During pregnancy, the mother and fetus are inseparable function units. Medications can cause undesirable effects on the fetus during pregnancy. During pregnancy and breastfeeding, a mother can experience various complaints or health problems that require medication. Some drugs can pose risks to maternal health and can affect the fetus.

The selection of analgesics as the painkiller becomes important. For fear of using drugs during pregnancy, some pregnant women prefer to withstand pain rather than treat the pain. So this article discusses the safety of analgesics for pregnant women.

Rationalize the Selection of Analgesics to Treat Pain During Pregnancy

The Food and Drug Administration (FDA) is aware of and understands the concerns arising from recent reports that question the safety of prescription and over-the-counter (OTC) drugs when used during pregnancy. Because of this uncertainty, pain medications use during pregnancy must be carefully considered. So the doctor should emphasize that pregnant women always discuss all medicines with health workers before using them.

There are two main categories of analgesics commonly used: systemic nonopioid analgesics (for example, acetaminophen, aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs)) and opioid analgesics (e.g., morphine, codeine, meperidine).


a. Acetaminophen / Paracetamol (TGA Category: A; FDA Category: C)

Paracetamol has demonstrated significant efficacy and safety at all stages of pregnancy at standard therapeutic doses. The safety profile established for its use has been demonstrated in recent studies of thousands of pregnant women without increasing the risk of congenital anomalies or other adverse pregnancy outcomes. Although it easily crosses the placental barrier in its unconjugated form, therapeutic doses do not seem to increase the risk of birth defects or other complications during pregnancy. A registry-based study from Denmark of 26,424 children exposed to paracetamol in utero during the first trimester found no increase in either the specific or overall birth defects rate compared with the unexposed control group.

Several prospective cohort studies have reported an increased relationship between paracetamol use in pregnancy and ADHD in children. The results assessed included a diagnosis of hyperkinetic disease (HKD) and behavior such as ADHD starting at the age of 5 years based on the mother's interview of the child's behavior at the age of 7 years. The study population included 64,322 pregnancies with information to assess drug use in HKD and ADHD cases and 40,916 pregnancies with information to determine child behavior. This study had many methodological limitations that made findings difficult to interpret. The author did not assess overall health markers, including the use of health services and/or drug use in the year before and during pregnancy, which might make the association observed incorrectly. No information was given on paracetamol's strength and the number of unit doses taken; Therefore, no conclusions could be made regarding the association of dose to the therapeutic response. Several studies in the last five years have not shown any link between ADHD and paracetamol administration.

In Andrade's study (2016), because pregnancy is a complicated factor, so far, paracetamol is still the safest analgesic in pregnancy. Jill et al. (2014), with the publication of a cohort study on 48,631 pregnancies in Norway, did not prove the association. Evie et al. (2016), with a cohort study in 4415 pregnancies, there was no link between ADHD and paracetamol. Based on the authors' evaluation of the research, the authors believed that existing scientific studies regarding the possible relationship between the use of paracetamol in pregnancy and ADHD in children had not been proven. It still makes paracetamol the first line of analgesics in pregnant women.

b. Aspirin (TGA Category: C; FDA Category: N)

Aspirin has several potential risks because it inhibits platelet function and can cause bleeding in the mother and fetus. Although aspirin has not been associated with other congenital anomalies, aspirin is associated with an increased risk of vascular disorders, especially gastroschisis, although this remains unproven. Overall, large trials show low-dose aspirin's relative safety and its generally positive effect on reproductive outcomes. Aspirin is rarely used to treat pain and fever during pregnancy. Obstetricians prescribe low-dose aspirin (often with heparin) aims to reduce the risk of complications in pregnant women with antiphospholipid syndrome and recurrent miscarriages.

Overall, aspirin is not associated with an increased risk of congenital malformations. In the later stages of pregnancy, aspirin should be avoided because it can prolong the duration of labor, cause severe blood loss during labor, and increase stillbirth incidence.

In experimental animal studies, prostaglandin synthesis inhibitors have shown to increase complications in the fetus. Epidemiological studies show an increased risk of miscarriage, cardiac malformations, and gastroschisis when used early in pregnancy; The absolute risk of cardiovascular defects increases from less than 1% to about 1.5%.

During the third trimester of pregnancy, aspirin can cause the closure of the fetal ductus arteriosus, oligohydramnios, fetal renal impairment, pulmonary hypertension, and prolongation of bleeding time. Giving during pregnancy and childbirth is not recommended; onset of labor may be delayed, and duration increases with a tendency for severe bleeding in mother and child.

