Dupilumab provides sustained effectiveness on patient-reported outcomes and favorable safety in patients with moderate-to-severe atopic dermatitis: Up to 5-year results from the daily practice BioDay registry.

BACKGROUND: Long-term daily practice data on patient-reported benefits of dupilumab for atopic dermatitis (AD) remains limited. OBJECTIVE: To evaluate patient-reported outcome measures (PROMs) and the safety of dupilumab in patients with moderate-to-severe AD over a follow-up period of up to 5 years. METHODS: Data were extracted from the prospective, multicenter BioDay registry (October 2017-2022) of patients with moderate-to-severe AD treated with dupilumab in daily practice. RESULTS: In total 1223 patients, 1108 adults and 115 pediatric patients were included. After ≥1 year of treatment, mean Patient-Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), Numeric rating scale (NRS)-pruritus ranged between 7.8 and 8.7, 3.5 and 4.2, and 2.9 and 3.1 in adults, respectively, whilst these patient-reported outcome measures (PROMs) ranged between 8.9 and 10.9, 4.4 and 6.4, and 3.0 and 3.7 in pediatric patients, respectively. At follow-up, overall work impairment decreased from 40.1% to 16.3% to 13.3% in adults. Furthermore, class I obesity and itch-dominant patients generally had less favorable treatment response. Of all patients, 66.8% reported ≥1 adverse event, with conjunctivitis being the most common (33.7%). LIMITATIONS: The overall percentage of missing values for selected PROMs was 26% in adults and 46% in pediatric patients. CONCLUSION: In addition to favorable safety, dupilumab has demonstrated sustained effectiveness across various PROMs, underscoring the treatment benefits from patients' perspectives.

Real-world Experience of Abrocitinib Treatment in Patients with Atopic Dermatitis and Hand Eczema: Up to 28-week Results from the BioDay Registry.

Limited daily practice data on the effect of abrocitinib in patients with atopic dermatitis are available. The aim of this multicentre prospective study is to evaluate the effectiveness and safety of abrocitinib in patients with atopic dermatitis treated in daily practice. In a subgroup, the effectiveness of abrocitinib on hand eczema was evaluated. A total of 103 patients from the BioDay registry were included in the study: week 4 (n = 95), week 16 (n = 61) and week 28 (n = 39). At week 28, the Eczema Area and Severity Index (EASI)-50/75/90 was achieved by 81.8%, 57.6%, and 18.2%, respectively, and the weekly average pruritus numerical rating scale ≤ 4 by 62.9%. The effectiveness of abrocitinib was not significantly different between dupilumab non-responders and dupilumab-naïve patients/responders, and between upadacitinib non-responders and upadacitinib-naïve patients/responders. Mean ± standard deviation Hand Eczema Severity Index decreased from 27.4 ± 27.7 at baseline to 7.7 ± 12.1 at week 28 (n = 31). Thirty-two patients (31.1%) discontinued treatment due to ineffectiveness (n = 17), adverse events (n = 9) or both (n = 3). The most frequently reported adverse event was nausea (n = 28). In conclusion, abrocitinib is an effective treatment for atopic dermatitis and can be effective for patients with previous inadequate response to dupilumab or upadacitinib. Furthermore, hand eczema can improve in patients treated with abrocitinib for atopic dermatitis.

Efficacy and safety of dupilumab in patients with severe chronic hand eczema with inadequate response or intolerance to alitretinoin: a randomized, double-blind, placebo-controlled phase IIb proof-of-concept study.

