Due to the hormonal changes that occur during pregnancy, there is a certain systemic susceptibility to periodontal disease, either in the form of gingivitis or periodontitis. 

RISKS OF GINGIVITIS AND PERIODONTITIS FOR PREGNANCY 

Pregnancy gingivitis occurs in between 60% and 75% of pregnant women, usually appearing between the third and eighth month of pregnancy according to data from the American Diabetes Association (ADA)⁽¹⁾. This pathology is aggravated by pre-existing gingivitis and by any accumulation of biofilm or dental plaque and calculus, or tartar. In addition, 50% of women with gingivitis prior to becoming pregnant may experience an exacerbation of the condition, even developing periodontitis during pregnancy. 

Likewise, about 25% of fertile women in Spain may already have periodontitis according to some data⁽²⁾, which would involve the destruction of tooth supporting tissue, and may have serious consequences both locally and systemically. The most important of these consequences locally would be the eventual loss of teeth. At the systemic level, the presence of periodontitis can be associated with adverse pregnancy outcomes, such as premature delivery and/or low birth weight babies, and pre-eclampsia, in the most severe cases. 

A preterm birth is that which occurs before the 37th week of pregnancy. Approximately 10% of all pregnancies in the world result in preterm birth, and the rate is rising. Spain, with around 8%, is the third country in Europe in terms of the number of such births, and the first in terms of the rate at which this problem is increasing, particularly for deliveries that take place before 32 weeks of pregnancy. It is one of the main causes of perinatal morbidity and mortality, both in developed countries and in the rest of the world. It has been suggested that maternal age, low socioeconomic status, and smoking and alcohol or drug use are potential risk factors for preterm birth⁽³⁾. 

Low birth weight (babies weighing under 2,500 grams) may be related to preterm birth or occur independently, and its prevalence is around 7.5%. Pre-eclampsia, which is due to placental hypertension, is also a serious complication of pregnancy, with a prevalence of approximately 1-2%. 

In addition to the factors discussed above, infections of any part of the body such as periodontitis can play an important role in the aetiopathogenesis of adverse pregnancy outcomes. During pregnancy, due to changes in the vascular permeability of the gums, bacteria from biofilm can more easily pass into the bloodstream and reach the placental tissue. 

Once there, because of the slow venous circulation and invasive properties of these microorganisms, they can penetrate the foetus and the amniotic fluid, where there will be an immune response involving a release of pro-inflammatory cytokines. If the organism is able to contain the infection there will be no sequelae, but, if not, there could be a rupture of membranes and premature delivery. In addition, these inflammatory compounds may negatively regulate the expression of genes necessary for a foetus to grow, causing low birth weight and structural damage to the placental blood circulation, thereby increasing the mother's blood pressure, as in pre-eclampsia. 

Other channels of foetoplacental unit involvement may be due to inflammation by-products deriving from the periodontal pocket or liver, such as C-reactive protein (CRP). 

SCIENTIFIC RESEARCH INTO THE RELATIONSHIP BETWEEN PREGNANCY AND PERIODONTAL DISEASE 

The scientific evidence available so far on this subject is divided into in vitro, preclinical and human studies. In most of the preclinical studies and in vitro experiments, hamsters, mice and rabbits were used, and either periodontopathogenic bacteria or their virulence factors (LPS) were injected into their blood, or they were put into metal chambers where the bacteria or their products were released into the bloodstream as a remote focal infection. 

The first experiments were performed before and during pregnancy with golden hamsters, which were exposed to Pg (Porphyromonas gingivalis) and Ec (Escherichia coli) LPS, or to the same bacteria together with Fn (Fusobacterium nucleatum) and Cr (Campylobacter rectus), applying both injection and chamber models, and in all cases adverse effects such as premature births, resorption, intrauterine growth restrictions, miscarriages and stillbirths were observed. In addition, in most cases, genetic material of the bacteria or an increase in inflammation markers were found systemically and in the placenta⁽⁴⁾. 

Both models may occur in pregnant women, since periodontitis is a chronic infection, as with the metal chamber, which produces transient bacteraemia as in injection into the blood in animals. Another important point is that bacteria, by themselves and not in the form of biofilm, can pass through to the foetoplacental unit and settle there - due to the lower immunity and the fact that it is a nutrient-rich environment - and end up causing disease and inflammation. 

