Maternal death and postpartum hemorrhage (PPH) management remain controversial subjects in the obstetrician’s daily practice and throughout the world. In spite of worldwide efforts coordinated by the WHO, the time period allotted to major coordinated activities that would promote human and social development, “The Millennium Declaration,” concluded in 2015. This Declaration included a set of eight objectives with the purpose of fighting extreme poverty and promoting human and social development, based on statistical data obtained during the 1990s; it was launched in the year 2000 with the signature of governments, specialized agencies, civil society, and various worldwide sponsors and was to be completed in the year 2015 (Fig. 15.2).

Specifically, the fifth objective referred to a 75 % decrease in maternal deaths based on the maternal mortality ratio (MMR). The MMR is a strong social marker reflecting women’s life conditions, the degree of population development, and the level of health system organization [5–7].

MMR analysis did reveal a significant decrease in maternal deaths, from 532,000 in 1990 to 303,000 in 2015, approximately a 43 % decrease [8, 9]. However, this decline was not sufficient to fulfill the millennium’s objective and led to the creation of the “Sustainable Development Goals” agenda whose purpose is to decrease world MMR to under 70 maternal deaths/100,000 live births (LB) between 2016 and 2030.

Not fulfilling the millennium’s objective is due to the great and persistent difference between various world regions, ranging from over 1000 maternal deaths per 100,000 LB in some developing countries to less than 10 per 100,000 LB in developed countries; hence, a woman’s estimated risk of death due to pregnancy and postpartum complications in high-income countries is 1 in 3,400 compared to 1 in 52 in low-income countries. In summary, 830 daily maternal deaths were recorded in 2015 due to pregnancy and delivery complications, 550 of which occurred in the sub-Saharan region of Africa and 180 in southern Asia; five maternal deaths were reported in developed countries, confirming a 33-fold increased risk of dying in underdeveloped, low-income countries, where 99 % of deaths occurred.

The programmed global MMR should have decreased 5 % annually in order to reach the planned MMR in the year 2015, but its drop was 1.2 % per year, between 1990 and 2000, and 3 % per year between 2000 and 2015, a difference hinging on each government’s and society’s efforts to implement public policies that would further better health development since the impact of maternal death is reflected in the family’s, the community’s, and the society’s structure. But most disturbing is the fact that most could have been prevented. We must underscore the fact that PPH recurrence can be modified if we count with appropriate health resources, access to health care, and the timely use of uterotonics.

Although a relevant facet of PPH is maternal death, another important aspect is its associated morbidity, including anemia, disseminated intravascular coagulation, the need for blood transfusions, hysterectomy, kidney, and liver failure [10, 11]. Based on these complications, the WHO conducted a survey evaluating PPH, its risks, and maternal outcomes [12]. In a total group of 274,985 women treated in 28 countries, 1.2 % developed PPH, 95 % required prophylactic uterotonics, 35 % required more than one tocolytic, a third was transfused, a fourth required antibiotics, and 17 % of births were associated to severe maternal outcomes (SMO): 14.5 % were classified as near misses due to the development of some form of organic failure, and 3.1 % resulted in maternal death [12].

Every year, 120 million women bear a child, and among these, approximately 12 million will develop PPH: about 200,000 will die and 60 million women will develop a complication leading to some form of medium- or long-term disability in 15–20 million cases. Thus, for every maternal death, 20–30 women will harbor some form of disability [13].

Based on these survey results, the WHO concluded that uterotonic use should be preventive and therapeutic in PPH and should be recommended in all treatment guidelines and obstetric care centers.

PPH prevention requires the identification of associated risk factors, but this is only possible in a third of cases.

The described associated risk factors include a past history of PPH (15 % increase in risk) [14, 15], nulliparity [14, 16, 17], uterine overdistension due to fetal causes (OR 1.9, 95 % CI 1.6–2.4) and fluid or tumors [14, 15, 18–20], placental abnormalities such as placenta previa and/or accreta [21], coagulation abnormalities [15, 22], anemia [16, 22], labor induction (OR 1.4, 95 % CI 1.1–1.7), prolonged expulsive phase (OR 1.4, 95 % CI 1.2–1.7), the use of epidural analgesia, retention of placental fragments (OR 3.5, 95 % CI 2.1–5.8), lack of labor progression (OR 3.4, 95 % CI 2.4–4.7), placental morbidity (OR 3.3, 95 % CI 1.7–6.4), lacerations (OR 2.4, 95 % CI 2.0–2.8), instrumented delivery (OR 2.3, 95 % CI 1.6–3.4), hypertensive disorder (OR 1.7, 95 % CI 1.2–2.1), obesity, multiparity, uterine infection, and uterine inversion [20].

