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The impact of maternal HBsAg carrier status on pregnancy outcomes: A case-control study
  Journal of Hepatology
Nov 2005
Ka Yu Tse, Lai Fong Ho, Terence Lao Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, 102, Pokfulum Road, Hong Kong, Hong Kong
Hepatitis B is endemic in Southeast Asia. The prevalence rate of chronic hepatitis B virus (HBV) infection is up to 20% in the populations of the Asia-Pacific region [1]. In Hong Kong, the overall prevalence of chronic HBV infection in the obstetric population is 10.0% [2]. Consequently, all pregnant women are screened for hepatitis B surface antigen (HBsAg) at the first antenatal visit. Despite its prevalence, there are little data on the effect of maternal chronic HBV infection on pregnancy outcomes. Of the handful of studies that have examined this issue, the findings appeared inconclusive [3-12]. On the other hand, a recent study from our centre suggested that maternal HBsAg carrier status was the explanation for the increased maternal serum ferritin found in association with gestation diabetes mellitus [13]. As serum ferritin acts as an acute phase reactant, the findings of this study suggest, an increased chronic inflammatory state in the HBV infected women. In view of the proposed association between systemic inflammatory state and pregnancy complications [14,15], we have performed a retrospective case-control study to examine again the impact of chronic HBV infection on antenatal and perinatal outcomes.
Background/Aims: To examine the impact of maternal HBsAg carrier status on pregnancy outcomes.
Methods: Two hundred and fifty-three carriers of hepatitis B surface antigen (HBsAg) with singleton pregnancy, were retrospectively compared with 253 controls matched for age and parity and year of delivery.
On univariable analysis, HBsAg carriers had higher incidences of threatened preterm labour at <37 weeks (11.9% vs. 6.3%, P=0.030), preterm birth at <34 weeks (4.7% vs. 1.2%, P=0.033), gestational diabetes mellitus (19.0% vs. 11.1%, P=0.012) and antepartum haemorrhage (11.5% vs. 5.5%, P=0.026).
Their infants had lower Apgar scores at the 1st (8.471.67 vs. 8.871.07, P=0.001) and 5th minute (9.561.29 vs. 9.800.54, P=0.007), and increased incidence of intraventricular haemorrhage (4.7% vs. 0.8%, P=0.007).
On multivariable analysis, the association between HBsAg carrier state with antepartum haemorrhage, gestational diabetes mellitus and threatened preterm labour were confirmed.
Conclusions: HBsAg carriers have increased risk of gestational diabetes mellitus, antepartum haemorrhage, and threatened preterm labour. This may be related to the chronic inflammatory state in these subjects. The role of chronic HBV infection in pregnancy complications has to be further elucidated.
The screening for maternal HBsAg carriage had been a routine antenatal investigation in Hong Kong since the early 1980s, and the result is known to the obstetric and nursing staff for the timely administration of hepatitis B immunoglobulin to the newborns [3]. Otherwise, the management of the maternal carriers was similar to that of the other parturients. Although other reports on the effects of chronic HBV infection indicated no association with adverse pregnancy outcomes in the carriers [4-6], there have been case reports and studies indicating an increased incidence of maternal and neonatal morbidity in HBV infection such as fetal distress, premature delivery and meconium peritonitis [7-13]. The underlying explanation for this phenomenon is not clear, but factors such as ethnic difference and the disease activity in the HBsAg carriers could have been contributing.
To examine the impact of HBsAg carrier status on pregnancy outcomes, our cases were matched with controls for age and parity because age and parity have important effects on pregnancy outcomes [14,15]. We have demonstrated a positive association between gestational diabetes mellitus and HBsAg carrier status, confirming the findings of a previous observation [16]. In addition, the incidence of antepartum haemorrhage overall was raised in the HBsAg carriers. This was related to increases in both the incidence of placenta praevia and placental abruption, but the difference of each of these complications failed to reach statistical significance likely because of the small number of subjects. HBsAg carriers were also at increased risk of delivery before 34 weeks, but this may have been related to some underlying factor since the association failed to achieve statistical significance in logistic regression analysis. The Apgar scores at 1st and 5th minutes were lower in the newborn of the HBsAg carriers, and there was higher risk of intraventricular haemorrhage as well, which was probably related to the higher incidence of preterm delivery.
The reports of hepatitis B-related adult-onset Still's disease, polyarteritis nodosa, glomerulonephritis and vasculitis [17-20], indicate that chronic HBV infection may be associated with a systemic inflammatory state that plays a causative role in these autoimmune diseases. Chronic HBV infection is associated with increased levels of pro-inflammatory cytokines such as IL-2, IL-6, IL-10, macrophage migration inhibitory factor, and tumour necrosis factor-alpha (TNF-_), which are more pronounced during active hepatitis [21,22]. Our findings of the association between the HBsAg carrier status with gestational diabetes mellitus, antepartum haemorrhage, and the trend towards preterm birth could have, therefore, represented the effect of an accentuation of the normal systemic inflammatory response seen in pregnancy [23].
