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Birth defects in a cohort of infants born to HIV-infected women in Spain, 2000-2009

BMC Infectious Diseases volume 14, Article number: 700 (2014) Cite this article

Abstract

Background

Antiretroviral therapy (ART) in pregnancy has resulted in a marked impact on reducing the risk of mother-to-child transmission (MCT) of HIV. However the safety of in utero ART exposure in newborns remains a concern.

Methods

A multicenter prospective observational study of HIV-infected mother and their infants was performed in Madrid, Spain, from 2000 to 2009. Children had regular visits with clinical examination according to protocol until the age of 24 months. An abdominal ultrasound and an echocardiogram were scheduled during follow up. Birth defects (BDs) were registered according to European Surveillance of Congenital Anomalies (EUROCAT).

Results

A total of 897 live births from 872 mothers were included. Overall the birth defects prevalence observed was 6.9% (95% CI 5.4-9.1).The most commonly reported birth defects types were in genital organs and urinary system (19 cases, 30.6%) and cardiovascular system (17 cases, 27.4%). There was no increased risk for infants exposed in the first trimester to ARVs compared with unexposed infants. No significant associations were observed between exposure to any individual antiretroviral agent during pregnancy and birth defects

Conclusion

A higher prevalence of BDs was observed, higher than previously reported. In utero exposure to ART was not proved to be a major risk factor of birth defects in infants. However the relatively small number of patients is a major limitation of this study.

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Background

Antiretroviral therapy (ART) in pregnancy has a marked impact on reducing the risk of mother-to-child transmission (MCT) of HIV [1]. In 1994, the use of zidovudine (ZDV) given during pregnancy and delivery to the mother and during the first weeks of life to the nonbreast-fed newborn was demonstrated to reduce transmission by about 67% [2]. It is now recommended worldwide that HIV-infected pregnant women receive combination ARV regimens during pregnancy [3]. An increasing number of pregnant women are receiving ART in Spain [4],[5]. The use of HAART during pregnancy in Spain has reduced the perinatal HIV transmission below 2% [5].

There are concerns about potential adverse events in newborns exposed to ART during pregnancy, including birth defects. Different prevalences of birth defects (BDs) have been reported in studies with large number of subjects from Europe and United States. While some studies have not detected an overall increase in the prevalences of birth defects (BDs) associated with ART exposure in pregnancy [6],[7], others studies have shown an increased prevalence [8],[9].

Some studies have reported elevated risks with specific exposures. Nucleoside reverse transcriptase inhibitors have a high transplacentary passage [10]-[12]. These drugs have been associated with mitochondrial DNA depletion and, in preliminary studies in monkeys, mitochondrial toxicity has been found in the skeletal and cardiac muscles and brain tissue [10],[12]. A significantly increased prevalence of hypospadias following first trimester zidovudine exposure, compared with later on or no exposure has been observed [13]. Recently, a specific association between in utero exposure to zidovudine and heart defects have been reported in the French Perinatal Cohort [14]. Likewise an increased BDs prevalence in infants exposed to didanosine in first trimester was reported by the Antiretroviral Pregnancy Registry [6].

Exposure to efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI) has been associated with central nervous system defects in monkeys [15], and case reports of neural tube defects in human patients are concerning [16],[17]. A recent meta-analysis has not shown increased risk of birth defects, including central nervous system defects, in newborns exposed to efavirenz during the first trimester of pregnancy (RR 0.85 (95% CI 0.61-1.20) [18]. This result was an important consideration by WHO recommendation for the use of efavirenz during pregnancy [19]. However new data about central nervous system defects published, beyond this meta-analysis, has been less reassuring in the consideration of the use of EFV during first trimestrer of pregnancy [14].

The continued surveillance of birth defects in newborns exposed to antiretrovirals in utero is required, more even when newer antiretroviral agents become available. The aim of our study was to estimate the prevalence of birth defects in children exposed in utero to ARV drugs and to assess the association between in utero exposure to antirretovirals and birth defects in the Madrid Cohort of HIV-infected mother-infants pairs.

Methods

Study population

The Madrid Cohort of HIV-infected mother-infants pairs is a multicenter prospective observational study of HIV-infected pregnant women and their infants followed up since birth. Beginning in 2000, pregnant women and infants were recruited in 8 hospitals in Madrid, Spain. All participants gave verbal informed consent and the study was approved by the Clinical Research Ethics Committee at Hospital Universitario de Getafe.

