Estelle Heggarty

Jeanne Sibiude

Laurent Mandelbrot

Christelle Vauloup-Fellous

Olivier Picone
email: olivier.picone@aphp.fr

Pr Olivier Picone

Genital herpes and pregnancy: Evaluating practices and knowledge of French health care providers

Keywords: Herpes Simplex Virus infection, genital herpes, pregnancy, neonatal herpes

BACKGROUND

Genital herpes during pregnancy is a frequent occurrence, whereas infection of newborns is rare but likely severe. In the absence of specific national guidelines from the CNGOF (French National College of Gynaecologists and Obstetricians) in France until December 2017, we supposed that knowledge of health care providers on the topic was not up to date.

OBJECTIVE

To assess health care provider knowledge of genital herpes and management practices during pregnancy, before the publication of national recommendations edited by the CNGOF.

STUDY DESIGN

A questionnaire on genital herpes during pregnancy was published on the CNGOF website and sent by e-mail to members of the French College of Fetal Ultrasound (CFEF). Questions focused on prevention and screening practices, epidemiological knowledge, and management of herpes infection during pregnancy and after birth.

RESULTS

Between April and June 2017, 354 health care providers completed the survey (263/354 (75%) Obstetrician-Gynaecologists, 85/354 (24%) Midwives and 6/354 (2%) General Practitioners). Overall, obstetricians were better informed about epidemiology of Herpes Simplex Virus (HSV), midwives were more familiar with neonatal risks in case of maternal primary infection but overestimated risks in case of maternal recurrence. 21% of health care providers never prescribed antiviral prophylaxis in the third trimester if genital herpes occurred during pregnancy. Finally, most practitioners were unaware of newborn management in case of maternal genital herpes at delivery.

CONCLUSION

Management of genital herpes in pregnancy appears to be heterogeneous due to varying degrees of knowledge among French health care providers. This highlights the urgent need for national guidelines, that were published 5 months after this study. They should be broadly disseminated and adapted to the shortcomings of health professionals. It would be interesting to repeat this study later to evaluate the impact of national guidelines.

4

Introduction

Genital herpes during pregnancy is a frequent situation every practitioner should be aware of. French epidemiology data on genital herpes is scarce but one study reported that only 12% of pregnant women have never been in contact with any Herpes Simplex Virus (HSV) [START_REF] Legoff | Unexpected high prevalence of herpes simplex virus (HSV) type 2 seropositivity and HSV genital shedding in pregnant women living in an East Paris suburban area[END_REF]. Genital herpes is usually a mild neurological sequelae [START_REF] Corey | Difference between herpes simplex virus type I and type 2 neonatal encephalitis in neurological outcome[END_REF]. The CNGOF (Colège National des Gynécologues et Obstétriciens Français, or French National College for Gynaecologists and Obstetricians) issued recommendations on HSV infection during pregnancy and neonatal period in December 2017 [START_REF] Sénat | Herpes and pregnancy: Guidelines for clinical practice-introduction[END_REF][START_REF] Picone | Genital herpes and pregnancy: Epidemiology, clinical manifestations, prevention and screening. Guidelines for clinical practice from the French College of Gynecologists and Obstetrician (CNGOF)[END_REF][START_REF] Vauloup-Fellous | Genital herpes and pregnancy: serological and molecular diagnostic tools. Guidelines for clinical practice from the French College of Gynecologists and Obstetricians (CNGOF)[END_REF][START_REF] Renesme | Neonatal herpes: Epidemiology, clinical manifestations and management. Guidelines for clinical practice from the French College of Gynecologists and Obstetricians (CNGOF)[END_REF][START_REF] Anselem | Management of pregnant women with recurrent herpes. Guidelines for clinical practice from the French College of Gynecologists, Obstetricians (CNGOF)[END_REF][START_REF] Sananes | Management of pregnant women with first episode of genital herpes. Guidelines for clinical practice from the French college of gynecologists and obstetricians (CNGOF)[END_REF]. Previously, practitioners could rely on several international guidelines (ACOG 2007 [START_REF] Acop | ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. No. 82[END_REF], CDC 2015 [START_REF] Workowski | Sexually transmitted diseases treatment guidelines, 2015[END_REF], RCOG 2014 [START_REF] Foley | Management of Genital Herpes in Pregnancy[END_REF], SA 2017 [START_REF] South | Neonatal and Gynaecology Community of Practice. South Australian Perinatal Practice Guidelines Genital Herpes Simplex (HSV) Infection in Pregnancy[END_REF], SOGC 2008 updated in 2017 [START_REF] Money | No. 208-Guidelines for the Management of Herpes Simplex Virus in Pregnancy[END_REF]) but information was sometimes contradictory (e.g. antiviral treatment recommended in case of HSV recurrence, or management of HSV infection during delivery). Moreover, not all situations were described (e.g. management in case of premature rupture of membranes). Therefore, management of genital and neonatal herpes in France was possibly heterogenous and health care providers knowledge not optimal.

Objective

Our aim was to evaluate health care provider knowledge, and to collect information on management of genital and neonatal herpes in France before the publication of national recommendations.

Methods

5

A Google Form survey with 40 questions on genital and neonatal HSV was designed (additional data). The link was published on the CNGOF website and sent by e-mail to CFEF (Collège Français d'Echographie Foetale, or French College of Fetal Ultrasound) members. The link was also posted on social media, such as Facebook, and was shared via e-mail to members of perinatal networks, by respondents themselves.

The estimated time to complete the survey was 10 minutes. The form was anonymous. Respondents were first asked to provide their age, area of practice, and professional field. The questionnaire included items on epidemiology, prevention and screening practices, HSV infection management during pregnancy, at birth and postpartum. Answers were collected between April and June 2017. There was neither patient nor public involvement in this study.

Multiple answers for each question were accepted. Results were compared between the different groups (midwives, obstetricians and general practitioners) using Fisher's exact test and Chi2 as appropriate for categorical variables.

Statistical analyses were performed using Excel and RStudio programming software.

Results

A total of 354 French health care professionals completed the survey: 263/354 (74%) were obstetricians, 85/354 (23%) were midwives, and 6/354 (2%) were general practitioners. Statistical comparison between groups was only performed between obstetricians and midwives due to the limited number 6 of general practitioners who answered the questionnaire.

Characteristics of the respondents are shown in Table 1.

Questions were classified as follows:

1. General knowledge on genital HSV epidemiology (Table 2) 2. Management of genital HSV primary infection during pregnancy (Table 3) 3. Management of genital HSV recurrence during pregnancy (Table 4) 4. Management of genital HSV infection during labour (Table 5)

