Changing diagnostic criteria for gestational diabetes (CDC4G) in Sweden: A stepped wedge cluster randomised trial.

BACKGROUND: The World Health Organisation (WHO) 2013 diagnostic criteria for gestational diabetes mellitus (GDM) has been criticised due to the limited evidence of benefits on pregnancy outcomes in different populations when switching from previously higher glycemic thresholds to the lower WHO-2013 diagnostic criteria. The aim of this study was to determine whether the switch from previous Swedish (SWE-GDM) to the WHO-2013 GDM criteria in Sweden following risk factor-based screening improves pregnancy outcomes. METHODS AND FINDINGS: A stepped wedge cluster randomised trial was performed between January 1 and December 31, 2018 in 11 clusters (17 delivery units) across Sweden, including all pregnancies under care and excluding preexisting diabetes, gastric bypass surgery, or multifetal pregnancies from the analysis. After implementation of uniform clinical and laboratory guidelines, a number of clusters were randomised to intervention (switch to WHO-2013 GDM criteria) each month from February to November 2018. The primary outcome was large for gestational age (LGA, defined as birth weight >90th percentile). Other secondary and prespecified outcomes included maternal and neonatal birth complications. Primary analysis was by modified intention to treat (mITT), excluding 3 clusters that were randomised before study start but were unable to implement the intervention. Prespecified subgroup analysis was undertaken among those discordant for the definition of GDM. Multilevel mixed regression models were used to compare outcome LGA between WHO-2013 and SWE-GDM groups adjusted for clusters, time periods, and potential confounders. Multiple imputation was used for missing potential confounding variables. In the mITT analysis, 47 080 pregnancies were included with 6 882 (14.6%) oral glucose tolerance tests (OGTTs) performed. The GDM prevalence increased from 595/22 797 (2.6%) to 1 591/24 283 (6.6%) after the intervention. In the mITT population, the switch was associated with no change in primary outcome LGA (2 790/24 209 (11.5%) versus 2 584/22 707 (11.4%)) producing an adjusted risk ratio (aRR) of 0.97 (95% confidence interval 0.91 to 1.02, p = 0.26). In the subgroup, the prevalence of LGA was 273/956 (28.8%) before and 278/1 239 (22.5%) after the switch, aRR 0.87 (95% CI 0.75 to 1.01, p = 0.076). No serious events were reported. Potential limitations of this trial are mainly due to the trial design, including failure to adhere to guidelines within and between the clusters and influences of unidentified temporal variations. CONCLUSIONS: In this study, implementing the WHO-2013 criteria in Sweden with risk factor-based screening did not significantly reduce LGA prevalence defined as birth weight >90th percentile, in the total population, or in the subgroup discordant for the definition of GDM. Future studies are needed to evaluate the effects of treating different glucose thresholds during pregnancy in different populations, with different screening strategies and clinical management guidelines, to optimise women's and children's health in the short and long term. TRIAL REGISTRATION: The trial is registered with ISRCTN (41918550).

Pregnancy outcomes for women with myasthenia gravis and their newborns: A nationwide register-based cohort study.

BACKGROUND AND PURPOSE: Few large-scale studies examine whether maternal myasthenia gravis (MG) is a risk factor for complications during pregnancy and childbirth. This study evaluated whether maternal MG is associated with an increased risk of adverse pregnancy, delivery, and neonatal outcomes. METHODS: We conducted a nationwide Swedish register-based cohort study of women who gave birth to singleton infants (≥22 gestational weeks) during 1987-2019. Exposed women were diagnosed with MG before or during the index pregnancy (N = 443). Unexposed women comprised 4249 women without a diagnosis of MG, matched for age, parity, hospital, and year of childbirth. The risks of adverse pregnancy, delivery, and neonatal outcomes for women with MG were estimated using regression modeling and presented as adjusted odds ratios (aOR). RESULTS: There was no increased risk of pregnancy complications in women with MG. Women with MG had a spontaneous onset of labor less often than women without MG (69.8% vs. 79.5%; aOR 0.59; p < 0.001) as well as higher labor induction rates and elective cesarean section deliveries (16.0% vs. 12.3%, aOR 1.42; p = 0.02 and 12.0% vs. 8.1%, aOR 1.59; p = 0.009). Infants of women with MG were born on average 2 days earlier (p = 0.002); however, these infants did not have a higher risk of having low APGAR, being small for gestational age, or having a congenital malformation. CONCLUSION: This first nationwide study of pregnancy in women with MG in Sweden demonstrates reassuring results overall, suggesting generally safe pregnancy outcomes for women with MG and their infants.

