Compliance with the pregnancy prevention program among women initiating isotretinoin treatment between 2014 and 2021: A nationwide cohort study on the French Health Data System (SNDS).

BACKGROUND: Despite the French pregnancy prevention program (PPP), a considerable number of pregnancies are potentially exposed to oral isotretinoin. New measures were taken by the French Medicines Agency, including the restriction of initial isotretinoin prescriptions to dermatology specialists in May 2015 and a new information campaign on teratogenicity in January 2019. OBJECTIVES: The aims were to: describe, between 2014 and 2021, compliance with PPP recommendations: isotretinoin use as a second-line treatment, first prescription by a dermatology specialist, monthly prescription renewal and pregnancy testing (PT); assess the effect of the 2015 and 2019 measures on PT compliance; and identify the determinants of PT noncompliance. METHODS: A retrospective cohort study was conducted among women aged 11-50 years initiating isotretinoin between 2014 and 2021 using the French Health Data System. PT compliance corresponded to pregnancy test completion and specific delays between prescription and dispensation. Time series analyses were performed to evaluate the effect of the 2015 and 2019 measures on PT compliance, and log-binomial and Poisson multivariate regression models were used to identify the determinants of PT noncompliance. RESULTS: Isotretinoin was prescribed as a second-line treatment in 64% of initiations, mainly by dermatology specialists (92%). A new monthly prescription was observed in 98% of dispensations. PT compliance reached 61%, 72% and 25% at initiation, renewals and end of treatment, respectively. The 2015 measure was associated with better PT compliance at initiation and renewals. The 2019 measure had no significant effect on PT compliance at the initiation or end of treatment but was associated with a decrease in PT compliance at renewals. Age, low socioeconomic level, initiation by a nondermatology specialist and during summer were associated with PT noncompliance. CONCLUSIONS: Understanding factors associated with PT noncompliance could help to target specific subpopulations of women treated with isotretinoin.

Prenatal natural history of congenital pulmonary malformations: MALFPULM population-based cohort study.

OBJECTIVES: To assess prenatal changes in the volume of congenital pulmonary malformations (CPM) and examine whether these changes differ in lesions that appear cystic on ultrasound compared with hyperechoic lesions, and to study the relationship between CPM volume and risk of fetal compression. METHODS: We conducted a nationally representative, multicenter, prospective cohort study, which included 579 ultrasound examinations in 176 pregnant women with a diagnosis of fetal CPM, between March 2015 and November 2016. Several ultrasound examinations were performed between diagnosis and delivery, including measurement of CPM volume. We modeled changes in CPM volume ratio (CVR) as a function of gestational age, overall and for cystic/mixed vs hyperechoic malformations, and examined the association between CVR and signs of compression during pregnancy. RESULTS: When modeling CVR changes over time, there was a statistically significant decrease in CVR with increasing gestational age (P < 0.001), but the pattern of change differed according to CPM phenotype at first ultrasound examination: cystic/mixed CPM were characterized by a monotonic decrease in CVR with increasing gestational age (P = 0.002), whereas hyperechoic CPM showed an initial increase in CVR up to 27 weeks of gestation, followed by a decrease thereafter (P < 0.001). Peak CVR values were predicted as early as 21-22 weeks for cystic/mixed CPMs compared with 25-26 weeks for hyperechoic malformations. Regardless of CPM phenotype, fetuses that showed no sign of compression at any point had substantially lower CVR at first CVR measurement, and the CVR remained relatively constant thereafter. Among the subpopulation of fetuses with no sign of compression at first CVR measurement, the odds of a subsequent compression was 7-fold higher (adjusted odds ratio, 7.0; 95% CI, 1.6-29.9) if initial CVR was > 0.4 vs CVR ≤ 0.4 cm2 . CONCLUSIONS: Predicted changes in CVR during pregnancy differ between cystic and hyperechoic malformations. This may be the result of different pathophysiological mechanisms or differences in the timing of occurrence of these different types of CPM. CVR measured at the initial diagnostic ultrasound examination was strongly associated with the odds of subsequent compression. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Prenatal diagnosis of pericallosal curvilinear lipoma: specific imaging pattern and diagnostic pitfalls.