The baseline characteristics of the cohort and the mother-to-child transmission of HIV data have been provided previously [5].A collaboration of infectious disease specialists, gynaecologists and paediatricians provided prospective and active follow-up as soon as pregnancy was detected in previously monitored HIV-positive women, or as soon as a pregnant woman was identified as HIV-positive, in order to determine the mother-to-child transmission rate, the effectiveness and safety of ART, the presence of birth defects and age-appropriate development in children follow-up.

The cohort for the current analyses includes pregnancies with a definitive outcome through December 31, 2009.

Characteristics of the study population and variables

Women were visited during pregnancy, at delivery and at postpartum. Women with a previous diagnosis of HIV infection were enrolled in the first visit of pregnancy. Women who were diagnosed with HIV infection during pregnancy were enrolled in the first visit after the diagnosis. Information on maternal demographic characteristics was recorded. At each visit, a medical history and a physical examination was performed. Blood count, biochemistry panel, HIV-1 viral load (plasma quantitative HIV-1 RNA level) and CD4+ lymphocyte counts and percentage were collected at each scheduled visit. Start and stop dates were recorded for each antiretroviral agent used. Maternal viral load less than 50 copies/ml was defined as ‘undetectable’.

Trimesters of pregnancy were defined as follows: first trimester, the first day of the last menstrual period through 13 completed weeks of gestation; second trimester, 14 through 28 completed weeks of gestation; and third trimester, beginning at 29 weeks of gestation until delivery.

ART in pregnant women was classified as: none, monotherapy with zidovudine, dual therapy and any combination of 3 or more drugs was categorized as HAART. HAART was further categorized according to whether a protease inhibitor (PI) or a nonnucleoside reverse transcriptase inhibitor (NNRTI) was included. ART treatment administered during pregnancy was recorded, with the dates when started and stopped. Exposure status for each drug was categorised as unexposed, exposed during first trimester, or exposed since the second or third trimester. Birth defects were studied associated to exposure to each drug in first or since second or third trimester compared to no exposure.

A self-report of illicit drug use or a positive urine test result for heroin or opiates, methadone or cocaine was registered. Other variables like cigarette smoking and alcohol use were also self-reported. Diabetes was included as a maternal condition in the analysis. However no other drugs different from ARV were analysed.

Stillbirths and termination of pregnancy are not considered in this analysis. Newborn/infant visits occurred at birth, after 2 or 3 and 6 weeks and thereafter 3, 6, 12, 18 and 24 months. Children had regular visits with clinical examination according to protocol until the age of 24 months. Each visit included a medical history and a physical examination. An abdominal ultrasound was also performed in the first month of life, and an echocardiogram during the first 24 months of life by protocol.

‘Premature birth’ was defined as children born before 37 weeks of pregnancy. ‘Low birth weight’ was defined as children born weighing from 1.500 to 2.500 g; ‘very low birth weight’ was defined as 1.499 g or less.

Birth defects

Birth defect was defined as a structural defect of the body or organ system that may affect viability, quality of life and often requiring surgery [20].

Abnormalities in the fetus/newborn/infant were determined from all available data, including prenatal ultrasound examinations, physical examinations in the newborn period and at each follow-up visit.

Abnormalities observed in the active surveillance system including abdominal ultrasound in neonatal period or echocardiograms during follow-up, as scheduled in the follow-up of this cohort, were also included.

BDs were recorded and classified according to EUROCAT (European Surveillance of Congenital Anomalies) [21], a simpler system than that proposed by the Antiretroviral Pregnancy Registry (APR) [22]. A baby with multiple defects was counted as a single outcome. Birth defects were grouped according to an organ system classification: central nervous system, eyes, face (including neck and ears), hepatic/digestive, musculoskeletal (including cranial bone alterations), cardiac, genitourinary, chromosomal, extremities and others [23].

“Minor” anomalies are excluded, when isolated, because they have lesser medical, functional or cosmetic consequences. We also exclude anomalies which are not always truly congenital in origin, sometimes associated with immaturity at birth.

Angiomas, congenital nevi, pre-auricular appendices, sinus nodules, sacral dimples, atresia of the tears ducts, ovarian cysts, hydrocele, hip dislocation not associated to dysplasia, renal pelvis dilatation of less than 10 mm (without hydronephrosis or urethral atresia), inguinal and umbilical hernias were not classified as BDs and therefore also not included.

