3.1. Dynamics of HSV-1 Seropositivity among Pregnant Women
In total, we examined 150 serum samples, of which 30 were negative for nonspecific IgM and G to HSV-1,2 and specific IgM and G to HSV-2. In total, 120 samples were positive for non-specific IgM and G to HSV-1, 2 and negative for specific IgM and G to HSV-2. A negative serological reaction to HSV-2 suggested that these study participants were latent carriers of HSV-1 only. Positive samples were titrated over time after 12 days. In 90 study participants, there was a fourfold or greater increase in IgG antibody titers, as well as the absence (negative test) of IgM and G to HSV-2, which can serve as a criterion for the current disease. The absence of IgM and G to HSV-2 and the absence of an increase in the level of IgG antibodies to HSV-1, 2 is considered as an asymptomatic, non-recurrent form of HSV-1 infection. Titers of antibodies IgG 1:12,800 and 1:6400 were regarded by us as high, 1:3200 and 1:1600 as moderate and 1:800 as low.
Indicators of IgG antibody titers in the group with recurrent HSV-1 and in the group with no recurrence of HSV-1 in the first trimester of pregnancy are presented in
Table 1. High titers of IgG antibodies were detected in 36.7% of participants in the group with recurrent HSV-1, which is higher (
p < 0.05) than in the group with no recurrence of HSV-1 (3.3%). An IgG antibody titer 1:12,800 was detected in 16.7% of participants in the group with recurrent HSV-1, and an antibody titer 1:6400 in 20% of participants (
p < 0.05), which is 1.33 times (1.13–1.56) more often than in the group with no recurrence of HSV-1 (3.3%). Moderate values of IgG antibody titers 1:3200 and 1:1600 were found in 18.9% and 23.3% of participants in the group with recurrent HSV-1, which is significantly lower (
p < 0.05) than in the group with no recurrence of HSV-1 (36.7% and 46.7%, respectively). The frequency of detecting low titers of IgG antibodies 1:800 in the group with recurrent HSV-1 and in the group with no recurrence of HSV-1 was not statistically significant (21.1% and 13.3%, respectively).
Thus, the recurrence of HSV-1 in the first trimester was often associated with the detection of high (36.7%) and moderate (42.2%) IgG antibody titers. No recurrence of HSV-1correlated with the detection of moderate IgG antibody titers (83.4%).
In the group with recurrent HSV-1 in the second trimester of pregnancy, the number of participants with moderate (44.4%) (
p < 0.05) and low (45.6%) IgG antibody titers increased (
Table 2). High titers of IgG antibodies were detected in 10% of participants in the group with recurrent HSV-1, of which 4.4% had IgG antibody titers 1:12,800 and 5.6% had IgG antibodies titers 1:6400 (
p < 0.05), which is significantly lower than in the group with no recurrence of HSV-1 (33.3%). Moderate titers of IgG antibodies in the group with HSV-1 recurrence in the second trimester were detected in 44.4% of participants, of which IgG antibody titers 1:3200 were found in 8.8% of participants (
p < 0.05), IgG antibody titers 1:1600 were found in 35.6% of participants (
p < 0.05). The antibody titer 1:1600 was found 1.34 times (1.12–1.60) more often than in the group with no recurrence of HSV-1. In the group with no recurrence of HSV-1, IgG antibody titers 1:3200 were detected in 56.7% of participants, and IgG antibody titers 1:1600 were found in 10% of participants. Low titers of IgG antibodies 1:800 were detected in 45.6% of participants in the group with HSV-1 recurrence in the second trimester of pregnancy.
Consequently, the recurrence of HSV-1 in the second trimester of pregnancy was often associated with moderate (44.4%) and low (45.6%) IgG antibody titers. No recurrence of HSV-1 correlated with moderate IgG antibody titers (66.7%).
