First-trimester use of antiseizure medications and the risk of miscarriage: a population-based cohort study.

BACKGROUND: Antiseizure medications (ASMs) during the first trimester of pregnancy have been associated with an increased risk of miscarriage. METHODS: We carried out a population-based cohort study using routinely collected healthcare data from the UK, 1995-2018. Pregnancies were identified in the Clinical Practice Research Datalink and we estimated the HR of miscarriage associated with prescriptions of ASMs during the first trimester of pregnancy, using Cox regression, adjusting for potential confounders, including ASM indications. RESULTS: ASMs were prescribed during the first trimester in 7832 (0.8%) of 1 023 787 included pregnancies. 14.5% of pregnancies with first-trimester exposure to ASMs ended in miscarriage, while 12.2% without ASM exposure in the first trimester ended in miscarriage; after adjustment, there was a 1.06-fold relative hazard of miscarriage (95% CI 1.00 to 1.13) in women with first-trimester ASM use. After restricting to women with specific ASM indications, this association was not evident in women with epilepsy (adjusted HR 0.98, 95% CI 0.89 to 1.08), but was observed in women with bipolar or other psychiatric conditions (1.08, 95% CI 1.00 to 1.16) although CIs overlapped. Compared with discontinuation of ASMs prior to pregnancy, there was no evidence of increased risk of miscarriage for first-trimester ASM use in women with bipolar or other psychiatric conditions (1.02, 95% CI 0.87 to 1.20). CONCLUSION: We found no clear evidence to suggest that first-trimester ASM use increased the risk of miscarriage. Taken together, our analyses suggest that apparent associations between first-trimester ASM use and miscarriage may be the result of confounding by the presence of a bipolar disorder or associated unmeasured variables.

Antidepressants in pregnancy: applying causal epidemiological methods to understand service-use outcomes in women and long-term neurodevelopmental outcomes in exposed children.

Background: Antidepressants are commonly prescribed during pregnancy, despite a lack of evidence from randomised trials on the benefits or risks. Some studies have reported associations of antidepressants during pregnancy with adverse offspring neurodevelopment, but whether or not such associations are causal is unclear. Objectives: To study the associations of antidepressants for depression in pregnancy with outcomes using multiple methods to strengthen causal inference. Design: This was an observational cohort design using multiple methods to strengthen causal inference, including multivariable regression, propensity score matching, instrumental variable analysis, negative control exposures, comparison across indications and exposure discordant pregnancies analysis. Setting: This took place in UK general practice. Participants: Participants were pregnant women with depression. Interventions: The interventions were initiation of antidepressants in pregnancy compared with no initiation, and continuation of antidepressants in pregnancy compared with discontinuation. Main outcome measures: The maternal outcome measures were the use of primary care and secondary mental health services during pregnancy, and during four 6-month follow-up periods up to 24 months after pregnancy, and antidepressant prescription status 24 months following pregnancy. The child outcome measures were diagnosis of autism, diagnosis of attention deficit hyperactivity disorder and intellectual disability. Data sources: UK Clinical Practice Research Datalink. Results: Data on 80,103 pregnancies were used to study maternal primary care outcomes and were linked to 34,274 children with at least 4-year follow-up for neurodevelopmental outcomes. Women who initiated or continued antidepressants during pregnancy were more likely to have contact with primary and secondary health-care services during and after pregnancy and more likely to be prescribed an antidepressant 2 years following the end of pregnancy than women who did not initiate or continue antidepressants during pregnancy (odds ratioinitiation 2.16, 95% confidence interval 1.95 to 2.39; odds ratiocontinuation 2.40, 95% confidence interval 2.27 to 2.53). There was little evidence for any substantial association with autism (odds ratiomultivariableregression 1.10, 95% confidence interval 0.90 to 1.35; odds ratiopropensityscore 1.06, 95% confidence interval 0.84 to 1.32), attention deficit hyperactivity disorder (odds ratiomultivariableregression 1.02, 95% confidence interval 0.80 to 1.29; odds ratiopropensityscore 0.97, 95% confidence interval 0.75 to 1.25) or intellectual disability (odds ratiomultivariableregression 0.81, 95% confidence interval 0.55 to 1.19; odds ratiopropensityscore 0.89, 95% confidence interval 0.61 to 1.31) in children of women who continued antidepressants compared with those who discontinued antidepressants. There was inconsistent evidence of an association between initiation of antidepressants in pregnancy and diagnosis of autism in offspring (odds ratiomultivariableregression 1.23, 95% confidence interval 0.85 to 1.78; odds ratiopropensityscore 1.64, 95% confidence interval 1.01 to 2.66) but not attention deficit hyperactivity disorder or intellectual disability; however, but results were imprecise owing to smaller numbers. Limitations: Several causal-inference analyses lacked precision owing to limited numbers. In addition, adherence to the prescribed treatment was not measured. Conclusions: Women prescribed antidepressants during pregnancy had greater service use during and after pregnancy than those not prescribed antidepressants. The evidence against any substantial association with autism, attention deficit hyperactivity disorder or intellectual disability in the children of women who continued compared with those who discontinued antidepressants in pregnancy is reassuring. Potential association of initiation of antidepressants during pregnancy with offspring autism needs further investigation. Future work: Further research on larger samples could increase the robustness and precision of these findings. These methods applied could be a template for future pharmaco-epidemiological investigation of other pregnancy-related prescribing safety concerns. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/80/19) and will be published in full in Health Technology Assessment; Vol. 27, No. 15. See the NIHR Journals Library website for further project information.

