Pregnancy complications in HIV-positive women: 11 ...

DOI: 10.1111/hiv.12142 HIV Medicine (2014)

© 2014 British HIV Association

ORIGINAL RESEARCH

Pregnancy complications in HIV-positive women: 11-year data from the Frankfurt HIV Cohort A Reitter,1 AU Stücker,1 R Linde,2 C Königs,2 G Knecht,3 E Herrmann,4 R Schlößer,5 F Louwen1 and A Haberl6 Department of Obstetrics and Gynaecology, University Hospital Frankfurt, Goethe University, Frankfurt, Germany, 2 Department of Pediatrics, Divison of Immunology, University Hospital Frankfurt, Goethe University, Frankfurt, Germany, 3Center for Infectious Diseases, Frankfurt, Germany, 4Department of Biostatistics and Mathematic Modeling, Goethe University, Frankfurt, Germany, 5Department of Pediatrics, Divison of Neonatology, University Hospital Frankfurt, Goethe University, Frankfurt, Germany and 6Department of Infectious Diseases, University Hospital Frankfurt, Goethe University, Frankfurt, Germany

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Objectives

The aim of the study was to assess pregnancy complications in HIV-positive women and changes in the rates of such complications over 11 years in the Frankfurt HIV Cohort. Methods

There were 330 pregnancies in HIV-positive women between 1 January 2002 and 31 December 2012. The rate of pregnancy-related complications, such as gestational diabetes mellitus (GDM), pre-eclampsia and preterm delivery, the mode of delivery and obstetric history were analysed. Maternal and neonatal morbidity/mortality as well as HIV mother-to-child transmission (MTCT) were evaluated. Results

In our cohort, GDM was diagnosed in 38 of 330 women (11.4%). Five women (1.5%) developed pre-eclamspia or hypertension. In 16 women (4.8%), premature rupture of membranes (PROM) occurred and 46 women (13.7%) were admitted with preterm contractions. The preterm delivery rate was 36.5% (n = 122), and 26.9% of deliveries (n = 90) were between 34+0 and 36+6 weeks of gestation. Over the observation period, the percentage of women with undetectable HIV viral load (VL) increased significantly (P < 0.001), from 26.1% to 75%, leading to obstetric changes, including an increase in the rate of vaginal deliveries (P < 0.001), from no vaginal births to 50%. The preterm delivery rate decreased significantly (P < 0.001), from 79.2% to 8.3%. There were no significant changes in the rate of GDM, pre-eclampsia, PROM or preterm contractions. Conclusions

In the 11 years of our analysis, there was a significant reduction in the rate of preterm deliveries and an increase in the vaginal delivery rate, possibly reflecting changes in treatment policies in the same period and the availability of more effective antiretroviral therapy options. The rates of complications such as GDM, pre-eclampsia, preterm contractions, PROM and postnatal complications were stable over the 11 years, but were still increased compared with the general population. Keywords: high-risk pregnancy, highly active antiretroviral therapy (HAART), HIV, gestational

diabetes mellitus (GDM), mother-to-child transmission (MTCT), preterm delivery Accepted 15 January 2014

Correspondence: Dr Anke Reitter, Department of Obstetrics and Gynaecology, University Hospital Frankfurt, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany. Tel: 0049 69 63016506; fax: 0049 69 63016507; e-mail: [email protected]

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Introduction The majority of women living with HIV are in their reproductive years (aged 15-49 years) [1]. Effective highly active antiretroviral therapy (HAART) has led to an improvement in quality of life and life expectancy [1,2], with more and more couples wanting their own children. Today, motherto-child transmission (MTCT) of HIV can be reduced to < 1%, mainly as a result of HAART. Effective HIV treatment can suppress the viral load (VL) to undetectable levels, which leads to new options for pregnant women living with HIV: a vaginal birth can be as safe as a planned caesarean section. Avoidance of breast feeding and neonatal post-exposure prophylaxis (PEP) lead to further reductions in MTCT [3–5]. Apart from data showing the success that has been achieved in reducing MTCT in high-income countries (where HAART is available) to < 1%, there appears to be a lack of data concerning pregnancy-related complications. There is still a fear of adverse pregnancy outcomes in women living with HIV. There are conflicting data regarding the risk of prematurity, and there may be an increased risk of gestational diabetes mellitus (GDM), pre-eclampsia and other possible adverse effects of HAART regimens in HIV-positive women [4,6,7] . According to the literature and our own data, there is no increased rate of fetal malformations as a result of HIV infection and HAART [6,8]. A pregnancy in an HIV-infected woman is considered a high-risk pregnancy; national guidelines for the care of HIV-infected women recommend intensified prenatal care, including referral for prenatal ultrasound screening. If a fetal anomaly is suspected, invasive prenatal testing can be offered after being on HAART suppressing the VL below the limit of detection. In these cases, present evidence suggests that MTCT is not higher than 1%, which is the known rate of transmission in optimal settings (e.g HAART and suppressed VL) [9]. HAART is given during pregnancy for two reasons: first, it is given to women requiring treatment for their own health and, secondly, it is given to pregnant women starting therapy purely as a prophylactic treatment to reduce MTCT. Data regarding the safety of HAART are collected in national and international registers [e.g. the Antiviral Pregnancy Registry (APR), the National Study of HIV in Pregnancy and Childhood (UK) (NSHPC), the European Collaborative Cohort (ECS), the French Perinatal Cohort (EPF) and the German HIV Pregnancy Registry] [10–12]. The malformation rate with HAART does not exceed the rate of 3–5% seen for pregnancies in HIV-negative women [13–15]. National treatment policies changed several times within the study period. The major changes were: (1) if VL was