Management of asymptomatic newborns born to mothers with genital

HSV primary infection during labour (Table 6) 6. Management of asymptomatic newborns born to mothers with genital HSV recurrence during labour (Table 7) 7. Knowledge and management of neonatal HSV infection acquired in the post-partum period (Table 8) 2) [START_REF] Legoff | Unexpected high prevalence of herpes simplex virus (HSV) type 2 seropositivity and HSV genital shedding in pregnant women living in an East Paris suburban area[END_REF](14)[START_REF] Tran | Changing epidemiology of genital herpes simplex virus infection in Melbourne, Australia, between 1980 and 2003[END_REF][START_REF] Gaytant | Seroprevalences of herpes simplex virus type 1 and type 2 among pregnant women in the Netherlands[END_REF][START_REF] Brown | Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor[END_REF][START_REF] Cone | Frequent detection of genital herpes simplex virus DNA by polymerase chain reaction among pregnant women[END_REF] Our results show that health care providers in general and especially midwives did not know that genital herpes can be due to HSV1 as well as HSV2 (94% of respondents were aware that HSV2 is a cause of genital herpes and 18.8 % of midwives versus 4.2% of obstetricians answered that HSV1 can never be responsible for it (p<0.001)). In literature, it is reported that 74% of genital herpes is secondary to HSV2, but that there is a growing part of HSV1 in newly 7 acquired genital HSV infections [START_REF] Tran | Changing epidemiology of genital herpes simplex virus infection in Melbourne, Australia, between 1980 and 2003[END_REF]. Up to 48% of respondents always ask patients about their personal history of genital herpes, but only 8.8% inquire about their partners' history of HSV infection. HSV serologies for screening purposes were prescribed by 12% of respondents in accordance with foreign recommendations [START_REF] South | Neonatal and Gynaecology Community of Practice. South Australian Perinatal Practice Guidelines Genital Herpes Simplex (HSV) Infection in Pregnancy[END_REF]. Prevalence of HSV (1 or 2) asymptomatic excretion during labour (0.4-10%) [START_REF] Brown | Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor[END_REF][START_REF] Cone | Frequent detection of genital herpes simplex virus DNA by polymerase chain reaction among pregnant women[END_REF][START_REF] Brown | The acquisition of herpes simplex virus during pregnancy[END_REF] is known by 84.5% of practitioners. 3) [START_REF] Sananes | Management of pregnant women with first episode of genital herpes. Guidelines for clinical practice from the French college of gynecologists and obstetricians (CNGOF)[END_REF][START_REF] Brown | Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant[END_REF][START_REF] Sheffield | Acyclovir prophylaxis to prevent herpes simplex virus recurrence at delivery: a systematic review[END_REF] Midwives were the most aware that in cases of genital lesions in women with no history of genital herpes, virologic confirmation by Polymerase Chain Reactions (PCR) and HSV specific-Immunoglobulin-G typing are necessary to confirm the diagnosis (62.4% vs 47.7%, respectively, p=0.003). In case of no known genital herpes history, HSV specific serology can help distinguish a primary infection from a recurrence since IgG can take up to 6 weeks to become positive [START_REF] Sauerbrei | Herpes genitalis: diagnosis, treatment and prevention[END_REF]. Following HSV primary infection during pregnancy, antiviral prophylaxis during the third trimester was recommended by only 68.4% of practitioners although it is recommended in all available international guidelines (9-13). 4) [START_REF] Anselem | Management of pregnant women with recurrent herpes. Guidelines for clinical practice from the French College of Gynecologists, Obstetricians (CNGOF)[END_REF] Although this is the management suggested by international guidelines 8 (9,10), only 2.7% of respondents do not prescribe any virologic confirmation, either by PCR or by HSV-specific serology. Only 59% of obstetricians and 43.5% of midwives declared never prescribing antiviral therapy in this situation (p<0.001). 5) [START_REF] Sananes | Management of pregnant women with first episode of genital herpes. Guidelines for clinical practice from the French college of gynecologists and obstetricians (CNGOF)[END_REF] In case of genital HSV primary infection during labour (with intact membranes), 84% of respondents recommend performing a cesarean delivery. In case of genital HSV recurrence, 82.5% also recommend a cesarean delivery, (no significant difference between obstetricians and midwives). 6) [START_REF] Brown | Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant[END_REF][START_REF] Kimberlin | Guidance on management of asymptomatic neonates born to women with active genital herpes lesions[END_REF][START_REF] Kimberlin | Herpes simplex virus infections in neonates and early childhood[END_REF] Both obstetricians and midwives (70.9% of total respondents) were aware that this situation is at high risk of transmission for newborns. 12.5% of respondents stated they would not admit to neonatal intensive care asymptomatic newborns born to mothers with genital HSV primary infection.

General knowledge on genital HSV epidemiology (Table

Management of genital HSV primary infection during pregnancy (Table

Management of genital HSV recurrence during pregnancy (Table

Management of genital HSV infection during labour (Table

Management of asymptomatic newborns born to mothers with genital HSV primary infection during labour (Table

32.5% of respondents believed that they do not require systematic antiviral treatment. In literature, it is known that newborns may not present skin lesions at the time of HSV infection [START_REF] Kimberlin | Natural history of neonatal herpes simplex virus infections in the acyclovir era[END_REF][START_REF] Whitley | Vidarabine therapy of neonatal herpes simplex virus infection[END_REF].

For each question concerning the management of asymptomatic newborns, 16 to 25% of respondents declared they did not know the expected answer. 9 7) [START_REF] Brown | Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant[END_REF][START_REF] Kimberlin | Guidance on management of asymptomatic neonates born to women with active genital herpes lesions[END_REF] Midwives overestimated the risk of severe neonatal herpes more often than obstetricians (51.8 vs 38.0%, respectively, p=0.03). Literature indicates that this risk is low (isolated cases) [START_REF] Brown | Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant[END_REF]. 8) [START_REF] Acop | ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. No. 82[END_REF][START_REF] Kimberlin | Herpes simplex virus infections in neonates and early childhood[END_REF][START_REF] Kimberlin | Guidance on management of asymptomatic neonates born to women with active genital herpes lesions[END_REF][START_REF] Bal | Fulminant hepatitis due to father-to-newborn transmission of herpes simplex virus type 1[END_REF][START_REF] Parra | Mammary herpes: a little known mode of neonatal herpes contamination[END_REF][START_REF] Hammerberg | An outbreak of herpes simplex virus type 1 in an intensive care nursery[END_REF] A majority (57.3%) of respondents stated that they never ask parents about their history of HSV infection in the postpartum period (no significant difference between midwives and obstetricians). In case of known history of HSV infection, 14.4% of respondents never gave prevention advice to parents. Information pamphlets were systematically given by only 10% of physicians to parents whose newborns are at high risk of perinatal infection. Health care providers were aware of the risk of transmission to newborns through oro-labial herpes or nipple lesions, and 84 % of them would contraindicate breastfeeding in case of nipple lesions. However, 46% of respondents did not know that HSV transmission to newborns can be hospital-related.

Management of asymptomatic newborns born to mothers with genital HSV recurrence during labour (Table

Knowledge and management of neonatal HSV infection acquired in the post-partum period (Table

Discussion

Main Findings

Our study illustrates that French health care provider knowledge of genital HSV during pregnancy is insufficient, and that there was an important need for 10 national recommendations. The respondents had fair knowledge of HSV epidemiology and transmission, but were less aware of the prevalence of genital herpes lesions during pregnancy or labour. In a 2007 meta-analysis on the efficiency of valaciclovir, Sheffield et al. [START_REF] Sheffield | Acyclovir prophylaxis to prevent herpes simplex virus recurrence at delivery: a systematic review[END_REF] showed that in case of an outburst during pregnancy (first episode or recurrent outburst), the risk of HSV recurrence at delivery was 15 % in the absence of treatment. Newly acquired HSV infection can be asymptomatic (14). Asymptomatic excretion of HSV was correctly estimated by 75% of respondents. Asymptomatic viral excretion has been reported using PCR detection of HSV in 0.3 to 10% of women at delivery [START_REF] Cone | Frequent detection of genital herpes simplex virus DNA by polymerase chain reaction among pregnant women[END_REF][START_REF] Brown | The acquisition of herpes simplex virus during pregnancy[END_REF]. Whereas 48% of providers stated that they systematically enquire about women's history of herpes, they usually do not ask about their partners' history.

CNGOF recommendations stated that questioning alone is not sufficient to establish a couple's history of HSV ( 4), which differs from the ACOG guidelines [START_REF] Acop | ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. No. 82[END_REF]. Serological screening is not recommended by CNGOF, or other international guidelines (9,10) , nor is it common practice, as illustrated by this study.

Despite this knowledge of epidemiology and transmission of HSV, one of the troubling results of this study is the number of participants who declared not prescribing antiviral prophylaxis in the third trimester for women at risk of lesions during labour. In a Cochrane meta-analysis published in 2008, Hollier [START_REF] Hollier | Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection[END_REF] showed that antiviral prophylaxis significantly reduces the incidence of outbursts at delivery and thus the number of cesarean sections due to HSV.

However, there was insufficient evidence to determine whether it also reduces the incidence of neonatal herpes. While several expert panels in different 11 countries already recommended acyclovir prophylaxis for this situation [START_REF] Acop | ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. No. 82[END_REF][START_REF] Workowski | Sexually transmitted diseases treatment guidelines, 2015[END_REF][START_REF] South | Neonatal and Gynaecology Community of Practice. South Australian Perinatal Practice Guidelines Genital Herpes Simplex (HSV) Infection in Pregnancy[END_REF], there were no specific guidelines on this matter on the available guidelines (31) in France until 2017. This lack of national consensus was likely to contribute to the lack of implementation of antiviral prophylaxis in high-risk situations.