In the group with recurrent HSV-1 in the third trimester of pregnancy, high titers of IgG antibodies were detected in 26.6% of the participants, which is not significant (
p > 0.05) compared with the group with no recurrence of HSV-1 (40%) (
Table 3). Antibody titers IgG 1:12,800 were detected in 3.3% of participants in the group with recurrent HSV-1. The detection rate of IgG antibody titers 1:6400 in the group with recurrent HSV-1 and in the group with no recurrence of HSV-1 did not differ significantly (
p > 0.05) and amounted to 23.3% and 40%, respectively. In 66.7% of the participants in the group with HSV-1 recurrence in the third trimester of pregnancy, moderate antibody titers were revealed: in 36.7% of participants, IgG antibodies titers 1:3200 were found (
p < 0.05), which is lower than in the group with no recurrence of HSV-1 (50%); 30% had IgG antibody titers 1:1600 (
p < 0.05), which is higher than in the group with no recurrence of HSV-1 (6.7%). Antibody titers IgG 1:1600 were found 1.35 times (1.14–1.59) more often than in the group with no recurrence of HSV-1. Low titers of IgG antibodies 1:800 were detected in 6.7% of participants in the group with recurrent HSV-1 in the third trimester of pregnancy and in 3.3% of participants in the group with no recurrence of HSV-1.
Consequently, the recurrence (66.7%) and no recurrence of HSV-1 (56.7%) in the third trimester of pregnancy were associated with moderate IgG antibody titers.
The comparison of serological data in the group with recurrent HSV-1 showed (
Table 4) that high titers of IgG antibodies are 1.9 times more common in the first trimester than in the second trimester. Moderate titers of IgG antibodies are more common in the third trimester than in the first and second trimester by 1.67 times and 1.6 times, respectively. Low titers of IgG antibodies are more common in the second trimester than in the first and third trimesters by 1.67 times and 2.37 times, respectively.
In the group without recurrent HSV-1, high titers of IgG antibodies are 2.23 times more common in the second trimester and 2.41 times more common in the third trimester than in the first trimester. Moderate titers of IgG antibodies are 2.14 times more common in the first trimester than in the third trimester. Low titers of IgG antibodies occur 1.69 times more often in the first trimester than in the third trimester.
The results obtained reflect the susceptibility to HSV-1 in women at different stages of pregnancy, which can affect the course and outcome of pregnancy and childbirth and the condition of newborns.
3.2. Socio-Demographic Characteristics and Pregnancy Parity in Women with HSV-1
In terms of social status, 83.3% of the participants in the group with HSV-1 recurrence during pregnancy were employees, 12.2% were housewives and 4.4% were students; in the group with no recurrence of HSV-1, these values were 90%, 6.7% and 3.3%, respectively; and in the group of seronegative women, these values were 86.7%, 6.7% and 6.7%, respectively (
Table 5). The frequency of clinical manifestations of HSV-1 during the year before the onset of present pregnancy in the group with HSV-1 recurrence during pregnancy was 5–6 times, while the frequency in the group with latent infection was 1–2 times. Clinically, the disease was manifested by general weakness; increased body temperature; rashes on the mucous membrane of the lips, the skin of the nasolabial triangle and the wings of the nose; and enlargement of the submandibular nodes. The duration of disease recurrence was on average 3–5 days.
Among the participants in the group with HSV-1 recurrence during pregnancy, 10% planned a present pregnancy, which is significantly lower than in the group with no recurrence of HSV-1 and in the group of seronegative women (p < 0.05, respectively).
At the onset of pregnancy, all study participants registered with the antenatal clinic for up to 12 weeks of gestation. The first clinical manifestation of HSV-1 in the first trimester of pregnancy was noted by all study participants, while relapses in the second trimester were found in 25 participants (27.8%) and relapses in the third trimester were found in 32 participants (35.6%). The recurrent course of the disease throughout pregnancy was observed in 10 (11.1%) participants.
