The death of the fetus during the intrauterine life is a dramatic and devastating event of any affected pregnancy, irrespective of the duration of the gestation. More than 2.5 million stillbirths have been reported worldwide when applying the 28-weeks gestational age cut-off suggested by the World Health Organization for international comparison [1]; however, when applying the lower limit of 20 weeks, the number of fetal deaths would more than double [2]: half of stillbirths occur before 28 weeks of gestation [3], with an overall estimation of five to six million stillbirths annually [4].

Although stillbirth may occur during an otherwise apparently uneventful pregnancy, some maternal conditions/diseases have been identified as able to increase the risk of fetal death [5]. These worldwide diffuse maternal conditions include obesity [6], pre-pregnancy hypertension and diabetes, especially when associated with advanced maternal age [7, 8]. In accordance with the global trends, in Italy these maternal risk factors have been increasing in the last years [9] leading to a wider number of women potentially at “high-risk pregnancy”. Ideally, high quality antenatal care should identify and address the maternally related stillbirth risk factors at the beginning of any pregnancy [3, 8], to offer a personalized plan for high quality care during gestation [8], avoiding preventable stillbirths. Nevertheless, in the last few years the reduction of stillbirth rates has been lower than what we hoped for [7] and ending preventable stillbirths still remains an unreached goal [8]. Correctly targeting the pregnancy as low versus high risk is crucial for the prevention of adverse pregnancy outcomes [10]. Therefore, our purpose is to explore the role of maternal conditions that can be ascertained at the beginning of pregnancy (i.e., demographic and medical conditions/diseases) and estimate the respective contribution of these conditions to stillbirth. An early identification of risk factors could offer to high-risk pregnancies a specific antenatal surveillance by trained staff [11] leading to a potential reduction of stillbirth rates.

The association between maternal risk factors and stillbirth is well established in the medical literature [1, 3, 5, 12]. Our data confirm that stillbirth occurs more frequently in infertile older mothers, in women with high body mass index and in women with high prevalence of diseases, such as diabetes and hypertension. Other retrospective investigations performed utilizing data that have been collected over 30 years like ours, highlighted the importance of understanding the maternal characteristics associated with stillbirth nowadays, as modern predictors of stillbirth risk [13]. Although many risk factors for stillbirths become apparent late in pregnancy, many maternal conditions can be ascertained and addressed early in pregnancy [14, 15], recognizing and potentially preventing their contribution to the adverse fetal outcome. Our results about the increasing of the risk of stillbirth associated with advanced maternal age and maternal diseases are in agreement with previous studies performed in the United States and United Kingdom aimed at identifying maternal risk factors known at the beginning of pregnancy [14, 16]. Accordingly, Yerlikaya et al. [16] provided an algorithm for prediction of stillbirth, developed on a model based on maternal characteristics and medical history recorded in early pregnancy. They stated that this model based on an early recognizing of risk factors can potentially predict one-third of subsequent stillbirths [16]. However, different geographic area may show different stillbirths risk factors. To our knowledge, this is the first Italian study that evaluates the role of maternal baseline characteristics as risk factors of stillbirth addressable at pregnancy confirmation. Moreover, the specific timeframe when these early ascertainable factors represent a significantly higher danger to the fetus needs more research worldwide. The present study stratifies the risk of stillbirth according to the baseline maternal conditions and the gestational age (before and after the 28th weeks of gestation).

The strength of our study is that we have focused our attention on baseline maternal conditions known at the beginning of pregnancy. This is a useful moment to plan effective antenatal care in any women-centered facility. The early awareness of risk factors may contribute to accelerated progress towards the prevention of stillbirths, for example by planning a specific and personalized antenatal surveillance by trained staff.

However, our study has some limitations: firstly, we utilized data that has been collected over 30 years, where there have been several changes in obstetric protocols and guidelines; this may have influenced the outcomes studied. However, the comparison between stillbirths and a large controls group of livebirths delivered in the same years limits the potential bias. In fact, the same antenatal care was offered to both groups. Moreover, our previous study, performed in the same study period, subdivided the population into different study sub-periods, in order to evaluate the prevalence in time and the association with stillbirth of the identified risk factors [9]. In that study we observed an increasing of the prevalence of women aged $\ge$40 years and pregnancies obtained by assisted reproductive technologies among bereaved mothers, highlighting the importance of the awareness of these risk factors in the modern medicine. Moreover, in our previous study [9] we observed a reduction of population attributable risk for stillbirth related to maternal disease (i.e., autoimmune disease, thrombophilia, diabetes, hematological disease, chronic hypertension, thyropathy) during the period 2007–2017, possibly related to the improvement of clinical management, highlighting again the importance of awareness of these clinical conditions.

Secondly, the study is retrospective which can lead to information being largely missed or not collected (such as ethnicity/racial origin, patterns of migration, smoking etc.). Thirdly, the study took place in a single maternity hospital which might reduce the generalizability of our results. However, many similarities between maternal risk factors observed in our cases were found in published literature from around the world [3, 5, 12], supporting the reliability of our data. Moreover, a mono-center study allows the homogeneity of pregnancy care between cases and controls.

Interestingly, our results highlight that maternal conditions can affect fetal outcome in a time-dependent manner.

Some conditions (i.e., pre-gestational hypertension and assisted reproductive technologies) represent a risk factor early in pregnancy while others (i.e., autoimmune disease, inherited thrombophilia, insulin dependent diabetes mellitus) manifest their effect mainly late in pregnancy.

