% during the post-introduction period. Spontaneous vaginal deliveries were registered less frequently with a decrease of about 17/1000 births in non-cephalic presentations. Labour complications and caesarean sections increased with about 80/1000 births. There was a reduction in newborns with birth weight less than 2500 g. The observed changes were stable over time. For most variables, a significant change could be detected after a few weeks. CONCLUSION: After the introduction of ambulance and delivery fees, an increase in labour complications and caesarean sections and a decrease in newborns with low birthweight were observed. This might indicate that women delay the decision to seek skilled birth attendance or do not seek help at all, possibly due to financial reasons. Lower rates of births in a safe health care facility like HLH is of great concern, as access to skilled birth attendance is a key requirement in order to further reduce perinatal mortality. Therefore, free delivery care should be a high priority.

Perinatal outcomes and survival predictors of severe red-cell alloimmunization treated by intrauterine transfusion.

OBJECTIVE: To evaluate perinatal survival rates and predictors in severely anemic fetuses that underwent intrauterine transfusion (IUT). METHOD: This was a retrospective study of both Turkish and Syrian patients who underwent IUT for fetal anemia due to Rh alloimmunization between 2015 and 2019. The association between pretransfusion factors and perinatal survival was evaluated by multivariate logistic regression. Receiver operating characteristics (ROC) curves were used to identify the level of fetal hemoglobin deficits that predict perinatal survival. RESULTS: Eighty-seven IUTs were performed in 42 pregnancies. Approximately 75% of fetuses were severely anemic and the overall perinatal survival rate was 50%. The survival rate was better in Syrian refugees compared to Turkish patients (71.4% vs. 39.3%, p < 0.05). In univariate analysis, hydrops presence (odds ratio [OR] = 0.2; 95% confidence interval [CI] = 0.05-0.7; p < 0.05), first IUT week (OR = 1.4; 95% CI = 1.1-1.8; p < 0.05), pretransfusion hemoglobin level (OR = 1.99; 95% CI = 1.22-3.27; p < 0.05), hemoglobin deficit (OR = 0.5; 95% CI = 0.3-0.8; p < 0.05), and birth week (OR = 2.3; 95% CI = 1.3-3.9; p < 0.05) were associated with survival. However in a multivariate analysis, only hemoglobin deficit (OR = 0.47; 95% CI = 0.22-0.99; p < 0.05) and birth week (OR = 3.3; 95% CI = 1.1-10.3; p < 0.05) were found to be associated with survival. On ROC analysis, a hemoglobin deficit of ≤6.25 g/dl showed a sensitivity of 0.95 and specificity of 0.62 for predicting perinatal survival. CONCLUSION: Despite the improvement in the treatment of fetal anemia, perinatal survival rate remains extremely low in severely anemic cases. Among pretransfusion factors, hemoglobin deficit seemed to be most important in predicting survival during fetal anemia.

A critical account of the policy context shaping perinatal survival in Nepal: policy tension of socio-cultural versus a medical approach.

BACKGROUND: Nepal formulated a range of policies related to maternal and neonatal survival, especially after the year 2000. Nevertheless, Nepal's perinatal mortality remains high, particularly in disadvantaged regions. Policy analysis can uncover the underlying values, strategies and policy formulation processes that shape the potential to reduce in-country health inequities. This paper provides a critical account of the main policy documents relevant to perinatal survival in Nepal. METHODS: Six key policy documents covering the period 2000-2015 were reviewed using an adapted framework and were analyzed through qualitative content analysis. RESULTS: The analysis shows that the policies focused mainly on the system: improvement in provision of birthing facilities; targeting staff (Skilled Birth Attendants) and health service users by providing cash incentives to staff for bringing patients to services, and to users (pregnant women) to attend health institutions. Despite a growing focus on saving women and newborn babies, there is a poor policy focus and direction on preventing stillbirth. The policy documents were found to emphasize tensions between birthing at home and at health institutions on the one hand, and between strategies to provide culturally appropriate, woman-centered care in communities and medically orientated services on the other. Policies acknowledge the need to provide and address woman-centered care, equity, social inclusion, and a rights-based approach, and identify the community based approach as the mode of service delivery. Over and above this, all policy documents are aimed at the national level, and there is no specific policy direction for the separate ecological, cultural or geographic regions such as the mountainous region, which continues to exhibit higher mortality rates and has different cultural and demographic characteristics to the rest of Nepal. CONCLUSIONS: To better address the continuing high perinatal mortality rates, particularly in disadvantaged areas, national health policies should pay more attention to the inequity in healthcare access and in perinatal outcomes by integrating both stillbirth prevention and neonatal survival as policy agenda items. To ensure effective translation of policy into practice, it is imperative to tailor the strategies according to acknowledged policy values such as rights, inclusion and socio-cultural identity.

A qualitative study about the gendered experiences of motherhood and perinatal mortality in mountain villages of Nepal: implications for improving perinatal survival.