In mice it has also been observed that bacteria such as Fn, Pg and Cr can invade and settle in the placenta and cause an inflammatory and immune response with increased proinflammatory cytokines and neutrophil infiltration, in addition to altering the structures of nutrient exchange between mother and foetus, causing both growth restrictions for the foetus and the possibility of pre-eclampsia in the mother. 

Finally, Cr infection could alter the expression of some genes in the foetus and even cause eventual developmental or cognitive problems in the babies⁽⁴⁾. 

In studies in humans, this relationship has been demonstrated by different mechanisms. One is the study of the immunospecific antibody response to periodontal pathogens. Thus, in several studies it has been observed that in mothers with a lack of antibodies against red complex bacteria and increased antibodies against orange complex bacteria, there is a higher rate of preterm births. However, in others, the opposite has been observed, which might be explained in two ways: that the lack of antibodies leaves the foetus unprotected from the infection or, on the contrary, an exaggerated response indicates a hyper-inflammatory profile that would also lead to preterm birth⁽⁴⁾. 

Another type of research in humans has been based on microbiological detection via PCR of the amniotic fluid. Thus, in several studies periodontal pathogens have been found in women who have had preterm deliveries and low birth weight babies. However, culture of these bacteria has been more difficult, and only one study has succeeded. Whether the bacteria reach the fluid alive or not and if they remain in a planktonic state or form biofilms is still a controversial issue, although there is one research study that has found biofilms in the placenta. The route of dissemination of bacteria, either from the genitourinary tract to the placenta or from the periodontium to the placenta, is also a matter of discussion. In two studies, identical clonal types have been found in dental bacterial plaque and in amniotic fluid, and these were not found either in the flora of the vagina or in the flora of the rectum⁽⁴⁾. 

Human studies have also explored the relationship between the increase in proinflammatory cytokines (type IL-1, IL-6, TNF-α) and mediators (PGE-2), both in the sulcus and in the serum and amniotic fluid, finding disparate results regarding the increase in adverse pregnancy outcomes. Likewise, disparate results have been found for the increase in CRP, which usually occurs in the liver due to the increase in systemic inflammation⁽⁴⁾. 

To establish the epidemiological association between periodontal disease and the different adverse outcomes of pregnancy (low birth weight infants, preterm births, low birth weight and premature infants, and pre-eclampsia), case-control studies, cross-sectional studies, prospective studies, and meta-analyses of all the above have been made. In general, a moderate association has been found between periodontal disease and the different adverse outcomes of pregnancy, due in large part to the heterogeneity of the studies and the variability in the definition of periodontal disease depending on the type of variables used. 

Thus, for low-weight babies, an odds ratio (OR) of 1 to 2 has been found when doing meta-analysis of case-control studies that have used dichotomous variables. When continuous variables have been used, and in the meta-analyses of prospective studies, the results have been mixed. For preterm babies, case-control meta-analyses have also found an association; on the other hand, for the prospective studies, the results have been conflicting. When both adverse effects have been combined, there have also been differences between the data from the different studies, and the results of the meta-analyses have depended considerably on the type of variables used. 

For pre-eclampsia, data from case-control studies, prospective studies and meta-analyses have also shown an association between poor oral condition and disease. In general, with the use of continuous variables, average probing depth, for example, and history of periodontal disease, such as the attachment level, a positive association is not usually found, while applying categorical and inflammation-related variables does favour the association more^(5). 

Concerning the effect of periodontal treatment, the results of randomised clinical trials conducted to date do not conclude an improvement in adverse pregnancy outcomes when periodontal treatment is performed in pregnant women. This may be due to different reasons. One of them is that both periodontal disease and adverse pregnancy outcomes share common risk factors, which may confound the results. 

The definition of periodontitis can also influence the results. It is also important to distinguish between different types of preterm delivery and low birth weight by creating subcategories. Perhaps periodontal treatment should be performed before a woman becomes pregnant in order to have a positive effect on the clinical outcome of the pregnancy^(6). 

In short, it is important to understand that more human studies are needed, since most of the conclusions have been drawn from animal and in vitro studies. In that sense, it is necessary to clarify which bacteria and in what quantity they must reach the foetoplacental unit and at what time it is necessary to intervene so that this does not occur. Quite often, clinical signs are not related to the actual situation at the microbiological level, delaying any possible intervention, which may explain why some intervention studies have not obtained the expected results.