Debunking the myth: usage of thiamine in cervical preparation and labour augmentation

Introduction / Введение

Thiamine (vitamin B₁) is important for human body due to its function as co-enzyme in cell powerhouse. Since its discovery by C. Eijkman (1890s) and establishment of B₁ structure by R.R. Williams (1933), number of research had grown in many fields and one of them in obstetric field [1]. Usage of thiamine in labour induction quite popular in 1940’s until 1960’s, nowadays its usage shifted to pregnancy supplement [2–8]. However it’s quite common in Indonesia, B₁ use for cervical priming and enhancing uterine contraction in midwife and hospital setting in conjunction with misoprostol and oxytocin. However, this practice has no clear evidence and clinical trials. In this article we wish to see why this practice has been considered and is it applicable in nowadays practice?

Thiamine and its function in cell energy pathway / Тиамин и его функция в энергетическом обмене клетки

Thiamin was first known by its deficiency and named ‘beriberi’ in English and ‘kakké’ in Japan and China [1]. Early hypothesis postulated beriberi was attributed to miasmas rising from wet soil and to an unknown infectious organism [1]. C. Eijkman in 1890s observed that chickens fed polished rice developed a polyneuritis, whereas chickens fed unpolished rice did not [1]. К. Takaki a naval surgeon in Japan also observed high occurrence of beriberi in warship crew in 1880s, after he loaded the navy with meat and dried milk the disease drastically reduce. К. Takaki then concluded that the disease experienced by the crew was closed related to foods [9][10]. Later on (1926), B.C.P. Jansen and his colleague W.F. Donath obtained anti-beriberi substance in crystal form obtained from the rice polishing process [11]. The research continued by R.R. Williams and J.K. Cline (1936) which define molecular structure of thiamin and later on could be manufactured in high volume [12].

Thiamin consists of a pyrimidine ring (2,5-dimethyl-6-aminopyrimidine) and a thiazolium ring (4-methyl-5-hydroxyethyl thiazole) linked by a methylene bridge. The primary sources of thiamin include meats, whole grains, liver, eggs, fish, legumes, and whole grains. Cooking processes involving heating, as well as the consumption of coffee and tea, can affect its availability [13][14]. Thiamin diphosphate (TDP) is a phosphorylated form of thiamin that serves as a crucial cofactor in various enzymatic reactions. Its three primary functions include activating the decarboxylation of pyruvate into the pyruvate dehydrogenase complex, decarboxylation in alpha-ketoglutarate dehydrogenase, an important component of the citric acid cycle, and in the macromolecular aggregation that decarboxylates keto acids [15][16].

Free thiamine is initially phosphorylated to form biochemically active TDP, synonymously known as thiamine pyrophosphate (TPP). TPP possesses a crucial structural element in the form of a thiazolium ring, a five-membered heterocyclic ring containing sulfur and positively charged nitrogen atoms (Fig. 1) [17]. TPP acts as a coenzyme for thiamine for transketolase (TK) in the pentose phosphate pathway, for pyruvate dehydrogenase (PDH) in the glycolysis, and for alpha-ketoglutarate dehydrogenase (AKD) in the Krebs cycle [17][18]. Each of these enzymes can only fulfill its function with thiamine help (Fig. 2). Then, acetyl-CoA will play a role in providing the acetyl molecule needed to initiate the Krebs cycle, which is an essential part of cellular metabolism and generates a lot of energy in the form of adenosine triphosphate (ATP) [18].

Due B₁ large involvement in energy pathways, the deficiency of thiamine limits the supply of enzymes to the Krebs cycle leading to decreased ATP, oxidative damage, and cell death [18][19]. Decreased TK activity impairs synthesis of nucleic acids and glutathione, mainly affect the central nervous system (CNS) which is highly dependent on ATP generated by oxidative decarboxylation. Through triggering N-methyl-D-aspartate (NMDA) toxicity and increasing apoptotic cell death Wernicke's encephalopathy and Korsakoff's psychosis occurs in B₁ deficiency [18][20].

Thiamine usage in labour induction and augmentation / Использование тиамина для индукции и стимуляции родов

From PubMed search engine we found that this practice is popular in 1940’s–1960’s [2–8]. The earliest article we could found is from S.S. Zilberman (1949) which stated thiamine could increase uterine activity in labour. The author explained from his experiment with animal subject pregnant uterus reacts to thiamine with increase of contractility and tone as shown in Figure 3. Не concluded thiamine stimulates uterine contractility with expressed as increase of uterine tone and frequency of contraction [2].

S. Lorand et al. (1952) perform large trial of thiamine with dosage of 50 mg and with/without 3 U of glanduitrin at parturient patient with 2 cm dilation. In 50 % of cases, the amplitude of contractions was increased followed by birth accelerated in one of third of cases. The authors also found intensity of pain was reduced in 38 % of cases and in 55 % of cases dilation progression was not accompanied by an increase in pain. They concluded acceleration of childbirth is due to increased function of the uterine body and lower uterine segment obliteration during labour which also responsible for the reduction of pain [6]. High variability in this study needed to be questioned as such the contraction mainly due to it already starts to adequate due time or the effect of oxytocin given in conjunction with B₁ (Fig. 4).