Cesarean section to reduce transmission to the newborn was suggested by most respondents in case of a lesion during labour with intact membranes. In case of genital HSV primary infection, this is in line with the French 2017 CNGOF recommendations [START_REF] Sananes | Management of pregnant women with first episode of genital herpes. Guidelines for clinical practice from the French college of gynecologists and obstetricians (CNGOF)[END_REF] as well as those of other guidelines (ACOG 2007 [START_REF] Acop | ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. No. 82[END_REF], SOGC 2008 updated in 2017 ( 13)). In case of genital recurrent HSV infection, international guidelines are contradictory: RCOG recommends vaginal delivery [START_REF] Foley | Management of Genital Herpes in Pregnancy[END_REF], while most other guidelines (9,10,13) recommend a cesarean section. This may explain our results. The new CNGOF guidelines leave the option of cesarean section open on a case-by-case basis.

In the situations at lower risk for the mother and child, the health care providers tend to overestimate the risks for the newborn. The procedure to be followed for newborns at risk of neonatal herpes must be clarified according to whether the mother had a primary infection or a recurrent outburst during labour.

Our results show that prevention of post-natal transmission of HSV infection is often neglected, although it is responsible for 10% of cases of neonatal herpes [START_REF] Kimberlin | Herpes simplex virus infections in neonates and early childhood[END_REF]. Importantly, CNGOF guidelines state that the rules for preventing postnatal transmission of HSV must be known by parents and persons in contact 12 with neonates, but also by health care workers. Continuous training of health care professionals is a lever for reducing the incidence of nosocomial transmission to the newborn, which was only recognized by half of the respondents.

Overall, there were few significant differences between the knowledge and practices of obstetricians and midwives.

Strengths and Limitations

The strength of this study is that it covers the most problematic situations which are targeted in the recent CNGOF guidelines. The number of respondents is comparable with one other study of the same type on CMV infection during pregnancy [START_REF] Cordier | Awareness and knowledge of congenital cytomegalovirus infection among health care providers in France[END_REF]. This is the first survey-type on the subject carried out in France. In a similar study in 1995, Brocklehurst sent a postal questionnaire to UK gynaecologists, drawing the conclusion that although practitioners were aware of the importance of prevention practices, there was little agreement on management of pregnant women [START_REF] Brocklehurst | The management of recurrent genital herpes infection in pregnancy: a postal survey of obstetric practice[END_REF]. Another study of this kind about screening beliefs and practices amongst obstetricians, conducted in Washington state USA, showed similar results, suggesting that discussing genital herpes was important in prenatal care [START_REF] Gardella | Prenatal[END_REF]. Two studies, in Scotland (35) and Australia (36), asking patients about their knowledge on genital herpes showed that this subject is reasonably understood and understandable by patients.

A weakness of this study is the voluntary response to the questionnaire, which selected practitioners who had subscribed to a learned society mailing list and were willing to devote time for research on HSV and pregnancy. It is impossible to determine if the study population is representative of the whole 13 population of medical practitioners, and the interest in the study of the participants may have overestimated the knowledge of practitioners. There were no pediatricians among the respondents, which explains why in questions related to newborns, more participants declare they did not know the expected answer. The length of the questionnaire may have been responsible for the number of unanswered questions.

Conclusion

Prior to the publication of national updated guidelines by CNGOF, knowledge on HSV infection was lacking in many fields, and declared management often inappropriate in France. We aim to repeat the same study in a few years in order to assess the impact of these guidelines.

Disclosure of Interests

The authors declare having no conflict of interest in this study.

Ethics approval

This research paper did not require approval from an ethics committee as participants were willing to answer and the results were made anonymous. No patient information was necessary for this study.

Contribution to authorship

Tables list

Table 1: Characteristics of respondents

Table 2 :

 2 General knowledge on genital HSV epidemiology

Table 3 :

 3 Management of genital HSV primary infection during pregnancy

Table 4 :

 4 Management of genital HSV recurrence during pregnancy

Table 5 :

 5 Management of genital HSV infection during labour

Table 6 :

 6 Management of asymptomatic newborns born to mothers with genital HSV primary infection during labour

Table 7 :

 7 Management of asymptomatic newborns born to mothers with genital HSV recurrence during labour

Table 8 :

 8 Knowledge and management of neonatal HSV infection acquired in the

	post-partum period

1 Tables *Total may add to >100% because respondents could both have public and private practice. **Other includes retired practitioners, substitute physicians, family planning center

Table 1 :

 1 Characteristics of respondents1

Table 2 :

 2 General knowledge on HSV epidemiology

		Obstetricians (a)	Midwives (b)	General	Total n=354 (%)
		n=263 (%)	n=85 (%)	Practitioners n=6		p a vs b
	HSV2 can be responsible for genital herpes
	NA	7 (2.7%)	4 (4.7%)	0 (0%)	11 (3.1%)
	Never	5 (1.9%)	4 (4.7%)	1 (16.7%)	10 (2.8%)	0.23
	Sometimes	21 (8%)	6 (7.1%)	0 (0%)	27 (7.6%)	1.00
	Often (14)	112 (42.6%)	22 (25.9%)	2 (33.3%)	136 (38.4%)	0.01
	Always	118 (44.9%)	49 (57.6%)	3 (50%)	170 (48%)	0.046
	NR	0 (0%)	0 (0%)	0 (0%)	0 (0%)	1.00
	HSV1 can be responsible for genital herpes
	NA	3 (1.1%)	3 (3.5%)	0 (0%)	6 (1.7%)
	Never	11 (4.2%)	16 (18.8%)	1 (16.7%)	28 (7.9%)	0.0001
	Sometimes (15)	111 (42.2%)	35 (41.2%)	3 (50%)	149 (42.1%)	0.90
	Often	88 (33.5%)	19 (22.4%)	1 (16.7%)	108 (30.5%)	0.06
	Always	50 (19%)	12 (14.1%)	1 (16.7%)	63 (17.8%)	0.33
	NR	0 (0%)	0 (0%)	0 (0%)	0 (0%)	1.00
	What is the prevalence of HSV1 positive serology in pregnant women?
	5%	13 (4.9%)	15 (17.6%)	0 (0%)	28 (7.9%)	0.0008
	10%	44 (16.7%)	20 (23.5%)	1 (16.7%)	65 (18.4%)	0.20
	25%	80 (30.4%)	16 (18.8%)	2 (33.3%)	98 (27.7%)	0.04
	50%	71 (27%)	21 (24.7%)	1 (16.7%)	93 (26.3%)	0.78
						0.26
	70% (16)	52 (19.8%)	12 (14.1%)	2 (33.3%)	66 (18.6%)
	NR	3 (1.1%)	1 (1.2%)	0 (0%)	4 (1.1%)	1.00
	What is the prevalence of HSV2 positive serology in pregnant women?
	5%	35 (13.3%)	24 (28.2%)	1 (16.7%)	60 (16.9%)	0.003
	10%	87 (33.1%)	24 (28.2%)	1 (16.7%)	112 (31.6%)	0.43
	25% (1, 17)	90 (34.2%)	30 (35.3%)	3 (50%)	123 (34.7%)	0.90
	50%	33 (12.5%)	4 (4.7%)	0 (0%)	37 (10.5%)	0.04
	70%	14 (5.3%)	2 (2.4%)	0 (0%)	16 (4.5%)	0.38
	NR	4 (1.5%)	1 (1.2%)	1 (16.7%)	6 (1.7%)	1.00
	What is the prevalence of asymptomatic excretion of HSV during labour?
	5% (17)	147 (55.9%)	57 (67.1%)	4 (66.7%)	208 (58.8%)	0.08
	10% (18)	70 (26.6%)	21 (24.7%)	0 (0%)	91 (25.7%)	0.78
	25%	23 (8.7%)	4 (4.7%)	1 (16.7%)	28 (7.9%)	0.35
	50%	9 (3.4%)	0 (0%)	0 (0%)	9 (2.5%)	0.12
	70%	1 (0.4%)	0 (0%)	1 (16.7%)	2 (0.6%)	1.00
	NR	13 (4.9%)	3 (3.5%)	0 (0%)	16 (4.5%)	0.77

Table 3 :

 3 Management of genital HSV primary infection during pregnancyMarqued in bold are the expected or acceptable answers, according to the reference cited. P-value obtained by Chi-square or exact test as appropriate.

