4. Discussion
The aim of the present study was to investigate the association of
maternal viral infections during pregnancy with pregnancy complications
and delivery outcomes. The results are based on the comparison of
mothers of cases and uninfected controls.
The major findings of our study are that viral infections during
pregnancy are associated with higher incidences of threatened
miscarriage, threatened preterm delivery and anaemia. On the contrary
the risk of gestational diabetes was decreased in infected mothers.
Gestational age was longer in the infected group as compared to
controls. Birth weight and the risk of preterm birth or IUGR did not
differ significantly between the two study groups. Hepatitis B infection
during pregnancy was associated with shorter gestational age and lower
birth weight.
Miscarriage occurs in about 20% of pregnancies and may result in severe
psychological and physiological issues for the patient. A thorough
analysis of the available literature has found that influenza infection
was associated with an elevated risk of spontaneous abortion, while the
effect of hepatitis B and herpes simplex virus remained
controversial.12 Our data also support the potential
deleterious effects of viral infections on the incidence of threatened
miscarriage. However, the database of the HCCSCA is not suitable for
analysing miscarriage data since it only contains records of preterm and
term new-borns.
Preterm birth affects approximately 12-15% of pregnancies and in more
than 50% of the cases no risk factors are known. Chronic hepatitis B
virus infection was found to increase the risk of preterm labour and
birth in pregnant women.13,14 Increased rates of
preterm birth are also reported in pregnant patients hospitalized with
influenza virus infection, however, the limited amount of data does not
permit firm conclusions.15,16 In our dataset we were
not able to confirm an elevated risk of preterm delivery in mothers
suffering from virus infections during pregnancy. A shorter gestational
age and lower birth weight was verified only in the case of hepatitis B
infection; however, these alterations did not reach the limits of
preterm birth. On the other hand, the prevalence of threatened preterm
labour (preterm uterine contractions or ultrasonographic signs exhibited
by the cervix and lower uterine segment) was increased significantly
among mothers with viral infections. The pathomechanism of viral
infections in inducing preterm birth is still debated. Viral infections
of the placenta may act as a factor sensitizing women to intrauterine
bacterial infection, resulting in an inflammatory response to even low
concentrations of bacteria.17 Intrauterine bacterial
infection may then lead to preterm uterine contractility.
Gestational diabetes mellitus (GDM) affects 1-22% of all pregnancies
globally, depending on the population and diagnostic criteria
used.18 It is largely associated with severe pregnancy
complications like prenatal morbidity, preterm labour, dystocia, etc. In
our dataset GDM was found to be significantly less frequent among
mothers affected by viral infections as compared to the control group.
Regarding this finding we were not able to identify substantive
publications in the literature. In the background of the development of
GDM, the role of many cytokines and other immunological factors have
been investigated.19 Pro-inflammatory cytokines and
other inflammatory markers have been shown as predictors of
diabetes.20,21 We only hypothesize that viral
infections may alter the activity of some anti-inflammatory cytokines
resulting in a protection against insulin resistance. On the other hand,
this finding of ours may also be incidental since the number of
investigated cases is relatively low (8 in 2,238 infected mothers vs.
458 in 54,993 controls).
In most countries of the world, the prevalence of anaemia in pregnancy
is over 20%.22 It has been associated with
prematurity, low birth weight, hypertensive disorders and adverse
pregnancy outcomes.23,24 In our study viral infections
during pregnancy were associated with a significantly elevated
prevalence of maternal anaemia as compared to uninfected control
mothers. We were unable to find significant data in the literature, that
could explain this relatedness. In non-pregnant individuals autoimmune
haemolytic anaemia has been reported in a number of viral
infections.25 Moreover, parvovirus infection has been
associated with red cell aplasia.26 In infants a mild
viral infection was found to induce a significant decrease in
haemoglobin that may persist for 14 to 30 days and may be difficult to
distinguish from iron deficiency.27 In a rodent model
it was suggested that viruses may trigger autoantibody-mediated anemia
by activating macrophages through gamma-interferon
production.28 On the other hand, anaemia may also act
as a causative factor, enhancing susceptibility of pregnant mothers to
viral infections.29
A further interesting finding of our study is that maternal smoking was
significantly more frequent among mothers affected by viral infections
as compared to the uninfected control group. Smoking is a
well-established risk factor of various infections,30therefore, this finding is not surprising. However, it is worth
mentioning that although maternal smoking is associated with
unfavourable pregnancy outcome,31,32 this correlation
could not be verified in the present study.
The strengths of our study are related to the large population-based
data set of the HCCSCA in an ethnically homogeneous Hungarian
(Caucasian) population. Pregnancy complications, gestational age and
birth weight can be estimated with high accuracy since data were
medically recorded. This study included all viral infections during
pregnancy and these exposure data were based on multiple sources
including prenatal maternity logbooks which provided prospective
medically recorded data. Exposure time and potential confounders were
also documented.
However, there are also some limitations of our study. The major
weakness of our dataset is that the diagnosis of viral infections was
based on reported data without serological evidence of the virus
infection. Maternal smoking data were based partly on retrospective
maternal information burdened by recall bias.33 A
previous validation study of our group showed the low reliability of
retrospective maternal self-reported information regarding smoking and
alcohol drinking during pregnancy.34 Another weakness
of our study is that only cases born between 1980 and 2009 were
evaluated, thus the results of the recent decade could not be analysed
in this field.
In conclusion the findings of this study suggest that viral infections
during pregnancy do not exert a deleterious effect on birth outcomes.
The incidences of threatened miscarriage threatened preterm birth and
maternal anaemia are higher in pregnancies affected by viral infections.
The incidence of gestational diabetes is lower after viral infections
during pregnancy. Maternal smoking is more frequent in pregnancies with
viral infections.