BACKGROUND: Effective treatment options for patients with chronic hand eczema (CHE) are scarce. Dupilumab is licensed for the treatment of moderate-to-severe atopic dermatitis and has shown promising results for the treatment of hand eczema in other studies. OBJECTIVES: To evaluate the efficacy and safety of dupilumab in adult patients with severe CHE (subtypes recurrent vesicular hand eczema or chronic fissured hand eczema) who have an inadequate response/intolerance to alitretinoin, or when alitretinoin is medically inadvisable. METHODS: In this 16-week, randomized, double-blind, placebo-controlled proof-of-concept phase IIb trial, patients with severe CHE were randomized 2 : 1 to dupilumab 300 mg or placebo subcutaneously every 2 weeks. Patients visited the outpatient clinic at the initiation of the study drug, and every 4 weeks until 16 weeks of treatment. The primary endpoint was the proportion of patients achieving at least a 75% improvement on the Hand Eczema Severity Index score (HECSI-75) at week 16. Adverse events were monitored during each visit. The study was registered on ClinicalTrials.gov (identifier NCT04512339). RESULTS: In total, 30 patients were randomized, and 29 patients received the assigned study drug (dupilumab n = 20, placebo n = 9). At week 16, more patients achieved HECSI-75 in the dupilumab group than in the placebo group {95% [95% confidence interval (CI) 73.1-99.7] vs. 33% [95% CI 9.0-69.1]}. Dupilumab also showed greater least square mean percentage change from baseline to week 16 in peak pruritus Numerical Rating Scale compared with placebo [-66.5 ± 10.7 (95% CI -88.6 to -44.5) vs. -25.3 ± 17.0 (95% CI -60.1-9.4)]. Adverse events were similar for the dupilumab and placebo groups and were mostly mild. There were no serious adverse events, nor did any of the adverse events lead to discontinuation of the study drug. CONCLUSIONS: Dupilumab was efficacious and well tolerated. Larger studies of longer duration are needed to provide more evidence on the -efficacy of dupilumab in CHE. Moreover, larger studies could also enable comparisons between clinical subtypes or aetiological -diagnoses.

Successful tapering of dupilumab in patients with atopic dermatitis with low disease activity: a large pragmatic daily practice study from the BioDay registry.

BACKGROUND: Limited data are available regarding patient-centred dosing of dupilumab for atopic dermatitis (AD) in daily practice. OBJECTIVES: To evaluate our patient-centred dupilumab dosing regimen in daily practice, to assess prognostic factors for successful tapering and to estimate medication-related cost savings. METHODS: This prospective multicentre study included adult patients with AD, participating in the BioDay registry, treated with dupilumab for ≥ 1.3 years. Interval prolongation was considered in the case of dupilumab standard dose for ≥ 1 year and persistent controlled AD [Eczema Area and Severity Index (EASI) ≤ 7; ≥ 6 months]. Primary endpoints were the mean EASI and Numeric Rating Scale (NRS)-pruritus after the start of tapering. Prognostic factors for successful tapering were analysed with logistic regression and a cost-savings analysis was performed. RESULTS: A total of 595 patients were included, of whom 401 patients [mean EASI 2.5 (SD 2.3); NRS-pruritus of 2.4 (SD 1.9) at the start of tapering] prolonged their dupilumab interval. In 83.3% of these patients tapering was successful; most patients used dupilumab every 3 or 4 weeks (Q3W/Q4W). A significant small increase was observed for EASI (highest mean 3.5) and NRS-pruritus (highest mean 3.2) (P < 0.001); however, scores remained low. Predicting successful tapering showed nonsignificant odds ratios for all incorporated variables. The estimated cost savings was €3 977 033.98 for 401 patients between January 2019 and June 2022. CONCLUSIONS: This study showed successful tapering of dupilumab in 83.3% of patients with AD who attempted tapering, while maintaining controlled disease and with the majority using Q3W/Q4W. Interval prolongation can be beneficial both for the patient and from a socio-economic perspective.

Decrease in perinatal mortality after closure of obstetric services in a community hospital in Amsterdam, the Netherlands. A retrospective cohort study.

