Polypharmacy refers to people taking two or more different medications at the same time. It has been increasing over the last 30 years, including in the pregnant women and birthing people. Side effects are possible for anyone taking prescription medicine and can be a bigger issue for people who are taking multiple medicines. There are also potential problems caused by the interaction between different medications.
We don’t have a good understanding of how much polypharmacy affects pregnant women and their babies, but it’s known that the changes that occur in the body during pregnancy mean that medications may not have the same effect as they do in someone who is not pregnant. The main reason for this lack of knowledge is that new medication is rarely tested on pregnant women due to concerns about the possible impact on the unborn baby. Using real-world data about women who have taken medications in pregnancy is a useful way to overcome this problem.
Our study will compare women/offspring who have had different pregnancy-related complications with those who hadn’t. We will investigate whether certain combinations of medications are more or less likely to have been prescribed in women with these complications. Findings will be discussed with researchers and clinicians to find drugs which should be investigated more rigorously.
Knowing the potential benefits and harms of consuming medications during pregnancy will help pregnant women and their health care professionals to make informed decisions about whether or not to continue or start medications in pregnancy.
Aims: Considering the high prevalence of polypharmacy in pregnant women and the knowledge gap in the risk-benefit safety profile of their often-complex drug regimens, more research is needed to optimise prescribing. This study aims to conduct a pharmacovigilance study to assess the effect of medications prescribed during the preconception period (3 months prior to conception) and first trimester of pregnancy.
Methods/design: A series of case control studies will be conducted to estimate measures of disproportionality (such as odds ratios from a series of logistic regression models), detecting signals of association between a range of pregnancy, delivery and offspring outcomes and exposure to individual and combinations of drugs.
Outcome: The MuM-PreDiCT and ConcePTION consortium have developed core outcome sets (a minimum set of recommended maternal and offspring outcomes) for studies of pregnant women with multiple long-term conditions.
Exposures: All medications prescribed within primary care, coded using the Dictionary of Medicines and Devices (DM+D) have a BNF item code associated with them. All the medications included in the dictionary will be used in the analysis excluding non-pharmacological agents such as dressing. Medications prescribed will be stratified according to their BNF item code (BNF chapter, section, paragraph and sub-paragraph) and by two crucial time windows: 1) preconception period; 2) first trimester of pregnancy.
Participants: Women aged between 15-49 years with a pregnancy recorded within the Pregnancy Register between 1st Jan 2000 and 31st July 2022 will be eligible when exploring pregnancy outcomes. Women who are further eligible for linkage to HES record, and have a record of delivery within the HES maternity tail will be eligible when exploring delivery outcomes. Furthermore, women linked to their baby records within primary care using mother-baby linked data will be eligible when exploring offspring outcomes.
Covariates: Demographic and health characteristics will be adjusted to account for confounding.
A list of core outcomes derived from the ConcePTION and the MuMPredict consortium will be analysed separately.
List of core outcomes from ConcePTION consortium
1) Gestational age at birth (in weeks or days) - ascertained using variable available in linked HES maternity tail data
2) Miscarriage - ascertained using a combination of (1) variable available in linked CPRD Gold Pregnancy Register, (2) Snomed CT codes recorded in CPRD Gold database within 30 weeks from the start of pregnancy (24 weeks + 6 weeks lag period to account for delay in recording) or (3) ICD-10 codes recorded in linked HES data within 30 weeks from the start of pregnancy (24 weeks + 6 weeks lag period to account for delay in recording)
3) Intrauterine death/ stillbirth/ perinatal death - ascertained using a combination of (1) variable available in linked CPRD Gold Pregnancy Register, (2) Snomed CT codes recorded in CPRD Gold database within 48 weeks from the start of pregnancy (42 weeks + 6 weeks lag period to account for delay in recording), (3) ICD-10 codes recorded in linked HES data within 48 weeks from the start of pregnancy (42 weeks + 6 weeks lag period to account for delay in recording) or (4) linked ONS data
4) Small for gestational age (SGA) - All births with birth weight <10th centile for gestational age identified using the INTERGROWTH 21st project, and their software tools, by comparing the birthweight and gestational age recorded in HES data to the international anthropometric standards – both gestational age and birthweight will be ascertained using variables available in HES maternity tail data
5) Preterm birth - All live births between 22 and 37 weeks and still births between 24 and 37 weeks – Gestational age, and still/live birth will be ascertained using variables available in HES maternity tail data
6) Overall Congenital anomalies (CA) – ascertained using a combination of Snomed CT codes recorded in CPRD Gold database for the offspring of the mothers. The patient IDs of the offspring will be obtained from the linked MBL data
7) Specific major congenital anomalies including termination of pregnancy due to foetal anomaly – Specific congenital anomalies with sufficient sample size will be explored as outcomes separately.