In early 1900’s a lot of researchers observed thiamine have a favorable effect in cases of uterine inertia. S. Timonen and K.A. Schroderus (1953) hypothesized that aneurin inhibits action of cholinesterase in which way delayed acetylcholine clearance [21]. This mechanism similar with prostigmin which was use in the past for labour induction or neostigmin in nowdays practice to reverse muscle relaxation during general anaesthesia for caesarean section [22][23].

H.J. Prill (1954) divided 171 patients as subject into 2 individual groups, first one 100 primiparous women over 18 years of age as group A and 71 primiparous and multiparous women with primary or secondary hypotonic labor weakness as group B, which both group received 900 mg of vitamin B₁ (Benerva, Betabion or Betaxin) intra-muscular found that vitamin B shortens duration of labour from 11.08 hours to 9.5 hours in 52 subjects [4]. Based on previous research, K.F. Zalevskaya (1961) performs an isolated study for labour induction using thiamine. She concluded that the most effective dose is 240 mg administered by two injections of 6 mL of 2 % thiamine solution with one hour interval. The author also hypothesize this positive outcome due the effect of vitamin B₁ on the uterine muscle, it’s promotes stimulation of uterine contractions by direct thiamine participation in development of nerve impulses that regulate and establish the rhythm of uterine contractions [24].

However in contrary, a lot of researchers contradict thiamine role in shortening of labour. Even H.J. Prill (1954) concluded general use of vitamin B₁ does not produced any statistically significant shortening of labour [4]. E. Szirmai (1961) also conducted the induction of labour with 50 mg of thiamine in 1962 and found in 29 births only 2 patients had their contraction increased and the rest of the cases it did not change [5].

Thiamine, oxytocin and neuroendocrine pathway of uterine contraction / Тиамин, окситоцин и нейроэндокринный путь сокращения матки

Thiamine has long-known effect on nervous system. Deficiency of thiamine leads to many dire situations such as thiamine-deficient disease we called beriberi. Early manifestation shows mainly in disturbance of peripheral nerve disease and in later stage manifest as encephalopathy (Wernicke’s encephalopathy) [18][25]. Previously it was hypothesized that thiamine plays same roles as acetylcholine in excitatory pathway of nerve and later it was hypothesized thiamine inhibits cholinesterase [20][26].

Oxytocin is a neuropeptide that produces by neurosecretory cells within the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) in the hypothalamus and secreted through neurohypophysis [30]. Oxytocin then released to blood and affect targeted organ, and in this case uterine contraction [29][30]. The brain and uterus connected with what so called Ferguson Reflex which is afferent neural pathway that involves mechanical stretching of the cervix enhances uterine activity [29][30]. Role of autonomic innervation in uterine contraction has been recognize in older research and publication but had not gain attention in newer research [32]. Y. Sato et al. (1996) showed stimulation of the efferent pelvic nerve with supramaximal intensity induced increase in uterine blood flow accompanied by uterine contraction. However, efferent hypogastric nerve stimulation caused decrease of uterine blood flow accompanied by uterine contraction. These founding leads to conclusion that terine contraction is produced by activation of both parasympathetic and sympathetic nerves via muscarinic cholinergic receptors [33]. This also supported by R.E. Papka et al. (1999) founding that paracervical parasympathetic ganglia contains a lot of muscarinic receptors which will respond acetylcholine [34].

Whether the activity of the autonomic nervous system plays a role in human labor and delivery is not known due degenerative changes during pregnancy, as demonstrated both in animal studies and in women [35]. H. Nakanishi and C. Wood (1971) found intrinsic cholinergic nerve supply of the human myometrium was found to be predominantly postganglionic and minimal. They also found markedly decreased sensitivity of pregnant muscle to acetylcholine when compared to non-pregnant muscle [36]. However, such degenerative changes do not occur in uterus cervix, where the innervation remains intact. Therefore, nervous activity may still play an important role in labor alongside oxytocin [32][35]. It could be concluded the most important function of thiamine largely contributes to the cellular energy metabolism because thiamine is an essential cofactor in the carbohydrates cycle [18].

Cervical ripening induced by PGE1 and PGE2 is associated with an increase in inflammatory mediators in the cervix, and remodeling of the cervical extracellular matrix through a decrease in collagen cross links and cervical glycosaminoglycans [38]. It’s quite contrary with thiamine which is anti-inflammatory. Thiamine itself has been proven to reduced C-reactive protein (CRP) and expression of tumor necrosis factor-alpha (TNF-α) in gestational diabetes patients [39]. Thiamine also has better antioxidant effect compared to ascorbic acid with reducing MMP-9 level in sepsis patients [40]. These facts already enough to debunk the myth of thiamine usage in labour induction or augmentation. Its effect on cell cycle indeed provides constant ATP within uterine muscle but not to the extent of enhancing contraction and help cervical ripening.

Conclusion / Заключение

Thiamine don’t have sufficient prove for usage in labour induction and augmentation. It’s has anti-inflammatory effects and contradict the misoprostol function which promotes the level of prostaglandin and others inflammatory cytokines in the cervix. Previously B₁ assumed to perform in neural excitation and help achieve routine contraction. However previous research at 1940–1960’s couldn’t provide clear mechanism and procedure on how thiamine works.