Among the participants in the studied groups, the number of primiparous and re-pregnant but primiparous respondents did not differ significantly (p > 0.05). Among multiparous respondents, there were significantly more participants (27.8%) in the group with HSV-1 recurrence during pregnancy (p < 0.05) than in the group with no recurrence of HSV-1 (10%) and in the group of seronegative women (16.7%). Of 25 multiparous women in the group with HSV-1 recurrence during pregnancy, two (8%) noted the death of children in infancy. In both cases, the cause was intrauterine infection with HSV-1 in a generalized form. In 20 (22.2%) re-pregnant but primiparous participants in the group with HSV-1 recurrence during pregnancy, there were 1–2 spontaneous abortions in the anamnesis, which is more frequent than in the group of seronegative women (p < 0.05). Legal abortions were noted by participants in all groups equally often (p > 0.05). The participants of the group with HSV-1 recurrence during pregnancy underwent the termination of pregnancy for medical reasons by the fetus due to malformations incompatible with life. In total, 4.4% of the group members had a missed abortion.
All group participants reported maternal and paternal hereditary burdens with the same frequency (p > 0.05). Matrilinear inheritance in the study groups was tainted by hypertensive disease, oncopathology and diabetes mellitus with the same frequency (p > 0.05). Congenital heart disease was indicated equally often by participants in the group with HSV-1 recurrence during pregnancy and in the group with no recurrence of HSV-1 (p > 0.05). Patrilineal inheritance in the studied groups was tainted by hypertensive disease and oncopathology with the same frequency (p > 0.05). Diabetes mellitus was equally often indicated by the participants in the group with HSV-1 recurrence during pregnancy and in the group with no recurrence of HSV-1 (p > 0.05). Congenital kidney disease was reported by 1.1% in the group with HSV-1 recurrence 1 during pregnancy.
Somatic diseases were detected in 57.8% of the participants in the group with recurrent HSV-1 during pregnancy (
p < 0.05), which is 1.46 times (1.18–1.82) more often than in the group with no recurrence of HSV-1 and 1.67 times (1.35–2.07) more often than in the group of seronegative women (
Table 6). Chronic pyelonephritis occurred 1.36 times (1.16–1.59) more often than in the group with no recurrence of HSV-1. The frequency of detection of chronic forms of bronchitis (13.3%), sinusitis (5.6%), tonsillitis (11.1%) and pharyngitis (4.4%) did not differ statistically significantly in the study groups (
p > 0.05). Of all the participants in the group with HSV-1 recurrence during pregnancy, two or more pathologies of respiratory diseases were detected in 8.9% of participants.
Acute respiratory infections (ARI) were detected in 65.6% of participants in the group with HSV-1 recurrence during pregnancy, which is 1.67 times (1.20–2.31) more often than in the group with no recurrence of HSV-1 and 2.24 (1.59–3.17) more often than in the group of seronegative pregnant women. In every third case, there was an acute onset of the disease with a rise in body temperature to 38 °C for 3 days. In 7.8% of cases, ARI was complicated by acute sinusitis, while in 2.2% of cases, it was complicated by the exacerbation of chronic bronchitis. Acute bronchitis was noted equally often (3.3%) by participants in the group with HSV-1 recurrence during pregnancy and with no recurrence of HSV-1 (p > 0.05).
Gynecological diseases were detected in 71.1% of participants in the group with HSV-1 recurrence during pregnancy, which is 1.59 times (1.21–2.08) more often than in the group with no recurrence of HSV-1 and 1.95 times (1.47–2.57) more often than in the group of seronegative women. The predominant diseases in the group with HSV-1 recurrence during pregnancy were cervical erosion and ectropion (29%) and chronic salpingo-oophoritis (21.1%) (p < 0.05). Cervical erosion and ectropion occurred 1.22 times (1.01–1.48) more often than in the group with no recurrence of HSV-1 and 1.34 times (1.13–1.58) than in the group of seronegative women. Salpingo-oophoritis occurred 1.34 times (1.14–1.57) more often than in the group with no recurrence of HSV-1. Acute vaginitis was diagnosed in 9% of participants in the group with HSV-1 recurrence during pregnancy. The frequency of chronic inflammatory disease of the uterus and oligomenorrhea detection did not differ significantly in the study groups (p > 0.05).
