key: cord-0704570-xpw9wek5
authors: Anchustegui-Mendizabal, P.; Arechabala-Palacios, L.; Fernandez-Gonzalez, L.; Garcia-Gil, C.; Hernandez-Guijo, J. M.; Martinez Perez, O.
title: Pilot study on the use of low molecular weight heparins in the prevention of thromboembolic disease during pregnancy and puerperium.
date: 2022-04-28
journal: nan
DOI: 10.1101/2022.04.26.22274264
sha: 492622915658d2fb29abbfe011fbbca884223bba
doc_id: 704570
cord_uid: xpw9wek5

A pregnant woman is 4 to 5 times more likely to suffer a thromboembolic event than a non-pregnant woman. Furthermore, an increase in these episodes has been observed in women infected with SARS-CoV-2. Consequently, the prophylactic prescription of low-molecular-weight heparins (LMWH) in pregnant women is undergoing an increase that has not been evaluated yet. The aim of this study was to determine the prevalence of LMWH prescription in pregnant women at the Hospital Universitario Puerta de Hierro Majadahonda (HUPHM), according to their level of risk and its variation due to SARS-CoV-2 infection. To answer this question, a retrospective cohort of 113 women who gave birth during the month of February at the HUPHM was designed. The level of individual risk of thromboembolism, according to the Royal College guidelines (37a), was calculated with an interview to complete a questionnaire and the analysis of their clinical records. 53.6% of the women were prescribed LMWH as indicated in the guidelines. This high prevalence is explained by the high age of the pregnant women (over 35 years), the wave of the omicron variant (December 2021) and a high rate of cesarean sections (25%). On the other hand, the percentage of patients with COVID-19 was 17.6% but only 53% of them had received LMWH. In conclusion, LMWH is a very common prescription in obstetrics, mostly during puerperium, and has become even more relevant due to the COVID-19 pandemic

In Western societies, the increase in life expectancy, changes in values, as well as the new assisted reproduction techniques have considerably delayed the age of having the first child.

A pregnant woman is 4 to 5 times more likely to suffer a thromboembolic event than a nonpregnant one, with venous thromboembolism being one of the leading causes of maternal death worldwide (1) . Due to the growing number of pregnant women with risk factors, the incidence of venous thromboembolic disease (VTE) has increased in recent decades (2) .

The mortality and morbidity of VTE are potentially preventable, as more than two-thirds of these women have identifiable risk factors and can benefit from adequate thromboprophylaxis 

There is a lack of knowledge about the distribution of VTE risk factors in the obstetric population, aggravated by the influence of the pandemic. Our hypothesis suggests that the prevalence of heparin prescription during pregnancy is high and has been increased due to the COVID-19 pandemic.

Consequently, the primary objective of this pilot study is to determine the prevalence of prescription of low molecular weight heparins (LMWH) in pregnant women, according to their level of risk for the development of VTE, as well as the variation of this risk due to SARS-CoV-2 infection. As secondary objectives, we sought to clarify whether LMWH prophylaxis was carried out according to the risk level of each patient and whether it conforms to the indications of the Royal College guidelines for the prophylactic treatment of VTE.

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The pilot study protocol was designed based on the variables of the ETV-OBS risk calculator (4). The design was based on a literature search in Pubmed on the use of antithrombotics in pregnancy and the Royal College guidelines (37a) on thromboembolic risk in pregnant women were studied.

A database was created by completing 3 questionnaires: first trimester (before week 14 of gestation), third trimester (between week 24 and 26) and postnatal; together with the analysis of medical records.

After this data collection, the results obtained were analyzed, comparing in each of the three periods analyzed the risk level of each patient and whether or not LMWH prophylaxis was carried out, according to the indications of the Royal College guidelines.

The database was constructed based on the variables presented below and measured in each patient.

The variables measured in the 1st and 3rd trimester were: age, weight (kg), height (m), body mass index (BMI), number of cigarettes/day, gravidity (number of pregnancies), parity (number of living children), family history of venous thromboembolic disease, personal history of venous thromboembolic disease, high risk thrombophilia, low risk thrombophilia without family history and low risk thrombophilia with family history, important medical comorbidities of the patient, varicose veins, long-term travel, immobility, hospitalization, surgery, infection, preeclampsia, multiple pregnancy, pregnancy after in vitro fertilization (IVF), hyperemesis or dehydration, type of heparin if administered, heparin dose and reason for administration, treatment with acetylsalicylic acid (ASA), dose and reason for administration.

The variables measured during postpartum were: all of the above except for pregnancy. Also added: gestational age (gestational week at birth), type of delivery (euthyroid, planned or emergency cesarean section and instrumental delivery), 24 hours or longer delivery, postpartum hemorrhage, abortion, preterm delivery (less than 37 weeks).