Autoimmune diseases are known conditions that can affect fetal outcomes, including an increased risk of fetal death [17, 18, 19, 20]. To improve the pregnancy outcome, it is important to individualize the correct risk profile for each woman [21]. Medical literature suggests that an accurate management of the mother (ideally starting at the preconception or at least at the beginning of pregnancy), will influence and optimize the fetal outcomes [21]. Close monitoring during pregnancy is an essential strategy to improve the placental functions [21] and, in turn, ending potentially preventable stillbirth. Our data suggest that the highest increase of the risk of fetal death starts from the 28th weeks of gestation. Therefore, from this gestational age is crucial to maintain a strict follow-up of the pregnancy affected by maternal autoimmune diseases.

Inherited thrombophilia is a disorder associated with an increased predisposition to developing thromboembolism including in the placenta vessels. Nevertheless, there is conflicting evidence with respect to the presence and the strength of associations between inherited thrombophilia and adverse pregnancy outcomes [22, 23, 24]. Previous studies observed an association between protein S deficiency, heterozygous for factor V Leiden or prothrombin gene and stillbirth [25]. However other studies have failed to demonstrate such association [23]. Moreover, conflicting results are available about the therapy, concluding that antithrombotic treatment appears unable to modify pregnancy outcome [23]. Our data show an increased prevalence of inherited thrombophilia in stillbirths than in livebirths, with a significant reduction in the fetal survival rate from the third trimester. We are aware that the thrombophilic defect found in mother of stillborn babies may not be viewed as the cause of the adverse pregnancy outcome but just as an association. Nevertheless, the significance of our results suggests that a close monitoring of thrombofilic women during the third trimester of pregnancy may be indicated.

Pre-gestational diabetes mellitus is a known risk factors for stillbirth [26, 27]. Fetal outcomes have been related with suboptimal maternal glucose control [28]. Substantial variations between clinics have been highlighted in medical literature, regarding glycemic control and, therefore, pregnancy outcomes [28]. In Minnesota (USA) reduction of the rate of diabetes-related stillbirth was obtained thanks to distribution of education materials to caregivers and patients, to optimize maternal conditions before conception and during all pregnancy [29]. Our observations support this contest of improving awareness about diabetes suggesting that fetal outcomes may benefit from a more strictly pregnancy monitoring, especially from the 28 weeks of gestation.

Interestingly, stillbirths at term show a prompt decrease of fetal survival after 38 weeks of gestation in cases with overt hyperthyroidism, although it is not statistically significant (possibly due to the low number of cases). Pregnancy loss in women suffering from hyperthyroidism has been previously described in case series [30, 31, 32, 33, 34] and previous population-based study speculated that high thyroid hormone levels in the late pregnancy could have direct effect on the fetus, leading to stillbirth [35]. It is well known that thyroid dysfunction may affect fetal health, particularly if hyperthyroidism is associated with thyroid autoimmunity [36]: thyroid-stimulating hormone receptor antibodies are able to cross the placenta leading to life-threatening fetal hyperthyroidism [37]. Our data are in agreement with the previously observed high risk of late stillbirth in hyperthyroidism, suggesting the helpfulness of a strict monitoring of fetal wellbeing at term of pregnancy, up to considering an appropriate timing of delivery.

Finally, our data highlights that the risk of stillbirth increases with the increasing of the number of conditions affecting the mother. It is difficult to suggest general indications for the management of pregnancy in women with multiple risk factors because each disease/condition has its own features. Moreover, epidemiological results are not sufficient to provided evidence-based recommendations. Nevertheless, in agreement with previous suggestion provided by other Authors [16], our study suggests the need for achievable early awareness of maternal risk factors and personalized management of the pregnancy which would contribute to avoid preventable stillbirths. However, the extent to which this early recognizing of maternal risk factors could prevent stillbirth remains to be determined.

Our results highlight that the risk of stillbirth increases as the increasing of the number of abnormal maternal clinical conditions, in a time-dependent manner. Early awareness of the maternal conditions addressable at the beginning of pregnancy is the first step to plan evidence-based accurate and effective antenatal care; timing and type of management depend on the different diseases and comorbidities, keeping in mind that maternal risk factors may have cumulative impact on the pregnancy concurring to increase the risk of fetal death.

Conception and design of the article by LA. LA performed the literature search, drafted the manuscript, collected, and analyzed data. SR expanded the literature research, performed statistical analysis, and drafted the manuscript. GB and AMM revised database and discussed results. VM, AV and CR actively discussed results. All authors read, edited, and approved the final manuscript.

The study was exempt from code number because, according to our National Code of Clinical Research, retrospective archive studies (performed using anonymized database) do not need ethics approval. Following Italian Data Protection Act 9/2013, material previously collected for diagnostic purposes can be used for research as long as the privacy is ensured.

The authors are grateful to parents and volunteers of CiaoLapo Charity for support and inspiration. The authors are thankful to Ms Dawn Savery for helpful commenting. SR would like to thank her stillborn daughter, Elisa, to give her motivation to collaborate in the present study.

This research received no external funding.

The authors declare no conflict of interest. Anna Maria Marconi and Laura Avagliano are serving as one of the Editorial Board members and Guest editors of this journal. We declare that Anna Maria Marconi and Laura Avagliano had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Luca Roncati.