We report the first series of cases of pericallosal curvilinear lipoma (CL) diagnosed prenatally and highlight the limitations in identifying a specific prenatal imaging pattern using ultrasound and magnetic resonance imaging (MRI). In all five of our cases, on ultrasound, the main feature leading to referral was a short corpus callosum. This subtle callosal dysgenesis was associated with a band of hyperechogenicity surrounding the corpus callosum, mimicking the pericallosal sulcus, which increased in size during the third trimester in three of the four cases in which sonographic follow-up was performed. On T2-weighted MRI, this band showed typical hypointensity in all cases; in contrast, on T1-weighted imaging, in only one case was there hyperintensity, suggestive of fat, as seen typically in the postnatal period. For appropriate prenatal counseling regarding outcome, it is important to identify or rule out CL when mild corpus callosal dysgenesis is observed. One should be aware of subtle diagnostic findings, such as a thin band of echogenicity surrounding the corpus callosum that is seen as a band of hypointensity on T2-weighted fetal MRI, and which may increase in size during gestation. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Prenatal unilateral cerebellar hypoplasia in a series of 26 cases: significance and implications for prenatal diagnosis.

OBJECTIVE: To define imaging patterns of unilateral cerebellar hypoplasia (UCH), discuss possible pathophysiological mechanisms and underline the etiology and prognosis associated with these lesions. METHODS: In this retrospective study we reviewed the charts of 26 fetuses diagnosed between 2003 and 2011 with UCH, defined by asymmetrical cerebellar hemispheres with or without decreased transverse cerebellar diameter. The review included analysis of the anatomy of the cerebellar hemispheres, including foliation, borders and parenchymal echogenicity, and of the severity of the hypoplasia. Data from clinical and biological work-up and follow-up were obtained. RESULTS: Our series could be divided into two groups according to whether imaging features changed progressively or remained constant during follow-up. In Group 1 (n = 8), the progression of imaging features, echogenic cerebellar changes and/or hyposignal in T2*-weighted MR images were highly suggestive of ischemic/hemorrhagic insult. In Group 2 (n = 18), imaging features remained constant during follow-up; UCH was associated with abnormal foliation in three proven cases of clastic lesions, a cystic lesion was noted in three cases of PHACE (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac abnormalities/aortic coarctation, eye abnormalities) syndrome and, in the remaining cases, UCH remained unchanged, with no imaging pattern typical of hemorrhage. In 24 cases the infant was liveborn and follow-up was continued in 23, for a mean period of 3 years. Among these, neurological complications were identified in seven (in one of seven (at a mean of 46 months) in Group 1 and in six of 16 (at a mean of 35 months) in Group 2). The surface loss of cerebellar hemisphere was > 50% in 19/24 fetuses and the vermis was clearly normal in appearance in 19/24. Predisposing factors for fetal vascular insult were identified in eight cases: these included maternal alcohol addiction, diabetes mellitus, congenital cytomegalovirus infection and pathological placenta with thrombotic vasculopathy and infarctions. CONCLUSION: UCH is defined as a focal lesion of the cerebellum that may be secondary to hemorrhage and/or ischemic insult, suggesting a clastic origin, particularly when imaging follow-up reveals changes over time. UCH may also be a clue for the prenatal diagnosis of PHACE syndrome. The amount of surface loss of cerebellar hemisphere does not correlate with poor prognosis. UCH with normal vermis is often associated with normal outcome.

Chemotherapy is not needed when complete evacuation of gestational choriocarcinoma leads to hCG normalization.