				General	Total n=354 (%)
			Midwives (b)	Practitioners n=6
		Obstetricians (a) n=263 (%)	n=85 (%)	(%)		p a vs b
	During pregnancy, you suspect genital HSV primary-infection. What do you recommend?
	No examination of samples	5 (1.4%)	2 (2.4%)	1 (16.7%)	2 (0.8%)	0.25
	HSV PCR on lesions + HSV
	serology (7)	169 (47.7%)	53 (62.4%)	2 (33.3%)	114 (43.3%)	0.003
	HSV PCR on lesions alone	129 (36.4%)	23 (27.1%)	1 (16.7%)	105 (39.9%)	0.04
	HSV serology alone	4 (1.1%)	3 (3.5%)	0 (0%)	1 (0.4%)	0.047
	Antiviral therapy (20)	47 (13.3%)	4 (4.7%)	2 (33.3%)	(15.6%)	0.01
	NR	0 (0%)	0 (0%)	0 (0%)	0 (0%)	1.00
	In case of genital HSV primary infection during pregnancy do you prescribe antiviral prophylaxis on the third trimester?
	NA	10 (3.8%)	6 (7.1%)	2 (33.3%)	18 (5.1%)	1.00
	Never	21 (8%)	7 (8.2%)	1 (16.7%)	(8.2%)	1.00
	Sometimes	15 (5.7%)	5 (5.9%)	0 (0%)	(5.6%)	0.02
	Often	37 (14.1%)	4 (4.7%)	0 (0%)	41 (11.6%)	0.89
	Always (21)	180 (68.4%)	59 (69.4%)	3 (50%)	242 (68.4%)	0.003
	NR	0 (0%)	4 (4.7%)	0 (0%)	4 (1.1%)

NR: not responded; NA: not applied in my situation 1

Table 4 :

 4 Management of genital HSV recurrence during pregnancyMarqued in bold are the expected or acceptable answers, according to the reference cited. P-value obtained by Chi-square or exact test as appropriate.

				General	Total n=354 (%)
		Obstetricians (a)	Midwives (b)	Practitioners n=6
		n=263 (%)	n=85 (%)	(%)		p a vs b
	During pregnancy, you suspect genital HSV recurrence. What do you recommend?
	No examination of samples (7)	8 (2.3%)	1 (1.2%)	0 (0%)	7 (2.7%)	0.69
	HSV PCR on lesions + HSV serology	119 (33.6%)	36 (42.4%)	1 (16.7%)	82 (31.2%)	0.07
	HSV PCR on lesions alone	101 (28.5%)	23 (27.1%)	2 (33.3%)	76 (28.9%)	0.78
	HSV serology alone	5 (1.4%)	2 (2.4%)	0 (0%)	3 (1.1%)	0.60
	Antiviral therapy	121 (34.2%)	23 (27.1%)	3 (50%)	95 (36.1%)	0.15
	NR	0 (0%)	0 (0%)	0 (0%)	0 (0%)	1.00
	If a woman does not report any recurrence during pregnancy but has an old history of genital herpes, do you prescribe antiviral prophylaxis on the third
	trimester?
	NA	13 (3.7%)	7 (8.2%)	1 (16.7%)	5 (1.9%)
	Never (7)	209 (59%)	37 (43.5%)	5 (83.3%)	167 (63.5%)	0.001
	Sometimes	35 (9.9%)	9 (10.6%)	0 (0%)	26 (9.9%)	0.84
	Often	21 (5.9%)	5 (5.9%)	0 (0%)	16 (6.1%)	1.00
	Always	74 (20.9%)	26 (30.6%)	0 (0%)	48 (18.3%)	0.02
	NR	2 (0.6%)	1 (1.2%)	0 (0%)	1 (0.4%)	0.43
	In case of recurrent HSV infection during pregnancy, do you prescribe antiviral prophylaxis on the third trimester?
	NA	19 (5.4%)	6 (7.1%)	2 (33.3%)	11 (4.2%)
	Never	75 (21.2%)	17 (20%)	0 (0%)	58 (22.1%)	0.76
	Sometimes	18 (5.1%)	4 (4.7%)	0 (0%)	14 (5.3%)	1.00
	Often	45 (12.7%)	10 (11.8%)	1 (16.7%)	34 (12.9%)	0.85
	Always (7)	195 (55.1%)	47 (55.3%)	3 (50%)	145 (55.1%)	1.00
	NR	2 (0.6%)	1 (1.2%)	0 (0%)	1 (0.4%)	0.43

Table 5 :

 5 Management of genital HSV infection during labourDuring labour, you suspect genital HSV infection in a patient with no history of genital herpes. Do you recommend:

		Obstetricians (a)	Midwives (b) n=85	General Practitioners
		n=263 (%)	(%)	n=) (%)	Total n=354 (%)	p a vs b
	Vaginal delivery	61 (17.2%)	18 (21.2%)	1 (16.7%)	42 (16%)	0.32
	Caesarean delivery (8)	293 (82.8%)	67 (78.8%)	5 (83.3%)	221 (84%)	0.32
	I don't know	0 (0%)	0 (0%)	0 (0%)	0 (0%)	1.00
	NR	0 (0%)	0 (0%)	0 (0%)	0 (0%)	1.00
	During labour, you suspect genital HSV recurrence. Do you recommend:
	Vaginal delivery	44 (12.4%)	15 (17.6%)	2 (33.3%)	27 (10.3%)	0.08
	Caesarean delivery	283 (79.9%)	63 (74.1%)	3 (50%)	217 (82.5%)	0.11
	I don't know	27 (7.6%)	7 (8.2%)	1 (16.7%)	19 (7.2%)	0.81
	NR	0 (0%)	0 (0%)	0 (0%)	0 (0%)	1.00

Marqued in bold are the expected or acceptable answers, according to the reference cited. P-value obtained by Chi-square or exact test as appropriate.

Table 6 :

 6 Management of asymptomatic newborns born to mothers with genital HSV primary infection during labourIs a newborn at high risk of neonatal herpes if born to a mother with genital HSV primary infection during labour?

			Midwives (b) n=85	General Practitioners n=6		p a vs b
		Obstetricians (a) n=263 (%)			Total n=354 (%)
			(%)	(%)
	Yes (20)	180 (68.4%)	67 (78.8%)	4 (66.7%)	251 (70.9%)	0.07
	No	13 (4.9%)	0 (0%)	0 (0%)	13 (3.7%)	0.04
	I don't know	14 (5.3%)	2 (2.4%)	1 (16.7%)	17 (4.8%)	0.38
	NR	56 (21.3%)	16 (18.8%)	1 (16.7%)	(20.6%)	0.76
	Must an asymptomatic newborn born to a mother with genital HSV primary infection during labour be bathed with an antiseptic agent?
	Yes	129 (49%)	48 (56.5%)	2 (33.3%)	179 (50.6%)	0.26
	No*	31 (11.8%)	8 (9.4%)	1 (16.7%)	(11.3%)	0.69
	I don't know	44 (16.7%)	13 (15.3%)	2 (33.3%)	(16.7%)	0.87
	NR	59 (22.4%)	16 (18.8%)	1 (16.7%)	(21.5%)	0.55
	Must an asymptomatic newborn born to a mother with genital HSV primary infection during labour receive antiviral eye drops?
	Yes	174 (66.2%)	63 (74.1%)	3 (50%)	240 (67.8%)	0.18
	No*	10 (3.8%)	1 (1.2%)	1 (16.7%)	12 (3.4%)	0.31
	I don't know	24 (9.1%)	5 (5.9%)	1 (16.7%)	30 (8.5%)	0.50
	NR	55 (20.9%)	16 (18.8%)	1 (16.7%)	72 (20.3%)	0.76
	Must an asymptomatic newborn born to a mother with genital HSV primary infection during labour undergo peripheral skin swabbing?
	Yes (23)	141 (53.6%)	54 (63.5%)	2 (33.3%)	197 (55.6%)	0.13
	No	15 (5.7%)	6 (7.1%)	1 (16.7%)	22 (6.2%)	0.61
	I don't know	44 (16.7%)	8 (9.4%)	2 (33.3%)	54 (15.3%)	0.12
	NR	63 (24%)	17 (20%)	1 (16.7%)	81 (22.9%)	0.55
	Must an asymptomatic newborn born to a mother with genital HSV primary infection during labour be treated with intra venous antiviral therapy?
	Yes (24)	127 (48.3%)	31 (36.5%)	0 (0%)	158 (44.6%)	0.06
	No	29 (11%)	15 (17.6%)	2 (33.3%)	46 (13%)	0.13
	I don't know	52 (19.8%)	22 (25.9%)	3 (50%)	77 (21.8%)	0.23
	NR	55 (20.9%)	17 (20%)	1 (16.7%)	73 (20.6%)	1.00
	Must an asymptomatic newborn born to a mother with genital HSV primary infection during labour be hospitalised and isolated from other
	patients?
	Yes*	116 (44.1%)	38 (44.7%)	2 (33.3%)	156 (44.1%)	1.00
	No	40 (15.2%)	18 (21.2%)	2 (33.3%)	60 (16.9%)	0.24
	I don't know	49 (18.6%)	13 (15.3%)	1 (16.7%)	63 (17.8%)	0.52
	NR	58 (22.1%)	16 (18.8%)	1 (16.7%)	75 (21.2%)	0.65
	*These practices have never been evaluated in literature. Marqued in bold are the expected or acceptable answers, according to the reference
	cited. P-value obtained by Chi-square or exact test as appropriate