8) Maternal death – record of death (1) during pregnancy during pregnancy and within 42 days of the end of pregnancy, and (2) more than 42 days but less than 1 year after the end of pregnancy (late maternal death) – ascertained using linked ONS data
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Additional list of core outcomes from MuM-PreDiCT consortium
1) Maternal outcomes:
a. Pre-eclampsia, eclampsia, HELLP syndrome - ascertained using a combination of (1) Snomed CT codes recorded in CPRD Gold database between 20 weeks and 48 weeks (42 weeks + 6 weeks lag period to account for delay in recording) from the start of pregnancy or (3) ICD-10 codes recorded in linked HES data between 20 weeks and 48 weeks (42 weeks + 6 weeks lag period to account for delay in recording) from the start of pregnancy
b. Placenta abruption - ascertained using a combination of (1) Snomed CT codes recorded in CPRD Gold database between 20 weeks and 48 weeks (42 weeks + 6 weeks lag period to account for delay in recording) from the start of pregnancy or (3) ICD-10 codes recorded in linked HES data between 20 weeks and 48 weeks (42 weeks + 6 weeks lag period to account for delay in recording) from the start of pregnancy
c. Venous thromboembolism - 1) Snomed CT codes recorded in CPRD Gold database between start of pregnancy and 54 weeks (42 weeks + 12 weeks lag period to account for delay in recording) from the start of pregnancy or (3) ICD-10 codes recorded in linked HES data between start of pregnancy and 54 weeks (42 weeks + 12 weeks lag period to account for delay in recording) from the start of pregnancy
d. Preterm premature rupture of membrane – ascertained using ICD-10 codes recorded in linked HES maternity tail records around the time of delivery for preterm births
e. Severe maternal morbidity – Composite a morbidities as included in the CDC definition: (1) Acute myocardial infarction, (2) Aneurysm, (3) Acute Renal Failure, (4) Adult respiratory distress syndrome, (5) Amniotic fluid embolism, (6) Cardiac arrest or ventricular fibrillation, (7) Disseminated intravascular coagulation, (8) Eclampsia, (9) Heart failure or arrest during surgery or procedure, (10) Puerperal cerebrovascular disorders, (11) Pulmonary edema or Acute heart failure, (12) Severe anesthesia complications, (13) Sepsis, (14) Shock, (15) Sickle cell disease with crisis, (16) Air and thrombotic embolism, (17) Conversion of cardiac rhythm, (18) Blood products transfusion, (19) Hysterectomy, (20) Temporary tracheostomy, (21) Ventilation – ascertained using ICD-10 codes or OPCS codes recorded in linked HES data after 3 months from the time of delivery
f. Postpartum haemorrhage – ascertained using ICD-10 codes recorded in linked HES data between the time of delivery and 3 months from delivery to account for secondary PPH
g. Self-harm/suicide – ascertained using a combination of ICD-10 codes and Snomed CT codes recorded in linked HES data and CPRD Gold Primary care data respectively during: (1) antenatal period, (2) 0-3 months post pregnancy end date, (3) 3-6 months post pregnancy end data and (6-12 months post pregnancy end date. In addition, this will be ascertained using linked ONS data
2) Children’s outcomes
a. Cerebral palsy - ascertained using a Snomed CT codes recorded in CPRD Gold database for the offspring of the mothers. The patient IDs of the offspring will be obtained from the linked MBL data
b. Neurodevelopmental conditions - ascertained using a Snomed CT codes recorded in CPRD Gold database for the offspring of the mothers. The patient IDs of the offspring will be obtained from the linked MBL data
Anuradhaa Subramanian - Chief Investigator - University of Birmingham
Jingya Wang - Corresponding Applicant - University of Birmingham
Katherine Phillips - Collaborator - University of Birmingham
Krishnarajah Nirantharakumar - Collaborator - University of Birmingham
Megha Singh - Collaborator - University of Birmingham
Siang Ing Lee - Collaborator - University of Birmingham
Steven Wambua - Collaborator - University of Birmingham
HES Admitted Patient Care;ONS Death Registration Data;Patient Level Index of Multiple Deprivation;Practice Level Index of Multiple Deprivation;CPRD GOLD Mother-Baby Link;CPRD GOLD Pregnancy Register