OBJECTIVE: To assess differences in adverse maternal and neonatal outcomes before and after closure of a secondary obstetric care unit of a community hospital in an urban district. STUDY DESIGN: Retrospective cohort study using aggregated data from National Perinatal Registry of the Netherlands (PERINED) in the very urban region of Amsterdam, consisting of data of five secondary and two tertiary hospitals. We assessed maternal and neonatal outcomes in singleton hospital births between 24+0 weeks of gestational age (GA) up to 42+6 weeks. Data of 78.613 births were stratified in two groups: before closure (years 2012-2015) and after closure (2016-2019). RESULTS: Perinatal mortality decreased significantly from 0.84 % to 0.63 % (p = 0.0009). The adjusted odds ratio (aOR) of the closure on perinatal mortality was 0.73 (95 % CI 0.62-0.87). Both antepartum death (0.46 % vs 0.36 %, p = 0.02) and early neonatal death (0.38 % vs 0.28 %, p = 0.015) declined after closure of the hospital. The number of preterm births decreased significantly (8.7 % vs 8.1 %, p=<0.007) as well as number of neonates with congenital abnormalities (3.2 % vs2.2 %, p=<0.0001). APGAR < 7 after 5 min increased (2.3 % vs 2.5 %, p = 0.04). There was no significant difference in SGA or NICU admission. Postpartum hemorrhage increased significantly from 7.7 % to 8.2 % (p=<0.003). Perinatal mortality from 32 weeks onwards was not significantly different after closure 0.29 % to 0.27 %. CONCLUSIONS: After closure of an obstetric unit in a community hospital in Amsterdam, there was a significant decrease in perinatal, intrapartum and early neonatal mortality in neonates born from 24+0 onwards. The mortality decrease coincides with a reduction of preterm deliveries. The increasing trend in asphyxia and postpartum hemorrhage is of concern.. Centralization of care and increasing birth volume per hospital may lead to improvement of quality of care. A broad integrated, multidisciplinary maternity healthcare system linked with the social domain can achieve health gains in maternity care for all women.

Experiences from daily practice of upadacitinib treatment on atopic dermatitis with a focus on hand eczema: Results from the BioDay registry.

BACKGROUND: Real-world data on the effectiveness of upadacitinib on atopic dermatitis (AD), hand eczema (HE) and HE in the context of AD are limited. OBJECTIVES: To evaluate the effectiveness and safety of upadacitinib on AD and on HE in patients with AD. METHODS: This prospective observational cohort study includes clinical outcomes: Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), Hand Eczema Severity Index (HECSI), Photographic guide; and PROMs: average pruritus and pain Numeric Rating Scale (NRS) score of the past week, Patient-Oriented Eczema Measure (POEM), Patient-Oriented Eczema, Dermatology Life Quality Index (DLQI), Atopic Dermatitis Control Tool (ADCT), Patient Global Assessment of Disease (PGAD), Quality Of Life Hand Eczema Questionnaire (QOLHEQ) at baseline, Week 4, and Week 16 of upadacitinib-treated patients. Adverse events were monitored during each visit. RESULTS: Thirty-eight patients were included, of which 32 patients had HE. At Week 16, EASI-75 was achieved by 50.0%. Absolute cutoff score NRS-pruritus ≤4 was reached by 62.5%, POEM ≤7 by 37.5%, DLQI ≤5 by 59.4%, ADCT <7 by 68.8%, and PGAD rating of at least 'good' by 53.1%. HECSI-75 was achieved by 59.3% and (almost) clear on the Photographic guide by 74.1%. The minimally important change in QOLHEQ was achieved by 57.9%. Sub-analysis in patients with concomitant irritant contact dermatitis showed no differences. Safety analysis showed no new findings compared to clinical trials. CONCLUSIONS: Upadacitinib can be an effective treatment for patients with AD and concomitant HE in daily practice. Future studies should focus on the effectiveness of upadacitinib on chronic HE, especially on the different etiological subtypes of HE, including HE in non-atopic individuals.

Dupilumab in daily practice for the treatment of pediatric atopic dermatitis: 28-week clinical and biomarker results from the BioDay registry.