undetectable, it was recommended that a vaginal birth should be offered and, if a caesarean delivery was chosen, then delivery should be delayed beyond 38 weeks; (2) the recommendation for initiation of HAART in treatmentnaïve pregnant women changed from 32 weeks of gestation to 28 weeks of gestation in singleton pregnancies to achieve complete VL suppression at the time of delivery; (3) new HAART regimes/options with better efficacy and possibly offering an overall improvement in maternal health were approved for use [16–18]. The aim of our study was to investigate the risk of pregnancy-related complications such as GDM, preeclampsia/hypertension, preterm labour, preterm rupture of membranes (PROM) and preterm delivery in HIV-infected pregnant women. Previous obstetric history and present maternal and neonatal morbidity were investigated. We suggest that a decrease in the complication rate has occurred over the last 11 years as a result of changes in treatment policies.

Methods In this retrospective study, pregnant women with HIV infection who presented at our obstetric tertiary referral centre from 1 January 2002 to 31 December 2012 were included in the study. Only pregnancies of ≥ 24 weeks of gestation were included. Three categories were used: very preterm delivery (24+0 to 33+6 weeks of gestation), preterm delivery (34+ to 36+6 weeks of gestation) and term delivery (≥ 37 weeks of gestation). Maternal information collected included age, ethnicity, gestational age at delivery, gravidity and parity, HAART starting before or during the pregnancy, VL (HIV-1 RNA copies/ml), CD4 count (cells/μl) prior to birth and other risk factors such as coinfection with hepatitis C virus (HCV). The last recorded VL prior to the delivery was classified into three groups: < 50, 50–399 and ≥ 400 copies/mL. A VL < 50 copies/mL was considered as ‘negative/undetectable’. The last CD4 count prior to birth was noted, and again three categories were used (< 200, 200–349 and ≥ 350 cells/μL). These categories were used following the recommendations for treatment in pregnancy in the German− Austrian Guidelines [19]. The mode of delivery was classified as (1) planned caesarean section, (2) elective caesarean section in labour (in cases of rupture of membranes and/or contraction), (3) emergency caesarean section, (4) caesarean section after trial of vaginal birth, (5) vaginal birth, (6) unplanned vaginal birth and (7) instrumental vaginal delivery. During the study period, the first planned vaginal birth was recorded in 2009. Before 2009, women in Germany were offered elective caesarean section

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Pregnancy complications in HIV-positive women 3

at around 37+0 weeks of gestation according to the German−Austrian Guidelines [3,19,20]. With increasing evidence for the safety of vaginal births with undetectable VL, the guidelines as well as the policy in the unit shifted towards planned vaginal births and, if a caesarean section was offered, in these cases the delivery was delayed until after > 37 weeks of gestation [19]. A detailed obstetric history, including previous vaginal deliveries, caesarean sections, miscarriages or termination of pregnancies, and previous history of a stillborn child or other death of a child, was retrieved from the case notes. A history of substance abuse was noted. The following pregnancy-related complications were examined: (1) GDM (diet- and insulin-dependent); (2) pre-eclampsia/hypertension; (3) PROM; (4) preterm contractions; and (5) preterm deliveries. GDM was diagnosed according to the national German guidelines [21], being defined as a glucose challenge test (GCT) of 50 g or a 75-g oral glucose tolerance test (oGTT). Pre-eclampsia or gestational hypertension was also diagnosed according to the national guidelines, being defined as an increase in blood pressure of ≥ 140/ 90 mmHg after 20 weeks of gestation and concomitant proteinuria for the diagnosis of pre-eclampsia [22]. Diagnosis of PROM with performance of a vaginal speculum examination, with either visible pool of amniotic fluid and/or a positive test for insulin-like growth factor binding protein-1 (IGFBP-1). The diagnosis of preterm labour was taken out of the hospital notes as a reason for admission in the hospital because of contractions and/or shortening of the cervical length which has been recorded as such [23]. Neonatal data included: APGAR (score system to evaluate the newborn, APGAR is the acronym for: Appearance, Pulse, Grimace, Activity, Respiration) score, arterial pH (apH), venous cord blood pH (vpH), base excess (BE), neonatal weight, and neonatal weight according to percentile (< 10th, 10–90th and > 90th percentiles). Newborns with intrauterine growth retardation (IUGR) were classified as those with a birth weight below the 10th percentile adjusted for gestational age. MTCT was confirmed by a positive HIV polymerase chain reaction (PCR) at the age of three months. Postnatal data obtained included the duration of hospital stay after delivery (in days). The last available haemoglobin measurement (in g/dl) prior to birth and the last haemoglobin measurement prior to discharge were obtained. Postnatal maternal complications were recorded, including wound infection, wound revision and requirements for blood transfusion. Information about the mother was retrieved from hospital records (from the Department of Obstetrics and Gynaecology, the Department of Infectious Diseases and the Ultrasound Department) and neonatal information was retrieved from medical records and paediatric discharge letters.