Obstetric anal sphincter injury in the second birth after perineal wound complication in the first birth: A nationwide register cohort study.

OBJECTIVE: To investigate whether perineal wound complications in the first birth, alone or in conjunction with obstetric anal sphincter injury (OASI), is associated with an increased risk of OASI in the second birth. DESIGN: Nationwide population-based cohort study. SETTING: Sweden. POPULATION: Women (n = 411 317) with first and second singleton vaginal births in Sweden, 2001-2019. METHODS: Data on diagnostic codes and surgical procedures were retrieved from the Swedish Medical Birth Register and the Swedish Patient Register. A perineal wound complication was defined as wound infection, dehiscence or perineal haematoma within 2 months of childbirth. MAIN OUTCOME MEASURES: Associations between wound complications in the first birth and OASI in the second birth were investigated with logistic regression and presented as adjusted odds ratios (aORs) with 95% confidence intervals (95% CIs). RESULTS: In total, 2619 (0.6%) women had a wound complication in the first birth, and 5318 (1.3%) had an OASI in the second birth. Women with a wound complication but no OASI in the first birth had more than doubled odds of OASI in the second birth (aOR 2.73, 95% CI 2.11-3.53). Women with OASI and a wound complication in the first birth had almost tenfold odds (aOR 9.97, 95% CI 6.53-15.24) of recurrent OASI. CONCLUSIONS: Perineal wound complication in the first birth increases the likelihood of OASI in a subsequent birth.

Biomarkers associated with cardiovascular disease in women with spontaneous preterm birth: A case-control study.

INTRODUCTION: Women with spontaneous preterm birth have an increased risk of cardiovascular disease later in life. Studies suggest potential pathophysiological mechanisms in common, but whether these could be identified by measurement of soluble circulating protein biomarkers in women with spontaneous preterm birth is unknown. The aim of this study was to determine if protein biomarkers associated with cardiovascular disease distinguish women with spontaneous preterm birth from healthy controls, both at pregnancy and at follow up. MATERIAL AND METHODS: Study participants were identified in the population-based Uppsala biobank of pregnant women in Sweden, where plasma samples were collected in mid-pregnancy. In a first screening phase, we identified participants who subsequently experienced spontaneous preterm birth (<37 weeks) in the index pregnancy (N = 13) and controls (N = 6). In these samples, differences in protein expression were examined by comparative mass spectrometry. In a second validation phase, we invited 100 cases with previous spontaneous preterm birth in the index pregnancy and 100 controls (matched for age, body mass index, and year of delivery) from the same source population, to a follow-up visit 4-15 years after pregnancy. At follow up, we collected plasma samples and data on cardiovascular risk factors. We measured concentrations of selected biomarkers identified in the screening phase, as well as lipid profiles in samples both from pregnancy (biobank) and follow up. CLINICALTRIALS: gov registration NCT05693285. RESULTS: In the screening phase, fibrinogen, cadherin-5, complement C5, factor XII, plasma kallikrein, apolipoprotein M, and vitamin D-binding protein differed significantly at pregnancy. In the validation phase, 65 women agreed to participate (35 cases and 30 controls), with a median follow-up time of 11.8 years since pregnancy. The concentration of fibrinogen (p = 0.02) and triglycerides (p = 0.03) were slightly higher in cases compared with matched controls at follow up. CONCLUSIONS: Compared with women without preterm birth, those with spontaneous preterm birth had slightly higher concentrations of fibrinogen, both at mid-pregnancy and a decade after pregnancy. Additionally, we found slightly higher concentration of triglycerides at follow up in women with previous spontaneous preterm birth. The relevance of this finding is uncertain but might indicate potential pathophysiological mechanisms in common between spontaneous preterm birth and cardiovascular disease.