About one in seven women experience depression during pregnancy. Left untreated, this may harm them and their unborn babies. However, the decision to take antidepressants during pregnancy is difficult because women often worry about the risks to their unborn baby. Research findings have been inconsistent, so women often do not have clear information to enable them to make informed decisions. We studied women's and children's outcomes after starting (compared with not starting) or continuing (compared with stopping) antidepressants in pregnancy. We used a large UK primary care database and several novel methods of analysis. We tracked 80,103 pregnancies of women with depression for up to 2 years after pregnancy. We also tracked 34,274 children from these pregnancies for at least 4 years to check for developmental outcomes. Women prescribed antidepressants were more likely than women not prescribed antidepressants to use general practice and mental health services during and after pregnancy, and to be prescribed antidepressants 2 years after pregnancy. This suggests that antidepressants were being prescribed to women with greater clinical need. Women who continued antidepressants in pregnancy had no higher likelihood than those who discontinued antidepressants of autism, attention deficit hyperactivity disorder or intellectual disability in their children. This should reassure women making the decision to continue taking their medications in pregnancy. Women who started antidepressants in pregnancy may possibly have had a slightly higher likelihood of autism in their children than those who did not start them. These findings were not seen in all analyses and were based on smaller numbers; therefore, they should be viewed with caution. Importantly, over 98 in every 100 children of women who initiated or continued antidepressants in pregnancy did not receive an autism diagnosis. The findings may help women and clinicians make informed decisions on treatment with antidepressants in pregnancy.

An evaluation into the use of procalcitonin levels as a biomarker of bacterial sepsis to aid the management of intrapartum pyrexia and chorioamnionitis.