Complications of pregnancy in the group with HSV-1 recurrence during pregnancy were 297.6 per 100 cases, while in the group with no recurrence of HSV-1 and seronegative women, these values were 73.3 and 46.7, respectively (
p < 0.05) (
Table 7).
Threatened abortion in the first trimester of pregnancy was found in 51.1% of participants in the group with HSV-1 recurrence during pregnancy, which is 1.28 times (1.04–1.57) more often than in the group of seronegative women. Threatened preterm labor was found in 21.1% of participants, which is 1.34 times (1.14–1.57) more often than in the group with no recurrence of HSV-1 and seronegative women, respectively. In total, 73.3% of participants had anemia, which is 1.83 times (1.37–2.45) more often than in the group with no recurrence of HSV-1 and 1.96 times (1.46–2.64) more often than in the group of seronegative women. All participants in the group with HSV-1 recurrence during pregnancy had clinical symptoms of threatened abortion; in 9 (10%) participants, choroidal detachment with the formation of a retrochorial hematoma was diagnosed by ultrasound, and 5 (5.6%) participants exhibited chorion presentation. Chronic placental insufficiency was diagnosed in 72.2% of participants in the group with HSV-1 recurrence during pregnancy (p < 0.05), which is 1.99 times (1.49–2.65) more often than in the group with no recurrence of HSV-1 and 2.13 times (1.59–2.84) more often than in the group of seronegative women. The compensated form of placental insufficiency was diagnosed in 84% of the participants (p < 0.05), which is 1.57 times (1.25–1.97) more often than in the group with no recurrence of HSV-1 and 1.63 times (1.30–2.04) more often than in the group of seronegative women. The detection rate of the subcompensated form of chronic placental insufficiency did not differ significantly in the group with HSV-1 recurrence during pregnancy (13.8%) and in the group with no recurrence of HSV-1 (6.7%) (p > 0.05). The decompensated form was found in 1.1% of the group members with HSV-1 recurrence during pregnancy. Chronic intrauterine fetal hypoxia was detected in 44.4% of participants in the group with HSV-1 recurrence during pregnancy (p < 0.05), which is 1.49 times (1.24–1.78) more often than in the group with no recurrence of HSV-1. The incidence of fetal growth restriction did not differ significantly in the group with HSV-1 recurrence during pregnancy (7.7%) and in the group with no recurrence of HSV-1 (3.3%) (p > 0.05).
3.3. The Course of Labor and the Early Postpartum Period in Women with HSV-1
All participants in the group with no recurrence of HSV-1 and seronegative women delivered at term per vias naturales; in the group with HSV-1 recurrence during pregnancy, 6 (6.9%) participants delivered prematurely at 36 weeks. The onset of preterm labor was spontaneous after the waters broke. The total duration of labor in the group with HSV-1 recurrence during pregnancy was significantly higher than in the group with no recurrence of HSV-1 (7.42 ± 0.33 h) and in the group of seronegative women (7.37 ± 0.48 h), at 8.90 ± 0.28 h (p < 0.05).
Of the 84 participants in the group with HSV-1 recurrence during pregnancy with full-term pregnancy, vaginal delivery occurred in 65 (72.2%) of cases, in which 19 children (21.1%) were delivered by caesarean section. Indications for elective cesarean section were as follows: incompetent postoperative uterine scar in multiparous women in combination with obstetric pathology, found in 6 (31.6%) participants; pelvic presentation and a big fetus weighing more than 3600 g in primiparous women, seen in 5 cases (26.3%). In the group of seronegative women, 26 (86.7%) out of 30 participants delivered per vias naturales, while in the group with no recurrence of HSV-1, this number was 25 (83.3%) (p > 0.05).
