Maternal HIV infection has been associated with adverse pregnancy-fetal outcomes; however, there is paucity of data regarding effect of HAART due to immune reconstitution inflammatory response syndrome in pregnancy. While the benefits of HAART for prevention of mother-to-child transmission of HIV (PMTCT) are undisputed, there have been some concerns regarding its possible adverse effects on pregnancy outcomes (16). There is growing evidence in published literature suggesting that ART might be causing adverse birth outcomes among pregnant women in developing countries with frequently observed adverse birth outcomes including low birth weight (LBW), Preterm Birth (PB), and Small for Gestational Age (SGA) (17). HIV infected women in pregnancy are put at a higher risk of complications such as an intra-uterine growth restriction (38). Since HIV was found to exist as an immune suppressing virus in 1980s, it has impacted negatively to maternal health at the same time contributing to pregnancy related adverse effects. HIV infected pregnant women initiating ART has an increased risk of adverse pregnancy-fetal outcomes (18). Although, PMTCT program was incepted in 2006 to mitigate the effects of maternal HIV infection and to prevent vertical HIV transmission in Kenya, HIV-infection treatment has indirectly been associated with adverse pregnancy-fetal outcomes like; LBW, preterm birth and neonatal mortality. Moreover, the incident rates of composite adverse pregnancy-fetal outcomes including PT, LBW, and SGA infants are higher than those among HIV negative women (19).
This study has demonstrated that, being diagnosed with maternal HIV immune reconstitution inflammatory response syndrome increases the incidence rate and risk of adverse pregnancy outcome in the bivariate analysis among IRIS exposed as compared to the non-IRIS exposed HIV positive ART naïve women. It has been reported that adverse birth and pregnancy outcomes are linked to co morbidities among pregnant women receiving ART therapy by posing a danger to pregnancy and leading to ultimate adverse maternal, birth or pregnancy outcomes. However, after controlling for confounding factors, the association of maternal–HIV IRIS with adverse pregnancy-fetal outcomes was found not to be significant. Hence the finding of this prospective cohort study supports the null hypothesis which states that “there is no significant difference in the incidence of adverse pregnancy-fetal outcomes between women with maternal HIV–Immune Reconstitution Inflammatory Syndrome and women without maternal HIV–Immune Reconstitution Inflammatory Syndrome women attending selected referral facilities in Kenya”. There is some evidence that HIV prevalence is higher among women as compared to men in Africa which is also replicated in Kenya (20). HIV-infection among pregnant women has been linked with multiple adverse pregnancy-fetal outcomes as compared to non-infected which was due to use of ART, as per the study done in China where adverse pregnancy-fetal outcomes were assessed by maternal HIV infection status and HIV-related factors using logistic regression analysis. The incidences of stillbirth (3.9% vs 1.1%), preterm birth (PTB) (8.9% vs 3.7%), low birth weight (LBW) (12.2% vs 3.1%) and small for gestational age (SGA) (21.3% vs 7.0%) were higher in HIV-infected women than HIV-uninfected women, with adjusted ORs of 2.77 (95%CI: 1.24–6.17), 2.37 (95%CI: 1.44–3.89), 4.20 (95%CI: 2.59–6.82) and 3.26 (95%CI: 3.26–4.64), respectively (21)
A Systematic Review study conducted by Fekadu et al in 2015 showed that, there is growing evidence in published literature suggesting that ART might be causing adverse birth outcomes among pregnant women in developing countries, an issue which still was not established if it was the immune responses following the ART therapy with the debate as to the role of maternal HAART as a risk factor for adverse pregnancy outcome having been on discussion (22). Subsequently, association between maternal ART in HIV among pregnant women and pregnancy outcomes in a systematic review study on use of antiretroviral agents in pregnant HIV-infected women has been reported to increase the risk of premature delivery (23) .In another study done in India, HIV-infected women were more likely to have PTB, IUGR, and anemia (9.4%, 9.9%, 5.2%) compared to uninfected women (7.6%, 5%, 3.8%), this did not reach statistical significance (P-value = > 0.05). Neonatal intensive care unit admissions were also significantly higher in infants born to HIV-infected women with preceding opportunistic infections following ART therapy(P-value = 0.0020 (24). Similarly, a study on the association between maternal HIV among ART treated women and perinatal outcome including neonatal mortality showed some positive association (OR = 1.1, 95%ci 0.63–1.93) (25).