BACKGROUND: The standard treatment for gestational choriocarcinoma is chemotherapy. OBJECTIVE: To describe the risk of recurrence with expectant management of gestational choriocarcinoma that has reached a normal human chorionic gonadotropin level after tumor removal without adjuvant chemotherapy. METHODS: A retrospective multicenter international cohort study was conducted from 1981 to 2017 involving 11 gestational trophoblastic disease reference centers with patient's follow-up extended until 2023. Clinical and biological data of included patients were extracted from each center's database. The inclusion criteria were i) histological diagnosis of gestational choriocarcinoma in any kind of placental tissue retrieved, ii) spontaneous normalization of human chorionic gonadotropin level following choriocarcinoma retrieval, iii) patient did not receive any oncological treatment for the choriocarcinoma, iv) and at least 6 months of follow-up after the first human chorionic gonadotropin level normalization. RESULTS: Among 80 patients with retrieved gestational choriocarcinoma and whose human chorionic gonadotropin level normalized without any other oncological therapy, none had a recurrence of choriocarcinoma after a median follow-up of 50 months. The median interval between choriocarcinoma excision and human chorionic gonadotropin level normalization was 48 days. The International Federation of Gynecology and Obstetrics/World Health Organization risk score was ≤6 in 93.7% of the cases. CONCLUSIONS: This multicenter international study reports that selected patients with gestational choriocarcinoma managed in gestational trophoblastic disease reference centers did not experience any relapse when the initial tumor evacuation is followed by human chorionic gonadotropin level normalization without any additional treatment. Expectant management may be a safe approach for highly selected patients.

Impact of molecular genotyping on the diagnosis and treatment of human chorionic gonadotropin-producing tumors.

OBJECTIVES: To assess the use of molecular genotyping to accurately diagnose and treat human chorionic gonadotropin (hCG)-producing tumors and to evaluate the discriminating capacity of molecular testing on prognosis and overall survival. METHODS: We conducted a retrospective descriptive study of patients registered with the French Reference Center for Trophoblastic Disease between 1999 and 2021. We included all patients with hCG-producing tumors for whom results of molecular genotyping were available. RESULTS: Fifty-five patients with molecular genotyping were included: 81.2 % (n = 45) had tumors of gestational origin, 12.7 % (n = 7) of non-gestational origin and 5.5 % (n = 3) of undetermined origin. The results of molecular genotyping influenced the treatment decisions for 17 % of patients in this cohort. Overall survival was 93.3 % for patients with gestational tumors (after a median follow-up of 74 months) compared to 71.4 % for patients with non-gestational tumors (after a median follow-up of 23 months). CONCLUSION: In atypical presentations of hCG-producing tumors, molecular genotyping is a valuable tool to guide diagnosis and tailor treatment recommendations.

Risk of gestational trophoblastic neoplasia after hCG normalisation according to hydatidiform mole type.

OBJECTIVE: The risk of gestational trophoblastic neoplasia (GTN) after a hydatidiform mole (HM) is well known. However, the risk of GTN after normalisation of hCG in HM is poorly reported. The aim of this study was to evaluate the risk of GTN after normalisation of hCG according to HM types. METHODS: This prospective cohort study carried out between 2000 and 2010 used the database of the French Trophoblastic Disease Centre (FTDC). A total of 2008 registered patients with ascertained types of HM were analysed. Cases of GTN occurring after normalisation of hCG were analysed. RESULTS: A GTN developed in 239 out of 1980 HMs (12.1%) and 6 out of these 239 post-molar GTN (2.5%) were diagnosed after normalisation of hCG. The risk of GTN after normalisation of hCG was 0.34% (6/1747) following a HM, 0% (0/593) after a partial HM (PHM), 0.36% (4/1122) after a complete HM (CHM), and 9.5% (2/21) after a multiple pregnancy with HM. CONCLUSIONS: The risk of post-molar GTN justifies hCG monitoring in all women with HM. However, after normalisation of hCG, monitoring of PHM can be stopped safely while it should be maintained for CHM and more importantly for multiple pregnancies with HM.