Self-rated health in primiparous women with congenital heart disease before, during and after pregnancy - A register study.

Background. Poor maternal self-rated health in healthy women is associated with adverse neonatal outcomes, but knowledge about self-rated health in pregnant women with congenital heart disease (CHD) is sparse. This study, therefore, investigated self-rated health before, during, and after pregnancy in women with CHD and factors associated with poor self-rated health. Methods. The Swedish national registers for CHD and pregnancy were merged and searched for primiparous women with data on self-rated health; 600 primiparous women with CHD and 3062 women in matched controls. Analysis was performed using descriptive statistics, chi-square test and logistic regression. Results. Women with CHD equally often rated their health as poor as the controls before (15.5% vs. 15.8%, p = .88), during (29.8% vs. 26.8% p = .13), and after pregnancy (18.8% vs. 17.6% p = .46). None of the factors related to heart disease were associated with poor self-rated health. Instead, factors associated with poor self-rated health during pregnancy in women with CHD were ≤12 years of education (OR 1.7, 95%CI 1.2-2.4) and self-reported history of psychiatric illness (OR 12.6, 95%CI 1.4-3.4). After pregnancy, solely self-reported history of psychiatric illness (OR 5.2, 95%CI 1.1-3.0) was associated with poor self-rated health. Conclusion. Women with CHD reported poor self-rated health comparable to controls before, during, and after pregnancy, and factors related to heart disease were not associated with poor self-rated health. Knowledge about self-rated health may guide professionals in reproductive counselling for women with CHD. Further research is required on how pregnancy affects self-rated health for the group in a long-term perspective.

Combined maternal central adiposity measures in relation to infant birth size.

Improvement of prenatal identification of large-for-gestational-age (LGA) infants could lower the risk for adverse outcomes. Therefore, we sought to evaluate the association of a combination of maternal waist circumference (WC) and abdominal fat depths with infant birth size. A cohort study including 1240 women was performed between 2015 and 2018 at Uppsala University Hospital, Sweden. Maternal WC was measured at the first antenatal visit, and visceral (VF) and subcutaneous (SCF) fat depths by ultrasound at the second-trimester anomaly scan. Waist circumference, VF, and SCF were categorized as low or high (cut-offs WC ≥ 88 cm, VF ≥ 54 mm, SCF ≥ 21 mm). Outcomes were birth weight standard deviation score (BWSDS) and LGA (BWSDS > 90th and > 97th percentile). Secondary outcome was small-for-gestational-age (SGA, BWSDS < 10th and < 3rd percentile). Univariate analysis of variance and logistic regression analyses were performed adjusted for maternal weight, height, parity, smoking, country of birth, pregestational diabetes, and chronic hypertension. For both high and low WC, high VF was positively associated with BWSDS and LGA. There was no association with SGA. The results did not demonstrate any value of the combination of WC and fat depth measures in predicting infant birth size but suggested VF as a marker for large infants.

Novel Associations Between Mid-Pregnancy Cardiovascular Biomarkers and Preeclampsia: An Explorative Nested Case-Control Study.