There is evidence that an exaggerated systematic inflammatory response could lead to certain obstetric complications. In pre-eclampsia, excessive inflammatory response is responsible for its pathogenesis [24,25]. It is believed that apoptotic placental debris shed from the syncytial surface of the placenta, and maternal clearance of this debris from the circulation, in turn, constitutes a systemic inflammatory response [26]. The pathogenesis of gestational diabetes mellitus is related to insulin resistance [27], which in turn is influenced by chronic subclinical inflammation in which immune markers are raised [28,29]. TNF-_ and its soluble receptors (sTNFR-1 and -2) were found to be elevated in patients with GDM [30]. It has been demonstrated that the levels of TNF and its receptors were raised in patients with chronic HBV infection [31,32]. Similarly, many studies have shown that increased serum concentrations of pro-inflammatory cytokines that include IL-2 receptors, IL-6, IL-8, TNF-_ and thrombin play an important role in premature labour and prelabour rupture of membranes [33-36]. Therefore, the additional systemic inflammatory response induced by chronic HBV infection could be the central explanation of the findings in our study.
As with previous studies, we found that within a high risk obstetric population, chronic HBV infection did not result in adverse perinatal outcomes except for lower Apgar scores. This could be related to the improvement in neonatal care. Nevertheless, positive HBsAg carrier status can be a risk factor on maternal and neonatal well being especially in the developing countries with a high rate of HBsAg carriage. More research is warranted to elucidate the potential role of chronic HBV infection in pregnancy complications in populations with a high rate of chronic HBV infection.
Among the 3348 singleton pregnancies delivered in this period, 253 HBsAg carriers (7.6%) and 253 HBsAg negative control mothers were identified. In the cohort, 94.9% of the patients were Chinese, the mean age was 30.45.5 years and 58.9% of them were primiparas. There was no significant difference in the demographic characteristics like BMI and haemoglobin level at booking, or medical history, between the cases and controls. Among the HBsAg carriers, the weight gain in those patients with gestational diabetes mellitus (GDM) was significantly less than those with those without GDM (9.78 vs. 11.74kg, P=0.050, 95% CI -3.92 to 0.00). Among the HBsAg non-carriers, the weight gain was also less in those with GDM compared with those without GDM, though the difference was not statistically significant because of the sample size (9.35 vs. 10.60kg, P=0.199, 95% CI -3.19 to 0.69). And among the GDM patients, the HBsAg carriers had more weight gain than the HBsAg non-carriers, but the difference was not statistically significant (9.78 vs. 9.35kg, P=0.732, 95% CI -2.07 to 2.93).
In the case group, there was a significantly higher incidence of gestational diabetes mellitus (19.0% vs. 11.1%, P=0.012, OR 1.89, 95% CI 1.14-3.13), as well as that of antepartum haemorrhage overall (11.5% vs. 5.5%, P=0.025, OR 2.21, 95% CI 1.14-4.29). However, further analysis showed the rates of placenta praevia (3.2% vs. 0.8%, P=0.106), placental abruption (2.8% vs. 0.4%, P=0.068) and antepartum haemorrhage of unknown origin (5.9% vs. 4.4%, P=0.547), were not significantly different individually. The incidence of threatened preterm labour was two-fold higher in the case group (11.9% vs. 6.3%, P=0.030, OR 1.99, 95% CI 1.06-3.76). This was associated with a significantly higher incidence of preterm birth at <34 weeks (4.7% vs. 1.2%, P=0.033, OR 4.15, 95% CI 1.16-14.89). But statistical significance was not reached for birth at <32 weeks (2.4% vs. 0.4%, P=0.122, OR 6.12, 95% CI 0.732-51.22) or <37 weeks (12.3% vs. 7.5%, P=0.074, OR 1.72, 95% CI 0.94-3.13). Although the incidence of pre-eclampsia was higher in the case group (4.4% vs. 2.8%), this difference was not statistically significant. There was no increased risk of prelabour rupture of membranes (PROM) in the case group, and no relationship was noted between preterm birth and premature prelabour rupture of the membranes (PPROM).
The effects of HBsAg status on the pregnancy and neonatal outcomes were also analysed. Although, the mean gestational age was slightly but significantly shorter in the case group (38.282.66 weeks vs. 38.681.59 weeks, P=0.043), there was no significant difference in the mean birth weight. The Apgar scores at 1st and 5th minutes were significantly lower in the case group than those in the control group, being 8.471.67 vs. 8.871.07 at 1st minute (P=0.001), and 9.561.29 vs. 9.800.54 at 5th minute (P=0.007). However, apart from intraventricular haemorrhage (4.7% vs. 0.8%, P=0.007, OR 6.25, 95% CI 1.38-28.21), there was no significant increase in perinatal complications such as meconium aspiration syndrome and neonatal jaundice in the case group.
Multivariable analysis was performed to examine the relationship between HBsAg status and the main pregnancy complications including antepartum haemorrhage, gestational diabetes mellitus, pre-eclampsia, PPROM, threatened preterm labour and preterm delivery at <34 weeks, taking into account the confounding factors of age ≥35, weight ≥70kg, and nulliparity. HBsAg carrier status was significantly associated with gestational diabetes mellitus (P=0.008, OR 2.04, 95% CI 1.21-3.44), antepartum haemorrhage (P=0.023, OR 2.18, 95% CI 1.11-4.26), and threatened preterm labour (P=0.046, OR 2.007, 95% CI 1.01-3.97). But the association with preterm delivery at <34 weeks failed to reach statistical significance (P=0.060, OR 3.52, CI 0.95-13.06). Neither pre-eclampsia nor PROM had significant relationship with HBsAg carrier status. Adjusting for the effects of parity, maternal weight, maternal age, and preterm birth at <37 weeks, HBsAg carrier status is not associated with fetal intraventricular haemorrhage.
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