BACKGROUND: We aim to examine the gendered contexts of poor perinatal survival in the remote mountain villages of Nepal. The study setting comprised two remote mountain villages from a mid-western mountain district of Nepal that ranks lowest on the Human Development Index (0.304), and is reported as having the lowest child survival rates in the country. METHODS: The findings are taken from a larger study of perinatal survival in remote mountain villages of Nepal, conducted through a qualitative methodological approach within a framework of social constructionist and critical theoretical perspectives. Data were collected through in-depth interviews with 42 women and their families, plus a range of healthcare providers (nurses/auxiliary nurses, female health volunteers, support staff, Auxiliary Health Worker and a traditional healer) and other stakeholders from February to June, 2015. Data were analysed with a comprehensive coding process utilising the thematic analysis technique. RESULTS: The social construction of gender is one of the key factors influencing poor perinatal survival in the villages in this study. The key emerging themes from the qualitative data are: (1) Gendered social construct and vulnerability for poor perinatal survival: child marriages, son preference and repeated child bearing; (2) Pregnancy and childbirth in intra-familial dynamics of relationships and power; and (3) Perception of birth as a polluted event: birth in Gotha (cowshed) and giving birth alone. CONCLUSIONS: Motherhood among women of a low social position is central to women and their babies experiencing vulnerabilities related to perinatal survival in the mountain villages. Gendered constructions along the continuum from pre-pregnancy to postnatal (girl settlement, a daughter-in-law, ritual pollution about mother and child) create challenges to ensuring perinatal survival in these villages. It is imperative that policies and programmes consider such a context to develop effective working strategies for sustained reduction of future perinatal deaths.

Human fetal growth is constrained below optimal for perinatal survival.

OBJECTIVE: The use of fetal growth charts assumes that the optimal size at birth is at the 50(th) birth-weight centile, but interaction between maternal constraints on fetal growth and the risks associated with small and large fetal size at birth may indicate that this assumption is not valid for perinatal mortality rates. The objective of this study was to investigate the distribution and timing (antenatal, intrapartum or neonatal) of perinatal mortality and morbidity in relation to birth weight and gestational age at delivery. METHODS: Data from over 1 million births occurring at 28-43 weeks' gestation from singleton pregnancies without congenital abnormalities in the period from 2002 to 2008 were collected from The Netherlands Perinatal Registry. The distribution of perinatal mortality according to birth-weight centile and gestational age at delivery was studied. RESULTS: In the 1 170 534 pregnancies studied, there were 5075 (0.43%) perinatal deaths. The highest perinatal mortality occurred in those with a birth weight below the 2.3(rd) centile (25.4/1000 births) and the lowest mortality was in those with birth weights between the 80(th) and 84(th) centiles (2.4/1000 births), according to routinely used growth charts. Antepartum deaths were lowest in those with birth weight between the 90(th) and 95(th) centiles. Data were almost identical when the analysis was restricted to infants born at ≥ 37 weeks' gestation. CONCLUSION: From an immediate survival perspective, optimal fetal growth requires a birth weight between the 80(th) and 84(th) centiles for the population. Median birth weight in the population is, by definition, substantially lower than these centiles, implying that the majority of fetuses exhibit some form of maternal constraint on growth. This finding is consistent with adaptations that have evolved in humans in conjunction with a large head and bipedalism, to reduce the risk of obstructed delivery. These data also fit remarkably well with those on long-term adult cardiovascular and metabolic health risks, which are lowest in cases with a birth weight around the 90(th) centile.

Correlated responses on litter size traits and survival traits after two-stage selection for ovulation rate and litter size in rabbits.

Farmer profit depends on the number of slaughter rabbits. The improvement of litter size (LS) at birth by two-stage selection for ovulation rate (OR) and LS could modify survival rate from birth to slaughter. This study was aiming to estimate direct and correlated response on LS traits and peri- and postnatal survival traits in the OR_LS rabbit line selected first only for OR (first period) and then for OR and LS using independent culling levels (second period). The studied traits were OR, LS measured as number of total born, number of kits born alive (NBA) and dead (NBD), and number of kits at weaning (NW) and young rabbits at slaughter (NS). Prenatal survival (LS/OR) and survival at birth (NBA/LS), at weaning (NW/NBA) and at slaughter (NS/NW) were also studied. Data were analysed using Bayesian inference methods. Heritability for LS traits were low, 0.07 for NBA, NW and NS. Survival traits had low values of heritability 0.07, 0.03 and 0.03 for NBA/LS, NW/NBA and NS/NW, respectively. After six generations of selection by OR (first period), a small increase in NBD and a slight decrease in NBA/LS were found. However, no correlated responses on NW/NBA and NS/NW were observed. After 11 generations of two-stage selection for OR and LS (second period), correlated responses on NBA, NW and NS were 0.12, 0.12 and 0.11 kits per generation, respectively, whereas no substantial modifications on NBA/LS, NW/NBA and NS/NW were found. In conclusion, two-stage selection improves the number of young rabbits at slaughter without modifying survival from birth to slaughter.

Frequent refresher training on newborn resuscitation and potential impact on perinatal outcome over time in a rural Tanzanian hospital: an observational study.