This retrospective study was conducted according to the ethical principles for medical research involving human subjects of the Declaration of Helsinki. Ethics approval was obtained from the Ethics Committee at the J. W. Goethe University, Frankfurt (final decision date 7 March 2013; Number 30/13.) For categorical variables and nominal variables, frequency tables were used for descriptive statistical analysis. For ordinal and quantative data, the mean and standard deviation (SD) or percentile were used. These data were further analysed using the Wilcoxon−Mann−Whitney test, the Kruskal−Wallis test, Spearman correlation, the χ2 test and Fisher’s exact test, as appropriate. All tests were two-sided and a P-value < 0.05 was considered statistically significant. Trends over the study period were assessed by Spearman correlation between calendar year of pregnancy and HAART, GDM, VL, CD4 count, mode of delivery, gestational age, pre- and postnatal haemoglobin measurements, duration of hospital stay, newborn weight < 10th percentile, and postnatal complications, respectively. Statistical analysis was performed using IBM SPSS 20 statistical software Version 20 (IBM SPSS Statistics Base 20 Frankfurt, Germany).

Results Overall, 330 pregnancies were recorded, with 322 (97.6%) singleton pregnancies and eight (2.4%) twin gestations. A total of 122 pregnancies (36.5%) were preterm deliveries and 90 of these (26.9%) were between 34+0 and 36+6 weeks of gestation. Maternal and neonatal characteristics are presented in total, and stratified by pregnancy duration, in Table 1. Data are given as mean ± SD or as absolute numbers (percentages) for categorical variables. Mean maternal age at presentation was 31.1 ± 5.7 years. Nearly half (n = 162; 49.7%) were primiparae. For the remaining 168 women, previous obstetric histories revealed that 147 women (43.9%) had had a previous miscarriage and/or a termination. Overall, 111 women had had a previous caesarean section (84.7% had had one, 13.5% had had two and 1.8% had had three previous caesarean sections). In 96 women, a previous vaginal birth was recorded (69.8% had had one, 20.8% had had two and 9.3% had had three or more vaginal births). In 16 women (4.8%), there was a history of a previous loss of a child, including intrauterine death. The majority of the women (n = 188; 66.4%) were of African ethnicity. In 79 (24.2%) cases, the first diagnosis of HIV infection was made during the pregnancy. Additionally, 24 women (9.4%) tested positive for HCV, but only 14 women (58.3%) had chronic active disease (positive HCV PCR). One-third of all women (116; 37.4%) were not on HAART at the

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Table 1 Maternal and neonatal characteristics according to duration of pregnancy Total (n = 330 pregnancies; n = 338 newborns) Maternal age at delivery (years) (mean ± SD) Gravidity (n = 326) [n (%)] 1 2 3 4 >5 Parity (n = 326) [n (%)] 1 2 3 4 >5 Ethnicity (n = 283) [n (%)] Caucasian African HIV diagnosis during pregnancy (n = 327) [n (%)] Yes No Mode of delivery (n = 332) [n (%)] Planned caesarean section Caesarean section during labour Emergency caesarean section Caesarean section after trial of vaginal birth Spontaneous vaginal delivery Unplanned vaginal delivery Instrumental vaginal delivery (e.g. forceps) CD4 count at delivery (n = 281) [n (%)] < 200 cells/μL 200–349 cells/μL ≥ 350 cells/μL Viral load at delivery (n = 301) [n (%)] < 50 copies/mL 50–399 copies/mL ≥ 400 copies/mL HAART before beginning of pregnancy (n = 289) [n (%)] Yes No HCV (positive anti-HCV test) (n = 280) [n (%)] Positive Negative 5-min APGAR (n = 330) [n (%)] 7.2 Fetal weight (g) (n = 333) (mean ± SD) Percentile (n = 335) [n (%)] < 10th 10–90th


31.1 ± 5.7

Subgroups according to gestational age (weeks + days) 24 + 0 to 33 + 6 (n = 32)

34 + 0 to 36 + 6 (n = 90)

32.5 ± 5.8

30.2 ± 5.8

37 + 0 to 42 (n = 212) 31.2 ± 5.6

89 (27.3) 104 (31.9) 71 (21.8) 38 (11.7) 24 (7.2)

7 (24.1) 9 (31) 7 (24.1) 3 (10.3) 3 (10.3)

21 (24.7) 28 (32.9) 19 (22.4) 9 (10.6) 8 (10.1)