These cases have not been reported previously to the Antiretroviral Pregnancy Registry or any other regulatory authorithy.

Statistical analysis

The categorical variables were expressed as frequencies and percentages, while numerical variables were presented as means, medians, standard deviation, and interquartile range. The categorical variables were compared using the chi square, linear tendency chi square or Fisher’s exact test when considered appropriate. Continuous variables were analyzed with ANOVA test, or, in case of non normal distributions, using a non-parametric test. Regression logistic model was used to estimate the strength of association between birth defect and ARV trimester exposure. Results are presented as crude and adjusted odds ratio and 95% confidence intervals (CIs) adjusted for alcohol and illegal drug use during pregnancy. All p values are two-sided p-values and a p value of < 0.05 was considered as statistically significant. The data were analysed with the SPSS (Chicago, IL) program, version 15.0 for Windows.

Results

Maternal and infants characteristics and antiretroviral therapy

During the study period 898 children, including 25 twins or triplets, were considered for this analysis.

The baseline characteristics of the mothers by antiretroviral exposure (exposure in first trimester, exposure in second/third trimester, no antiretroviral exposure in pregnancy) are compared in Table 1. The median gestational age at inclusion was 12 weeks (interquartile range 8–19 months). Women receiving ART during first trimester were more likely to be white and older. Women without antiretroviral therapy were more likely to use illicit drugs or to drink alcohol.

Table 1 Baseline characteristics of HIV infected mothers and time of earliest antiretroviral therapy during pregnancy
Full size table

Women had a good immunological condition status at baseline, and there was no significant difference observed in CD4 lymphocyte counts between the three groups.

Eighty women (8.9%) did not receive treatment during pregnancy. For those who treatment was known during pregnancy, ten women (1.2%) received monotherapy with zidovudine; 21 women (2,6%) received dual therapy (zidovudine plus lamivudine or nevirapine) and 709 (86.6%) received HAART. More than a third of infants (36.7%) had early in-utero exposure.

Four hundred and seventy one infants (52.9%) were males. The median gestational age was 38 completed weeks [interquartile range (IQR): 37–39 weeks]. One hundred and ninety four infants were premature (22.8%); 221 infants (25.6%) presented low weight at birth. The median time of follow-up of the children was 18 months (interquartile range 12–24 months).

Birth defects

Among the study population, major birth defects were recorded in 62 infants, presenting an overall prevalence of 6.9% (95% CI: 5.3-8.7). There were 70 anomalies identified in these 62 infants. Minor defects, classified according EUROCAT, were excluded.

The prevalence of birth defects among HIV-infected women with first-trimester antiretroviral exposure was 7.0% (95% CI: 4.5-10.3). No significant differences were found in the BD prevalence of children receiving intrauterine ART during the first trimester of pregnancy compared with those who started later [7.0% (23/329) vs 6.8% (39/568); p = 1.00] or those non exposed to antiretroviral treatment during pregnancy [7.0% (23/329) vs 7.5% (6/80); p = 0.80].

The most commonly reported birth defects were in genital organs and urinary system (19 cases, 30.6%), cardiovascular system (17 cases, 27.4%), musculoskeletal (8 cases, 12.9%) and digestive system (6 cases, 9.7%) (Table 2).

Table 2 Listing of birth defects detected by timing of antiretroviral therapy exposure
Full size table

The risk of birth defects was not significantly associated with maternal age or ethnic origin. There were no differences either with smoking or using illicit drugs during pregnancy. When we analyzed immunological and virological factors no differences were found in BD prevalences associated with maternal CD4 lymphocytes count in first trimester or maternal viral load in third trimester (Table 3).

Table 3 Risk factors for congenital abnormalities
Full size table

Birth defects were associated with low birth weight in our cohort (11.3 vs 5.4%, p < 0.01) but although there was a slight difference, the association did not reach significance for preterm delivery (9.8 vs 6.1%, p = 0.07).

The type of treatment received by their mothers (none, monotherapy, dual therapy or HAART) was not associated with BD (Table 3).