Abnormalities of forces of labor occurred in 46.8% of participants in the group with HSV-1 recurrence during pregnancy (
p < 0.05) (
Table 8), which is 1.35 times (1.12–1.62) more often than in the group with no recurrence of HSV-1 and 1.45 times (1.22–1.73) more often than in the group of seronegative women.
Abnormalities of forces of labor were revealed in 28% of the participants in the group with HSV-1 recurrence during pregnancy (p < 0.05), which is 1.31 times (1.14–1.52) more often than in the group of seronegative women. There were no significant differences between the study groups in the frequency of premature rupture of membrane (p > 0.05). Intrapartum and postpartum hemorrhage in participants of the group with HSV-1 recurrence during pregnancy was detected in 5.1% of cases, while placenta accrete was found in 7.7% of cases. Chronic inflammatory disease of the uterus was equally often diagnosed in the group with recurrent HSV-1 during pregnancy (19%) and in the group with no recurrence of HSV-1 (11.5%).
3.4. The Condition of Newborns in the Early Neonatal Period in Women with HSV-1
Sixty full-term babies were born in the group with no recurrence of HSV-1 and in the group of seronegative women. In the group with HSV-1 recurrence, 91 live babies were born during pregnancy, of which 84 (92.3%) were full-term and 7 (7.6%) were premature, and there was 1 case of dichorionic diamniotic twins. One child from the dichorionic diamniotic twins died in the early neonatal period due to sepsis.
In the group of seronegative women, all children at birth were rated 7–10 points on the Apgar scale (
Table 9).
In the group with recurrent HSV-1 infection during pregnancy, 83.5% of children were born with a score of 7–10 points, 15.4% were in a state of moderate asphyxia, and one premature twin (1.1%) was in a state of high severity. The average Apgar score at 1 min in the group with recurrent HSV-1 infection during pregnancy was not statistically significant and amounted to 7.31 ± 0.13 points; in the group with no recurrence of HSV-1, the score was 7.43 ± 0.14 points, and in the group of seronegative women, this score was 7.57 ± 0.10 points. At 5 min, the average Apgar scores in the group with HSV-1 recurrence during pregnancy were 8.11 ± 0.12 points, while those in the group with no recurrence of HSV-1 were 8.12 ± 0.11 points and in the group of seronegative women were 8.50 ± 0.10 points. In the group with HSV-1 recurrence during pregnancy, the weight of two premature infants was less than 2000 g, with a weight of 2000–2499 g for three children, of which two were premature and one was small-for-gestational-age. For the rest of the indicators, no significant differences were found in the study groups (
p > 0.05). In newborns in the group with HSV-1 recurrence during pregnancy, the incidence of diseases in the early neonatal period was 123.3 per 100 cases. In terms of the structure of diseases, infections specific for the perinatal period prevailed (
p < 0.05) (
Table 10) and were detected 1.32 times (1.12–1.54) more often than in the group with no recurrence of HSV-1. Of 91 newborns in the group with HSV-1 recurrence during pregnancy, 40.6% developed an infection in the early neonatal period (
p < 0.05); 3.3% of newborns were diagnosed with generalized forms (meningitis, pneumonia, sepsis), skin vesicles prevailed in the structure of local forms in 21% of cases, with pyoderma in 3.3% of cases. Of the 30 newborns in the group with no recurrence of HSV-1, infections in the early neonatal period amounted to 10% in the form of skin vesicles (6.7%) and conjunctivitis (3.3%).