Table 7 :

 7 Management of asymptomatic newborns born to mothers with genital HSV recurrence during labourMarqued in bold are the expected or acceptable answers, according to the reference cited. P-value obtained by Chi-square or exact test as

	appropriate

Table 8 :

 8 Knowledge and management of neonatal HSV infection acquired in the post-partum period

		Obstetricians (a) n=263 (%) Midwives (b) (n=85) (%) General Practitioners n=6 (%) Total n=354 (%) p a vs b
	Do you ask parents about their history of herpes infection?
	NA	(25.5%)	27 (31.8%)	2 (33.3%)	96 (27.1%)	0.26
	Never	151 (57.4%)	50 (58.8%)	2 (33.3%)	203 (57.3%)	0.90
	Sometimes	29 (11%)	7 (8.2%)	1 (16.7%)	37 (10.5%)	0.54
	Often	(1.1%)	1 (1.2%)	1 (16.7%)	5 (1.4%)	1.00
	Always	(2.3%)	0 (0%)	0 (0%)	6 (1.7%)	0.34
	NR	(2.7%)	0 (0%)	0 (0%)	7 (2%)	0.20
	In case of herpes history in parents, do you give them prevention advice?
	NA	(21.7%)	24 (28.2%)	2 (33.3%)	83 (23.4%)	0.24
	Never	(15.2%)	11 (12.9%)	0 (0%)	51 (14.4%)	0.73
	Sometimes	(25.5%)	18 (21.2%)	1 (16.7%)	86 (24.3%)	0.47
	Often	(13.3%)	14 (16.5%)	2 (33.3%)	51 (14.4%)	0.48
	Always	(21.7%)	15 (17.6%)	1 (16.7%)	73 (20.6%)	0.54
	NR	(2.7%)	3 (3.5%)	0 (0%)	10 (2.8%)	0.71
	In case of no herpes history in parents, do you give them prevention advice?
	NA	(21.7%)	24 (28.2%)	2 (33.3%)	83 (23.4%)	0.24
	Never	160 (60.8%)	49 (57.6%)	2 (33.3%)	211 (59.6%)	0.61
	Sometimes	(11.8%)	7 (8.2%)	0 (0%)	38 (10.7%)	0.43
	Often	(1.1%)	2 (2.4%)	0 (0%)	5 (1.4%)	0.60
	Always	(1.9%)	2 (2.4%)	2 (33.3%)	9 (2.5%)	0.68
	NR	(2.7%)	1 (1.2%)	0 (0%)	8 (2.3%)	0.69
	Do you give an information pamphlet to parents of newborns at risk of neonatal HSV infection?
	NA	(24.3%)	24 (28.2%)	2 (33.3%)	90 (25.4%)	0.48
	Never	115 (43.7%)	42 (49.4%)	2 (33.3%)	159 (44.9%)	0.38
	Sometimes	(10.6%)	5 (5.9%)	0 (0%)	33 (9.3%)	0.29
	Often	18 (6.8%)	4 (4.7%)	0 (0%)	22 (6.2%)	0.61
	Always	29 (11%)	7 (8.2%)	2 (33.3%)	38 (10.7%)	0.54
	NR	(3.4%)	3 (3.5%)	0 (0%)	12 (3.4%)	1.00
	Is post-partum transmission of HSV to newborns mainly due to HSV1?
	Yes (24)	164 (62.4%)	56 (65.9%)	3 (50%)	223 (63%)	0.61
	No	(34.6%)	26 (30.6%)	3 (50%)	120 (33.9%)	0.51
	I don't know	0 (0%)	0 (0%)	0 (0%)	0 (0%)	1.00
	NR	8 (3%)	3 (3.5%)	0 (0%)	11 (3.1%)	0.73
	Can HSV be transmitted to newborns by direct contact with oral herpes?

Marqued in bold are the expected or acceptable answers, according to the reference cited. P-value obtained by Chi-square or exact test as appropriate. NR: not responded; NA: not applied in my situation

Marqued in bold are the expected or acceptable answers, according to the reference cited. P-value obtained by Chi-square or exact test as appropriate.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.


Maria Gabriela

Gusmão Cacho

Patricia Pimenta-Barros

Maxime Argoud

Christophe Navarro

Kaumba Sakavuyi

Raluca Tiron

Nicolas Possémé

Etching of sub-10 nm half-pitch high chi block copolymers for directed self-assembly (DSA) application

Keywords: Plasma Etching, Block Copolymers, Directed Self-Assembly, High Chi, Pattern Transfer

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

I. INTRODUCTION

Since the introduction of integrated circuits, there has always been a great interest, driven by both economic and performance aspects, to increase the number of transistors on a wafer. This has been achieved by constantly reducing the size of the transistors, thus increasing the number of transistors on the same surface [START_REF] Moore | Cramming More Components onto Integrated Circuits[END_REF][START_REF] Moore | Progress in digital integrated electronics[END_REF].

However, as we approach the sub-10nm technologic nodes, conventional lithography has achieved its limit in terms of pattern scaling [START_REF] Stoykovich | Block copolymers and conventional lithography[END_REF]. New patterning techniques, such as extreme ultraviolet lithography, directed self-assembly (DSA) and multiple patterning, are being studied as alternatives to continue pattern miniaturization [START_REF] Posseme | Plasma Etching Process for CMOS Devices Realization[END_REF]. This article will focus on the DSA of block copolymers (BCPs), which is a promising low cost solution to obtain high density sub-10 nm patterns. It uses the self-assembling property of these materials to reach nanoscale dimensions and, at the same time, meet the constraints of manufacturing, like cost and equipment availability [START_REF] Stoykovich | Block copolymers and conventional lithography[END_REF].

Block copolymers consist of two different polymer chains connected by a covalent bond. They are able to microphase separate, spontaneously forming a dense array of different ordered nanostructures, like cylinders or lamellae, with domain dimensions of around 5 to 50 nm [START_REF] Stoykovich | Block copolymers and conventional lithography[END_REF]. Polystyrene-b-poly(methyl methacrylate) (PS-b-PMMA) is the most commonly used block copolymer for the DSA application because of its well-known properties and easy synthesis [START_REF] Argoud | 300mm pilot line DSA contact hole process stability[END_REF].

To remain attractive for the smaller technological nodes, the BCPs pitch has been constantly reduced. Since the minimum pitch for the PS-b-PMMA system is limited to around 24 nm due to its low chi, new systems have been developed to achieve higher resolution by improving its microphase separation strength, thus obtaining the "high chi" BCPs [START_REF] Feng | Block Copolymers: Synthesis, Self-Assembly, and Applications[END_REF]. They also reportedly present better Line Edge Roughness (LER) and Line Width Roughness (LWR) compared to PS-b-PMMA [START_REF] Miyazoe | High chi block copolymer DSA to improve pattern quality for FinFET device fabrication[END_REF]. In this paper, the organic high chi BCP system being studied is a modified PS-b-PMMA that presents an 18-nm pitch and lamellar morphology.

A major etching challenge for DSA integration concerns the PMMA removal selectively to PS. To transfer the line/space pattern into the subjacent layers, we must completely remove the PMMA and conserve enough PS budget. This can be achieved by either wet or dry etching. Wet etching allows for quasi-infinite selectivity between both blocks, but presents a pattern collapse risk due to capillary forces [START_REF] Gharbi | PMMA removal options by wet development in PS-b-PMMA block copolymer for nanolithographic mask fabrication[END_REF]. Plasma etching is more compatible with narrow lines, thus limiting the risk of pattern collapse. However, the main difficulty with this approach is to obtain high selectivity between PMMA and PS films.