In analysis there was no significant association with exposure to specific drugs. (Table 4). There were 42 infants exposed in utero to efavirenz; three of them, (7.1%) had birth defects. This percentage did not differ significantly from the prevalence of BD in infants without efavirenz exposure [7.1% (3/42) versus 7.0% (56/793); p = 1.00]. Only two children exposed to EFV in first trimester had BD (two hydronephrosis). No central nervous system anomalies were observed in infants exposed in utero to efavirenz. Two hundred eighty-seven children were exposed to ZDV in first trimester. Eighteen children exposed to ZDV in first trimester had BD (eight patients with birth defects in genital organs and urinary system and seven with birth defects in cardiovascular system). Two of the three cases of hypospadias were in infants exposed to zidovudine in utero. Fifty-nine children were exposed to ddI in first trimester and five of them were exposed to ddI in first trimester had BD (8.4%)

Table 4 Prevalence of birth defects according to type of antiretroviral drug
Full size table

We observed a high prevalence of defects after atazanavir exposure, even when we broke down this result by trimester of exposure (16.7% in first trimester and 15.8% in second/third trimester). The defect after atazanavir exposure in first trimester was oesophageal atresia, and the defects after atazanavir exposure in second/third trimester were Pierre Robin syndrome, hydronephrosis and atrial septal defect.

As we observed differences between baseline characteristics of HIV infected mothers and time of earliest antiretroviral therapy during pregnancy, we analysed the association between birth defect and ARV treatment exposure adjusted for age, alcohol and illegal drug use, but not significant differences were found (Table 4).

Discussion

A major birth defects prevalence of 6.9% was observed in this cohort. This population of infants born to HIV-infected women was similar to other European cohorts in aspects such as the characteristics of the mothers and rates of perinatal HIV transmission. However, the prematurity rates in our cohort are higher than in other cohorts [1],[5],[24]-[26]. The prevalence of BD in this cohort is higher than previously described. Knapp et al. compared different European [27],[28] and American studies [8],[13],[29] evaluating ARV exposure and congenital anomalies and observed a prevalence from 1.5 to 6.1% [9] Overall in most of these studies the physicians evaluated the infants for BD based on physical examinations during scheduled visits.

A difference has to be established between passive surveillance systems (most of which only recording defects based on physical examinations detected in scheduled visits) and active surveillance systems, which include ultrasound scans and echocardiogram in all infants with follow-up from birth. Active surveillance systems, usually show higher BD prevalences. In more than thirty thousand of German newborns not exposed to ART, an active vigilance study showed a BD prevalence of 6.9% [30].

We have reported 17 cardiac malformations, including 9 atrial septal defects and 4 ventricular septal defects. Some authors have reported that early screening echocardiography can detect important subclinical malformations and produce prevalences of cardiac defects of 5% to 10% higher than expected [31],[32]. We also reported two hepatic vascular anomalies and a renal duplicity, detected by ultrasonography. These BDs may not have been otherwise detected in a passive surveillance study. However we could not measure the impact of an active surveillance system used in our cohort.

There are obviously ethnic and environmental factors related to BDs. However we could not show any association between ethnic group and BD in our cohort (Table 3). In previous studies in Spanish general population in the last ten years, BDs prevalence was 2% based on two classification systems [33],[34]. Although these results differs considerably from the BD prevalence published in our study, they were not based on EUROCAT classification system. In these registries either systematic ultrasounds or long follow-up of the children were not included.

Preterm birth and birth defects, especially congenital heart defects have been previously associated. Based on these results, it has been suggested that an underlying mechanism or a genetic disorder could explain this association [35]. We could not report the association between preterm delivery and BD (9.8 vs 6.1%, p = 0.07), but we have observed an association with low weight at birth (11.3 vs 5.4%, p < 0.01). Interestingly, in our cohort 40% (25 cases) of BD were observed in patients with low weight at birth.

The use of illicit drugs during pregnancy (cocaine, heroine or methadone) was not associated with BD. Two cases of foetal alcoholic syndrome were documented. Mothers of these two children reported to consume large amounts of alcohol. However, we could not observe an association between alcohol consumption and BD. Alcohol was a self-reported variable, and it was an important limitation for its analysis.