Cerebral ischemia in newborns in the group with HSV-1 recurrence during pregnancy was diagnosed in 26.4% (p < 0.05), which is 1.3 times (1.10–1.55) more often than in the group with no recurrence of HSV-1. Respiratory distress syndrome was diagnosed in 19.8% of newborns (p < 0.05), which is 1.32 times (1.13–1.56) more often than in the group with no recurrence of HSV-1. Neonatal jaundice was diagnosed in 6.6% in the group with HSV-1 recurrence during pregnancy.
3.5. Influence of HSV-1 Seropositivity in Women during Pregnancy on the Development of Complications of Pregnancy, Childbirth and the Early Postpartum Period and the Condition of Newborns
The analysis of the effect of seropositivity on HSV-1 on the development of pregnancy complications showed that, in the group with recurrent infection in the first trimester with low titers of IgG antibodies 1:800, the risk of miscarriage increased by 1.85 times (
Table 10). The risk of pregnant women developing anemia with high titers of IgG antibodies 1:12,800–1:6400 in the first trimester of pregnancy was 2.25 times greater, that with moderate titers of IgG antibodies 1:3200–1:1600 was 2.10 times greater, and that with low titers of IgG antibodies 1:800 was 3.07 times greater. The risk of chronic placental insufficiency with high antibody titers was 2.18 times greater, that with moderate antibody titers was 1.94 times greater, and that with low IgG antibody titers 1:800 was 2.97 times greater. The incidence of chronic intrauterine fetal hypoxia was increased with low antibody titers to 1.64 times. High antibody titers in pregnant women with HSV-1 recurrence in the second trimester of pregnancy increased the risk of miscarriage to 2.38 times and preterm birth to 1.45 times. There was a risk of anemia, which was increased 3.85 times with high antibody titers, 1.92 times with moderate antibody titers and 1.88 times with low antibody titers. The risk of chronic placental insufficiency developing with high antibody titers was increased 3.72 times, with moderate antibody titers 1.86 times and with low antibody titers 1.82 times. The risk of chronic intrauterine fetal hypoxia was associated with high antibody levels and amounted to an increase of 1.92 times. Low antibody titers in pregnant women with HSV-1 recurrence in the third trimester of pregnancy increased the risk of threatened premature birth by 1.66 times. The risk of anemia in pregnant women in the third trimester of pregnancy with high antibody titers was increased 2.75 times, with moderate antibody titers 2.01 times and with low antibody titers 4.13 times. The risk of chronic placental insufficiency developing with high antibody titers was increased 2.66 times, with moderate antibody titers 1.94 times and with low antibody titers 3.99 times. An increased risk of chronic intrauterine fetal hypoxia was associated with the presence of high titers by 1.45 times and low antibody titers by 2.33 times in women in the third trimester of pregnancy.
The risk of birth and early postpartum period complications—namely, labor abnormalities—was associated with high antibody titers in women with HSV-1 recurrence in the second trimester of pregnancy, increasing by1.56 times, while the development of inflammatory diseases of the uterus was associated with low antibody titers in women with HSV-1 recurrence in the third trimester of pregnancy, increasing by 1.59 times (
Table 11).
Complications of the early neonatal period—namely, an increased risk of cerebral ischemia by 1.45 and 1.82 times and respiratory distress syndrome by 1.45 and 1.63 times for newborns—were associated with high antibody titers in women with HSV-1 recurrence in the second trimester of pregnancy and low antibody titers with disease recurrence in the third trimester of pregnancy, respectively (
Table 12). In the structure of local congenital forms of infection, the frequency of detection of skin vesicles (vesiculosis) in newborns from women with HSV-1 recurrence in the second trimester and high antibody titers increased 1.45 times, while women with low antibody titers increased 1.67 times with HSV-1 recurrence in the third trimester of pregnancy.
According to the results obtained, it can be concluded that the risk of complications of pregnancy, childbirth and the early postpartum period, congenital infection and increased morbidity in newborns is associated with low or high IgG antibodies to HSV-1, determined by the timing of infection recurrence during pregnancy.