BACKGROUND: Procalcitonin is an established biomarker for bacterial sepsis in the nonpregnant population with better diagnostic and prognostic value for bacterial infections. OBJECTIVE: This study aimed to evaluate whether procalcitonin levels could be used in the diagnosis and management of intrapartum sepsis in women and their neonates suspected of intrapartum bacterial sepsis. STUDY DESIGN: A prospective observational cohort study was conducted at the University Hospitals of Bristol and Weston NHS Foundation Trust. Overall, 117 women and their neonates managed for suspected intrapartum sepsis from June 2020 to October 2020 were included. Procalcitonin levels were measured in addition to routine biomarkers white cell count and C-reactive protein in women and their neonates during the initial septic screen and follow-up blood samples. The placentas underwent detailed histopathology. Maternal and neonatal parameters were used to categorize cases into "high-suspicion bacterial sepsis," "equivocal bacterial sepsis," and "low-suspicion bacterial sepsis." The Kruskal-Wallis test was used to compare categories with biomarker values and placental histology scores. RESULTS: Procalcitonin level was increased in 6 women in the initial septic screen sample, compared with 100 women with an increased C-reactive protein level. There was a significant difference in maternal postnatal procalcitonin results between "high-suspicion bacterial sepsis" and "low-suspicion bacterial sepsis" categories (P=.004). Moreover, 71.2% of placentas showed varying degrees of chorioamnionitis. CONCLUSION: In our cohort of women, 94.6% had normal procalcitonin levels while in labor at the time of the septic screen, consistent with the low number of confirmed bacteremia. The result provided a basis that procalcitonin may complement clinical judgment and interpretation of already used prognostic and diagnostic tests, improving patient care in the management of intrapartum sepsis.

Neonatal outcomes of pregnancies affected by haemolytic disease of the foetus and newborn and managed with intrauterine transfusion: a service evaluation.

BACKGROUND: This study, conducted in the tertiary Foetal Medicine Unit at St Michael's Hospital, Bristol, was designed to obtain information regarding neonatal outcomes of pregnancies affected by haemolytic disease of the foetus and newborn and managed by intrauterine transfusion, and to determine whether a change in intrauterine transfusion protocol in 2004 had improved safety. The new protocol included attendance of two Foetal Medicine Unit consultants, foetal sedation and use of the intrahepatic vein as an alternative route to placental cord insertion if deemed safer. MATERIALS AND METHODS: Data for pregnancies affected by haemolytic disease of the foetus and newborn as a result of haemolytic red cell alloimmunisation and managed with intrauterine transfusion at St Michael's Hospital between 1999 and 2009 were retrospectively collected using local databases, and medical note review. RESULTS: Overall, 256 relevant intrauterine transfusions were performed. The median number of intrauterine transfusions per pregnancy was two. Ninety-three per cent of the live deliveries had 5-minute APGAR scores ≥9 and 98% were admitted to a Neonatal Intensive Care Unit/Special Care Baby Unit, requiring phototherapy (96%), top-up transfusions (44%: 23.2% immediate, 13.4% late, 7.3% both), and exchange transfusion (37%). An association was found between increased intrauterine transfusion number and reduced phototherapy duration and hospital admission: each additional intrauterine transfusion reduced the duration of phototherapy by 16% (95% CI: 0.72-0.98), and Neonatal Intensive Care Unit/Special Care Baby Unit admission by 44% (95% CI: 0.48-0.66). Following the change in intrauterine transfusion protocol, there was a significant reduction in the number of emergency Caesarean sections occurring directly after an intrauterine transfusion (n =5 vs 0; P =0.02). The foetal loss rate within 48 hours of an intrauterine transfusion was 1.9% per pregnancy, or 0.8% per intrauterine transfusion: no losses occurred under the new protocol (n =3 vs 0; P = NS). DISCUSSION: Although the majority of neonates required admission to a Neonatal Intensive Care Unit/Special Care Baby Unit and phototherapy, the medium-term outcomes were positive. Importantly, the safety of the intrauterine transfusion procedure has improved significantly since the change in protocol.

Mardini-Nyhan association (lung agenesis, congenital heart, and thumb anomalies): three new cases and possible recurrence in a sib-is there a distinct recessive syndrome?