We did not detect any significant association between BD prevalence and type or timing of ART in pregnancy. First-trimester antiretroviral exposure was not significantly associated with birth defects. This fact is consistent with most of the reports concerning BD and ART, which do not show an increased risk of teratogenesis in infants exposed to ART in the first trimester of pregnancy. However, others studies have found higher rates of BD associated a specific ARV drugs. Exposure to zidovudine in first trimester have been associated to higher prevalence of hypospadias [13] but also to heart defects [14]. In our study, we included more than 200 children with ZDV exposure in first trimester, and we didn’t observe an increased risk of BD. However in the French Perinatal Cohort with more than 3000 children exposed to ZDV in first trimester, a significant association was found with congenital heart defects.

According to the type of drug used (Table 4), no significant increase in BD prevalence was found for each drug, not even with EFV (6.67% in intrautero exposed infants vs 8.33% in no exposed infants; p = 0.98) neither ddI (8.47% vs 13.16%; p =0.27). In the case of atazanavir the rates were higher, but that because of the small number of women exposed, the confidence intervals were large and it was not possible to conclude.

Recently a significant association was found between indinavir and head and neck defects. In our cohort, we observed a higher prevalence of defects in children exposed to indinavir in the first trimester, however, this difference did not reach significance and did not concern head or neck defects.

This study has several limitations. In prospective cohorts the confounding factors are not sufficiently controlled and can lead to bias due to the interpretation of the results. We have not consider for analysis stillbirths and termination of pregnancy. Data as smoking or using illicit drugs during pregnancy were self reported. Also no other drugs used during pregnancy were analysed in this report. The major limitation of our study is the small number of children exposed to ARV in first trimester. We have not analysed any association of specific BDs with each ARV drug. For this reason, no conclusion could be assessed when the number of exposures in first trimester is low. Cohort collaborations and long term follow up are required to further analysis.

Conclusion

In conclusion, a higher prevalence on BDs in infants born to HIV-infected women was observed in this report. However, in utero exposure to ART was not associated to BD. The relatively small number of patients is a major limitation for further analysis in this study.

Appendix 1: Members of the Madrid Cohort of HIV-Infected Mother-Infant Pairs

Hospital Universitario 12 de Octubre: MI González-Tomé, E Muñoz, O Nieto, P Rojo, JM Hernández-García, R Rubio, F Pulido, D Lora, A Gómez de la Cámara, M de Matías, B Fraile, D Blázquez, LI González-Granado, A Navas.

Hospital Universitario La Paz: MI de José, JM Peña, M González, MJ Mellado, L Escosa.

Hospital General Universitario Gregorio Marañón: ML Navarro, J Saavedra, MD

Gurbindo, MC Viñuelas, P Miralles.

Hospital General de Móstoles: MA Roa, C Garaulet.

Hospital Severo Ochoa: I Olabarrieta, MJ Santos, N Martínez, G Alonso.

Hospital Príncipe de Asturias: J Beceiro, S Oñate.

Hospital Ramón y Cajal: A Holguín, P Rojas, C Fernández.

Hospital Universitario de Getafe: JT Ramos, B Soto, A Álvarez, M Fernández Ibieta, S Guillén, E Iglesias, I Cuadrado, I Solis, G Gaspar, L Prieto, I García de Diego.

References

  1. European Collaborative Study: Mother-to-child transmission of HIV infection in the era of highly active antiretroviral therapy. Clin Infect Dis. 2005, 40: 458-465. 10.1086/427287.

    Article  Google Scholar 

  2. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O'Sullivan MJ, VanDyke R, Bey M, Shearer W, Jacobson RL, et al: Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS clinical trials group protocol 076 study group. N Engl J Med. 1994, 331: 1173-1180. 10.1056/NEJM199411033311801.

    Article  CAS  PubMed  Google Scholar 

  3. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed 20 August 2014.

  4. Grupo de expertos de la Secretaría del Plan Nacional sobre el Sida (SPNS), Grupo de Estudio de Sida (GeSIDA)/Sociedad Española de Ginecología y Obstetricia (SEGO) y Sociedad Española de Infectología Pediátrica (SEIP) Documento de Consenso para el seguimiento de la infección por el VIH en relación con la reproducción, embarazo, parto y profilaxis de la transmisión vertical del niño expuesto. January 2013. Available at: http://www.msssi.gob.es/. Accessed 23 September 2014.