Whether any risk factor is predictive of non-response to conventional uterotonic treatment remains unknown [12]. Logistic regression analysis was conducted in an attempt to predict PPH according to the described risk factors, and an increased risk was established for the following variables: age above 35 years (OR 1.42; 95 % CI 1.26–1.60), nulliparity (OR 1.12; 95 % CI 1.01–1.25), parity ≥3 (OR 1.32; 95 % CI 1.09–1.59), gestational age at birth <37 weeks or >41 weeks versus 37–41 weeks (ORs 2.63; 95 % CI 2.28–3.04 and 1.56; 95 % CI 1.02–2.38, respectively), labor induction (OR 1.55; 95 % CI 1.20–2.00), cesarean section (OR 1.46; 95 % CI 1.20–1.79), and residence in the Middle East compared to Africa (OR 1.79; 95 % CI 1.20–2.67, 12). Obstetric hemorrhage remains one of the main causes of worldwide morbidity and mortality, in both developed and developing countries. Hemorrhage before delivery occurs in approximately 6 % of pregnancies, and in half of these cases, its cause is unknown and may lead to postpartum hemorrhage. Postpartum hemorrhage will occur around 10 % of all pregnancies and results from one basic process or the combination of four, known as the four “Ts”: uterine atony (tone), placental retention (tissue), genital tract injury (trauma), and coagulation disorders (thrombin) [23].

Postpartum hemorrhage is defined as the loss of 500 mL or more of blood after delivery or within the first 24 h or the loss of 1,000 mL during a cesarean section [24]; severe postpartum hemorrhage refers to a blood loss greater than 1,000 mL during delivery or cesarean section [25]. PPH has specifically increased in the last decade, ranging between 0.3 and 3.8 % in Africa, 0.7–2.7 % in Asia, and 1.7–5.5 % in Europe [26].

The incidence of PPH could be substantially decreased with the use of prophylactic uterotonics during the third phase of labor if managed in a timely manner [19, 27, 28]. Hence, the active management of the third stage of labor (AMTSL) is pivotal to the decrease in postpartum hemorrhage and should be included in government-sponsored strategies worldwide (Fig. 15.3). It decreases the risk of hemorrhages >500 mL (RR 0.34, 95 % CI 0.27–0.44), the need for maternal transfusion (RR 0.34, 95 % CI 0.22–0.55), and average blood loss by 79 mL or less [29].

AMTSL basically encompasses three elements: the administration of a uterotonic immediately after the delivery of the newborn, controlled traction of the umbilical cord for placental delivery, and early clamping of the umbilical cord. These elements have changed since first proposed as a result of evidence-based findings.

Massage of the uterine fundus after delivery is also often included although the WHO does not consistently recommend it in women who have received oxytocin; however, certification of the uterine tone by abdominal palpation of the uterine fundus is essential to the identification of uterine atony. Early clamping of the umbilical cord has tended to disappear as a result of the positive effects of late clamping on the newborn [30]. However, a recent meta-analysis publish by Heidi Al-Wassia (JAMA Pediatr 2015;169:18) showed that milking the cord has the same effect as delayed cord clamping.

A multicenter study conducted by the WHO and published in 2012 [31] demonstrated that controlled cord traction (CCT) does not significantly reduce hemorrhage and characterizes this measure as optional and it is not included as a recommendation in the last WHO guidelines [33]; however, CCT is the first-choice intervention in the management of placental retention. In accordance with this information, the most important tool in the management of AMTSL in PPH is the use of uterotonics (oxytocin) both prophylactically and therapeutically.