In 1985, Mardini and Nyhan described three patients from consanguineous families with unilateral complete/partial lung agenesis, congenital cardiac defects, and ipsilateral thumb anomalies. Although there have been many reports of lung agenesis with other malformations, especially hemifacial microsomia and radial ray anomalies, very few demonstrate this triad of defects. We describe three patients with the Mardini-Nyhan association which may represent a distinct entity, although this remains uncertain at present. A fourth patient is also described, the sister of one of the other patients, with complex congenital cardiac disease and bilateral lung lobation abnormalities. This is the first reported incidence of a possible recurrence within a family and suggests, together with the consanguinity observed by Mardini and Nyhan, that recessive inheritance should be considered in genetic counseling for this disorder.

Pelvic floor morbidity up to one year after difficult instrumental delivery and cesarean section in the second stage of labor: a cohort study.

OBJECTIVE: This study was undertaken to assess symptoms of pelvic floor morbidity at 6 weeks and at 1 year after difficult instrumental vaginal delivery or cesarean section during the second stage of labor. STUDY DESIGN: Prospective cohort study of 393 women with term, singleton, cephalic pregnancies who required operative delivery in surgery at full dilatation between February 1999 and February 2000. Postal questionnaires were used for follow-up at 6 weeks and at 1 year. RESULTS: Instrumental delivery was associated with a greater risk of urinary incontinence at 6 weeks and at 1-year postdelivery, adjusted odds ratio [OR] 7.8 (95% CI, 2.6-23.6) and OR 3.1 (95% CI, 1.3-7.6), respectively. Although instrumental delivery was associated with an increased risk of moderate-to-severe dyspareunia at 6 weeks, adjusted OR 3.35 (95% CI, 1.36-8.25), this difference was not significant at 1 year. Cesarean section after attempted instrumental delivery was associated with an increased risk of moderate-to-severe pain during intercourse at 1 year compared with immediate cesarean section, (18% vs 9%) P=.01. CONCLUSION: Although cesarean section at full dilatation does not completely protect women from pelvic floor morbidity, those that followed instrumental delivery had a significantly greater prevalence of urinary symptoms and dyspareunia. Urinary symptoms persist up to 1 year after delivery.

Women's views on the impact of operative delivery in the second stage of labour: qualitative interview study.

OBJECTIVE: To obtain the views of women on the impact of operative delivery in the second stage of labour. DESIGN: Qualitative interview study. SETTING: Two urban teaching hospitals in the United Kingdom. PARTICIPANTS: Purposive sample of 27 women who had undergone operative delivery in the second stage of labour between January 2000 and January 2002. KEY THEMES: Preparation for birth, understandings of the indications for operative delivery, and explanation or debriefing after birth. RESULTS: The women felt unprepared for operative delivery and thought that their birth plan or antenatal classes had not catered adequately for this event. They emphasised the importance of maintaining an open mind about the management of labour. They had difficulty understanding the need for operative delivery despite a review by medical and midwifery staff before discharge. Operative delivery had a noticeable impact on women's views about future pregnancy and delivery. CONCLUSIONS: Women consider postnatal debriefing and medical review important deficiencies in current care. Those who experienced operative delivery in the second stage of labour would welcome the opportunity to have a later review of their intrapartum care, physical recovery, and management of future pregnancies.

Cohort study of operative delivery in the second stage of labour and standard of obstetric care.