BACKGROUND: Dupilumab has proven to be an effective and safe treatment for atopic dermatitis (AD) in pediatric patients in clinical trials. However, few daily practice studies are available. The aim of this study is to evaluate the effect of 28 weeks dupilumab treatment on effectiveness, safety, and serum biomarkers in pediatric patients with moderate-to-severe AD in daily practice. METHODS: Patients visited the outpatient clinic at baseline, 4, 16, and 28 weeks of treatment. Disease severity was assessed by the Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Numeric Rating Scale (NRS)-pruritus and -pain, and the Patient-Oriented Eczema Measure (POEM). Side effects were evaluated. Nineteen severity-associated serum biomarkers were measured. Predicted-EASI (p-EASI) was calculated. RESULTS: Sixty-one patients were included. Respectively 75.4%, 49.2%, and 24.6% reached EASI-50, EASI-75, and EASI-90 and 36.1% achieved an IGA-score (almost) clear. Improvement of ≥4 points on POEM, NRS-pruritus, and NRS-pain was reached by 84.7%, 45.3%, and 77.4%, respectively. Most reported side effects were conjunctivitis (n = 10) and headache (n = 4). Biomarkers TARC, PARC, periostin, sIL-2Ra, and eotaxin-3 significantly decreased during treatment. The p-EASI showed a significant correlation with disease severity. CONCLUSION: Dupilumab treatment significantly improved disease severity and disease-associated symptoms and decreased severity-associated serum biomarkers in pediatric AD patients in daily practice.

Daily Practice Experience of Baricitinib Treatment for Patients with Difficult-to-Treat Atopic Dermatitis: Results from the BioDay Registry.

Clinical trials have shown that baricitinib, an oral selective Janus kinase 1/2 inhibitor, is effective for the treatment of moderate-to-severe atopic dermatitis. However, daily practice data are limited. Therefore, this multicentre prospective study evaluated the effectiveness and safety of 16-weeks' treatment with baricitinib in adult patients with moderate-to-severe atopic dermatitis in daily practice. A total of 51 patients from the BioDay registry treated with baricitinib were included and evaluated at baseline and after 4, 8 and 16 weeks of treatment. Effectiveness was assessed using clinician- and patient-reported outcome measurements. Adverse events and laboratory assessments were evaluated at every visit. At week 16, the probability (95% confidence interval) of achieving Eczema Area and Severity Index ≤ 7 and numerical rating scale pruritus ≤ 4 was 29.4% (13.1-53.5) and 20.5% (8.8-40.9), respectively. No significant difference in effectiveness was found between dupilumab non-responders and responders. Twenty-two (43.2%) patients discontinued baricitinib treatment due to ineffectiveness, adverse events or both (31.4%, 9.8% and 2.0%, respectively). Most frequently reported adverse events were nausea (n = 6, 11.8%), urinary tract infection (n = 5, 9.8%) and herpes simplex infection (n = 4, 7.8%). In conclusion, baricitinib can be an effective treatment option for moderate-to-severe atopic dermatitis, including patients with non-responsiveness on dupilumab. However, effectiveness of baricitinib is heterogeneous, which is reflected by the high discontinuation rate in this difficult-to-treat cohort.

Unexplained infertility: Is it over-diagnosed and over-treated?

Unexplained infertility is defined as the absence of conception despite 12 months of unprotected intercourse, not explained by anovulation, poor sperm quality, tubal pathology or any known cause of infertility. The two most applied treatments for unexplained infertility are intra-uterine insemination and in vitro fertilisation. As these treatments do not target a specific mechanism but rather increase the probability of conception as compared to natural conception chances, they should be weighed against the prognosis of natural conception. The use of prognostic models could facilitate in identifying who benefits from treatment and who can delay treatment for 6 months, thus aiming for natural conception. This is important, as treatments can have side effects for the woman and her offspring, and their cost may jeopardise access to care.

Spontaneous and iatrogenic preterm birth rates among unselected women in three consecutive pregnancies.