For the standard PS-b-PMMA, different etching chemistries have been developed.

The most common plasma etching used for the selective PMMA removal are based on O2 [START_REF] Miyazoe | High chi block copolymer DSA to improve pattern quality for FinFET device fabrication[END_REF][START_REF] Tsai | Two-dimensional pattern formation using graphoepitaxy of PS-b-PMMA block copolymers for advanced FinFET device and circuit fabrication[END_REF], Ar/O2 [START_REF] Nealey | Plasma etch removal of poly(methyl methacrylate) in block copolymer lithography[END_REF][START_REF] Yamashita | Exploration of suitable dry etch technologies for Directed Self-Assembly[END_REF] and CO/H2 [START_REF] Miyazoe | Highly selective dry etching of polystyrene-poly(methyl methacrylate) block copolymer by gas pulsing carbon monoxide-based plasmas[END_REF]. Cyclic approaches based on CO/H2 + CO [START_REF] Miyazoe | Highly selective dry etching of polystyrene-poly(methyl methacrylate) block copolymer by gas pulsing carbon monoxide-based plasmas[END_REF][START_REF] Sarrazin | PMMA removal selectivity to polystyrene using dry etch approach[END_REF] or Ar/O2 + Ar [START_REF] Delgadillo | 28 nm pitch of line/space pattern transfer into silicon substrates with chemo-epitaxy Directed Self-Assembly (DSA) process flow[END_REF] have also been studied. The O2-based chemistries are very reactive [START_REF] Farrell | Monitoring PMMA elimination by reactive ion etching from a lamellar PS-b-PMMA thin film by ex situ TEM methods[END_REF][START_REF] Delalande | Development of plasma etching processes to pattern sub-15 nm features with PS-b-PMMA block copolymer masks: Application to advanced CMOS technology[END_REF] and present low PMMA:PS selectivity (around 2.0). The CO + CO/H2 plasma cycles were shown to be suitable for the cylindrical application [START_REF] Imamura | Highly selective removal of poly(methyl methacrylate) from polystyrene-block-poly(methyl methacrylate) by CO/H2 plasma etching[END_REF], but present limitations for lamellar application: higher PS consumption due to a higher amount of oxygen (coming from PMMA) released during etching. Therefore, an oxygen-free chemistry based on CH4/N2 was developed to obtain high selectivity with line/space patterns for standard PS-b-PMMA with a 38-nm pitch [START_REF] Sarrazin | New CH4-N2 dry etch chemistry for PMMA removal without consuming PS[END_REF].

In this paper, we propose to evaluate the process window of this dry etch chemistry for an organic high chi block copolymer by varying the CH4/N2 ratio and studying the etch mechanisms thanks to X-ray photoelectron spectroscopy (XPS). Then, the results obtained for the 18-nm pitch high chi PS-b-PMMA are presented, highlighting the challenges encountered due to its smaller dimensions.

II. EXPERIMENTAL SETUP

A. Materials

All the materials are provided by Brewer Science Inc. and Arkema.

PS and PMMA homopolymer solutions with the modified high chi chemistry were spin-coated on 300mm silicon blanket wafers and then annealed on Sokudo Duo™ track to obtain 50-nm films.

Two different lamellar block copolymers were used on this study. The first one was a standard PS-b-PMMA with period L0=38nm. The BCP solution is spin-coated and annealed on 300mm wafers using a Sokudo Duo™ track. A thin brush layer composed of PS-r-PMMA random copolymer is spin-coated on the substrate before the BCP deposition in order to neutralize the surface and obtain the vertical lamellae morphology.

The brush and BCP layer thicknesses are around 8 and 52 nm, respectively.

The second block copolymer used was a high chi modified PS-b-PMMA with period L0=18nm. The deposition process is similar to that of the standard PS-b-PMMA explained above. The brush and BCP layer thicknesses are around 5 and 16 nm, respectively. Figure 1 represents the material stack used. The stack was the same for both block copolymers, with only the brush layer and block copolymer thickness changing according to the values presented in Table I.

B. Etching setup

The plasma etching experiments were carried out on a 300mm Kiyo FX® reactor from LamResearch®. This inductively coupled plasma (ICP) reactor is powered by a RF generator of 13.56MHz. The pressure, bias voltage and plasma power of the CH4/N2

plasma were set at 10mTorr, 200V and 500W, respectively. The gas ratio was variated in order to establish a process window.

C. Characterization setup

PMMA:PS selectivity and etch rates were determined using the thickness measurements obtained by ellipsometry before and after plasma etching of high chi PS and PMMA homopolymers coated on blanket wafers. The tool used is the Atlas XP+™ from Nanometrics® with an incident angle of 65°. For both materials, a Cauchy transparent model was for wavelengths between 500 and 1000 nm, since these materials exhibit no absorption (k=0) in this wavelength range. The refractive index was also adjusted in the model during the thickness fitting. At 620 nm, as deposited PS has a refractive index of 1.49 while as deposited PMMA has an index of 1.59. No refractive index modifications were observed after etching nor between modified (high chi) and non-modified (standard) PS-b-PMMA. The as deposited homopolymer thicknesses for high chi PS and PMMA films were measured at 55 and 52 nm, respectively.

Quasi in-situ X-ray photoelectron spectroscopy (XPS) analysis were conducted to understand the surface etching mechanisms. A Thermo Fisher Scientific® Theta 300™ spectrometer with a monochromatic Al Kα x-ray source (hʋ = 1486.6 eV) was used. The concentrations of C, O and N atoms were extracted from the C1s, O1s and N1s core-level energy regions, respectively. Binding energies in all XPS spectra were calibrated using the C1s C-C peak (285 eV). All peaks were de-convoluted by a fitting routine consisting of a combination of Lorentzian and Gaussian functions (using Avantage™ software).

Each element concentration was obtained by dividing the calculated peak areas by the corresponding Scofield cross section (O1s: 2.88; C1s: 1.0; N1s 1.68). The sum of the concentrations for the different elements on the analyzed surfaces is equal to 100%.

XPS measurements were carried out on parallel angle resolved mode with takeoff angles varying between 23.75° and 76.25° to probe different depths of the material (maximum depth = 10 nm). For each element, the measurements consisted of five scans with a dwell time of 500 ms, a pass energy of 100 eV and an energy step size of 0.1 eV.

Two types of Scanning Electron Microscope (SEM) were used for morphological observations, each one with a specific application. The critical dimension SEM (CD-SEM) used for top-view observation was the Verity 4i+™ tool from Applied Materials®.

SEM images were acquired with an accelerating voltage of 800V and a probe current of 71 pA. After top-view observations, a cross-section SEM was used to determine the effectiveness of PMMA removal and observe the morphology of the line/space patterns.

The tool used was a Hitachi® S5500™ microscope. Cross-sectional samples were precoated with a gold-palladium metallization during 25s to reduce charging effect characteristic of the polymer reaction to electron beam. All images were acquired with an accelerating voltage of 5.0 kV, a probe current of 15 μA and using a tilt of -20°.

III. RESULTS AND DISCUSSION

A. Modified PS and PMMA homopolymer results

Figure 2 summarizes high chi modified PS and PMMA homopolymer consumption as a function of plasma process time for different CH4/N2 ratios.

The graph shows that for the ratio 1:2, both materials consumptions are linear.

After 60s of etching, around 42 nm of PMMA and 9 nm of PS are etched, corresponding to a selectivity of 4.7, approximately. As for the ratio 1:1, after 60s, 16 nm of PMMA are etched while a deposition of around 5 nm is observed on top of PS, which means the ratio 1:1 presents infinite selectivity on blanket wafers. Finally, ratio 2:1 presents the same tendencies as ratio 1:1. However, for the PMMA consumption, it seems to reach a plateau after 25s of etching. To understand the etching mechanisms and plasma/surface interactions involved, quasi in-situ XPS analysis were carried out on these blanket high chi homopolymers for ratios 1:1 and 1:2 with different etching times. The results are shown in Figure 3.