Severe second-trimester obstructive ventriculomegaly related to disorders of diencephalic, mesencephalic and rhombencephalic differentiation.

By review of a series of cases, we set out to identify sonographic features suggestive of an obstructive mechanism in second-trimester fetuses with ventriculomegaly and describe developmental disorders related to pathological differentiation of the diencephalon, mesencephalon and rhombencephalon that lead to obstruction of cerebrospinal fluid flow. We studied retrospectively 11 fetuses referred for severe second-trimester ventriculomegaly of undetermined origin. Neurosonography was performed with detailed analysis of the third ventricle, thalami, cerebral aqueduct and cerebellum. The cerebral imaging data were compared with neuropathological data in eight patients, with a focus on the level and etiology of the obstruction. Parenchymal thinning and reduction of the pericerebral spaces were highly suggestive of ventriculomegaly due to an obstructive mechanism. The ventriculomegaly was related to diencephalosynapsis (thalamic fusion and third ventricle atresia) in five cases and partial/complete aqueduct stenosis in six; it was associated with cerebellar hypoplasia in six cases, including rhombencephalosynapsis in two cases. In nine patients, disorders of the diencephalon, mesencephalon and rhombencephalon were present. In cases of severe isolated ventriculomegaly in which sonographic features are suggestive of an obstructive mechanism, close examination of the third ventricle, thalami, aqueduct of Sylvius and cerebellum may reveal pathological differentiation of the diencephalon, mesencephalon or rhombencephalon, often in combination.

Impact of prenatal estimation of the risk of respiratory distress in neonates with congenital pulmonary malformations on the choice of delivery site.

BACKGROUND: The vast majority of prenatally diagnosed congenital pulmonary malformations (CPM) remain asymptomatic at birth. The maximal value of the CPM volume ratio (CVRmax) predicts the risk of neonatal respiratory distress (NRD), and should allow for better assessment of the level of expertise needed at the delivery site. AIM: This study evaluated the level of maternity units currently chosen for the delivery of CPMs, and determined the impact of the choice of delivery site based on the CVRmax, with a threshold of 0.4 cm2. METHODS: Data were extracted from the French prospective MALFPULM cohort, with inclusion between March 2015 and June 2018. RESULTS: The final study population consisted of 383 women. Deliveries in level 1 or 2 maternity units (n = 98, 25%) involved CPMs with lower CVRmax (p<0.001), causing fewer signs of prenatal compression (p = 0.025). Among the 62 children (16%) who presented with NRD, only seven (11%) were born in level 1 or 2 units (p = 0.0078). Choosing the maternity level according to the CVRmax would have increased the number of births in level 1 or 2 maternity hospitals by 70%. In these maternity units, the percentage of children with NRD would have increased from 8% in the actual distribution to 10% in the new strategy. CONCLUSION: Our results showed an overuse of level 3 maternity hospitals for the delivery of newborns with a prenatal diagnosis of CPM. The use of CVRmax should enable a reduction in the use of expertise centers without an adverse impact on newborns.

A report on the large measles outbreak in Lyon, France, 2010 to 2011.

In 2010 and 2011, the city of Lyon, located in the Rhône-Alpes region (France), has experienced one of the highest incidences of measles in Europe. We describe a measles outbreak in the Lyon area, where cases were diagnosed at Lyon University hospitals (LUH) between 2010 and mid-2011. Data were collected from the mandatory notification system of the regional public health agency, and from the virology department of the LUH. All patients and healthcare workers who had contracted measles were included. Overall, 407 cases were diagnosed, with children of less than one year of age accounting for the highest proportion (n=129, 32%), followed by individuals between 17 and 29 years-old (n=126, 31%). Of the total cases, 72 (18%) had complications. The proportions of patients and healthcare workers who were not immune to measles were higher among those aged up to 30 years. Consequently, women of childbearing age constituted a specific population at high risk to contract measles and during this outbreak, 13 cases of measles, seven under 30 years-old, were identified among pregnant women. This study highlights the importance of being vaccinated with two doses of measles vaccine, the only measure which could prevent and allow elimination of the disease.