OBJECTIVE: To assess the risk of sPTB and iPTB in women with three consecutive singleton pregnancies and the impact of the outcome of the 1st and 2nd pregnancy on the (recurrent) PTB risk in the 3rd pregnancy. STUDY DESIGN: A nationwide retrospective cohort study using the population based longitudinal linked dataset of the Netherlands. We included all nulliparous women with three consecutive singleton pregnancies ending between 22 and 44 weeks of gestation between 1999 and 2009. We excluded congenital abnormalities and stillbirths. We compared the incidence of sPTB and iPTB in the three pregnancies (<37, <34 and <30 weeks). Logistic regression analysis was performed to predict PTB in the 3rd pregnancy, adjusting for maternal age, fetal gender, socio-economic status, hypertension, interpregnancy interval, artificial reproductive technology, and small for gestational age. Analyses were also performed stratified by prior PTB subtype, gestational age and combined outcome of the 1st and 2nd pregnancy. RESULTS: We studied 52,978 women. PTB occurred in 7.0%, 3.7% and 3.4% in the 1st, 2nd and 3rd pregnancy, respectively. The outcome of the 2nd pregnancy is more predictive for PTB in the 3rd pregnancy then the outcome of the 1st pregnancy (sPTB aOR7.3 (95%CI 6.3-8.4) and iPTB (aOR 5.9 (95% CI 4.5-7.9) in 2nd pregnancy vs. sPTB aOR 3.0 (95% CI 2.6-3.4) and iPTB aOR 2.7 (95% CI 2.1-3.4) in the 1st pregnancy). In the prediction of sPTB in the 3rd pregnancy, sPTB in the 2nd pregnancy is most predictive (aOR8.2 (95% CI 7.1-9.6) and for prediction iPTB in the 3rd pregnancy, iPTB in the 2nd pregnancy is most predictive (aOR12.1 (95% CI 8.5-17.2). CONCLUSION: We studied a population with three subsequent singleton deliveries within 10 year. The incidence of PTB decreased with 50% from the 1st to the 2nd pregnancy, to then stay relative stable in the 3rd pregnancy. Compared to PTB in the 1st pregnancy, PTB in the 2nd pregnancy is more predictive for the occurrence of PTB in the 3rd pregnancy.

Effect of Cervical Cancer Screening Programs on Preterm Birth: A Decision and Cost-Effectiveness Analysis.

OBJECTIVE: To assess the effect of age at initiation and interval of cervical cancer screening in women of reproductive age on the risk of future preterm birth and subsequent adverse neonatal outcome relative to maternal life-years gained and cost of both screening and preterm birth. METHODS: In this decision and cost-effectiveness analysis, we compared eight cytology-based screening programs varying in age of onset (21, 24, 25, 27, or 30 years) and screening interval (3 or 5 years) in a fictive cohort of 100,000 women. We used the microsimulation screening analysis model to estimate number of cervical intraepithelial neoplasia diagnoses, large loop excisions of the transformation zone (LLETZs), life-years gained, cervical cancer cases, deaths, and costs of screening and treatment. We used the number of LLETZs to calculate additional preterm births, subsequent neonatal morbidity, mortality, and associated costs. RESULTS: The number of LLETZs per 100,000 women varied from 9,612 for the most intensive screening (every 3 years from age 21 years) to 4,646 for the least intensive screening (every 5 years from age 30 years). Compared with the least intensive program, the most intensive program increased maternal life-years gained by 9% (10,728 compared with 9,839), decreased cervical cancer cases by 67% (52 compared with 158), and cervical cancer deaths by 75% (four compared with 16) at the expense of 250% (158 compared with 45) more preterm births and 320% (four compared with one) more neonatal deaths while increasing total costs by $55 million ($77 compared with $23 million). The number of maternal life-years gained per additional preterm birth varied from 68 to 258 with subsequent total costs per maternal life-years gained of $7,212 and $2,329. CONCLUSION: Cervical cancer screening every 3 years and subsequent treatment in women aged younger than 30 years yield limited life-years but may have substantial perinatal adverse effects. Consequently, women who plan to have children may benefit from a more cautious screening approach, taking into account their risk for both cancer and preterm birth.

The Effect of Interpregnancy Interval on the Recurrence Rate of Spontaneous Preterm Birth: A Retrospective Cohort Study.