First, it is important to notice that as deposited high chi PS and PMMA present a composition very similar to that of the standard PS and PMMA [START_REF] Beamson | High Resolution XPS of Organic Polymers: The Scienta ESCA300 Database[END_REF]. PS consists of only carbon and hydrogen and its XPS analysis presents two peaks. The one at 285.0 eV corresponds to two different bonds (aliphatic carbon at 284.7 eV and carbon from phenyl cycle at 285.0 eV) that cannot be dissociated due to the energy pass. In this paper, these peaks will be represented together as C-C, C=C. The other peak is observed at 292.0 eV and represents a shake-up peak characteristic of the aromatic cycle, represented as pi pi* [START_REF] Beamson | High Resolution XPS of Organic Polymers: The Scienta ESCA300 Database[END_REF]. and 3(d) that the etching presents the same tendencies as the ratio 1:1 with a higher C-N content, which is to be expected from the increase of the N2 flow. These same etching mechanisms were observed for standard PS-b-PMMA in previous works [START_REF] Sarrazin | New CH4-N2 dry etch chemistry for PMMA removal without consuming PS[END_REF].

B. Application to PS-b-PMMA films with lamellar morphology

Standard PS-b-PMMA with 38 nm pitch

First, different CH4/N2 ratios were tested on standard 38 nm pitch PS-b-PMMA with 52 nm initial thickness in order to compare the PMMA:PS selectivity of free surface and blanket wafers. The cross-section and top-view SEM images post PMMA removal, as well as the calculated selectivity, are presented in Figure 4. As expected, the greater the CH4 content, the better the selectivity since CH4 is the major passivating component of this etching chemistry. However, Figure 4(c) shows that when the CH4/N2 ratio is too important, the PS lines thickness is increased due to too much carbon passivation on the PS flanks. The highlighted section on the top-view image in Figure 4(c) presents the consequent pattern collapse caused by the lines thickening, which prevents the correct pattern transfer into the underlayers. Therefore, we selected the ratios 1:2 and 1:1 to continue our studies for the high chi PS-b-PMMA.

It is also important to notice that, for all CH4/N2 ratios studied, the selectivity on free surface is lower compared to that of blanket wafers. This indicates that new etching mechanisms come into place when the two block copolymer's phases interact. As we have seen on the XPS analysis (section III.A), the loss of C-O and C=O bonds is characteristic of PMMA etching. The oxygen-containing by-products of the PMMA etching probably interact with the PS phase, inducing its consumption.

High chi PS-b-PMMA with 18 nm pitch

For the etching of the 18-nm pitch high chi PS-b-PMMA, we estimate that there should be at least 15 nm of PS plus brush layer left after PMMA removal to ensure the correct pattern transfer into the subjacent silicon oxide layer, which means that the high chi BCP requires a higher selectivity than the standard PS-b-PMMA due to its reduced thickness (16 nm). Since the initial thickness of the PS-b-PMMA and brush layer stack is approximately 21 nm, this translates to a desired selectivity of around 3.5.

Figure 5 presents the cross-section and top-view SEM images after PMMA removal, as well as the calculated selectivity for the ratios 1:2 and 1:1. First, it is important to notice that, for the same dry process, the 18-nm pitch high chi BCP presents lower selectivity compared to the 38-nm pitch standard PS-b-PMMA. This might be due to the block copolymers modified chemistry or to the fact that the etching time is shorter for smaller thickness. It should also be noticed that the cross-section SEM measurements are approximations, due to its low precision when using higher magnification. Therefore, the main high chi PS-b-PMMA dry etching difficulties come from the trade-off between obtaining a high PMMA:PS selectivity and avoiding bridge formation due to carbon passivation. This inspired the idea to alternate etching and deposition steps to avoid bridge formation and improve selectivity, using a cyclic approach based on different CH4/N2 ratios.

Cyclic approach

Figure 6 presents the schema for the cyclic approach. The idea is to have a first step with a lower carbon content (ratio 1:2) to etch both PS and PMMA followed by a step with a higher carbon content (ratio 2:1) to etch the PMMA and form a CN-type deposit on the PS. These two steps together make one cycle and are then repeated until all PMMA has been removed and no PS has been consumed. FIG 6. (Color online) Schema for the cyclic approach with different CH4/N2 ratios in order to fully remove the PMMA selectively to PS.

Figure 7 summarizes the results obtained. First, this cyclic approach was tested on high chi PS and PMMA homopolymers. The graph in Figure 7(a) shows that, expected, the PMMA is continuously etched with the increasing number of cycles while the PS is not consumed. However, as we can see in Figures 7(b) and 7(c), when the same cyclic etching is applied to free surface high chi PS-b-PMMA, there is no visible improvement of the PMMA:PS selectivity when compared to the non-cyclic approach presented in the previous section. Furthermore, some bridge formation is observed in Based on these results, a cyclic etching with lower CH4 flow (ratio 1:5) on the first step was also tested. As was seen on the previous sections, the reduced CH4 flow leads to lower PMMA:PS selectivity (around 1.6), which then prevents correct pattern transfer.

No PMMA etch stop was observed thanks to the reduced carbon content on the etching step. However, bridge formation is only slightly delayed in comparison to the previous approach, with bridges forming between third and fourth cycles, as can be seen in Figure 8(a).

In order to avoid bridge formation altogether, a third cyclic approach was tested: alternating short CH4/N2 and Ar/O2 steps. Ar/O2 is known to effectively remove the PMMA phase and present low LER and LWR. However, it presents very low selectivity (around 1.0 for high chi PS-b-PMMA), which explains the presence of the CH4/N2 step to improve the PMMA:PS selectivity. The results can be found in Figure 8(b). No bridge is formed with these cycles, which confirms the theory that bridge formation comes from too much carbon deposit on the PS lines. After 4 cycles, the PMMA is completely removed, however there is not enough PS remaining (around 7 nm) for pattern transfer into the SiO2 hard mask. Therefore, we conclude that the cyclic approach still presents the same etching difficulties that we observed for the non-cyclic process. This means the full dry etching approach cannot find the right balance between high selectivity and bridge formation for the high chi PS-b-PMMA, mostly due to its small dimensions, namely its initial thickness and pitch.

C. Mixed wet and dry etching approach

Based on the results obtained with the full dry approach, we have proposed a mixed wet and dry etching approach in order to successfully remove the PMMA and open the brush layer, conserving enough PS budget for pattern transfer. This approach consists of a wet PMMA removal in order to obtain an infinite PMMA:PS selectivity, followed by a dry brush layer opening step to allow for pattern transfer into the SiO2 layer.

The wet PMMA removal for the high chi PS-b-PMMA consists of two steps: an UV exposure followed by a solvent rinse [START_REF] Gharbi | PMMA removal options by wet development in PS-b-PMMA block copolymer for nanolithographic mask fabrication[END_REF]. With the appropriate dose, the UV exposure is responsible for breaking the PMMA chains, which allows these broken chains to be later removed by the solvent rinse; and hardening the PS lines, which helps avoid possible pattern collapse due to capillary forces. The optimal dose was found to be 30 mJ/cm² with a 172 nm wavelength. As for the second step, the solvent chosen was isopropyl alcohol (IPA) and the rinse time is 30 seconds. The cross-section and top-view SEM images after wet PMMA removal are presented in Figure 9. The PMMA is completely removed while no PS nor brush layer are consumed. The second step necessary in order to proceed to pattern transfer is the brush layer opening plasma etching step. Two different chemistries were proposed: CF4 and Ar/O2.

In order to validate their interest, we proceeded to the pattern transfer into the SiO2 subjacent layer using a CHF3/CF4 plasma. Figure 10 shows the results obtained after wet PMMA removal, brush layer opening and transfer into the SiO2 layer. We observe in Figure 10(a) that the CF4 brush layer opening plasma leads to some wiggling, while Figure 10(b) shows that the Ar/O2 plasma was too aggressive and did not conserve enough PS budget for pattern transfer.

The Ar/O2 ratio was then improved to 24:1 instead of 10:1 while conserving the other parameters presented on Table II. This ratio improvement is expected to provide a less isotropic etching and to conserve more PS budget. and the SiO2 etching (represented as "ME" for main etch step). Three different brush presented some bridge formation on top of the lines, which were formed due to intensive sidewalls passivation and to a species confinement effect accentuated by the small pitch.

We then concluded that the main high chi PS-b-PMMA dry etching difficulties come from the trade-off between obtaining high selectivity and avoiding bridge formation.