68 (28.8) 67 (31.6) 45 (21.2) 26 (12.3) 13 (10.7)

162 (49.7) 108 (33.1) 36 (11) 12 (3.7) 8 (2.4)

16 (55.2) 6 (20.7) 4 (13.8) 0 3 (10.3)

42 (49.4) 30 (35.3) 9 (10.6) 3 (3.5) 1 (1.2)

104 (49.1) 72 (34) 23 (10.8) 9 (4.2) 4 (1.8)

95 (33.6) 188 (66.4)

5 (22.7) 17 (77.3)

27 (38.6) 43 (61.4)

63 (33) 128 (67)

79 (24.2) 243 (75.8)

9 (30) 21 (70)

19 (22.1) 67 (77.9)

51 (24.2) 160 (75.8)

252 (77.4) 30 (9) 1 (0.3) 13 (3.9) 29 (8.7) 1 (0.3) 1 (0.3)

26 (83.9) 5 (16.1) 0 0 0 0 0

70 (78.6) 15 (16.9) 0 0 3 (3.4) 1 (1.1) 0

161 (75.9) 10 (4.7) 1 (0.5) 13 (6.1) 26 (12.3) 0 1 (0.5)

30 (10.5) 76 (27) 175 (62.5)

2 (8) 12 (48) 11 (44)

6 (8.3) 14 (19.4) 52 (72.2)

22 (12) 50 (27.2) 112 (60.9)

168 (55.8) 88 (29.2) 45 (15)

9 (36) 7 (28) 9 (36)

27 (34.6) 32 (41) 19 (24.4)

132 (66.7) 49 (24.7) 17 (8.6)

P = value* 0.102 > 0.20

> 0.20

> 0.20

> 0.20

< 0.001

0.075

< 0.001

> 0.20 188 (62.6) 116 (37.4)

17 (66.7) 10 (33.3)

41 (55.4) 33 (44.6)

123 (65.4) 65 (34.6)

24 (9.37) 256 (90.6)

2 (8) 23 (92)

10 (13.2) 66 (86.8)

12 (7.2) 167 (92.8)

0 5 (1.5) 325 (98.5)

0 5 (17.2) 24 (82.8)

0 0 90 (100)

0 0 211 (100)

0 2 (0.6) 16 (4.9) 309 (94.5)

0 0 3 (10) 27 (90)

0 0 3 (3.4) 85 (96.6)

0 2 10 (4.8) 197 (95.2)

0 0 5 (1.6) 296 (98.4) 2837 ± 656

0 0 1 (4.8) 21 (95.5) (n = 32) 1573.28 ± 517.98 (n = 32) 1 (3.3) 28 (84.7)

> 0.20

< 0.001

0.088

0.009

30 (9) 291 (86.9)

0 0 0 80 (100) (n = 90) 2634.56 ± 463.12 (n = 90) 7 (8.2) 80 (88.3)

0 0 4 (2) 195 (98) (n = 211) 3115.14 ± 460.06 (n = 211) 21 (9.9) 183 (86)

< 0.001 > 0.20

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Table 1 (Contd.)

> 90th Any fetal anomaly (pre- and postnatal diagnosis) [n (%)] Gestational diabetes [n (%)] Pre-eclampsia/hypertension [n (%)] Haemoglobin measurement prior to delivery (g/dl) (mean ± SD) First postnatal haemoglobin measurement (g/dl) (mean ± SD) Drug abuse, methadon [n (%)] Hospital stay duration Duration of hospital stay after delivery (days) (n = 300) (mean ± SD) ≤ 6 days [n (%)] 7–10 days [n (%)] > 10 days [n (%)] Preterm rupture of membranes [n (%)] Preterm contractions [n (%)] Complications in postnatal period (e.g. wound infection, wound revision or blood transfusion) [n (%)] Scar dehiscence as a result of previous CS (n) Previous vaginal birth [n (%)] 1 2 3 >3 Previous caesarean section [n (%)] 1 2 3 Miscarriage/termination of pregnancy [n (%)] Previous history of death of a child [n (%)]

Total (n = 330 pregnancies; n = 338 newborns)

24 + 0 to 33 + 6 (n = 32)

34 + 0 to 36 + 6 (n = 90)

37 + 0 to 42 (n = 212)

P = value*

14 (4.2) 15 (4.5) 38 (11.4) 5 (1.5) 11.26 ± 1.34 9.95 ± 1.28 22 (6.6)

3 (10) 4 (13.3) 4 (13.3) 3 (9.3) 10.88 ± 1.52 9.82 ± 1.13 1 (3.1)

3 (3.5) 2 (2.4) 9 (10.6) 0 (0) 10.98 ± 1.31 9.83 ± 1.27 10 (11.1)

> 0.20 0.013 0.018 0.056 > 0.20 0.022

6.72 ± 2.54

5.64 ± 1.87

7 (3.3) 9 (4.2) 25 (11.8) 2 (0.9) 11.34 ± 1.25 10.01 ± 1.3 11 (5.1) 5.54 ± 2.07

260 (86.6) 32 (10.6) 8 (2.6) 16 (4.8) 46 (13.7) 17 (5.1)