Objective We assessed, in women with a previous spontaneous preterm birth, the effect of interpregnancy interval on the subsequent preterm birth rate. Design Retrospective cohort study. Setting A nationwide longitudinal dataset of the the Netherlands Perinatal Registry. Population Women with three sequential singleton pregnancies between 1999 and 2009 and a spontaneous preterm birth <37 weeks in the first pregnancy. Methods We evaluated the impact of interpregnancy interval on the course of the next pregnancies. Antenatal death and/or congenital abnormalities were excluded. Conventional and conditional logistic regression analysis were applied. We adjusted for maternal age, ethnicity, socioeconomic status, artificial reproductive techniques, and year of birth. Main Outcome Measures Outcomes studied were preterm birth <37 weeks, <32 weeks, low birth weight <2500 g, and small for gestational age <10th percentile. Results Among 2,361 women with preterm birth in the first pregnancy, logistic regression analysis indicated a significant effect of a short interpregnancy interval (0-5 mo) on recurrent preterm birth <37 weeks (odds ratio [OR], 2.22; 95% confidence interval [CI], 1.62-3.05), <32 weeks (OR, 2.90; 95% CI, 1.43-5.87), and low birth weight (OR, 2.69; 95% CI, 1.79-4.03). In addition, a long interval (≥60 mo) had a significant effect on preterm birth <37 weeks (OR, 2.19; 95% CI, 1.29-3.74). Conditional logistic regression analysis confirmed the effect of a short interval on the recurrence of preterm birth rate <37 weeks and low birth weight. Conclusion In women with a previous spontaneous preterm birth, a short interpregnancy interval has a strong impact on the risk of preterm birth before 37 weeks and low birth weight in the next pregnancy, irrespective of the type of analysis performed.

The predictive value of quantitative fibronectin testing in combination with cervical length measurement in symptomatic women.

BACKGROUND: The combination of the qualitative fetal fibronectin test and cervical length measurement has a high negative predictive value for preterm birth within 7 days; however, positive prediction is poor. A new bedside quantitative fetal fibronectin test showed potential additional value over the conventional qualitative test, but there is limited evidence on the combination with cervical length measurement. OBJECTIVE: The purpose of this study was to compare quantitative fetal fibronectin and qualitative fetal fibronectin testing in the prediction of spontaneous preterm birth within 7 days in symptomatic women who undergo cervical length measurement. STUDY DESIGN: We performed a European multicenter cohort study in 10 perinatal centers in 5 countries. Women between 24 and 34 weeks of gestation with signs of active labor and intact membranes underwent quantitative fibronectin testing and cervical length measurement. We assessed the risk of preterm birth within 7 days in predefined strata based on fibronectin concentration and cervical length. RESULTS: Of 455 women who were included in the study, 48 women (11%) delivered within 7 days. A combination of cervical length and qualitative fibronectin resulted in the identification of 246 women who were at low risk: 164 women with a cervix between 15 and 30 mm and a negative fibronectin test (<50 ng/mL; preterm birth rate, 2%) and 82 women with a cervix at >30 mm (preterm birth rate, 2%). Use of quantitative fibronectin alone resulted in a predicted risk of preterm birth within 7 days that ranged from 2% in the group with the lowest fibronectin level (<10 ng/mL) to 38% in the group with the highest fibronectin level (>500 ng/mL), with similar accuracy as that of the combination of cervical length and qualitative fibronectin. Combining cervical length and quantitative fibronectin resulted in the identification of an additional 19 women at low risk (preterm birth rate, 5%), using a threshold of 10 ng/mL in women with a cervix at <15 mm, and 6 women at high risk (preterm birth rate, 33%) using a threshold of >500 ng/mL in women with a cervix at >30 mm. CONCLUSION: In women with threatened preterm birth, quantitative fibronectin testing alone performs equal to the combination of cervical length and qualitative fibronectin. Possibly, the combination of quantitative fibronectin testing and cervical length increases this predictive capacity. Cost-effectiveness analysis and the availability of these tests in a local setting should determine the final choice.

Fetal Gender of the First Born and the Recurrent Risk of Spontaneous Preterm Birth.