  5. Prieto LM, González-Tomé MI, Muñoz E, Fernández-Ibieta M, Soto B, Del Rosal T, Cuadrado I, Navarro ML, Roa MA, Beceiro J, de José MI, Santos MJ, Lora D: Ramos JT; Madrid Cohort of HIV-Infected Mother-Infant Pairs: Low rates of mother-to-child transmisión of HIV-1 and risk factors for infection in Spain: 2000–2007. Pediatr Infect Dis J. 2012, 31: 1053-1058. 10.1097/INF.0b013e31823d942e.

    Article  PubMed  Google Scholar 

  6. Antiretroviral Prgenancy Steering Committee. Antiretroviral pregnancy registry international interim report for 1 January 1989 through 31 July 2008. Wilmington, NC: Registry Coordinating Center; 2008. Available at: www.APRegistry.com. Accessed 20 August 2013.

  7. European Collaborative Study: Does highly active antiretroviral therapy increase the risk of congenital abnormalities in HIV-infected women?. J Acquir Immune Defic Syndr. 2005, 40: 116-118. 10.1097/01.qai.0000156854.99769.a5.

    Article  Google Scholar 

  8. Brogly SB, Abzug MJ, Watts DH, Cunningham CK, Williams PL, Oleske J, Conway D, Sperling RS, Spiegel H, Van Dyke RB: Birth defects among children born to human immunodeficiency virus-infected women: pediatric AIDS clinical trials protocols 219 and 219C. Pediatr Infect Dis J. 2010, 29: 721-727. 10.1097/INF.0b013e3181e74a2f.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Knapp KM, Brogly SB, Muenz DG, Spiegel HM, Conway DH, Scott GB, Talbot JT, Shapiro DE, Read JS: Prevalence of congenital anomalies in infants with in utero exposure to antiretrovirals. Pediatr Infect Dis J. 2012, 31: 164-170. 10.1097/INF.0b013e318235c7aa.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Capparelli E, Rakhmania N, Mirochnick M: Pharmacotherapy of perinatal HIV. Sem Fetal Neonat Med. 2005, 10: 161-175. 10.1016/j.siny.2004.10.001.

    Article  Google Scholar 

  11. Siu SS, Hok-Keung J, Pang MW, Chiu PY, Lau TK: Placental transfer of zidovudine in first trimester of pregnancy. Obstet Gynecol. 2005, 106: 824-827. 10.1097/01.AOG.0000178160.38042.04.

    Article  CAS  PubMed  Google Scholar 

  12. Thorne C, Newell ML: Safety of agents used to prevent mother- to-child transmission of HIV. Drug Saf. 2007, 30: 203-213. 10.2165/00002018-200730030-00004.

    Article  CAS  PubMed  Google Scholar 

  13. Watts DH, Li D, Handelsman E, Tilson H, Paul M, Foca M, Vajaranant M, Diaz C, Tuomala R, Thompson B: Assesment of birth defects according to maternal therapy among infants in the women and infants transmission study. J Acquir Immune Defic Syndr. 2007, 44: 299-305. 10.1097/QAI.0b013e31802e2229.

    Article  PubMed  Google Scholar 

  14. Sibiude J, Mandelbrot L, Blanche S, Le Chenadec J, Boullag-Bonnet N, Faye A, Dollfus C, Tubiana R, Bonnet D, Lelong N, Khoshnood B, Warszawski J: Association between Prenatal Exposure to Antiretroviral Therapy and Birth Defects: An Analysis of the French Perinatal Cohort Study (ANRS CO1/CO11). PLoS Med 11(4): e1001635. doi:10.1371/journal.pmed.1001635

  15. Taylor GP, Low-Beer N: Antiretroviral therapy in pregnancy—focus on safety. Pract Drug Saf. 2001, 24: 683-702. 10.2165/00002018-200124090-00004.

    Article  CAS  Google Scholar 

  16. De Santis M, Carducci B, de Santis L, Cavaliere AF, Straface G: Periconcepcional exposure to efavirenz and neural tube defects. Arch Intern Med. 2002, 162: 190-10.1001/archinte.162.3.355.

    Article  Google Scholar 

  17. Saitoh A, Hull AD, Franklin P, Spector SA: Myelomeningocele in an infant with intrauterine exposure to efavirenz. J Perinatol. 2005, 25: 555-556. 10.1038/sj.jp.7211343.

    Article  PubMed  Google Scholar 

  18. Ford N, Calmy A, Mofenson L: Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS. 2011, 25: 2301-2304. 10.1097/QAD.0b013e32834cdb71.