The inclusion criteria followed were: that the patients were over age, that they signed the informed consent form, that they had given birth, and that they were admitted to the gynecology and obstetrics department of the Hospital Universitario Puerta de Hierro Majadahonda (HUPHM). We went to this hospital during the month of February 2022. If one or more of the above criteria were not met, the patient was excluded from the study.

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Prior to the start of this study, the members of the study took the courses offered by The Global

Health Network: "Introduction to Clinical Research" and "Good Clinical Practice Guidelines ICH E6 (R2) ".

The trial was conducted in accordance with Good Clinical Practice guidelines and was sent for assessment by the Bioethics Committee of the HUPHM. The participants were informed of the characteristics and objectives of the study, as well as the confidentiality and protection of the data to be collected, and written informed consent was obtained from all the participants. The method of anonymization followed was the assignment of a consecutive number to each patient.

The data were collected by the investigators, analyzed and interpreted by the same. The authors are responsible for the accuracy and completeness of the data as well as for the fidelity of the trial to the protocol.

Of the patients admitted, 15 patients did not meet the inclusion criteria as they were hospitalized for reasons other than given birth. The 113 women who met the inclusion criteria were offered informed consent. Five of them refused consent, while 108 gave consent (see Figure 1 ). 

Demographics of the series . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 28, 2022. ; https://doi.org/10.1101/2022.04.26.22274264 doi: medRxiv preprint Figure 2 summarizes the demographic characteristics of the 108 patients included in the study at the first obstetric visit that could impact the baseline risk for VTE in pregnant women. Of the 108 women, 38% were older than 35 years, 31.5% of the total were between 36 and 40 years of age and 6.5% between 41 and 45 years. Only 1.9% were between 21 and 25 years of age, 15.7% were in the 26-30 age range and, the vast majority of the series, 44.4% were between 31 and 35 years of age, both included. Of all women, 61.1% had normal weight, 7.4% were obese and 22.2% were overweight compared to 9.3% who were underweight. Of the patients studied, 11.1% were smokers during pregnancy. The percentage of primigravidae It is grouped by 5-year age ranges. Weight is measured in kilograms, height in meters and BMI is grouped into 4 ranges (corresponding to underweight, normal weight, overweight and obesity). Gravidity (pregnancy) is determined in ranges of 1, 2 and greater than or equal to 3 and parity in ranges of 0, 1 or 2 and greater than or equal to 3.

After the demographic analysis, the VTE-related history of the patients in the series was studied ( Figure 3 ). None had a personal history of previous VTE.

However, there was a family history of VTE in 1.8% of the patients. Finally, we counted the number of patients who had been immobilized during pregnancy, and the result was 1.8% in . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 28, 2022. ; https://doi.org/10.1101/2022.04.26.22274264 doi: medRxiv preprint the first trimester, corresponding to women who had taken a long trip. In the third trimester, none of the patients had suffered immobilization.

Of note was the increase in the number of women diagnosed with SARS-CoV-2 infection in the third trimester (13.9%) compared to the first trimester of gestation (0.9%). and 17.6% in the third trimester. The percentage of pregnant women with three positive variables at low risk in the first trimester was 4.6%, in contrast to 6.5% in the third trimester.

In the first trimester, 0.9% of the patients presented four risk variables and in the third trimester there were no patients with four variables. The percentage of pregnant women with five variables was 0% in the first trimester and 0.9% in the third trimester.

The number of pregnant women with heparin prophylaxis was of 2 patients in the first trimester, of which one was due to risk of VTE and previous miscarriages and another due to risk of VTE, . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 28, 2022. ; https://doi.org/10.1101/2022.04.26.22274264 doi: medRxiv preprint previous miscarriages and IVF, and none due to COVID-19. This number rose to 11 in the third trimester, with 100% of the indications for SARS-CoV-2, and of these, 9.1% were also indicated for VTE risk, previous miscarriage and IVF.

There were 2 patients with prescription of ASA in the first trimester of gestation, of whom 50% had an indication for this drug due to risk of preeclampsia, and the other 50% due to family history. However, in the third trimester, 6 patients had an indication for ASA: 50% had a risk of preeclampsia, 16.7% had a prescription due to repeated miscarriages and another 16.7% due to family history. The remaining percentage had no clear indication. ; the number of pregnant women with LMWH prophylaxis and how many of these women had indication for it due to COVID-19; the number of patients with prescription of ASA and how many of these patients had indication for ASA due to risk of preeclampsia. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 28, 2022. ; https://doi.org/10.1101/2022.04.26.22274264 doi: medRxiv preprint Figure 6 shows the parity of the women in the series (number of deliveries, including the one studied). Of the 108 patients, the delivery studied was the first in 51.9% of the women. In 36.1% of the women this delivery was the second, although one of them was primigravidae but she delivered twins, in 6.5% of the patients it was their third delivery and in 5.6% of the women it was the fourth.