2 (6.6) 7 (23.3) 2 (6.6)

10 (11.7) 27 (31.8) 8 (9.4)

4 (1.9) 12 (5.7) 7 (3.3)

> 0.20 > 0.20 > 0.20

4 (1.2) 96 (29.1) 67 (69.8) 20 (20.8) 8 (8.3) 1 (1) 111 (33.6) 94 (84.7) 15 (13.5) 2 (1.8) 147 (43.9) 16 (4.8)

7 (23.3) 3 (10) 4 (13.3) 0 0 7 (23.3) 5 (16.6) 1 (3.3) 1 (3.3) 13 (43.3) 0

24 (28.2) 18 (21.2) 3 (3.5) 3 (3.5) 0 27 (31.7) 21 (24) 5 (5.8) 1 (1.2) 34 (40) 8 (9.4)

65 (30.6) 46 (21.7) 13 (6.1) 5 (2.4) 1 (0.5) 77 (36.3) 68 (32.1) 9 (4.2) 0 100 (47.2) 8 (3.7)

> 0.20

Subgroups according to gestational age (weeks + days)

> 0.20

0.01 0.010

CS, caesarean section; HAART, highly active antiretroviral therapy; HCV, hepatitis C virus; SD, standard deviation. *P-values were calculated without significance correction. The Kruskal−Wallis test was used for maternal age, gravidity, parity, APGAR (score system to evaluate the newborn, APGAR is the acronym for: Appearance, Pulse, Grimace, Activity, Respiration) score, arterial pH, venous cord pH, fetal weight and percentile, gestational diabetes, haemoglobin pre- and postnatal measurements, substance abuse, discharge, preterm labour, preterm rupture of membranes, complications, previous birth, miscarriage, and previous poor obstetric outcome. The χ2 test was used for the other variables.

beginning of their pregnancy. The different HAART regimes used over the study period are presented in Figure 1. The variation in regimes was significant (P < 0.001). The vast majority of the women (252; 77.4%) delivered by planned caesarean section; only in one case (0.3%) was an emergency caesarean section performed. In 13 cases (4%), a caesarean section was performed during labour. Twenty-nine women (8.7%) delivered vaginally. The number delivering vaginally significantly increased in later years (P < 0.001). The CD4 count prior to birth was > 350 cells/μL in the majority of women (n = 175; 62.5%). The VL was suppressed to < 50 copies/mL in 55.8% of all women (n = 168), while 88 (29.2%) had a VL between 50 and 399 copies/mL and 45 (15%) had a VL of ≥ 400 copies/ml. The number of women with a suppressed VL (VL < 50 copies/ ml) increased significantly (P < 0.001), whereas the number of women with CD4 counts > 350 cells/μL prior to birth increased nonsignificantly (P > 0.20) (Fig. 2). Furthermore,


there was a significant change towards delaying delivery until term over the last 11 years (P < 0.001; Fig. 3). Over the period of study there was a significant change in the mode of delivery (P < 0.001). In the early years the deliveries were all by planned caesarean section, which has now shifted towards vaginal delivery (Fig. 4). GDM according to national guidelines was detected in 38 women (11.4%), of whom six (1.8%) were insulin dependent and 32 (9.6%) diet controlled. There was no significant change over the study period in the rate of diagnosis of GDM (P > 0.20). Only five women (1.5%) had pre-eclampsia or hypertension. In 46 women (13.7%), hospital admission occurred because of preterm labour, and 16 women (4.8%) had PROM. There was no significant change over the study period in the rate of diagnosis of pre-eclampsia/ hypertension (P > 0.20) or PROM (P = 0.081). By contrast, the rate of diagnosis of preterm contractions decreased significantly over the years (P < 0.001).

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Fig. 1 Changes in highly active antiretroviral therapy (HAART) regimes over the study period (including the numbers of patients treated with the different regimes) (P < 0.001). PI, protease inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; ZDV, zidovudine. (a)

(b)

Fig. 2 Changes in CD4 count (P > 0.20) (a) and viral load (VL) control (P < 0.001) (b) at birth over the study period.

The neonatal data showed a 5-min APGAR score ≥ 7 in 319 cases (98.9%), apH > 7.2 in 302 (94.4%) and vpH > 7.2 in 290 (98%). Median (± SD) fetal weight was 2837 g (± 656 g). Twenty-nine newborns (8.9%) had weights below the 10th percentile and were classified as IUGR [24]. Over the study period there was no significant change in the rate of diagnosis of IUGR (P = 0.119). The overall fetal malformation rate in our study population (4.5%) was the same as that reported for the general population [25]. There were two cases of postna-


tal diagnosis of trisomy 21. Three cases (0.9%) of MTCT were noted and all three pregnancies were delivered by caesarean section (Table 2). Altogether there were six perinatal death. One intrauterine death, three cases in the neonatal period (one very preterm infant due to sepsis and respiratory distress syndrome, one infant with multiple malformations, another with a chromosomal anomaly). One very preterm baby just died after the neonatal period at 4 weeks of age after a bowl volvulus and another infant died at 9 months as a result of a sudden infant death.