OBJECTIVE: To assess the maternal and neonatal morbidity following operative delivery in the second stage of labour in relation to the standard of obstetric care. DESIGN: Cohort study. SETTING: Maternity units in two teaching hospitals in Bristol, United Kingdom. Three hundred and ninety-three women with term, singleton, cephalic pregnancies who required operative delivery in theatre at full dilatation between February 1999 and February 2000. METHODS: Morbidity was compared for completed instrumental delivery, failed instrumental delivery and immediate caesarean section in relation to duration of second stage of labour, number of pulls at attempted instrumental delivery, number of instruments used and operator experience. MAIN OUTCOME MEASURES: Maternal trauma, admission to special care baby unit, neonatal trauma. RESULTS: Failed instrumental delivery after a long second stage of labour was associated with increased maternal trauma (adjusted odds ratios [OR] 4.1, 95% confidence interval [CI] 1.1, 16.5). More than three pulls at attempted instrumental delivery was associated with increased neonatal trauma for completed (adjusted OR 4.2, 95% CI 1.6, 9.5) and failed deliveries (adjusted OR 7.2, 95% CI 2.1, 24.0). Babies delivered after failed instrumental delivery with more than three pulls were at increased risk of admission to special care baby unit (adjusted OR 6.2, 95% CI 1.6, 22.8) The use of multiple instruments was associated with increased neonatal trauma (adjusted OR 3.1, 95% CI 1.5, 6.8; adjusted OR 4.4, 95% CI 1.3, 14.4, for completed and failed deliveries, respectively). Excessive pulls and multiple instrument use were associated with an initial attempt at vaginal delivery by an inexperienced operator, 25/48 (52%) and 34/75 (45%). CONCLUSIONS: Guidelines for safe operative delivery in the second stage of labour should be developed and adhered to in order to reduce morbidity, particularly neonatal trauma.

Cohort study of maternal views on future mode of delivery after operative delivery in the second stage of labor.

OBJECTIVE: The purpose of this study was to assess maternal views on the future mode of delivery after either previous instrument vaginal delivery or cesarean delivery at full dilatation. STUDY DESIGN: We conducted a prospective cohort study of 393 women with term singleton cephalic pregnancies. RESULTS: More than one half of the cohort intended to have a further pregnancy, with no significant differences between the instrument vaginal delivery and caesarean delivery groups (51% vs 54% before discharge; adjusted odds ratio, 1.04; 95% CI, 0.2, 6.0), and there was little change in maternal views over time. Women were more likely to aim for a future vaginal delivery after an instrument vaginal delivery (79% vs 39% before discharge; adjusted odds ratio, 4.5; 95% CI, 2.2, 9.2), but the proportion decreased over time (68% vs 42% at 1 year; adjusted odds ratio, 3.6; 95% CI, 1.6, 8.1). There were no significant differences in preferred future mode of delivery for women who had a caesarean delivery after a failed instrument delivery and those who were delivered by immediate caesarean delivery. CONCLUSION: A high proportion of women who have had a previous difficult instrument vaginal delivery would still prefer vaginal delivery in a future pregnancy.

Effect of operative delivery in the second stage of labor on breastfeeding success.

BACKGROUND: Operative delivery rates are currently rising in many countries, but the effects of this factor on the initiation and duration of breastfeeding are unclear. The purpose of this study was to evaluate breastfeeding success after instrumental vaginal delivery or cesarean section at full dilatation, and to investigate whether timing of discharge after operative delivery affects breastfeeding rates. METHODS: A prospective cohort study was conducted of 393 women with term, singleton, live, cephalic pregnancies who required delivery in theater during the second stage of labor between February 1999 and February 2000. Postal questionnaires were mailed to participants at 6 weeks and 1 year. Logistic regression models were used to explore the relationships between infant feeding and mode of delivery, controlling for factors previously correlated with breastfeeding success. RESULTS: Rates of exclusive breastfeeding at discharge and 6 weeks postpartum were 70 and 44 percent, respectively. No significant differences occurred when instrumental vaginal delivery was compared with cesarean section, adjusted OR 0.84 (95% CI 0.50, 1.41) and 1.15 (95% CI 0.69, 1.93) respectively. Breastfeeding rates after failed instrumental delivery were similar to those after immediate cesarean section, adjusted OR 0.99 (95% CI 0.72, 1.38) and 1.28 (95% CI 0.91, 1.78). Women who had a longer in-patient stay after cesarean section were more likely to achieve exclusive breastfeeding at hospital discharge (78% vs 66%, p = 0.03). CONCLUSIONS: Method of operative delivery in the second stage of labor does not appear to influence initiation or duration of exclusive breastfeeding. A longer inpatient stay may help cesarean-delivered women to initiate breastfeeding.