OBJECTIVES: Globally, perinatal mortality remains high, especially in sub-Saharan countries, mainly because of inadequate obstetric and newborn care. Helping Babies Breathe (HBB) resuscitation training as part of a continuous quality improvement (CQI) programme may improve outcomes. The aim of this study was to describe observed changes in perinatal survival during a 6-year period, while adjusting for relevant perinatal risk factors. SETTING: Delivery rooms and operating theatre in a rural referral hospital in northern-central Tanzania providing comprehensive obstetric and basic newborn care 24 hours a day. The hospital serves approximately 2 million people comprising low social-economic status. PARTICIPANTS: All newborns (n=31 122) born in the hospital from February 2010 through January 2017; 4893 were born in the 1-year baseline period (February 2010 through January 2011), 26 229 in the following CQI period. INTERVENTIONS: The HBB CQI project, including frequent HBB training, was implemented from February 2011. This is a quality assessment analysis of prospectively collected observational data including patient, process and outcome measures of every delivery. Logistic regression modelling was used to construct risk-adjusted variable life adjusted display (VLAD) and cumulative sum (CUSUM) plots to monitor changes in perinatal survival (primary outcome). RESULTS: During the 6-year CQI period, the unadjusted number of extra lives saved according to the VLAD plot was 150 despite more women admitted with pregnancy and labour complications and more caesarean deliveries. After adjusting for these risk factors, the risk-adjusted VLAD plot indicated that an estimated 250 extra lives were saved. The risk-adjusted CUSUM plot confirmed a persistent and steady increase in perinatal survival. CONCLUSIONS: The risk-adjusted statistical process control methods indicate significant improvement in perinatal survival after initiation of the HBB CQI project with continuous focus on newborn resuscitation training during the period, despite a concomitant increase in high-risk deliveries. Risk-adjusted VLAD and CUSUM are useful methods to quantify, illustrate and demonstrate persistent changes in outcome over time.

Intrauterine transfusion for fetal anemia due to red blood cell alloimmunization: 14 years experience in Leuven.

OBJECTIVE: The purpose of this study is to report on the pregnancy and neonatal outcome of intrauterine transfusion (IUT) for red blood cell (RBC-)alloimmunization. MATERIAL AND METHODS: Retrospective cohort study of all IUT for RBC-alloimmunization in the University Hospital of Leuven, between January 2000 and January 2014. The influence of hydrops, gestational age and technique of transfusion on procedure related adverse events were examined. RESULTS: 135 IUTs were performed in 56 fetuses. In none of the cases fetal or neonatal death occurred. Mild adverse events were noted in 10% of IUTs, whereas severe adverse events occurred in 1.5%. Hydrops and transfusion in a free loop were associated with an increased risk of adverse events whereas gestational age (GA) at transfusion after 34 weeks was not. Median GA at birth was 35.6 weeks and 9% was born before 34 weeks. Besides phototherapy 65.4% required additional neonatal treatment for alloimmune anemia. Non-hematologic complications occurred in 23.6% and were mainly related to preterm birth. CONCLUSION: In experienced hands, IUT for RBC-alloimmunization is a safe procedure in this era. Patients should be referred to specialist centers prior to the development of hydrops. IUT in a free loop of cord and unnecessary preterm birth are best avoided.

Perinatal survival and health after maternal influenza A(H1N1)pdm09 vaccination: A cohort study of pregnancies stratified by trimester of vaccination.

Large cohort studies demonstrated the safety of vaccination with the AS03 adjuvanted pandemic influenza vaccine, but data on first trimester vaccination safety are limited. We conducted a nationwide register-based retrospective cohort study in Finland, included singleton pregnancies present on 01 November 2009 and followed them from 01 November 2009 until delivery. Pregnancies with abortive outcome, pregnancies that started before 01 February 2009 and pregnancies of women, who received the AS03 adjuvanted pandemic influenza vaccine prior to the onset of pregnancy, were excluded. Our main outcome measures were hazard ratios comparing the risk of stillbirth, early neonatal death, moderately preterm birth, very preterm birth, moderately low birth weight, very low birth weight, and being small for gestational age between pregnancies exposed and unexposed to maternal influenza A(H1N1)pdm09 vaccination. The study population comprised 43,604 pregnancies; 34,241 (78.5%) women were vaccinated at some stage during pregnancy. The rates of stillbirth, early neonatal death, moderately preterm birth, and moderately low birth weight were similar between pregnant women exposed and unexposed to influenza A(H1N1)pdm09 vaccination. After adjusting for known risk factors, the relative rates were 0.90 (95% confidence interval 0.55-1.45) for very preterm birth, 0.84 (0.61-1.16) for very low birth weight, and 1.17 (0.98-1.40) for being small for gestational age. Also, in the subanalysis of 7839 women vaccinated during the first trimester, the rates did not indicate that maternal vaccination during the first trimester had any adverse impact on perinatal survival and health. The risk of adverse pregnancy outcomes was not associated with the exposure to the AS03 adjuvanted pandemic influenza vaccine. This study adds reassuring evidence on the safety of AS03 adjuvanted influenza vaccines when given in the first trimester and supports the recommendation of influenza vaccination to all pregnant women through all stages of pregnancy.