    Article  CAS  PubMed  Google Scholar 

  19. WHO. Use of efavirenz during pregnancy: A public health perspective. 2012. Disponible en http://www.who.int/hiv/pub/treatment2/efavirenz Accessed 20 August 2013.

  20. EUROCAT (2012) EUROCAT Special Report: Congenital anomalies are a major group of mainly rare diseases. EUROCAT Central Registry, University of Ulster. Available at: http://www.eurocat-network.eu/content/Special-Report-Major-Group-of-Mainly-Rare-Diseases.pdf Accessed 20 August 2014

  21. EUROCAT. EUROCAT Statistical Monitoring Report −2006. 2009. Available at: http://www.eurocat.ulster.ac.uk. Accessed 20 August 2014

  22. Scheuerle A, Tilson H: Birth defect classification by organ system: a novel approach to heighten teratogenic signalling in a pregnancy registry. Pharmacoepidemiol Drug Saf. 2002, 11: 465-475. 10.1002/pds.726.

    Article  PubMed  Google Scholar 

  23. EUROCAT (2005) EUROCAT Guide 1.3 and reference documents. Instructions for the Registration and Surveillance of Congenital Anomalies. Available at: http://www.eurocat-network.eu/aboutus/datacollection/guidelinesforregistration/guide1_3instructionmanual Accessed 20 August 2014

  24. Warszawski J, Tubiana R, Le Chenadec J, Blanche S, Teglas JP, Dollfus C, Faye A, Burgard M, Rouzioux C, Mandelbrot L, ANRS French Perinatal Cohort: Mother-to-child transmission despite anti-retroviral therapy in the ANRS French perinatal cohort. AIDS. 2008, 22: 289-299. 10.1097/QAD.0b013e3282f3d63c.

    Article  PubMed  Google Scholar 

  25. Goetghebuer T, Haelterman E, Marvillet I, Barlow P, Hainaut M, Salameh A, Ciardelli R, Gerard M, Levy J: Vertical transmission of HIV in Belgium: a 1986–2002 retrospective analysis. Eur J Pediatr. 2009, 168: 79-85. 10.1007/s00431-008-0717-y.

    Article  PubMed  Google Scholar 

  26. von Linstow ML, Rosenfeldt V, Lebech AM, Storgaard M, Hornstrup T, Katzenstein TL, Pedersen G, Herlin T, Valerius NH, Weis N: Prevention of mother-to-child transmission of HIV in Denmark, 1994–2008. HIV Med. 2010, 11: 448-456.

    CAS  PubMed  Google Scholar 

  27. Townsend CL, Willey BA, Cortina-Borja M, Peckham CS, Tookey PA: Antiretroviral therapy and congenital abnormalities in infants born to HIV-infected women in the UK and Ireland, 1990–2007. AIDS. 2009, 23: 519-524. 10.1097/QAD.0b013e328326ca8e.

    Article  PubMed  Google Scholar 

  28. Patel D, Thorne C, Fiore S, Newell ML, the European Collaborative Study: Does highly active antiretroviral therapy increase the risk of congenital abnormalities in HIV-infected women?. J Acquir Immune Defic Syndr. 2005, 40: 116-118. 10.1097/01.qai.0000156854.99769.a5.

    Article  PubMed  Google Scholar 

  29. Joao EC, Calvet GA, Krauss MR, Freimanis Hance L, Ortiz J, Ivalo SA, Pierre R, Reyes M, Heather Watts D, Read JS, NISDI Perinatal Study Group: Maternal antiretroviral use during pregnancy and infant congenital anomalies: the NISDI perinatal study. J Acquir Immune Defic. 2010, 53: 176-185. 10.1097/QAI.0b013e3181c5c81f.

    Article  Google Scholar 

  30. Queisser-Luft A, Stolz G, Wiesel A, Schlaefer K: Malformations in newborn: Results based on 30940 infants and fetuses from the Mainz congenital birth defect monitoring system (1990–1998). Arch Gynecol Obstet. 2002, 266: 163-167. 10.1007/s00404-001-0265-4.