There are many alternatives to the use of uterotonics in the prevention of PPH, but the WHO recommends oxytocin as the gold standard followed by misoprostol and ergot derivatives if oxytocin is unavailable; but its use should not be generalized due to its adverse effects, and in the case of cesarean sections, oxytocin is preferably administered via the intravenous or intramuscular route. The use of carbetocin, an oxytocin analogue, is associated to a decrease in the need for rescue uterotonics and also complements treatment with tranexamic acid, fibrinogen, etc. After an early diagnosis of PPH, uterine massage should be initiated as well as volume replacement with crystalloids and blood products [20, 29].

If bleeding continues, the uterus should be packed with compresses, intrauterine balloons, or inflated condoms or glove. Alternatively the uterine arteries can be embolized if the needed resources are available and/or followed by surgical procedures.

Based on the fact that uterine atony is the main cause of obstetric hemorrhage, uterotonics are the first-line therapy and should be used prophylactically and in the management of active hemorrhaging. The questions that usually arise in terms of all existing drugs are: What is the sequence to follow when using uterotonics? When should I use them and how long should I evaluate their effects?

The answer to these questions requires full knowledge of the drugs, their side effects, and their specific use, so no strict sequence can be proposed. Clinical practice guidelines recommend the use of uterotonics during AMTSL and if active hemorrhage is present, as soon as possible; depending on the drug used, continuous evaluation of the response to the uterotonic or uterotonics is needed since the pharmacological response or lack thereof must be determined within the first 30 min after administration; if there is no response, the appropriate measures must be taken to restore the lost volume, request the necessary support, and determine the adequate invasive management in a timely manner.

Worldwide pharmacology includes the following drugs.

It is a nonapeptide with eight different amino acids (Figs. 15.4 and 15.5) that act on myometrial receptors and promote uterine contractility; it is perhaps the most frequently used uterotonic, and it is the first-choice drug in many clinical practice guidelines, including the WHO’s [32]. There are close to 2013 systematic reviews supporting its use [32]. Its peak action occurs 1 min after administration, but its half-life is very short, between 3 and 5 min, so it requires continuous and well-monitored infusion.

Usually administered as an infusion, it may require a dosage increase. One can begin with 40 units in 1 L of isotonic saline IV or 10 units IM (including the intra-myometrial route). The half-life of oxytocin is 1–5 min so the uterine tone must be continually monitored during the infusion; if it does not respond, 10–20 U may be added without exceeding 800 units in 500 mL over 30 min [33–35], since a rapid oxytocin bolus may lead to peripheral vasodilation, an increase in cardiac output, tachycardia, and hypotension. Myocardial ischemia has also been reported which is why a slowly administered bolus is recommended [36, 37].

If there is no response, other rescue uterotonics may be used such as methylergonovine, prostaglandins, and even carbetocin. This last drug can only be administered once the oxytocin infusion is stopped in order to free the myometrial receptors and allow it to act as an oxytocin analogue.

Their use was described in 1532 (Claviceps purpurea) but was in reality purified from rye in 1932 by Mooir and Dale (Fig. 15.6a, b) that described their mechanism of action on adrenergic receptors and calcium channels, their interaction with actin-myosin, and, hence, their systemic effect on smooth muscle. A 2007 systematic review demonstrated the advantages of their use compared to not using uterotonic drugs [38].

They are frequently used as oxytocin rescue drugs, although they can be a rescue drug for any other uterotonic as long as there are no contraindications.

The recommended administration route is intramuscular or directly into the myometrium; the intravenous route is not currently recommended. The recommended methylergonovine dose is 0.2 mg IM, and it can be repeated every 2–4 h; it leads to strong and sustained myometrial contraction (uterine tetany). If there is no response to the first dose, one must decide whether to switch to a different uterotonic. It may also lead to alpha-adrenergic activity, particularly vasoconstriction, and is thus contraindicated in patients with pregnancy-associated hypertensive states, a previous history of myocardial ischemia, pulmonary hypertension, Raynaud’s phenomenon, scleroderma, or a history of migraine headaches [20].

Compared to placebo, it decreases bleeding by an average of 83 mL and limits bleeding to <500 mL (RR 0.38, 95 % CI 0.21–0.69). In spite of its protective effect when compared to oxytocin, it did not prove to better prevent postpartum hemorrhage (RR 0.76, 95 % CI 0.61–0.94) [20].

This is a drug combining oxytocin’s rapid action and the sustained and more prolonged effect of ergonovine and can therefore provide both benefits; it is unfortunately not available in many countries (Fig.15.7).