Regarding gestational age (the number of weeks of the baby born), it was observed that 9.3% of the deliveries were preterm (less than 37 weeks) and the rest were at term. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 28, 2022. 

After following all the methodological steps of a research study, the risk factors of 108 women were analyzed longitudinally from the first trimester to the puerperium following uniform criteria. There are no studies in Spain that have longitudinally followed the risk factors in such depth throughout the entire pregnancy. This contrasts with the great relevance of LMWH during this period in the life of many women. Despite being a pilot study and, therefore, not having a large number of subjects, data and percentages similar to those of the Spanish population were obtained. Furthermore, the loss rate was only 4.4%.

It is noteworthy that 39.8% of the women were primigravidae. In addition, 11.1% smoked during pregnancy. The most relevant aspect of the family and personal history is the overall increase of 13 points in patients with COVID-19 due to the wave of the omicron variant that temporarily coincided with the third trimester of gestation of the women in the series. This is reflected in an increase in the prescription of LMWH in the third trimester. However, there is not a change in the baseline risk since there were no clear criteria and the SARS-CoV-2 infection was not considered a risk variable.

There was a drop of 49 points in the number of patients at low risk from the first trimester to the puerperium, due to the addition of patients who gave birth by cesarean section to those who were already at risk during pregnancy. The cesarean section rate obtained is 25%, much higher than the 15% recommended by the World Health Organization (WHO). This value is not concordant with the average for this hospital, which was last calculated in 2019, obtaining a value of 19.8%. However, it does coincide with the Spanish average estimated by the Instituto Nacional de Estadística (INE) corresponding to 25%.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 28, 2022. ; https://doi.org/10.1101/2022.04.26.22274264 doi: medRxiv preprint LMWH is a very common medication in pregnant women, with 53.6% of them requiring at least 10-14 days of heparin. The prescription rate in the HUPHM is in accordance with the Royal College guidelines 37a. The percentage of LMWH prescription is so high due to the high age of the pregnant women (38% over 35 years of age), a high rate of cesarean sections (25%), a high SARS-CoV-2 infection (17.6%) and an IVF rate of 11.1%. All this requires that patients receive information, training and that they are discharged with the prescribed drug for selfadministration.

The relevance of our study lies in the fact that 80.6% of the patients had at least one risk factor in the postpartum period and, from the second onwards, the prescription of heparin is recommended. Given that 34.3% of women had a risk factor, it is important to look for another possible factor involving the administration of LMWH. The importance of this relies on the fact that pulmonary thromboembolism is responsible for 20-30% of maternal deaths, being the seventh cause of mortality in these women (5) . The percentage of patients with COVID-19 was 17.6%, but only 53% of these received LMWH. This reflects an evident heterogeneity in the criteria for prescribing this medication due to a lack of studies supporting prophylaxis in women infected with SARS-CoV-2. All this leads professionals to position themselves in two groups: a conservative one that does not administer the drug because there is no consensus on the scientific evidence and, another group that, empirically, decides to prescribe this medication seeking a balance between benefit and risk.

Given that the study is a pilot trial, it would be necessary to replicate the results with a larger number of participants.

80.6% of the women in the study had some risk factor, therefore, the determination of these factors is critical. In conclusion, an assessment of thrombotic risk factors should be made in all pregnant women at the beginning of pregnancy, and should be repeated if any change in the variables is produced, as well as at the time of delivery and postpartum.

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The copyright holder for this preprint this version posted April 28, 2022.

Prophylaxis with LMWH in pregnant women is very common in Spain, especially in the puerperium. This is due to the obstetric and demographic characteristics and, exceptionally, to the COVID-19 pandemic.

Finally, the heterogeneity in the prescription of LMWH in pregnant women infected with SARS-CoV-2 highlights the clear need for the development of clear protocols.

Thromboembolism in Pregnancy

Pharmacological Thromboprophylaxis during Pregnancy and the Puerperium: Recommendations from Current Guidelines and their Critical Comparison

Prevención del tromboembolismo venoso durante el embarazo y el puerperio en Atención Primaria y Especializada

We would like to thank Dr. Hernández Guijo who, beyond his work as a tutor, gave us enough autonomy to make decisions according to our preferences without ceasing to be a point of reference. We would like to thank Dr. Martínez Pérez for his clinical support, his enthusiasm and dedication to research, as well as his commitment to our training. We cannot forget to thank all the participants and their families for their time, kindness and good disposition in such a special moment of life.