    Article  CAS  PubMed  Google Scholar 

  31. Lai WW, Lipshultz SE, Easley KA, Starc TJ, Drant SE, Bricker JT, Colan SD, Moodie DS, Sopko G, Kaplan S: Prevalence of congenital cardiovascular malformations in children of human immunodeficiency virus-infected women: the prospective P2C2 HIV Multicenter Study. J Am Coll Cardiol. 1998, 32: 1749-1755. 10.1016/S0735-1097(98)00449-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hoffman JI, Kaplan S: The incidence of congenital heart disease. J Am Coll Cardiol. 2002, 39: 1890-1900. 10.1016/S0735-1097(02)01886-7.

    Article  PubMed  Google Scholar 

  33. Martinez-Frias ML, Bermejo E: Frecuencia basal de defectos congénitos en España y su evolucion en el tiempo: utilidad y significado de las distintas cifras de frecuencia. Med Clin(Barc). 1999, 113: 459-462. 35

    CAS  Google Scholar 

  34. Salvador Peral J, García-Miñaur Rica S, Caballín Fernández MR, Mosquera Tenreiro C, Baena Díez N, García López E, Castro Laiz V, Guitart Feluibadaló M, Gabau Vila E, Plasència Taradach A: Registros poblacionales de defectos congénitos en España. An Pediatr (Barc). 1999, 48: 575-582.

    Google Scholar 

  35. Laas E, Lelong N, Thieulin AC, Houyel L, Bonnet D, Ancel PY, Kayem G, Goffinet F, Khoshnood B, EPICARD Study Group: Preterm birth and congenital heart defects: a population-based study. Pediatrics. 2012, 130: e829-e837. 10.1542/peds.2011-3279.

    Article  PubMed  Google Scholar 

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Acknowledgements

We would like to thank all the mothers and their children.

The authors acknowledge the financial support that was provided by FIPSE (Fundación para la Investigación y Prevención del SIDA en España): FIPSE grant number 36531/05 and FIPSE grant number 36737/08.

Sources of support

Financial support that was provided by FIPSE (Fundación para la Investigación y Prevención del SIDA en España): FIPSE grant number 36531/05 and FIPSE grant number 36737/08.

Author information

Authors and Affiliations

  1. Department of Paediatrics, Hospital Universitario de Getafe, Madrid, Spain

    Luis M Prieto, María Fernández-Ibieta, Beatriz Soto, Ana Álvarez & José Tomás Ramos

  2. Department of Immunodeficiencies, Hospital Universitario 12 de Octubre, Madrid, Spain

    María Isabel González- Tomé

  3. Department of Gynecology, Hospital Universitario 12 de Octubre, Madrid, Spain

    Eloy Muñoz

  4. Department of Pediatric Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain

    Maria Luisa Navarro

  5. Department of Paediatrics, Hospital General de Móstoles, Madrid, Spain

    Miguel Ángel Roa

  6. Department of Paediatrics, Hospital Principe de Asturias, Madrid, Spain

    José Beceiro

  7. Department of Pediatric Infectious Diseases, Hospital Universitario La Paz, Madrid, Spain

    María Isabel de José

  8. Department of Paediatrics, Hospital Severo Ochoa, Madrid, Spain

    Iciar Olabarrieta

  9. Department of Epidemiology, Hospital Universitario 12 de Octubre, Madrid, Spain

    David Lora

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  1. Luis M Prieto
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  2. María Isabel González- Tomé
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  13. José Tomás Ramos
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Consortia

the Madrid Cohort of HIV-Infected Mother-Infant Pairs

Corresponding author

Correspondence to Luis M Prieto.

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Competing interests

The authors declare that they have no significant competing financial, professional or personal interests that might have influenced the performance or presentation of the work described in this manuscript.

Authors’ contributions

LMP and JTR devised and supervised the study, analysed the results and was mainly responsible for writing the paper. MIGT, EM, MFI, BS, AA, MLN, MAR, JB, MIJ, IO enrolled patients and gathered data. DL was responsible for the statistical analysis. JTR took part in the design of the protocol, analysed results and wrote the paper.All authors read and approved the final manuscript.

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Prieto, L.M., González- Tomé, M.I., Muñoz, E. et al. Birth defects in a cohort of infants born to HIV-infected women in Spain, 2000-2009. BMC Infect Dis 14, 700 (2014). https://0-doi-org.brum.beds.ac.uk/10.1186/s12879-014-0700-3

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  • DOI: https://0-doi-org.brum.beds.ac.uk/10.1186/s12879-014-0700-3

Keywords

BMC Infectious Diseases

ISSN: 1471-2334

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