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Fig. 3 Distribution of gestational age at birth over the study period (P < 0.001).

Fig. 4 Change in mode of delivery over the study period (P < 0.001). CS, caesarean section; VB, vaginal birth.

The maternal median (± SD) haemoglobin measurement prior to birth was 11.26 ± 1.34 g/dl and the median postnatal haemoglobin measurement was 9.95 ± 1.28 g/dl. The maternal median haemoglobin concentration prior to delivery significantly increased over time (P = 0.007), but the postnatal haemoglobin concentration did not change (P = 0.051). Hospital discharge within 6 days after delivery


was recorded in the majority of cases (260; 86.6%), and in 32 women (10.6%) discharge was delayed until 7−10 days postnatally. A prolonged hospital stay of > 10 days was noted in only eight women (2.6%). In the study period there was no change in the length of hospital stay postnatally (P = 0.125). In 17 women (5.1%) postnatal complications were recorded; in four of these cases, the complications

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Table 2 Mother-to-child transmission

Year

Mode of delivery

Gestational age at delivery (weeks + days)

2003 2004 2010

Emergency caesarean section Planned caesarean section Planned caesarean section

33 + 6 36 + 4 36 + 3

VL at delivery (copies/mL)

Risk of transmission*

HAART

Coinfection

Weight (g)

APGAR score

90 1900 4830

High Medium Medium

CBV NVP CBV NVP NVP TVD† T20

HCV HBV No No

2380 (10–90th percentile) 2280 (< 10th percentile) 2630 (10–90th percentile)

9/10/10 9/9/10 9/10/10

APGAR, score system to evaluate the newborn, APGAR is the acronym for: Appearance, Pulse, Grimace, Activity, Respiration; CBV, zidovudine/lamivudine; HAART, highly active antiretroviral therapy; HBV, hepatitis B virus; HCV, hepatitis C virus; NVP, nevirapine; T20, enfuvirtide; TVD, tenofovir/emtricitabine; VL, viral load. *Risk of transmission according to the recommendations of the German−Austrian Guidelines at the time of delivery [16–18]. † HAART regime tenofovir/emtricitabine and intensified (directly observed) with T20 application because of nonadherence and high VL.

were attributable to previous uterine surgery and scar dehiscence. There was no change in the rate of postnatal complications within the study period (P > 0.20).

Discussion Our cohort data cover 11 years in which significant changes in HIV treatment policies occurred. Over the study period HAART regimes changed and became more effective in controlling the VL and leading to an increase in the CD4 count. In our population, VL control improved significantly over the years and there was a nonsignificant increase in CD4 count (P = 0.835) (Fig. 2). The current national guidelines state that it is acceptable to delay caesarean section until term in women with suppressed VL [19]. The delivery policy therefore shifted from recommending elective caesarean section towards a preference for spontanous delivery [19]. Our results reflect these changes over time, with vaginal delivery rates increasing significantly (P < 0.001). Table 3 compares our results with data from other published studies [5,20,26–29]. There is a general lack of data regarding pregnancy complications which are leading to hospital admission such as preterm contractions and PROM. Preterm delivery rates are a major problem in high-risk pregnancies, and is a risk factor for MTCT [5,28,30] . The high preterm delivery rate of 36.5% is consistent with that found in other studies (Table 3). In our population, 26.9% of deliveries were late preterm deliveries (34−36 +6 weeks of gestation) which have been mostly iatrogenic due to previous guidelines recommending delivery in any case of threatened labour [26]. The overall preterm delivery rate decreased significantly from 79.2% to 8.3% over the study period (P < 0.001); this was mainly attributable to a reduction in the rate of late preterm deliveries as a result of caesarean sections to prevent MTCT of HIV being performed later in pregnancy. Very preterm deliveries were less affected by this change and had multiple causes. However, a decrease in the rate of preterm delivery was found from as early as 2005 onwards; the reason for this is not completely