[Toxoplasmosis in pregnancy: Practical Management]. / Toxoplasmose pendant la grossesse : proposition actuelle de prise en charge pratique.

The burden of congenital toxoplasmosis has become small in France today, in particular as a result of timely therapy for pregnant women, fetuses and newborns. Thus, the French screening and prevention program has been evaluated and recently confirmed despite a decline over time in the incidence of toxoplasmosis. Serological diagnosis of maternal seroconversion is usually simple but can be difficult when the first trimester test shows the presence of IgM, requiring referral to an expert laboratory. Woman with confirmed seroconversion should be referred quickly to an expert center, which will decide with her on treatment and antenatal diagnosis. Although the level of proof is moderate, there is a body of evidence in favor of active prophylactic prenatal treatment started as early as possible (ideally within 3 weeks of seroconversion) to reduce the risk of maternal-fetal transmission, as well as symptoms in children. The recommended therapies to prevent maternal-fetal transmission are: (1) spiramycin in case of maternal infection before 14 gestational weeks; (2) pyrimethamine and sulfadiazine (P-S) with folinic acid in case of maternal infection at 14 WG or more. Amniocentesis is recommended to guide prenatal and neonatal care. If fetal infection is diagnosed by PCR on amniotic fluid, therapy with P-S should be initiated as early as possible or continued in order reduce the risk of damage to the brain or eyes. Further research is required to validate new approaches to preventing congenital toxoplasmosis.

Predictive values of hCG clearance for risk of methotrexate resistance in low-risk gestational trophoblastic neoplasias.

BACKGROUND: Early identification of patients at high risk for chemoresistance among those treated with methotrexate (MTX) for low-risk gestational trophoblastic neoplasia (GTN) is needed. We modeled human chorionic gonadotropin (hCG) decline during MTX therapy using a kinetic population approach to calculate individual hCG clearance (CL(hCG)) and assessed the predictive value of CL(hCG) for MTX resistance. PATIENTS AND METHODS: A total of 154 patients with low-risk GTN treated with 8-day MTX regimen were retrospectively studied. NONMEM was used to model hCG decrease equations between day 0 and day 40 of chemotherapy. Receiver operating characteristic curve analysis defined the best CL(hCG) threshold. Univariate/multivariate survival analyses determined the predictive value of CL(hCG) and compared it with published predictive factors. RESULTS: A monoexponential equation best modeled hCG decrease: hCG(t) = 3900 x e(-0.149 x t). Median CL(hCG) was 0.57 l/day (quartiles: 0.37-0.74). Only choriocarcinoma pathology [yes versus no: hazard ratio (HR) = 6.01; 95% confidence interval (CI) 2.2-16.6; P < 0.001] and unfavorable CL(hCG) quartile (< or =0.37 versus >0.37 l/day: HR = 6.75; 95% CI 2.7-16.8; P < 0.001) were significant independent predictive factors of MTX resistance risk. CONCLUSION: In the second largest cohort of low-risk GTN patients reported to date, choriocarcinoma pathology and CL(hCG) < or =0.37 l/day were major independent predictive factors for MTX resistance risk.

Fetal right ventricular diverticulum with pericardial effusion: report of a new case treated by in utero pericardiocentesis.

Right ventricular diverticulum associated with pericardial effusion was diagnosed in a male fetus at 13 weeks of gestation. Screening for infectious, chromosomal, or structural disease was negative. Because there was concern about pulmonary hypoplasia, fetal pericardiocentesis was performed at 17 weeks of gestation. The pericardial fluid did not reaccumulate, and the diverticulum decreased and finally disappeared before the third trimester. The diverticulum could not be seen on the neonatal echocardiography scan performed on the full-term live baby, who was delivered vaginally. The child is doing well at 11 months of age. Given the good outcome of this case, in utero drainage should be considered in similar cases.