A study of treatment with low-dose aspirin (60 mg per day) to prevent and treat preeclampsia in 9364 pregnant women (the Collaborative Low-dose Aspirin Study in Pregnancy - CLASP) did not support the provision of prophylactic or therapeutic antiplatelets on a routine basis for pregnant women with the pregnant risk of preeclampsia.

c. NSAIDs (TGA Category: C; FDA Categories: C for gestational age <30 weeks, D> 30 weeks)

NSAIDs, including ibuprofen, naproxen, indomethacin, and diclofenac, are widely used to treat mild to moderate pain and fever. NSAIDs work to reduce pain through peripheral inhibition of cyclooxygenase and prostaglandin synthesis. To date, many studies have failed to show evidence of a consistent increase in teratogenic effects in humans or animals after therapeutic doses during the first trimester. However, short-term use of NSAIDs in late pregnancy is associated with a substantially increased risk of premature ductal closure.

A study in California also showed an increased risk of miscarriage by 80%, related to the use of both aspirin and NSAIDs in the first trimester. A suggested mechanism for explaining an increased risk of miscarriage is implantation disorders due to the prostaglandin pathway's effects.

After 30 weeks of pregnancy, NSAID use is contraindicated because of the potential for causing premature closure of fetal ductus arteriosus and persistent pulmonary hypertension. High dose NSAIDs in the third trimester can also reduce fetal renal perfusion and reduce fetal urine output. Most decreased output cases are reversible, but there have been reports of partial resolution and even death due to anuric kidney failure. The main focus of COX-2 inhibitors is the ductus arteriosus and fetal/neonatal renal/fetal perfusion.

Topical NSAIDs are generally negligible and will be considered relatively safe in pregnancy even though absorption increases with use over large surface areas. The FDA reviewed five observational studies evaluating the risk of spontaneous pregnancy loss before week 20 with the use of NSAIDs

Miscarriages in the general population have an incidence of about one in six pregnancies. Three retrospective case control studies covering more than 100,000 subjects reported a positive relationship between non-aspirin exposure with NSAID exposure and miscarriage (odds ratio [aOR] = 7.0, 95% confidence interval [CI] = 2.8-17.7; aOR = 3.4, 95% CI = 0.9-12.8; and aOR = 2.4, 95% CI = 2.1-2.8).

That result is difficult to interpret because of methodological limitations in the study design. For example, this study did not identify reasons for using NSAIDs; Women in this study could use NSAIDs for symptoms of miscarriage (i.e., cramps), so it cannot be determined whether NSAID use occurs before or after the onset of miscarriage. This study also excludes potential NSAID users whose pregnancies end in a therapeutic (induction) abortion, possibly resulting in findings of less NSAID use among controls compared to cases of miscarriage.

The last, the study did not consider the time of study entry (i.e., the time during gestation when the subject was chosen for this study). It is an important consideration because the risk of miscarriage varies substantially in gestational age and, by definition, cannot occur after 20 weeks' pregnancy.

Opioids (TGA category: C; FDA category: C)

Opioids such as codeine, oxycodone, hydromorphone, hydrocodone, and morphine, as well as drugs such as pethidine and tramadol, are used to treat moderate to severe pain. Overall, opioid analgesics have not been associated with increased congenital disabilities or other complications, such as miscarriage. There are also convincing data about the long-term follow-up of nerve development in exposed infants. The main concern about this drug is that continuous use can cause dependence and tolerance in the mother with withdrawal that results in neonates.

Sometimes alternative drugs, including tricyclic antidepressants, can help control persistent pain and reduce opioid exposure. Tricyclic antidepressants have not been associated with an increased rate of congenital disabilities or long-term neurodevelopmental effects.

Researchers reviewed two retrospective control case studies that reported opioid exposure in early pregnancy and the risk of neural tube defects / NTD. The study used interviews to gather information from more than 28,000 women regarding the use of opioids during pregnancy. Both studies found that mothers of babies with NTD were more likely to occur than mothers who did not have NTD to report opioid use in early pregnancy (aOR = 2.2, 95% CI = 1.2-4.2; aOR = 2.0, 95% CI = 1.3-3.2).

Although both studies were generally designed to assess the relationship between opioids and NTD, both have study limitations. Specifically, the use of interviewing pregnant women can influence the validity of the findings of this study. For example, mothers of babies with NTD may remember more about opioid exposure during pregnancy than mothers of babies who do not have congenital disabilities. Chronic use of this drug in subsequent pregnancies has been linked to neonatal withdrawal. Neonatal respiratory depression may occur if morphine is used in labor. Equipment for neonatal resuscitation must be available if morphine is to be used in labor.

Source: Alomedika
Author: dr. Khrisna Rangga Permana
Source picture: https://www.universityobgynassoc.com

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