understood. The study by Schulte et al. supports our findings; they reported a decline in the rates of low-birthweight infants and preterm infants [31]. Parallel to the above-mentioned changes in the delivery policy, we observed a reduction in the MTCT rate to 0.9%, which has been confirmed by other groups. Our data indicate that viral control, which is a major factor in reducing MTCT, has improved dramatically over the last 11 years. In the study population, 55.8% of all pregnant women had a VL < 50 copies/mL prior to delivery. By starting HAART early enough we were able to achieve full viral suppression at the time of delivery. One-third of all the women were treated with a protease inhibitor (PI) plus nucleoside reverse transcriptase inhibitor (NRTI) regime (36.7%), 26.6% of the study population were treated with triple NRTI regimes and 21.2% were on nonnucleoside reverse transcriptase inhibitor (NNRTI) plus NRTI regimes (see Fig. 1). In light with the previously described association of PI regimes with preterm birth (< 37 weeks), we calculated the unadjusted risk of preterm birth according to exposure to a PI regime versus a non-PI regime [6]. The relative risk of preterm birth was 0.64 [95% confidence interval (CI) 0.44–0.91; P = 0.008]. The frequencies of medical problems in PI-exposed and non-PI-exposed women were very similar. Therefore, no adjustments were made for these. Using logistic regression there was no association for preterm birth and the use of PI regimes. We adjusted for CD4 count at birth, VL at birth, birth weight percentile and year of birth, and identified as the only predictor the year of birth. Therefore, we could not demonstrate a clear association between preterm birth and PI regimes. The majority of pregnant women in our cohort (188; 66.4%) were of African origin. In 79 women (24.2%), HIV infection was first diagnosed during the pregnancy. The high percentage of women with a first diagnosis of HIV infection in the ongoing pregnancy (24.2%) highlights the importance of further improving screening policies. In Germany, an opt-in system has been established, as in some other European countries. Gingelmaier et al. reported, in 2005,

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© 2014 British HIV Association 5930 731 (12.7%) 3171 (55%)

775 (13.2%) 5100 (86.8%) > 500 cells/μL: 1595 (35.1%) 2648 (56.4%) 1075 (24.1%)

61 (1.2%)

21 (0.4%) 3368 (57.1%) 1310 (22.2%) 176 (3%) 1223 (20.7%)

330 122 (36.5%) 79 (24.2%) 30 (9%) 95 (33.6%) 188 (66.4%) ≥ 350 cells/μL: 175 (62.5%) 168 (55.8%) 188 (62.6%) 6 (1.8%) 46 (13.7%) 16 (4.8%) 38 (11.4%) 3 (0.9%) 15 (4.5%) (minor included) 1 (0.3%) 5 (1.5%) 301 (90.6%) 31 (9.3%) 1 (0.3%) 43 (13.2%)

UK and Ireland 2000–2006 Townsend et al.*

585 (97.6%) 10 (1.6%) 74 (12.3%)

56 (21.1%)

1 (0.2%)

10 (1.7%) 13 (2.5%) (only major)

21.3% 4.7%

68%

243 (40.6%)

53.3%

599 20.3% 203 (33.8%)

Germany 1999–2003 Gingelmaier et al.

236 (88.8%) 28 (10.5%)

167 (62.7%) 7 (2.6%) 69 (26%) 16 (6.2%) 7 (2.6%) 0

92 (34.6%) 174 (65.4%) ≥ 350 cells/μL: 132 (62.9%) 192 (78.7%)

266 72 (27%) 67 (25.2%) 11 (4.1%)

Switzerland 2003–2008 Aebi-Popp et al.

1576 (19.2%)

4515 (55.1%) 3624 (44.3%)

238 (2.9%)

117 (1.4%)

4593 (56.1%) ≥ 350 cells/μL: 4870 (59.4%) < 500 4085 (49.9%)

8192 906 (11.1%)

France 1990–2006 Briand et al.*

1998 (54.4%) 2326 (44.4%) 670 (12.8%)

143 (2.7%)

3424 (65.4%) 1814 (34.6%) ≥ 500 cells/μL: 850 (16.3%) 617 (11.7%)

1934 (36.9%)

5238

European Collaborative Study (ECS) 1985–2007*

54 (38%) 89 (62%) 22 (16%)

3 (2.1%)

2 (1.4%) 0

37 (26%) 5 (3.5%) 3 (2.1%)

27 (19%) 116 (81%) ≥ 500 cells/μL: 19 (13%) 108 (75%)

143 23 (16%)

Netherlands AmRo study 1997–2003 Boer et al.

Values are n (%) unless otherwise specified. CS, caesarean section; GDM, gestational diabetes mellitus; HAART, highly active antiretroviral therapy; IUGR, intrauterine growth retardation; MTCT, mother-to-child transmission; PROM, preterm rupture of membranes; SB, stillbirth; VL, viral load. *The chronological stratified cohorts have been destratified for comparability.

Fetal loss/SB>24 weeks Postnatal All CS Vaginal birth Unplanned vaginal birth CS in labour

Pregnancies (n) Preterm delivery First diagnosis of HIV in pregnancy IUGR Ethnic origin Caucasian African (or reported as Non-Caucasian) CD4 count ≥ 350, > 500 or ≥ 500 cells/μL at time of delivery VL < 20/50 copies/mL at time of delivery HAART before pregnancy Pre-eclampsia/hypertension Preterm contractions PROM GDM MTCT Malformations

Germany 2002–2012 Reitter et al.