Prediction of women at high risk of preeclampsia is important for prevention and increased surveillance of the disease. Current prediction models need improvement, particularly with regard to late-onset preeclampsia. Preeclampsia shares pathophysiological entities with cardiovascular disease; thus, cardiovascular biomarkers may contribute to improving prediction models. In this nested case-control study, we explored the predictive importance of mid-pregnancy cardiovascular biomarkers for subsequent preeclampsia. We included healthy women with singleton pregnancies who had donated blood in mid-pregnancy (~ 18 weeks' gestation). Cases were women with subsequent preeclampsia (n = 296, 10% of whom had early-onset preeclampsia [< 34 weeks]). Controls were women who had healthy pregnancies (n = 333). We collected data on maternal, pregnancy, and infant characteristics from medical records. We used the Olink cardiovascular II panel immunoassay to measure 92 biomarkers in the mid-pregnancy plasma samples. The Boruta algorithm was used to determine the predictive importance of the investigated biomarkers and first-trimester pregnancy characteristics for the development of preeclampsia. The following biomarkers had confirmed associations with early-onset preeclampsia (in descending order of importance): placental growth factor (PlGF), matrix metalloproteinase (MMP-12), lectin-like oxidized LDL receptor 1, carcinoembryonic antigen-related cell adhesion molecule 8, serine protease 27, pro-interleukin-16, and poly (ADP-ribose) polymerase 1. The biomarkers that were associated with late-onset preeclampsia were BNP, MMP-12, alpha-L-iduronidase (IDUA), PlGF, low-affinity immunoglobulin gamma Fc region receptor II-b, and T cell surface glycoprotein. Our results suggest that MMP-12 is a promising novel preeclampsia biomarker. Moreover, BNP and IDUA may be of value in enhancing prediction of late-onset preeclampsia.

Does Developing Interpregnancy Hypertension Affect the Recurrence Risk of Preeclampsia? A Population-Based Cohort Study.

BACKGROUND: Preeclampsia in a first pregnancy is a strong risk factor for preeclampsia in a second pregnancy. Whether chronic hypertension developed after a first pregnancy (interpregnancy hypertension) affects the recurrence risk of preeclampsia is unknown. METHODS: This is a population-based cohort study of 391,645 women with their first and second singleton births between 2006 and 2017. Exposure groups were women with preeclampsia in their first pregnancy, interpregnancy hypertension, or both risk factors. Women with neither risk factor were used as a reference group. We calculated the adjusted relative risk (aRR) with 95% confidence intervals (CIs) for overall preeclampsia in the second pregnancy as well as preterm (<37 gestational weeks) and term (≥37 gestational weeks) subgroups of the disease. RESULTS: Women with preeclampsia in their first pregnancy who did or did not develop interpregnancy hypertension had rates of preeclampsia in their second pregnancy of 21.5% and 13.6%, respectively. In the same population, the corresponding rates of preterm preeclampsia were 5.5% and 2.6%, respectively. After adjusting for maternal factors, women with preeclampsia in their first pregnancy who developed interpregnancy hypertension and those who did not have almost the same risk of overall preeclampsia in their second pregnancy (aRRs with 95% CIs: 14.51; 11.77-17.89 and 12.83; 12.09-13.62, respectively). However, preeclampsia in the first pregnancy and interpregnancy hypertension had a synergistic interaction on the outcome of preterm preeclampsia (aRR with 95% CI 26.66; 17.44-40.80). CONCLUSIONS: Women with previous preeclampsia who developed interpregnancy hypertension had a very high rate of preterm preeclampsia in a second pregnancy, and the two risk factors had a synergistic interaction.

Heart disease in pregnancy and risk of pre-eclampsia: a Swedish register-based study.

BACKGROUND AND AIMS: Pre-eclampsia complicates 3-5% of pregnancies worldwide and is associated with adverse outcomes for the mother and the offspring. Pre-eclampsia and heart failure have common risk factors, including hypertension, obesity and diabetes. It is not known whether heart failure increases the risk of pre-eclampsia. This study examines whether pregestational heart failure increases the risk of pre-eclampsia. METHODS: In a registry-based case-cohort study that included all pregnancies in Sweden (n=3 125 527) between 1990 and 2019, all pregnancies with pre-eclampsia (n=90 354) were identified and up to five control pregnancies (n=451 466) for each case were chosen, matched on the mother's birth year. Multiple logistic regression analysis was used to evaluate the impact of heart failure on the risk of pre-eclampsia, with adjustment for established risk factors and other cardiovascular diseases. RESULTS: Women with heart failure had no increased risk for pre-eclampsia, OR 1.02 (95% CI 0.69 to 1.50). Women with valvular heart disease had an increased OR of preterm pre-eclampsia, with an adjusted OR of 1.78 (95% CI 1.04 to 3.06). Hypertension and diabetes were independent risk factors for pre-eclampsia. Obesity, multifetal pregnancies, in vitro fertilisation, older age, Nordic origin and nulliparity were more common among women who developed pre-eclampsia compared with controls. CONCLUSION: Women with heart failure do not have an increased risk of pre-eclampsia. However, women with valvular heart disease prior to pregnancy have an increased risk of developing preterm pre-eclampsia independent of other known risk factors.