OBJECTIVE: To study, in women with a spontaneous preterm birth (sPTB) in the first pregnancy, the effect of fetal sex in that first pregnancy on the recurrent sPTB risk. STUDY DESIGN: A nationwide retrospective cohort study (data from National Perinatal Registry) on all women with two sequential singleton pregnancies (1999-2009) with the first delivery ending in sPTB <37 weeks. We used logistic regression analysis to study the association between fetal gender in the first pregnancy and the risk of recurrent sPTB. We repeated the analysis for sPTB < 32 weeks. RESULTS: The overall incidence of sPTB <37 weeks in the first pregnancy was 4.5% (15,351/343,853). Among those 15,351 women, the risk of recurrent sPTB <37 weeks was increased when the first fetus was female compared when that fetus was male (15.8 vs. 15.2%; adjusted odds ratio [aOR] 1.2; 95% confidence interval [CI] 1.05-1.3). A similar effect was seen for sPTB <32weeks (8.2 vs. 5.9%; aOR 4.5; 95% CI 1.5-13). CONCLUSION: Women who suffer sPTB of a female fetus have an increased risk of recurrent sPTB compared with women who suffer sPTB of a male fetus. This information provides proof for the hypothesis that sPTB is due to an independent maternal and fetal factor.

The risk of preterm birth of treated versus untreated cervical intraepithelial neoplasia (CIN): a systematic review and meta-analysis.

Cervical surgery is associated with preterm birth (PTB) and neonatal morbidity. However, it is unknown whether this increased risk is due to the surgery itself or to the cervical intraepithelial neoplasia (CIN) underlying the surgery. Our objective was to assess the risk for PTB in women with treated and untreated CIN. We performed an electronic literature search in MEDLINE, Embase and CENTRAL for studies that reported on pregnancy outcome after treated and untreated CIN. The methodological quality was scored using the STROBE combined checklist for observational studies. We extracted data on PTB<37 weeks, very PTB<32 weeks, spontaneous PTB<37 weeks, (preterm) premature rupture of membranes ((P)PROM), perinatal mortality and section caesarean each before and after treatment for CIN. We used the Mantel-Haenszel method to estimate summarizing odds ratios. Our search identified 620 studies, of which 20 were reporting on pregnancy outcome for a total of 12,159,293 women. There were 20,832 women who gave birth after treatment for CIN before pregnancy, 52 women who gave birth after treatment for CIN during pregnancy, 64,237 women with CIN who gave birth before treatment, and 8,902,865 women who gave birth without CIN. Compared to women with untreated CIN, women treated for CIN before or during pregnancy, had a significantly higher risk of PTB<37 weeks (OR 1.7, 95% CI 1.0-2.7). When comparing women treated for CIN before pregnancy (n=20,832) to women with untreated CIN (n=64,162), we found an OR of 1.4 with a 95% confidence interval of 0.85-2.3. Women treated during pregnancy had a clearly increased risk for PTB (OR 6.5, 95% CI 1.1-37), and (P)PROM (OR 1.8, 95% CI 1.4-2.2). In women with cervical surgery, the risks for spontaneous PTB<37 weeks (OR 0.87, 95% CI 0.54-1.4), caesarean section (OR 1.0, 95% CI 0.71-1.5) and perinatal mortality (OR 1.0, 95% CI 0.38-2.8) were not increased. The increased risk of PTB in women who underwent cervical surgery for CIN is especially increased when performed during pregnancy. When performed before pregnancy the risk of PTB is increased, although insignificant.

Ongoing pregnancy qualifies best as the primary outcome measure of choice in trials in reproductive medicine: an opinion paper.

The most appropriate primary outcome measure for reproductive medicine has been discussed frequently. In 2003 the European Society for Human Reproduction and Embryology recommended that the outcome measure of assisted reproductive technology (ART) and non-ART should be singleton live birth. Although live birth is indeed the aim of clinical practice, and there is no discussion that it should be reported in infertility trials, we hereby provide arguments that plead for using ongoing pregnancy as the primary outcome in such trials. We feel that ongoing pregnancy best serves the many purposes of a primary outcome and best reflects the effectiveness of a treatment.