Table 3 Comparison of studies on HIV infection and pregnancy complications


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10 A Reitter et al.

that 33.9% of women were diagnosed with HIV infection during the pregnancy [29]. The lower rate in our study may reflect the effect of a change in the German national guidelines in 2007, which recommended a mandatory offer of testing to all pregnant women. Porip et al. reported an HIV testing rate in all pregnancies of 66% in 2010 after the change in the German national guidelines in 2007 [32]. The prevalence of GDM in non-HIV-infected pregnant women is 2-5% in industrialized countries [33]. There is an urgency to detect GDM early in pregnancy and to treat it. HAART has been demonstrated to have an effect on insulin resistance, and use of PIs has been linked to the development of diabetes in nonpregnant women as well as in pregnant women. Data on GDM in HIV-infected women are often contradictory [30]. In our data, the rate of GDM was 11.4% and there was no change in the incidence of GDM during the study period (P > 0.20). Our data are supported by those of Gonzales-Tome et al., who reported an increased prevalence of GDM in HIV-infected women. They further concluded that older age and PI exposure were independent risk factors for GDM [30]. The high rate of any complication of 55% previously reported by Gingelmaier et al. could not be confirmed with our study. The rate of development of pre-eclampsia/hypertension in our data was low and showed no change over the study period (P > 0.20). The rate of postnatal complications was also low, and did not change during the study period (P > 0.20). The median maternal haemoglobin concentration prior to birth increased significantly over the study period (P = 0.007) indicating improved maternal health and less aneamia, but postnatal haemoglobin concentration showed no significant change (P = 0.051). The previous findings of an association between IUGR and HAART [5,34] were not supported by the study by Briand et al. [27] or the present study. In our study, there were 30 newborns (9%) with IUGR. There was no significant change in the rate of diagnosis of IUGR over the study period (P = 0.119). Some previous studies have found higher rates of IUGR, but these included low birth weight, which has not been defined. This leads to difficulties in comparing data. Improved maternal health (as a result of HAART and successful viral control) and prenatal care have led to improved fetal and neonatal development [31]. In our study, we found that the fetal malformation rate in pregnant women living with HIV was low, and did not differ from that found in HIV-uninfected pregnant women [13]. Fetal malformation showed no simple pattern, and we conclude that the malformations detected pre- and postnatally had no association with a particular HAART regimen or other maternal characteristics [15]. It remains a remarkable achievement that the MTCT rate is 0.9%. This compares with data from the UK register,


where perinatally acquired infection of infants happens in approximately 5% of women who are not diagnosed during antenatal care or during labour [5] . Testing and identifying women at risk is of major importance. In addition, a focus on pregnancy-related complications and collection of additional data is warranted. Most studies (Table 3) reported that 25–55% of pregnant women were first diagnosed with HIV infection during the pregnancy. Women who were already known to be HIV-infected may have been diagnosed as a result of testing in a previous pregnancy. So, the estimated true number of first HIV diagnoses during pregnancy will presumably be higher. Following the successful reduction in MTCT, it is time to move forward to ensure a high standard of care and to diagnose and treat pregnancy-related complications to prevent adverse outcomes. A limitation of our retrospective study was limited access to data on previous obstetric history [in 16 cases (4.8%) the woman reported a previous stillbirth or neonatal death]. The reason for the poor obstetric outcome is often missing, as many of these births took place in the country of origin before immigration. The study period has been subdivided in many larger multicentre studies. This is allowing to highlight the influence of treatment policy changes as well as HAART changes. A comparison of pregnancy complications in pregnant women with HIV infection and HIV-negative women was carried out only in the work by Boers et al. [20].

Conclusions Pregnant women with HIV infection should be referred to specialized units, and a multidisciplinary approach to their care is recommended. HAART should follow national and international recommendations and is very effective at preventing MTCT. In recent years, complete viral control has been achieved in the majority of HIV-infected pregnant women, leading to changes such as vaginal birth becoming a safe option. The rate of HIV MTCT in our cohort was low, with the last transmission occurring in 2010 and being attributable to poor adherence and high VL. Overall, 24.2% of women were diagnosed during the pregnancy, which highlights the importance of screening pregnant women. To summarize, national treatment policies appear to be effective in guiding the treatment of women living with HIV infection in their pregnancies. Our findings show that a low MTCT rate has been achieved in conjunction with offering HIV-infected women choices about HIV treatment and mode of delivery according to the national guidelines. Now we have to focus on other relevant pregnancy complications. Our data provide evidence that there is an increased rate of some adverse pregnancy outcomes (e.g. a higher incidence of GDM and diagnosis of preterm

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contractions) in HIV-infected women, suggesting that such outcomes should be monitored carefully and more data should be collected in national and international registers.

Acknowledgements The authors would like to acknowledge Betty-Anne Daviss and Ken Johnson for assistance with writing the manuscript. Conflicts of interest: The authors state that there are no conflicts of interest regarding the publication of this article. AR and AEH have previously received funding for research, travel grants, consultancy fees and lecture fees from Bristol-Meyers Squibb and Abbott Laboratories (AR) and funding for research, travel grants, consultancy fees and lectures fees from Abbott Laboratories, Boehringer Ingelheim, Bristol-Meyers Squibb, Gilead, Janssen Merck and ViiV (AEH). EH served as a consultant for Roche and Novartis Pharmaceuticals in a different context. CK received research funding from Abbott as well as lecture fees from Abbott and Bristol-Meyers Squibb.

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