Breastfeeding in primiparous women with congenital heart disease - a register study.

BACKGROUND: The number of pregnant women with congenital heart disease (CHD) is rising, and the disease poses increased risks of cardiovascular and obstetric complications during pregnancy, potentially impacting breastfeeding success. This study aimed to investigate breastfeeding in primiparous women with CHD compared to primiparous women without CHD, and to examine potential hindering factors for breastfeeding in women with CHD. METHODS: The data were gathered between 2014 and 2019 and obtained by merging the Swedish Congenital Heart Disease Register (SWEDCON) with the Swedish Pregnancy Register. Primiparous women ≥ 18 years of age with CHD (n = 578) were matched by age and municipality to 3049 women without CHD, giving birth after 22 gestational weeks. Multivariable logistic regression analysis was used to identify factors associated with non-breastfeeding in women with CHD. RESULTS: Fewer women with CHD breastfed than women without CHD two days (94% vs. 97%, p = 0.001) and four weeks after birth (84% vs. 89%, p = 0.006). When all women were analysed, having CHD was associated with non-breastfeeding at both two days and four weeks after birth. For women with CHD, body mass index (BMI) ≥ 30 (OR 3.1; 95% CI 1.4, 7.3), preterm birth (OR 6.4; 95% CI 2.1, 19.0), self-reported history of psychiatric illness (OR 2.4; 95% CI 1.2, 5.1), small for gestational age (OR 4.2; 95% CI 1.4, 12.2), and New York Heart Association Stages of Heart Failure class II - III (OR 6.0; 95% CI 1.4, 26.7) were associated with non-breastfeeding two days after birth. Four weeks after birth, factors associated with non-breastfeeding were BMI ≥ 30 (OR 4.3; 95% CI 2.1, 9.0), self-reported history of psychiatric illness (OR 2.2; 95% CI 1.2, 4.2), and preterm birth (OR 8.9; 95% CI 2.8, 27.9). CONCLUSIONS: The study shows that most women with CHD breastfeed, however, at a slightly lower proportion compared to women without CHD. In addition, factors related to the heart disease were not associated with non-breastfeeding four weeks after birth. Since preterm birth, BMI ≥ 30, and psychiatric illness are associated with non-breastfeeding, healthcare professionals should provide greater support to women with CHD having these conditions.

Time to childbirth and assisted reproductive treatment in women with congenital heart disease.

OBJECTIVE: To investigate the time to first childbirth and to compare the prevalence of assisted reproductive treatment (ART) in women with congenital heart disease (CHD) compared with women without CHD. METHODS: All women in the national register for CHD who had a registered first childbirth in the Swedish Pregnancy Register between 2014 and 2019 were identified. These individuals (cases) were matched by birth year and municipality to women without CHD (controls) in a 1:5 ratio. The time from the 18th birthday to the first childbirth and the prevalence of ART was compared between cases and controls. RESULTS: 830 first childbirths in cases were identified and compared with 4137 controls. Cases were slightly older at the time for first childbirth (28.9 vs 28.5 years, p=0.04) and ART was more common (6.1% vs 4.0%, p<0.01) compared with controls. There were no differences in ART when stratifying for the complexity of CHD. For all women, higher age was associated with ART treatment (OR 1.24, 95% CI 1.20 to 1.28). CONCLUSIONS: Women with and without CHD who gave birth to a first child did so at similar ages. ART was more common in women with CHD, but disease severity did not influence the need for ART. Age was an important risk factor for ART also in women with CHD and should be considered in consultations with these patients.