Technical aspects of laparoscopic ovarian autograft in ewes after cryopreservation by slow-cooling protocol.

Iatrogenic ovarian failure and infertility are long term-term side effects of anticancerous gonadotoxic treatments in children or women of reproductive year. Ovarian cortex cryopreservation can be a solution to preserve immature germinal cells before gonadotoxic treatment, for later transplantation. The aim of our study was to prove the efficiency of a laparoscopic technique for orthotopic graft after a slow-freezing/thawing protocol, and to evaluate the effect of ovarian cryopreservation and autograft on the primordial follicle survival rate. Experimental surgical study was performed on 6- to 12-month-old ewes. The study was approved by the ethic committee of the Lyon-veterinary-school. The left ovary was removed by laparoscopy and cut in half, and medulla was excised. In group 1 (n = 6), autograft was performed immediately on the right ovary, and in group 2 (n = 6), graft was performed after a slow-freezing/thawing protocol. The second hemi-ovary served as an ungrafted control fragment. A polypropylene/polyglactin mesh was included between graft and base to separate the two structures, to help histological analysis. The mean graft performance time was 71 +/- 8 min in the first group and 57 +/- 10 min in the second. Freezing did not affect the number of primordial follicles. In the ungraft control fragments, the global anomaly rate (cytoplasm plus nuclear anomaly) increased after freezing (p < 0.05). Others results did not reach signification. Pelvic adhesion occurred only once. The post-graft primordial follicle survival rate was 5.1 +/- 2.8% in the non-frozen group vs. 6.3 +/- 2.3% after freezing/thawing. Kruskal-Wallis and Wilkoxon non-parametric tests were used for statistical analysis. Laparoscopy seems to be a well-adapted technique for ovarian tissue orthotopic autograft. The main follicle loss occurs before graft revascularization. Our orthotopic graft's procedure has to be improved to obtain a better graft's neovascularization, and to have a better long-term post-graft primordial follicle survival rate.

Campomelic dysplasia: echographic suspicion in the first trimester of pregnancy and final diagnosis of two cases.

OBJECTIVE: Campomelic dysplasia (CD) is a rare skeletal dysplasia characterized by marked femoral and tibial angulations, hypoplasic scapulae, normal upper limbs and sex reversal in 3/4 of 46,XY fetuses. Most cases are lethal in the neonatal period. Heterozygous mutations in the SOX9 gene are responsible for CD. The diagnosis is not usually made until the mid-second trimester or later. METHODS: We describe 2 cases of CD suspected by ultrasonography in the first trimester. RESULTS: The 2 cases presented with hygroma colli along with anomalies in the lower but not the upper limbs. Terminations of pregnancy were obtained at 14+3 and 20+6 gestational weeks. Fetopathological examinations confirmed sonographic findings. CONCLUSION: When first trimester hygroma colli is accompanied by specific findings of the lower limbs, the diagnosis of CD can be investigated through SOX9 mutation analysis.

[Utility of fetal ultrasonography in the prenatal diagnosis of Smith-Lemli-Opitz syndrome]. / Apport de l'échographie foetale dans le diagnostic prénatal du syndrome de Smith-Lemli-Opitz.

Smith-Lemli-Opitz syndrome is a rare autosomal recessive genetic disorder which diagnosis is usually made postnatally. We describe a case of a prenatal diagnosis based only on specific ultrasound findings: intra-uterine growth retardation with facial dysmorphia, polydactyly and genital anomalies. We suggest giving more consideration to the ultrasound scanning for the diagnosis of the syndrome in the prenatal period.

Could fetal reduction induce facial cleft? Report of a case.

We describe a paramedian cleft of the lower lip that cannot be explained by embryological development in a child with only one predisposing factor, which was fetal reduction for a multiple pregnancy. To the best of our knowledge, there has been no report of a cleft that has been induced by the reduction of a multifetal pregnancy.