In another study, among women initiating ART in pregnancy, HAART use was associated with higher odds of preterm delivery (AOR, 1.4; 95% CI, 1.2, 1.8), SGA (AOR, 1.5; 95% CI, 1.2, 1.9), and SB (AOR, 2.5; 95% CI, 1.6, 3.9) (38). However, these studies are not related to this current prospective cohort study as they were carried out either on the direct relation of HIV infection adverse pregnancy-fetal outcomes as well as HAART in relation to adverse pregnancy or birth outcomes without focusing on the immune reconstitution inflammatory response syndrome which is purported in this study. Again they were conducted some in diverse populations without focusing on pregnant women, some were also on pregnant women who had already been initiated on ART therapy, while others concentrated possibly on ART combination and possible adverse drug effects on pregnancy without looking in to the salient issue behind immune reconstruction following ART therapy. Adverse pregnancy-fetal outcomes have, however, been reported more commonly in a number of African studies including complications of both early and late pregnancy. HIV may be the direct cause or a marker of a complex interaction of related medical and social conditions that affect pregnancy (26). Moreover, there are no studies conducted on the indirect effect of ART institution among ART naïve pregnant women on the immune reconstitution response and its possible predictor of adverse pregnancy-fetal outcomes. Again, this prospective study looked at a baseline risk of adverse pregnancy-fetal outcomes as HIV infection and only focused on the exposure of interest for adverse pregnancy outcome as maternal HIV- IRIS, a syndrome which may not be addressed during pregnancy yet it may have negative impacts on pregnancy outcome.
The research findings support the fact that, other factors other than maternal HIV-IRIS predict the adverse pregnancy-fetal outcomes. Maternal health during pregnancy which may be due to IRIS is associated with adverse pregnancy-fetal outcomes. Excess adverse pregnancy-fetal outcomes in HIV-infected ART naïve pregnant women is not primarily explained by the associated opportunistic infections due to IRIS but was strongly associated with HIV-RNA-loads of > 50 copies/ml at baseline, and possibly, any form of hypertensive disorder during pregnancy or maternal placental syndrome, similar to a study done in USA and Haiti (39); (27) respectively.
Maternal HIV infection has been noted to be associated with increased risks of stillbirth, PTB, LBW and SGA, even on the condition that most HIV-infected pregnant women are usually started on ARV therapy following a positive test for HIV (21). HIV infection among pregnant women has a peculiar clinical and immunological scenario due to the immunological changes meant to cater for the developing fetus, as well as the possible pharmacological effects of the HAART medication. The combination of these two factors seemingly complicates the gestational journey as compared to women who are HIV negative and not on any ART medication (28). There is also a possibility of HIV transmission from mother to child during pregnancy, labor, delivery or breastfeeding (perinatal transmission). Perinatal HIV transmission is the most common way children are infected with HIV with possible consequential adverse pregnancy and related birth outcomes (29).
Presence of any hypertensive disorder during pregnancy, although being protective at reduced model for adverse pregnancy-fetal outcomes, it was at the borderline and seemingly predicted the outcome but not conclusive as a risk factor associated with adverse pregnancy-fetal outcomes (AOR = 0.1, 95% CI: (0.0–1.0); P = .052).Similar to this finding, in a systematic review and meta-analysis study, no single test of hypertensive disorder was a strong independent predictor of an adverse pregnancy outcome. The most promising prediction was with multivariable models, especially when oxygen saturation, or chest pain/dyspnea were included, just at borderline showing other inter-related clinical courses (30). In another cohort study, there was a mixed prediction of both protective and significant association for adverse pregnancy and birth outcomes: decreased risk of LGA (OR 0.65, 0.51–0.83), with a recommendation that; hypertensive disorder should be combined with other maternal characteristics, medical and obstetric history when calculating an individualized adjusted risk for adverse pregnancy complications. It was found that, hypertensive disorder increases the risk for stillbirth, PE, SGA, GDM, iatrogenic PTB and elective CS and reduces the risk for LGA (31). A study done in a facility based setting in China predicted adverse birth outcomes in a similar manner, precisely still birth which, the risk decreased as gestational age increased for all women and for all subtypes of hypertensive disorder and it was similar in hypertensive and normo-tensive women younger than 20 years of age. Among women with a hypertensive disorder in pregnancy, the stillbirth rate was strongly influenced by socio-demographic characteristics. Moreover, a stillbirth was more likely if the woman had received few antenatal care visits, was poorly educated, was single, widowed or divorced, had a vaginal delivery, had high parity or was older than 40 years (32). Likewise, a study conducted on 9133 singleton nulliparous pregnancies, neither blood pressure nor blood pressure and proteinuria are accurate predictors of severe adverse maternal and peri-natal outcomes with protective but borderline effect (P = 0.053).