The second approach proposed was a mixed wet and dry etching process. The wet PMMA removal presents infinite selectivity on high chi modified PS-b-PMMA. The UV exposure causes the PMMA chains to break and the PS lines to harden, and the IPA rinse removes the broken PMMA chains without modifying the PS lines. A dry etching process to open the brush layer using an Ar/O2 plasma with high argon content was developed in order to obtain a highly anisotropic etching and to conserve more PS budget. With this mixed wet and dry etching approach, the complete pattern transfer of an 18-nm pitch high chi organic block copolymer into the SiO2 and silicon bulk layers was validated.

FIG 2 .

 2 FIG 2. (Color online) Modified PS and PMMA homopolymer consumption for different CH4/N2 ratios.

FIG 3 .

 3 FIG 3. (Color online) Modified PS (a) and (b); and modified PMMA (c) and (d) surface compositions determined by quasi in-situ XPS for two different ratios: (a) and (c) ratio 1:1; (b) and (d) ratio 1:2.

Figure 3

 3 Figure 3 also shows the XPS results after etching with CH4/N2 for two different

FIG 4 .

 4 FIG 4. Cross-section and top-view SEM images of standard PS-b-PMMA with 38-nm pitch after etching with different CH4/N2 ratios: (a) ratio 1:2; (b) ratio 1:1; and (c) ratio 2:1.

FIG 5 .

 5 FIG 5. Cross-section and top-view SEM images of high chi PS-b-PMMA after etching with different CH4/N2 ratios: (a) ratio 1:2; (b) ratio 1:1.

Figure 5 (

 5 Figure 5(a) shows the results for the ratio 1:2, which presents a selectivity of

Figure 7 (

 7 Figure 7(c) after the third cycle. Finally, for both number of cycles presented in Figures

FIG 8 .

 8 FIG 8. Cross-section and top-view SEM images of high chi PS-b-PMMA after 4 cycles of two different cyclic approaches: (a) alternating 5s CH4/N2 steps with ratios 1:5 and 2:1; (b) 5s CH4/N2 step with ratio 1:1 followed by a 3s Ar/O2 step with ratio 24:1.

FIG 9 .

 9 FIG 9. Cross-section and top-view SEM images of high chi PS-b-PMMA after the wet PMMA removal consisting of an UV exposure followed by an IPA rinse.

Figure 10 (

 10 FIG 10. Cross-section and top-view SEM images of high chi PS-b-PMMA after the wet PMMA removal, the brush layer dry opening (represented as "BT" for breakthrough step)

TABLE I .

 I Pitch and thickness values for the standard and high chi PS-b-PMMA.

	Block copolymer	Pitch (nm) Initial thickness (nm) Brush layer (nm)
	Standard PS-b-PMMA	38	52	8
	High chi PS-b-PMMA	18	16	5
	FIG 1. (Color online) Material stack used on the study of both standard and high chi PS-
	b-PMMA etching. Brush layer and block copolymer thickness are indicated in Table I.

TABLE II .

 II Plasma parameters of the chemistries tested for the dry etching of the brush and

	SiO2 layers.
		Pressure	Power	Bias	Flow	Temperature	Time
		(mTorr)	(W)	(V)	(sccm)	(°C)	(s)
	CF4	10	625	70	150	60	5
	Ar/O2	10	220	200	50/5	35	5
	CHF3/CF4	4	625	110 50/50	35	8

ACKNOWLEDGMENTS

This work has been supported by the French National Research Agency (ANR) within the IMPACT program, under contract N° ANR-10-EQPX-33.

layer opening plasmas are presented: (a) CF4; (b) Ar/O2 with ratio 10:1; and (c) Ar/O2 with ratio 24:1.

Finally, Figure 11 presents the results after the complete stack etching: wet PMMA removal, dry brush layer opening using the optimized Ar/O2 plasma, SiO2 etching using the CHF3/CF4 plasma, Si bulk layer etching with an HBr/O2 plasma, and remaining PS stripping with an O2 plasma. Therefore, we demonstrate the pattern transfer of an 18 nm pitch high chi organic block copolymer into SiO2 and silicon bulk layers using a mixed wet and dry etching removal process.

IV. SUMMARY AND CONCLUSIONS

In this paper, we have studied the PMMA removal selectively to PS on high chi PS-b-PMMA films with an 18-nm pitch. The first approach proposed was a full dry etching based on CH4/N2. While for PS and PMMA homopolymers we succeeded in etching the PMMA without consuming the PS thanks to a CxNy thin deposition layer formed on the PS surface, the same could not be applied to the high chi PS-b-PMMA block copolymer assembled on a free surface. The high chi BCP requires higher selectivity than standard PS-b-PMMA due to its smaller thickness. Moreover, it also


MD, MSc Pierrick Le Borgne
email: pierrick_med@yahoo.fr

- C Brunhuber

-P Bilbault

Woman with sore throat, fever and abdominal pain

Keywords:

Internal Medicine flashcards

Woman with sore throat, fever and abdominal pain Presentation A 32-year-old woman, presented to the Emergency Department (ED) with a 15-days fever, and a sore throat recently associated with a growing abdominal pain. At admission in the ED, the patient had normal vital parameters and her history showed no underlying comorbidities.

On physical examination, abdominal tenderness was observed with an important (8/10) left upper quadrant pain associated with a palpable splenomegaly. The rest of the clinical examination was normal except for a mild odynophagia. Six days before the ED admission, the patient had consulted her General Practitioner who prescribed a complete blood test.

These laboratory results showed a white blood cell count of 10,65x10 9 /L with 56.4% lymphocytes, a normal platelet count and an elevated level of ALAT (150 UI/L) and ASAT (183 UI/L) with a mild inflammatory syndrome (CRP: 39 mg/L). Serologic viral screening was negative for hepatitis B and C viruses, human immunodeficiency virus and cytomegalovirus. However, serological testing detected EBV viral capsid antigen immunoglobulin M (VCA-IgM) antibodies at high titer. These results were compatible with mononucleosis primo-infection. In this context, abdominal CT was performed due to the intense and persistent pain (Figure 1).

Diagnosis: Spleen infarction due to acute Epstein-Barr virus infection

Infectious mononucleosis (IM) is commonly caused by Epstein-Barr (EBV), which is characterized by non-specific symptoms like fever, sore throat and cervical lymphadenopathy.

In IM, the spleen is usually increased to 3-4 times normal size but splenic complications such as rupture or infarction have been rarely reported, the exact frequency remains uncertain probably due to underdiagnosis [START_REF] Heo | Splenic infarction associated with acute infectious mononucleosis due to Epstein-Barr virus infection: Splenic Infarction Following Infectious Mononucleosis by EBV Infection[END_REF]. Splenic infarction can have a wide range of clinical presentations from asymptomatic (20-30%) to fatal hemorrhage [START_REF] Heo | Splenic infarction associated with acute infectious mononucleosis due to Epstein-Barr virus infection: Splenic Infarction Following Infectious Mononucleosis by EBV Infection[END_REF]. In the acute setting, contrast-enhanced CT represents the gold standard in this pathology, it has much more sensitivity than ultrasonography [START_REF] Antopolsky | Splenic infarction: 10 years of experience[END_REF]. Usually, conservative management and symptomatic treatments are recommended in splenic infarction in IM patients, but a close follow-up is mandatory because infarcts may recur or progress to splenic rupture or other complications (abscess, pseudocyst, hemorrhage). The pathogenesis of splenic infarction during IM is not yet fully understood and several hypotheses have been advanced. Firstly, arterial blood supply may be insufficient (hypoxemia) for the hypercellular spleen during the acute phase of IM.

Secondly, the present of a transient hypercoagulable state has been proposed. Anticardiolipin antibodies or other transient pro-thrombotic factors could be detected. Thereby, a thrombophilia screening should be performed in patients with the association splenic infarction and IM. Anticoagulant therapy is not systematic but will only be used in case of permanent hypercoagulable disorders. Finally, an increased level of circulating immune complexes (excess B cell proliferation), promoting leukocyte aggregation and adhesiveness, has also been associated with splenic infarction [START_REF] Li | Splenic Infarction: An Under-recognized Complication of Infectious Mononucleosis?[END_REF]. Our patient was admitted for symptomatic treatment (antipyretics, pain management) and was discharged after a week of observation.

The spleen size decreased to normal size at the 30-day follow-up (ultrasound).

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