Evaluation and Management of Women who Have Experienced Stillbirth in Their Previous Pregnancies

OBJECTIVE: To evaluate the subsequent pregnancy outcomes of women who have experienced unexplained stillbirth in their previous gestations. STUDY DESIGN: This retrospective cohort consisted of 14 pregnancies who had stillbirth (without known risk factors) in their previous pregnancies. These patients had been included in a special preconceptional care program to be evaluated in terms of etiological risk factors for stillbirth. At least one of the risk factors, such as methylenetetrahydrofolate reductase (MTHFR) polymorphisms, hereditary thrombophilias and autoimmune problems, were defined in this study population. After detection of pregnancy, the patients were administered low-dose low-molecular-weight heparin (LMWH) (enoxaparin, 1×2000 Anti-XA IU/0.2 mL/day), low-dose salicylic acid (100 mg/day) and low-dose corticosteroid (methylprednisolone, 1×4 mg/day orally) in necessary cases. RESULTS: Out of 14 pregnancies, 4 (28.5%) ended up with miscarriages at 9, 11, 11 and 15 gestational weeks, respectively. The remaining 10 pregnancies ended up with alive deliveries. The mean gestational week at birth was 36.4±0.51, while the mean birthweight was 2882±381.01 g. Out of 10 pregnancies, only one was diagnosed as IUGR. Only two newborn necessitated hospitalization in the neonatal intensive care unit (NICU) due to respiratory problems. Both newborns were discharged from the NICU without any further complication at the post-partum 5 day. CONCLUSION: Patients with a prior stillbirth should be screened for MTHFR polymorphisms, autoimmune problems and hereditary thrombophilias, especially in case of absence of any etiological factor. Management of these patients with low-dose aspirin, low-dose low molecular weight heparin and corticosteroids seemed to be beneficial for increasing live birth rates and avoiding obstetric complications.


Introduction
Stillbirth is defined as fetal death prior to total expulsion of the fetus from the mother.The definition of stillbirth ranges from gestational weeks 16 to 28 and birthweights of 400g to 1000g (1).Despite these definitions, the most common cut-off values for gestational week and birthweight in the definition of birth (11).Additionally, methylenetetrahydrofolate reductase (MTHFR) polymorphisms are linked to increased risk of fetal loss (12).Management of these patients with low-dose aspirin and enoxaparin was found to be beneficial for further pregnancies in some studies (13).
In this study, we evaluated the pregnancy outcome of patients with a history of stillbirth with a special treatment protocol.

Material and Method
We retrospectively evaluated the outcome of pregnancies with a history of stillbirth in their previous pregnancies.Stillbirth defined as an intrauterine fetal demise reaching 500 gr or 22 nd gestational week.The required data was obtained from Hacettepe University, Division of Perinatology registries and the electronic database of our institutions between the years 2015-2018.Stillbirths due to known risk factors (chromosomal abnormality, congenital malformation, preeclampsia, diabetes mellitus, etc.) were excluded from our data.Finally, 14 patients had been investigated for various types of additional risk factors between their last two pregnancies.At least one of the following risk factors, such as MTHFR polymorphisms, additional hereditary thrombophilias and any autoimmune disease or autoantibody positivity, were described in all patients.A methionine restricted diet was applied for at least 3 months for patients with MTHFR polymorphism(s) and hyperhomocysteinemia.After detection of pregnancy, the patients were adminis-tered low-dose low-molecular-weight heparin (LMWH) (enoxaparin, 1×2000 Anti-XA IU/0.2 mL/day), low-dose salicylic acid (100 mg/day) and low-dose corticosteroid (methylprednisolone, 1×4 mg/day orally) in necessary cases.Lowdose corticosteroid was used for patients with autoimmune problems and complement system activation.
Any patients with at least one described risk factor were included in this study.The demographic information including obstetric history of the patients, maternal ages and gestational week of the stillbirth were recorded.Pregnancy outcomes including gestational week at birth or abortion, birthweight and admission to the neonatal intensive care unit (NICU) and any Apgar score ≤7 at the 1 st , 5 th or 10 th minute were also recorded.

Results
This study consisted of 14 patients fulfilling all the study criteria.Demographic information of the patients, any existing additional risk factor and obstetric outcomes of the patients are summarized in table 1

Discussion
Management of patients with a history of stillbirth is challenging both for physicians and parents.Prognosis and management closely depend on the defined etiological factors.Patients with a stillbirth due to placental pathologies are more prone to placental complications in latter pregnancies (14).Managing patients with an unexplained stillbirth may be more challenging since there is no specific protocol determined for preventing further complications (15).On the other hand, physicians deliver patients earlier more often by cesarean section (16).
Thrombophilias or autoimmune disorders result in inflammatory processes at the maternal-fetal interface (injury of intervillous space structures, endothelial cells in spiral veins, syncytiotrophoblasts covering the chorionic villi, superficial and glandular epithelial cells in the decidua, endovascular trophoblasts etc.), which may cause impaired fetal perfusion and result in fetal death (17).Adverse outcomes were reported in autoimmune diseases such as Behcet disease, Celiac disease, inflammatory bowel diseases, Systemic lupus erythematosus (SLE) and Hashimoto's thyroiditis (18)(19)(20)(21).MTHFR polymorphisms are also related to poor perinatal outcome and necessitate special antenatal care (12,22).These patients may constitute some part of the patients with unexplained stillbirths and defining risk factors may give physicians a chance to provide appropriate management in subsequent pregnancies.Lowdose aspirin and low-molecular-weight heparin have been found to increase live birth rates in patients with autoimmunity, thrombophilia and MTHFR polymorphisms (13,22,23).
In our series, 71.4% of the pregnancies ended up with a healthy newborn.This finding is important since the subsequent pregnancies of these patients are more likely to be complicated (24).
The limitations of this study were the relatively low number of cases and the retrospective design.Single center design and definition of a novel treatment approach are the strengths of this study.
In conclusion, patients with a prior stillbirth should be screened for MTHFR polymorphisms, autoimmunity and hereditary thrombophilias, especially in case of absence of any etiological factor.Management of these patients with lowdose aspirin, low-dose low-molecular-weight heparin and corticosteroids seem to be beneficial for increasing live birth rates and avoiding obstetric complications.
:Conflict of Interest: The authors declare no conflict of interest.This is not funded by any company or third person.
The acquired data were evaluated via descriptive statistics.All statistical calculations were performed with the Statistical Package for Social Sciences (SPSS) for Windows (SPSS version 23; SPSS Inc., Chicago, IL) statistical software package.
. The mean maternal age was The mean gestational week of stillbirth at prior pregnancy was 27.93±4.12.Out of 14 pregnancies, 4 (28.5%)ended up with spontaneous abortions at the 9 th , 11 th , 11 th and 15 th gestational weeks, respectively.The remaining 10 pregnancies ended up with an alive fetus and no stillbirths occurred in this study group.The mean gestational week at birth was 36.4±0.51, while the mean birthweight was 2882±381.01g.Out of 10 pregnancies, only one was diagnosed as IUGR.Four newborns had an Apgar score of seven or less at ten minutes, while only two of them necessitated hospitalization in the NICU.Indication for hospitalization was respiratory problems for both cases.Both newborns left the NICU on the 5 th day.