Woman’s general health during pregnancy and at delivery is a very key area of concern on the birth outcome. Mother’s general health was highly significant for adverse pregnancy-fetal outcomes in this prospective cohort study. There are mechanisms thought to account for the synergy between neonatal mortality outcome and infections during pregnancy and delivery that lead to neonatal mortality by affecting proper fetal growth and development. Regarding this, women who were defined ‘sick’ case in this study had four times incident of adverse pregnancy-fetal outcomes compared to women who were not defined as sick within the same periods of time[OR = 4 ; 95%CI:1.8–9.1; P = .001], which is reflective to a case control study done in Jimma University on determinants of adverse pregnancy-fetal outcomes where; mothers who had illness during current pregnancy had seven times to be experience an adverse birth outcome than those who were nit ill, AOR = 7.22, 95% CI:1.65–31.58] (33). Another similar trend with Detection of A (H1N1) pdm09-specific antibodies was associated with a lower 10th percentile of birth weight, β = − 159 g (95% CI − 309, − 9), with influenza infection during pregnancy predicting reduction of only but the birth weight of the smallest children (34). In another Chinese hospital based study, maternal HBsAg carriage was associated with increased risk of pregnancy-induced hypertension [adjusted odds ratio (aOR) = 2.20; 95% confidence interval (CI), 1.30–3.73], fetal distress (aOR = 1.40; 95% CI, 1.09–1.78), cesarean delivery (aOR = 1.70; 95% CI, 1.45–1.99), and macrosomia (aOR = 1.68; 95% CI, 1.19–2.37)(35). This finding compare well with study examining maternal characteristics associated with adverse pregnancy-fetal outcomes of a carried out by (19). Similarly, a study under the bulletin of WHO showed a pooled estimates of neonatal mortality were 12.3%(95% CI: 9.3–16.2) among women with syphilis and 3.0%(95%CI: 2.1–4.3) among women without, for an absolute difference of 9.3% showing more risk among women with syphilis and untreated (36).
HIV-RNA viral load of > 50 copies/ml at the baseline during the first trimester among the HIV positive ART naïve women was found to be associated almost three times with adverse pregnancy-fetal outcomes as compared to HIV-RNA viral load of < 50 copies/ml. This was in regard to being a risk factor for IRIS identification which was the main predictor variable for adverse pregnancy-fetal outcomes. This correlates with another USA based study on burden of viral load which showed that, extent of HIV replication during pregnancy, as represented by plasma HIV RNA viral load, predicted an adverse pregnancy outcome; the risk of pregnancy loss for those with log10 viral load > 4.00 before pregnancy ended was 1.59 (95% confidence interval (CI): 0.99, 2.56) times as high as the risk for women whose log10 viral load was ≤ 1 (28). In a study, which although compared HIV positive women and HIV negative women, there was a significantly higher risk of low birth weight (RR 2.29, 95% CI 1.34–3.92; P = 0.03) and prematurity (< 37 weeks) (RR 1.93, 95% CI 1.35–2.77; P = 0.0003) among symptomatic HIV-infected women when compared with HIV‐uninfected women. This symptomatic status in HIV is associated with higher viral load as compared to asymptomatic. It concluded that, HIV‐infected women, particularly those who are symptomatic, are at a higher risk of adverse pregnancy-fetal outcomes (37) and (25).
The study indicates that adverse pregnancy-fetal outcomes were significantly associated with opportunistic infections OR = 2.3; 95%CI: (1.1–4.8); P = .013) in bivariate analysis, but it did not predict neonatal mortality outcome in multivariate level. This imitates a conference paper by Charlene and Megan, 2017. This fact of opportunistic infections predicting adverse pregnancy-fetal outcomes is commensurate with mothers general well being at delivery in this study which shows a four-fold prediction rate for adverse pregnancy-fetal outcomes at logistic regression, reduced model.